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What was the outcome of reaction 'Epstein-Barr virus infection reactivation'? | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | Recovering | ReactionOutcome | CC BY-NC-ND | 33622999 | 19,047,119 | 2021-02-24 |
What was the outcome of reaction 'Eye haemorrhage'? | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | Recovering | ReactionOutcome | CC BY-NC-ND | 33622999 | 19,053,028 | 2021-02-24 |
What was the outcome of reaction 'Haemorrhage'? | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | Recovering | ReactionOutcome | CC BY-NC-ND | 33622999 | 19,009,695 | 2021-02-24 |
What was the outcome of reaction 'Hepatomegaly'? | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | Recovering | ReactionOutcome | CC BY-NC-ND | 33622999 | 19,047,119 | 2021-02-24 |
What was the outcome of reaction 'Hepatotoxicity'? | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | Recovering | ReactionOutcome | CC BY-NC-ND | 33622999 | 19,053,028 | 2021-02-24 |
What was the outcome of reaction 'Intentional product misuse'? | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | Recovering | ReactionOutcome | CC BY-NC-ND | 33622999 | 19,053,028 | 2021-02-24 |
What was the outcome of reaction 'Nephropathy toxic'? | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | Recovering | ReactionOutcome | CC BY-NC-ND | 33622999 | 19,053,028 | 2021-02-24 |
What was the outcome of reaction 'Papilloedema'? | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | Recovering | ReactionOutcome | CC BY-NC-ND | 33622999 | 19,053,028 | 2021-02-24 |
What was the outcome of reaction 'Renal impairment'? | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | Recovering | ReactionOutcome | CC BY-NC-ND | 33622999 | 19,047,119 | 2021-02-24 |
What was the outcome of reaction 'Self-medication'? | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | Recovered | ReactionOutcome | CC BY-NC-ND | 33622999 | 19,047,119 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blindness unilateral'. | Topical Corticosteroids for Infectious Keratitis Before Culture-Proven Diagnosis.
In clinical practice we sometimes encounter patients with severe corneal ulcers who have been treated with topical corticosteroids. This study reviewed the clinical features and visual outcomes of these patients and investigated the background of the prescription of topical corticosteroids.
The medical records of patients who visited the Cornea Service at Fujita Health University Bantane Hospital and were treated for infectious keratitis from April 2016 to March 2020 were retrospectively reviewed. Patients treated with topical corticosteroids before a culture-proven diagnosis were studied in terms of demographics, best-corrected visual acuity at arrival and at last visit, the clinical course after visit, ocular history, and combination therapy by the previous ophthalmologist.
Out of the 200 eyes of 197 patients with infectious keratitis, 14 eyes of 14 patients were treated with topical corticosteroids before a culture-proven diagnosis. All 14 patients were referred, as they had severe keratitis that could not be cured with topical antibiotics and corticosteroids. Based on the culture results, we diagnosed Acanthamoeba keratitis (AK) in six patients, fungal keratitis (FK) in two patients, bacterial keratitis (including a suspected case) in two patients, and unknown cause in four patients. Two patients with AK, FK, and unknown keratitis had unfortunate clinical courses and poor visual outcomes. From the information in the referral letters, at least six of the 14 patients were treated with either acyclovir ocular ointment or valaciclovir tablets, along with topical corticosteroids.
Application of topical corticosteroids for keratitis that does not respond to empirical antibiotic therapy is harmful since AK or FK is likely involved in these topical antibiotic-resistant cases. Microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed when prescribing topical corticosteroid for the treatment of suspected infectious keratitis.
Plain Language Summary
In the corneal clinic of a university hospital in a metropolitan area, we sometimes encounter referred patients with severe corneal ulcers who have been treated with topical corticosteroids as well as antibiotic eye drops. Why were these topical corticosteroids prescribed? We retrospectively reviewed clinical records of patients with infectious keratitis treated with topical corticosteroids before a culture-proven diagnosis. During an investigative period of 4 years, 14 eyes of 14 patients were evaluated. All the patients were prescribed topical corticosteroids for the keratitis owing to unresponsive empirical antibiotic therapy, and at least six patients were treated for stromal keratitis due to herpes simplex virus.
Why did the corneal lesions of these patients worsen? Based on culture results, we diagnosed Acanthamoeba keratitis in six patients and fungal keratitis in two patients. Apart from bacterial keratitis, other microorganisms responsible for keratitis do not respond to antibiotic therapy, and the condition is worsened by the topical corticosteroids without appropriate anti-amoebic or anti-fungal therapy.
Application of topical corticosteroids for keratitis without microbiological evidence is harmful, and a differential diagnosis of herpetic stromal keratitis as well as fungal and Acanthamoeba keratitis is needed when using topical corticosteroid for the treatment of suspected infectious keratitis.
Introduction
The definitive diagnosis and specific therapy for microbial keratitis should only be determined by microbiological evaluation.1–3 Nevertheless, the application of empirical antibiotic therapy without the use of smears or cultures cannot be rejected, as topical fluoroquinolone is associated with of a high success rate; moreover, the time and cost involved in performing cultures and maintaining the necessary materials are reduced.4–6
During the treatment of microbial keratitis, adjunctive topical corticosteroids are used to reduce the inflammatory response and subsequent corneal scarring, to obtain better visual outcomes, despite the possible risk of enhanced microbial replication, corneal melting, and steroid glaucoma.6–8 The safety and efficacy of topical corticosteroids for microbial keratitis have been reported9–17 in the Steroids for Corneal Ulcers Trial (SCUT)9,10 and other randomized control studies.11,12 The consensus of these studies was that unlike the use of topical antibiotics, the empirical use of topical corticosteroids for suspected microbial keratitis is not recommended. According to the Bacterial Keratitis Preferred Practice Pattern® 2018, 24–48 hours after the causative organism has been identified and/or infection is responding to therapy, corticosteroids may be considered, and close follow-up by a corneal specialist is recommended. Corticosteroids should be avoided in bacterial keratitis caused by slow-cycling microbes such as Nocardia,10 and fungal keratitis,7,11,18 while in Acanthamoeba keratitis, maintaining adequate anti-amoebic therapy is needed if a topical corticosteroid is used.19–23 Therefore, these microorganisms should be ruled out and a definitive diagnosis of bacterial keratitis based on smear and culture or by confirming the response to anti-microbial therapy is suggested before topical corticosteroids.24
At the corneal clinic of our institution and hospital in a metropolitan area, which serves a population of 4 million, we sometimes encounter referred patients with severe corneal ulcers who have been treated with topical corticosteroids. The purpose of this study was to review the clinical features and the visual outcomes of these patients, and to elucidate the effect of the empirical use of topical corticosteroids on the clinical course of this condition and the background of steroid applications in such patients.
Patients and Methods
We retrospectively reviewed the medical records of patients who visited the Cornea Service at Fujita Health University Bantane Hospital and were treated for infectious keratitis from April 2016 to March 2020. The diagnosis of microbial infectious keratitis was confirmed by culture, but because the antibiotic therapy had already been started before the patients arrived at our institution, many of them were solely diagnosed based on the corneal findings and the clinical course.
Suspected infectious keratitis patients treated with topical corticosteroids before culture-proven diagnosis were retrospectively studied in terms of demographics, best-corrected visual acuity at arrival and at the last visit, clinical course after the initial visit, ocular history, and combination therapy by the previous ophthalmologist. We used this information to determine the influence of topical steroid therapy and to determine the factors that led to the steroid prescription.
This study was approved by the institutional review board of the Fujita Health University Faculty of Medicine (Approval number: C120-135). Informed consent was obtained from each patient for use in clinical records for future research.
Results
Patients’ Visits
Two hundred eyes of 197 patients were treated for microbial infectious keratitis in the investigation period. Among the 197 patients, 195 eyes of 192 patients were referred from a hospital or ophthalmic clinic. Almost all the referred patients had already been empirically treated with topical or systemic antibiotic therapy, and the reason for the referral was a poor response to the antibiotic therapy.
Among the referred patients, 14 eyes of 14 patients had been treated with corticosteroid eye drops before arrival (Table 1).Table 1 Patients in Whom Topical Corticosteroids Were Applied Before Culture: Demographics and Past Treatments Other Than Topical Antibiotics
Case No. Age (Years) Sex Laterality Onset-Arrival (Days) Steroid Eye Drops Prescribing Doctor Steroid Use (Days) CL User Ocular History Anti-HSV Drugs Diagnosis
1 32 Male L 7 Unknown Previous doctor 4 Yes BK
2 82 Male R 50 0.1% BM+Fra Referral doctor 30 DMR, Rubeotic gla BK susp
3 39 Male R 12 0.1% FLM Previous doctor 7 Yes ACV AK
4 24 Male R 30 0.1% BM+Fra Previous doctor 28 Yes Herpetic keratitis VACV AK
5 53 Female L 75 0.1% BM Previous doctor 60 Yes Herpetic keratitis AK
6 31 Male R 18 0.1% BM Previous doctor 10 Yes AK
7 56 Male L 14 0.1% BM Referral doctor 8 Yes ACV AK
8 33 Female L 240 Unknown Referral doctor 30 Herpetic keratitis AK
9 46 Female R 20 0.1% BM+Fra Previous doctor 15 Yes FK
10 48 Female R 21 0.1% FLM Referral doctor 7 ACV, VACV FK
11 44 Female L 14 0.1% BM Referral doctor 3 Yes Unknown
12 19 Female L 30 Unknown Previous doctor 21 Yes Unknown
13 51 Male R 14 0.1% BM Referral doctor 3 ACV, VACV Unknown
14 35 Male L 40 0.1% BM Previous doctor 28 Herpetic keratitis ACV Unknown
Abbreviations. No., number; CL, contact lenses; HSV, herpes simplex virus; R, right; L, left; FLM, fluorometholone; BM, betamethasone sodium phosphate; BM+Fra, combined betamethasone sodium sulfate and fradiomycin sulfate; AK, Acanthamoeba keratitis; BK, bacterial keratitis; FK, fungal keratitis; PDR, proliferative diabetic retinopathy; rubeotic gla, rubeotic glaucoma; ACV, acyclovir ocular ointment; VACV, valaciclovir tablets.
Use of Topical Corticosteroids
Corticosteroid eye drops were not used before keratitis occurred but were used to treat the corneal lesions. Out of the 14 patients, six patients were prescribed topical corticosteroids by the referring doctor, and eight patients were prescribed these drugs by another doctor (Table 1). The details of the medical practice, other than the referring doctor, at the previous doctor’s clinic were unknown, but the prescribed corticosteroid eye drops were 0.1% betamethasone sodium phosphate for nine patients, 0.1% fluorometholone for two patients, and unknown steroid eye drops for three patients. Among the nine patients who were treated with 0.1% betamethasone sodium phosphate, combined corticosteroid-antibiotic eye drops (betamethasone sodium sulfate/fradiomycin sulfate) were prescribed for at least three patients (Table 1).
All patients visited the ophthalmic clinic with a complaint of ocular pain, red eye, and visual disturbance. Nine patients were contact lens wearers (Table 1).
History of Herpetic Keratitis
The history of herpetic keratitis and treatment is described in Table 1. According to the referral letters, four patients (cases 4, 5, 8, and 14) had a past history of herpetic keratitis, but the details and the accuracy of the diagnosis were unknown. At least six of the 14 patients were treated with either acyclovir ocular ointment or valaciclovir tablets, along with topical corticosteroids (cases 3, 4, 7, 10, 13, 14). Although we could not exclude concurrent herpetic stromal keratitis because our institution did not have the facility to perform either the immune chromatography or the real-time polymerase chain reaction, the corneal findings and the clinical course of the patients’ eyes were not suggestive of herpetic necrotic keratitis.
Culture and Diagnosis
Corneal scraping and culture were performed for 13 patients (Table 2); however, because the cornea was already perforated and Acanthamoeba was proven by the referral doctor, culture was not performed for case 8. As listed in Table 2, based on the results of the cultures, we diagnosed keratitis as follows: bacterial keratitis in two patients including one suspected case, Acanthamoeba keratitis in six patients, fungal keratitis in two patients, and unknown cause in four patients. Case 2 had a corneal ulcer with a 3.0-mm diameter and hypopyon at the first visit, but the inflammation subsided within 3 weeks of topical antibiotic therapy, and we thus diagnosed the patient with bacterial keratitis even though the culture was negative. In four patients with unknown causes (cases 11−14), the diagnosis of microbial infectious keratitis was made from the clinical presentation at the first visit (Figure 1), but it was not possible to determine whether these were bacterial, fungal, or Acanthamoeba keratitis cases based on the clinical course.Table 2 Patients Topical Corticosteroids Were Applied Before Culture: Culture Results and Prognosis
Case No. BCVA at First Visit BCVA at Last Visit Weeks Taken to Settle Down Cultured Microorganisms Diagnosis Corneal Perforation
1 HM 0.3 3 Pseudomonas aeruginosa BK
2 NLP NLP 8 No growth BK susp
3 0.4 1.0 17 Amoeba, Staphylococcus epidermis, GM Pos bacilli AK
4 LP 0.4 22 Amoeba, Staphylococcus epidermis AK
5 CF HM 50 Amoeba AK
6 HM 0.9 15 Amoeba AK
7 0.3 0.9 19 Amoeba AK
8 LP LP 8 Amoeba at referring doctor AK Yes
9 HM NLP Evisceration Fusarium sp. FK Yes
10 LP NLP Evisceration Fusarium sp. FK Yes
11 0.03 0.8 3 No growth Unknown
12 CF 0.5 6 No growth Unknown
13 LP 0.05 25 No growth Unknown Yes
14 0.04 0.04 30 Staphylococcus epidermis (MRSE) Unknown
Abbreviations: BCVA, best-corrected visual acuity; HM, hand motion; NLP, no light perception; LP, light perception; CF, counting fingers; GM Pos bacilli, Gram-positive bacilli; AK, Acanthamoeba keratitis; BK, bacterial keratitis, FK, fungal keratitis; MRSE, methicillin-resistant Staphylococcus epidermis.
Figure 1 Cases of suspected infectious keratitis who were treated with topical corticosteroids without culture-proven diagnosis and before presentation to our clinic. (A) Case 11; Forty-four-year-old female. Although fungal keratitis was suspected based on corneal findings, it took only 3 weeks to cure the inflammation by a combination of topical antibiotics and anti-fungal therapy. (B) Case 12; Eighteen-year-old female. Early stage of Acanthamoeba keratitis was suspected based on the findings, but no organism could be cultured, even after co-culture with Escherichia coli. (C) Case 13; Fifty-one-year-old male. Despite treatment with a combination topical antibiotic and antifungal therapy, corneal perforation occurred 2 weeks after the first visit. (D) Case 14; Thirty-five-year-old male. Culture was attempted 3 times from the first visit, and at the second time of culture, 1 week after the intensive topical antibiotic therapy was started, methicillin-resistant Staphylococcus epidermis was detected by enrichment culture, but the significance of this result was unclear.
Prognosis
The prognosis is summarized in Table 2. The patients with bacterial keratitis (cases 1 and 2) responded well to the topical antibiotic therapy, and the corneal lesion healed as a scar after 3 weeks, after which corticosteroid eye drops were started again to settle the infiltration.
The prognosis for the vision of the two patients with Acanthamoeba keratitis (cases 5 and 8) whose anti-amoebic therapy was started more than 10 weeks after the onset was poor (Table 1). In patients with Acanthamoeba keratitis in whom appropriate anti-amoebic therapy was started at least within 2 weeks from the onset, the visual prognosis was good, even though topical corticosteroids were applied before the diagnosis (cases 3, 6, and 7).
Both patients with fungal keratitis visited the specialist clinic 3 weeks after the onset of the complaint (Table 1). The delay in the diagnosis and identification of the causative organism (Fusarium species), in addition to the use of topical corticosteroid before diagnosis, may have caused a corneal perforation and loss of sight in the affected eyes (cases 9 and 10).
In the five culture-negative cases, we could not determine the causative microorganism based on the corneal appearance and the clinical course in four cases (Figure 1). Favorable recovery of vision has still not been obtained in two of the cases (cases 13 and 14). This may be due to the difficulty in establishing a treatment plan because the empirical topical antibiotic and corticosteroid treatment has masked the appearance of the corneal lesion.
Discussion
Similar to the findings of the SCUT study, in our cases, the use of topical steroids along with antibiotics did not affect the vision prognoses in the eyes with bacterial keratitis; however, vision was lost in two eyes with fungal keratitis (Table 2). Even though this poor outcome may be attributed to the Fusarium sp. that was involved in two of our cases, topical corticosteroids should not be used for fungal keratitis.6,7,18 For the eyes with Acanthamoeba keratitis, topical corticosteroids are not contraindicated as long as appropriate anti-amoebic therapy is applied.19–21 However, two of the six Acanthamoeba keratitis eyes lost vision in our study (Table 2). In the Acanthamoeba keratitis patients (cases 5 and 8) as well as in two fungal keratitis patients (cases 9 and 10) and two unknown keratitis patients (cases 13 and 14), one of the reasons for the undesirable visual prognosis could be the delay in proper diagnosis (Table 1), caused by the masked clinical findings (Figure 1) and the reactions to the empirical use of topical antibiotics and corticosteroids.25,26
From the referral letter information, at least eight patients were assumed to be treated with topical corticosteroids after being diagnosed with stromal herpetic keratitis. Three of the six Acanthamoeba keratitis patients, one of the two fungal keratitis patients, and two of the four unknown keratitis patients were treated with acyclovir ointment or valaciclovir tablets (Table 1). In addition to these patients who were treated with anti-herpes virus drugs, two Acanthamoeba keratitis patients had a history of herpetic keratitis, according to the referral letter (Table 2). These facts show that we have to distinguish whether the keratitis is stromal keratitis related to herpes simplex virus or microbial infectious keratitis.
From the results of this study, we concluded that it is important to evaluate the patient for fungal keratitis and Acanthamoeba keratitis before deciding on the use of topical corticosteroids for the treatment of the keratitis. Because correct differentiation of bacterial or fungal keratitis by the clinical signs or findings is difficult even for a corneal specialist,27 it is important to make a biologically proven diagnosis by smear and culture before prescribing topical corticosteroids. In addition, it is important to stop the application of topical corticosteroids immediately when keratitis does not improve by these steroids.
A combination of 0.1% betamethasone sodium sulfate and fradiomycin sulfate was prescribed in at least three of the 14 cases. Along with the possibility of stromal herpetic keratitis, another possible reason for the immediate use of topical corticosteroids could be the commercial availability of corticosteroid-antibiotic combination eye drops. As O’Day DM pointed out,28 these preparations have the potential to violate the rule of combined corticosteroid–antibiotic therapy for infectious keratitis.
Accordingly, microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed when prescribing topical corticosteroids for the treatment of infectious keratitis. Although corticosteroid-antibiotic combination eye drops seem safe, they are meaningless or unsafe for treating infectious keratitis other than culture-proven bacterial keratitis.
In addition to its retrospective nature, the main limitation of this study was the single-center study design. As almost all the patients had already been treated empirically with topical antibiotics by the previous ophthalmologist, it was difficult to distinguish the causative microorganism by culture. Thus, we had to diagnose the keratitis as infectious keratitis, particularly bacterial keratitis, based on the corneal findings and clinical course. Additional information from other institutions is needed to clarify the merits and demerits, as well as the background for the empirical use of topical corticosteroids for suspected microbial infectious keratitis.
Conclusion
This study reported a series of severe infectious keratitis cases referred to a specialized medical institution, who were given an antibiotic-steroid combination treatment. Our findings show that it is harmful to apply topical corticosteroids for keratitis that does not respond to empirical antibiotic therapy, since Acanthamoeba keratitis or fungal keratitis are likely involved in these topical antibiotic-resistant cases.
The use of topical corticosteroids along with empirical antibiotic therapy make it difficult to distinguish the causative agent of the infection in suspected keratitis, either by culture or by the corneal findings and clinical course, and as a result, may delay the appropriate treatment and cause unfortunate outcomes. Therefore, we conclude that the use of topical corticosteroids, merely owing to ineffective empirical antibiotic therapy for keratitis, should be avoided. Microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed before prescribing topical corticosteroids for the treatment of suspected infectious keratitis.
Abbreviations
AK, Acanthamoeba keratitis; FK, fungal keratitis; SCUT, Steroids for Corneal Ulcers Trial.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Ethics Approval and Consent to Participate
Written informed consent was obtained from each patient. This study was approved by the Research Ethics Committee of Fujita Health University and was performed in accordance with the Declaration of Helsinki.
Consent for Publication
Written informed consent was obtained from the participants for publication of the research article and any accompanying images.
Author Contributions
KH followed all the patients in this study and wrote the manuscript. KH, HT, and KK analyzed and interpreted the data on the clinical features of the patients. KK and KA-S made critical comments on the manuscript and provided input regarding the clinical outcome of the series of patients with infectious keratitis in whom topical corticosteroids were used. All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agree to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for aspects of the work.
Disclosure
The authors report no conflicts of interest in this work. | ACYCLOVIR, FLUOROMETHOLONE, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33623362 | 19,684,175 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Topical Corticosteroids for Infectious Keratitis Before Culture-Proven Diagnosis.
In clinical practice we sometimes encounter patients with severe corneal ulcers who have been treated with topical corticosteroids. This study reviewed the clinical features and visual outcomes of these patients and investigated the background of the prescription of topical corticosteroids.
The medical records of patients who visited the Cornea Service at Fujita Health University Bantane Hospital and were treated for infectious keratitis from April 2016 to March 2020 were retrospectively reviewed. Patients treated with topical corticosteroids before a culture-proven diagnosis were studied in terms of demographics, best-corrected visual acuity at arrival and at last visit, the clinical course after visit, ocular history, and combination therapy by the previous ophthalmologist.
Out of the 200 eyes of 197 patients with infectious keratitis, 14 eyes of 14 patients were treated with topical corticosteroids before a culture-proven diagnosis. All 14 patients were referred, as they had severe keratitis that could not be cured with topical antibiotics and corticosteroids. Based on the culture results, we diagnosed Acanthamoeba keratitis (AK) in six patients, fungal keratitis (FK) in two patients, bacterial keratitis (including a suspected case) in two patients, and unknown cause in four patients. Two patients with AK, FK, and unknown keratitis had unfortunate clinical courses and poor visual outcomes. From the information in the referral letters, at least six of the 14 patients were treated with either acyclovir ocular ointment or valaciclovir tablets, along with topical corticosteroids.
Application of topical corticosteroids for keratitis that does not respond to empirical antibiotic therapy is harmful since AK or FK is likely involved in these topical antibiotic-resistant cases. Microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed when prescribing topical corticosteroid for the treatment of suspected infectious keratitis.
Plain Language Summary
In the corneal clinic of a university hospital in a metropolitan area, we sometimes encounter referred patients with severe corneal ulcers who have been treated with topical corticosteroids as well as antibiotic eye drops. Why were these topical corticosteroids prescribed? We retrospectively reviewed clinical records of patients with infectious keratitis treated with topical corticosteroids before a culture-proven diagnosis. During an investigative period of 4 years, 14 eyes of 14 patients were evaluated. All the patients were prescribed topical corticosteroids for the keratitis owing to unresponsive empirical antibiotic therapy, and at least six patients were treated for stromal keratitis due to herpes simplex virus.
Why did the corneal lesions of these patients worsen? Based on culture results, we diagnosed Acanthamoeba keratitis in six patients and fungal keratitis in two patients. Apart from bacterial keratitis, other microorganisms responsible for keratitis do not respond to antibiotic therapy, and the condition is worsened by the topical corticosteroids without appropriate anti-amoebic or anti-fungal therapy.
Application of topical corticosteroids for keratitis without microbiological evidence is harmful, and a differential diagnosis of herpetic stromal keratitis as well as fungal and Acanthamoeba keratitis is needed when using topical corticosteroid for the treatment of suspected infectious keratitis.
Introduction
The definitive diagnosis and specific therapy for microbial keratitis should only be determined by microbiological evaluation.1–3 Nevertheless, the application of empirical antibiotic therapy without the use of smears or cultures cannot be rejected, as topical fluoroquinolone is associated with of a high success rate; moreover, the time and cost involved in performing cultures and maintaining the necessary materials are reduced.4–6
During the treatment of microbial keratitis, adjunctive topical corticosteroids are used to reduce the inflammatory response and subsequent corneal scarring, to obtain better visual outcomes, despite the possible risk of enhanced microbial replication, corneal melting, and steroid glaucoma.6–8 The safety and efficacy of topical corticosteroids for microbial keratitis have been reported9–17 in the Steroids for Corneal Ulcers Trial (SCUT)9,10 and other randomized control studies.11,12 The consensus of these studies was that unlike the use of topical antibiotics, the empirical use of topical corticosteroids for suspected microbial keratitis is not recommended. According to the Bacterial Keratitis Preferred Practice Pattern® 2018, 24–48 hours after the causative organism has been identified and/or infection is responding to therapy, corticosteroids may be considered, and close follow-up by a corneal specialist is recommended. Corticosteroids should be avoided in bacterial keratitis caused by slow-cycling microbes such as Nocardia,10 and fungal keratitis,7,11,18 while in Acanthamoeba keratitis, maintaining adequate anti-amoebic therapy is needed if a topical corticosteroid is used.19–23 Therefore, these microorganisms should be ruled out and a definitive diagnosis of bacterial keratitis based on smear and culture or by confirming the response to anti-microbial therapy is suggested before topical corticosteroids.24
At the corneal clinic of our institution and hospital in a metropolitan area, which serves a population of 4 million, we sometimes encounter referred patients with severe corneal ulcers who have been treated with topical corticosteroids. The purpose of this study was to review the clinical features and the visual outcomes of these patients, and to elucidate the effect of the empirical use of topical corticosteroids on the clinical course of this condition and the background of steroid applications in such patients.
Patients and Methods
We retrospectively reviewed the medical records of patients who visited the Cornea Service at Fujita Health University Bantane Hospital and were treated for infectious keratitis from April 2016 to March 2020. The diagnosis of microbial infectious keratitis was confirmed by culture, but because the antibiotic therapy had already been started before the patients arrived at our institution, many of them were solely diagnosed based on the corneal findings and the clinical course.
Suspected infectious keratitis patients treated with topical corticosteroids before culture-proven diagnosis were retrospectively studied in terms of demographics, best-corrected visual acuity at arrival and at the last visit, clinical course after the initial visit, ocular history, and combination therapy by the previous ophthalmologist. We used this information to determine the influence of topical steroid therapy and to determine the factors that led to the steroid prescription.
This study was approved by the institutional review board of the Fujita Health University Faculty of Medicine (Approval number: C120-135). Informed consent was obtained from each patient for use in clinical records for future research.
Results
Patients’ Visits
Two hundred eyes of 197 patients were treated for microbial infectious keratitis in the investigation period. Among the 197 patients, 195 eyes of 192 patients were referred from a hospital or ophthalmic clinic. Almost all the referred patients had already been empirically treated with topical or systemic antibiotic therapy, and the reason for the referral was a poor response to the antibiotic therapy.
Among the referred patients, 14 eyes of 14 patients had been treated with corticosteroid eye drops before arrival (Table 1).Table 1 Patients in Whom Topical Corticosteroids Were Applied Before Culture: Demographics and Past Treatments Other Than Topical Antibiotics
Case No. Age (Years) Sex Laterality Onset-Arrival (Days) Steroid Eye Drops Prescribing Doctor Steroid Use (Days) CL User Ocular History Anti-HSV Drugs Diagnosis
1 32 Male L 7 Unknown Previous doctor 4 Yes BK
2 82 Male R 50 0.1% BM+Fra Referral doctor 30 DMR, Rubeotic gla BK susp
3 39 Male R 12 0.1% FLM Previous doctor 7 Yes ACV AK
4 24 Male R 30 0.1% BM+Fra Previous doctor 28 Yes Herpetic keratitis VACV AK
5 53 Female L 75 0.1% BM Previous doctor 60 Yes Herpetic keratitis AK
6 31 Male R 18 0.1% BM Previous doctor 10 Yes AK
7 56 Male L 14 0.1% BM Referral doctor 8 Yes ACV AK
8 33 Female L 240 Unknown Referral doctor 30 Herpetic keratitis AK
9 46 Female R 20 0.1% BM+Fra Previous doctor 15 Yes FK
10 48 Female R 21 0.1% FLM Referral doctor 7 ACV, VACV FK
11 44 Female L 14 0.1% BM Referral doctor 3 Yes Unknown
12 19 Female L 30 Unknown Previous doctor 21 Yes Unknown
13 51 Male R 14 0.1% BM Referral doctor 3 ACV, VACV Unknown
14 35 Male L 40 0.1% BM Previous doctor 28 Herpetic keratitis ACV Unknown
Abbreviations. No., number; CL, contact lenses; HSV, herpes simplex virus; R, right; L, left; FLM, fluorometholone; BM, betamethasone sodium phosphate; BM+Fra, combined betamethasone sodium sulfate and fradiomycin sulfate; AK, Acanthamoeba keratitis; BK, bacterial keratitis; FK, fungal keratitis; PDR, proliferative diabetic retinopathy; rubeotic gla, rubeotic glaucoma; ACV, acyclovir ocular ointment; VACV, valaciclovir tablets.
Use of Topical Corticosteroids
Corticosteroid eye drops were not used before keratitis occurred but were used to treat the corneal lesions. Out of the 14 patients, six patients were prescribed topical corticosteroids by the referring doctor, and eight patients were prescribed these drugs by another doctor (Table 1). The details of the medical practice, other than the referring doctor, at the previous doctor’s clinic were unknown, but the prescribed corticosteroid eye drops were 0.1% betamethasone sodium phosphate for nine patients, 0.1% fluorometholone for two patients, and unknown steroid eye drops for three patients. Among the nine patients who were treated with 0.1% betamethasone sodium phosphate, combined corticosteroid-antibiotic eye drops (betamethasone sodium sulfate/fradiomycin sulfate) were prescribed for at least three patients (Table 1).
All patients visited the ophthalmic clinic with a complaint of ocular pain, red eye, and visual disturbance. Nine patients were contact lens wearers (Table 1).
History of Herpetic Keratitis
The history of herpetic keratitis and treatment is described in Table 1. According to the referral letters, four patients (cases 4, 5, 8, and 14) had a past history of herpetic keratitis, but the details and the accuracy of the diagnosis were unknown. At least six of the 14 patients were treated with either acyclovir ocular ointment or valaciclovir tablets, along with topical corticosteroids (cases 3, 4, 7, 10, 13, 14). Although we could not exclude concurrent herpetic stromal keratitis because our institution did not have the facility to perform either the immune chromatography or the real-time polymerase chain reaction, the corneal findings and the clinical course of the patients’ eyes were not suggestive of herpetic necrotic keratitis.
Culture and Diagnosis
Corneal scraping and culture were performed for 13 patients (Table 2); however, because the cornea was already perforated and Acanthamoeba was proven by the referral doctor, culture was not performed for case 8. As listed in Table 2, based on the results of the cultures, we diagnosed keratitis as follows: bacterial keratitis in two patients including one suspected case, Acanthamoeba keratitis in six patients, fungal keratitis in two patients, and unknown cause in four patients. Case 2 had a corneal ulcer with a 3.0-mm diameter and hypopyon at the first visit, but the inflammation subsided within 3 weeks of topical antibiotic therapy, and we thus diagnosed the patient with bacterial keratitis even though the culture was negative. In four patients with unknown causes (cases 11−14), the diagnosis of microbial infectious keratitis was made from the clinical presentation at the first visit (Figure 1), but it was not possible to determine whether these were bacterial, fungal, or Acanthamoeba keratitis cases based on the clinical course.Table 2 Patients Topical Corticosteroids Were Applied Before Culture: Culture Results and Prognosis
Case No. BCVA at First Visit BCVA at Last Visit Weeks Taken to Settle Down Cultured Microorganisms Diagnosis Corneal Perforation
1 HM 0.3 3 Pseudomonas aeruginosa BK
2 NLP NLP 8 No growth BK susp
3 0.4 1.0 17 Amoeba, Staphylococcus epidermis, GM Pos bacilli AK
4 LP 0.4 22 Amoeba, Staphylococcus epidermis AK
5 CF HM 50 Amoeba AK
6 HM 0.9 15 Amoeba AK
7 0.3 0.9 19 Amoeba AK
8 LP LP 8 Amoeba at referring doctor AK Yes
9 HM NLP Evisceration Fusarium sp. FK Yes
10 LP NLP Evisceration Fusarium sp. FK Yes
11 0.03 0.8 3 No growth Unknown
12 CF 0.5 6 No growth Unknown
13 LP 0.05 25 No growth Unknown Yes
14 0.04 0.04 30 Staphylococcus epidermis (MRSE) Unknown
Abbreviations: BCVA, best-corrected visual acuity; HM, hand motion; NLP, no light perception; LP, light perception; CF, counting fingers; GM Pos bacilli, Gram-positive bacilli; AK, Acanthamoeba keratitis; BK, bacterial keratitis, FK, fungal keratitis; MRSE, methicillin-resistant Staphylococcus epidermis.
Figure 1 Cases of suspected infectious keratitis who were treated with topical corticosteroids without culture-proven diagnosis and before presentation to our clinic. (A) Case 11; Forty-four-year-old female. Although fungal keratitis was suspected based on corneal findings, it took only 3 weeks to cure the inflammation by a combination of topical antibiotics and anti-fungal therapy. (B) Case 12; Eighteen-year-old female. Early stage of Acanthamoeba keratitis was suspected based on the findings, but no organism could be cultured, even after co-culture with Escherichia coli. (C) Case 13; Fifty-one-year-old male. Despite treatment with a combination topical antibiotic and antifungal therapy, corneal perforation occurred 2 weeks after the first visit. (D) Case 14; Thirty-five-year-old male. Culture was attempted 3 times from the first visit, and at the second time of culture, 1 week after the intensive topical antibiotic therapy was started, methicillin-resistant Staphylococcus epidermis was detected by enrichment culture, but the significance of this result was unclear.
Prognosis
The prognosis is summarized in Table 2. The patients with bacterial keratitis (cases 1 and 2) responded well to the topical antibiotic therapy, and the corneal lesion healed as a scar after 3 weeks, after which corticosteroid eye drops were started again to settle the infiltration.
The prognosis for the vision of the two patients with Acanthamoeba keratitis (cases 5 and 8) whose anti-amoebic therapy was started more than 10 weeks after the onset was poor (Table 1). In patients with Acanthamoeba keratitis in whom appropriate anti-amoebic therapy was started at least within 2 weeks from the onset, the visual prognosis was good, even though topical corticosteroids were applied before the diagnosis (cases 3, 6, and 7).
Both patients with fungal keratitis visited the specialist clinic 3 weeks after the onset of the complaint (Table 1). The delay in the diagnosis and identification of the causative organism (Fusarium species), in addition to the use of topical corticosteroid before diagnosis, may have caused a corneal perforation and loss of sight in the affected eyes (cases 9 and 10).
In the five culture-negative cases, we could not determine the causative microorganism based on the corneal appearance and the clinical course in four cases (Figure 1). Favorable recovery of vision has still not been obtained in two of the cases (cases 13 and 14). This may be due to the difficulty in establishing a treatment plan because the empirical topical antibiotic and corticosteroid treatment has masked the appearance of the corneal lesion.
Discussion
Similar to the findings of the SCUT study, in our cases, the use of topical steroids along with antibiotics did not affect the vision prognoses in the eyes with bacterial keratitis; however, vision was lost in two eyes with fungal keratitis (Table 2). Even though this poor outcome may be attributed to the Fusarium sp. that was involved in two of our cases, topical corticosteroids should not be used for fungal keratitis.6,7,18 For the eyes with Acanthamoeba keratitis, topical corticosteroids are not contraindicated as long as appropriate anti-amoebic therapy is applied.19–21 However, two of the six Acanthamoeba keratitis eyes lost vision in our study (Table 2). In the Acanthamoeba keratitis patients (cases 5 and 8) as well as in two fungal keratitis patients (cases 9 and 10) and two unknown keratitis patients (cases 13 and 14), one of the reasons for the undesirable visual prognosis could be the delay in proper diagnosis (Table 1), caused by the masked clinical findings (Figure 1) and the reactions to the empirical use of topical antibiotics and corticosteroids.25,26
From the referral letter information, at least eight patients were assumed to be treated with topical corticosteroids after being diagnosed with stromal herpetic keratitis. Three of the six Acanthamoeba keratitis patients, one of the two fungal keratitis patients, and two of the four unknown keratitis patients were treated with acyclovir ointment or valaciclovir tablets (Table 1). In addition to these patients who were treated with anti-herpes virus drugs, two Acanthamoeba keratitis patients had a history of herpetic keratitis, according to the referral letter (Table 2). These facts show that we have to distinguish whether the keratitis is stromal keratitis related to herpes simplex virus or microbial infectious keratitis.
From the results of this study, we concluded that it is important to evaluate the patient for fungal keratitis and Acanthamoeba keratitis before deciding on the use of topical corticosteroids for the treatment of the keratitis. Because correct differentiation of bacterial or fungal keratitis by the clinical signs or findings is difficult even for a corneal specialist,27 it is important to make a biologically proven diagnosis by smear and culture before prescribing topical corticosteroids. In addition, it is important to stop the application of topical corticosteroids immediately when keratitis does not improve by these steroids.
A combination of 0.1% betamethasone sodium sulfate and fradiomycin sulfate was prescribed in at least three of the 14 cases. Along with the possibility of stromal herpetic keratitis, another possible reason for the immediate use of topical corticosteroids could be the commercial availability of corticosteroid-antibiotic combination eye drops. As O’Day DM pointed out,28 these preparations have the potential to violate the rule of combined corticosteroid–antibiotic therapy for infectious keratitis.
Accordingly, microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed when prescribing topical corticosteroids for the treatment of infectious keratitis. Although corticosteroid-antibiotic combination eye drops seem safe, they are meaningless or unsafe for treating infectious keratitis other than culture-proven bacterial keratitis.
In addition to its retrospective nature, the main limitation of this study was the single-center study design. As almost all the patients had already been treated empirically with topical antibiotics by the previous ophthalmologist, it was difficult to distinguish the causative microorganism by culture. Thus, we had to diagnose the keratitis as infectious keratitis, particularly bacterial keratitis, based on the corneal findings and clinical course. Additional information from other institutions is needed to clarify the merits and demerits, as well as the background for the empirical use of topical corticosteroids for suspected microbial infectious keratitis.
Conclusion
This study reported a series of severe infectious keratitis cases referred to a specialized medical institution, who were given an antibiotic-steroid combination treatment. Our findings show that it is harmful to apply topical corticosteroids for keratitis that does not respond to empirical antibiotic therapy, since Acanthamoeba keratitis or fungal keratitis are likely involved in these topical antibiotic-resistant cases.
The use of topical corticosteroids along with empirical antibiotic therapy make it difficult to distinguish the causative agent of the infection in suspected keratitis, either by culture or by the corneal findings and clinical course, and as a result, may delay the appropriate treatment and cause unfortunate outcomes. Therefore, we conclude that the use of topical corticosteroids, merely owing to ineffective empirical antibiotic therapy for keratitis, should be avoided. Microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed before prescribing topical corticosteroids for the treatment of suspected infectious keratitis.
Abbreviations
AK, Acanthamoeba keratitis; FK, fungal keratitis; SCUT, Steroids for Corneal Ulcers Trial.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Ethics Approval and Consent to Participate
Written informed consent was obtained from each patient. This study was approved by the Research Ethics Committee of Fujita Health University and was performed in accordance with the Declaration of Helsinki.
Consent for Publication
Written informed consent was obtained from the participants for publication of the research article and any accompanying images.
Author Contributions
KH followed all the patients in this study and wrote the manuscript. KH, HT, and KK analyzed and interpreted the data on the clinical features of the patients. KK and KA-S made critical comments on the manuscript and provided input regarding the clinical outcome of the series of patients with infectious keratitis in whom topical corticosteroids were used. All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agree to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for aspects of the work.
Disclosure
The authors report no conflicts of interest in this work. | ACYCLOVIR, BETAMETHASONE SODIUM PHOSPHATE, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33623362 | 19,087,364 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Eye pain'. | Topical Corticosteroids for Infectious Keratitis Before Culture-Proven Diagnosis.
In clinical practice we sometimes encounter patients with severe corneal ulcers who have been treated with topical corticosteroids. This study reviewed the clinical features and visual outcomes of these patients and investigated the background of the prescription of topical corticosteroids.
The medical records of patients who visited the Cornea Service at Fujita Health University Bantane Hospital and were treated for infectious keratitis from April 2016 to March 2020 were retrospectively reviewed. Patients treated with topical corticosteroids before a culture-proven diagnosis were studied in terms of demographics, best-corrected visual acuity at arrival and at last visit, the clinical course after visit, ocular history, and combination therapy by the previous ophthalmologist.
Out of the 200 eyes of 197 patients with infectious keratitis, 14 eyes of 14 patients were treated with topical corticosteroids before a culture-proven diagnosis. All 14 patients were referred, as they had severe keratitis that could not be cured with topical antibiotics and corticosteroids. Based on the culture results, we diagnosed Acanthamoeba keratitis (AK) in six patients, fungal keratitis (FK) in two patients, bacterial keratitis (including a suspected case) in two patients, and unknown cause in four patients. Two patients with AK, FK, and unknown keratitis had unfortunate clinical courses and poor visual outcomes. From the information in the referral letters, at least six of the 14 patients were treated with either acyclovir ocular ointment or valaciclovir tablets, along with topical corticosteroids.
Application of topical corticosteroids for keratitis that does not respond to empirical antibiotic therapy is harmful since AK or FK is likely involved in these topical antibiotic-resistant cases. Microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed when prescribing topical corticosteroid for the treatment of suspected infectious keratitis.
Plain Language Summary
In the corneal clinic of a university hospital in a metropolitan area, we sometimes encounter referred patients with severe corneal ulcers who have been treated with topical corticosteroids as well as antibiotic eye drops. Why were these topical corticosteroids prescribed? We retrospectively reviewed clinical records of patients with infectious keratitis treated with topical corticosteroids before a culture-proven diagnosis. During an investigative period of 4 years, 14 eyes of 14 patients were evaluated. All the patients were prescribed topical corticosteroids for the keratitis owing to unresponsive empirical antibiotic therapy, and at least six patients were treated for stromal keratitis due to herpes simplex virus.
Why did the corneal lesions of these patients worsen? Based on culture results, we diagnosed Acanthamoeba keratitis in six patients and fungal keratitis in two patients. Apart from bacterial keratitis, other microorganisms responsible for keratitis do not respond to antibiotic therapy, and the condition is worsened by the topical corticosteroids without appropriate anti-amoebic or anti-fungal therapy.
Application of topical corticosteroids for keratitis without microbiological evidence is harmful, and a differential diagnosis of herpetic stromal keratitis as well as fungal and Acanthamoeba keratitis is needed when using topical corticosteroid for the treatment of suspected infectious keratitis.
Introduction
The definitive diagnosis and specific therapy for microbial keratitis should only be determined by microbiological evaluation.1–3 Nevertheless, the application of empirical antibiotic therapy without the use of smears or cultures cannot be rejected, as topical fluoroquinolone is associated with of a high success rate; moreover, the time and cost involved in performing cultures and maintaining the necessary materials are reduced.4–6
During the treatment of microbial keratitis, adjunctive topical corticosteroids are used to reduce the inflammatory response and subsequent corneal scarring, to obtain better visual outcomes, despite the possible risk of enhanced microbial replication, corneal melting, and steroid glaucoma.6–8 The safety and efficacy of topical corticosteroids for microbial keratitis have been reported9–17 in the Steroids for Corneal Ulcers Trial (SCUT)9,10 and other randomized control studies.11,12 The consensus of these studies was that unlike the use of topical antibiotics, the empirical use of topical corticosteroids for suspected microbial keratitis is not recommended. According to the Bacterial Keratitis Preferred Practice Pattern® 2018, 24–48 hours after the causative organism has been identified and/or infection is responding to therapy, corticosteroids may be considered, and close follow-up by a corneal specialist is recommended. Corticosteroids should be avoided in bacterial keratitis caused by slow-cycling microbes such as Nocardia,10 and fungal keratitis,7,11,18 while in Acanthamoeba keratitis, maintaining adequate anti-amoebic therapy is needed if a topical corticosteroid is used.19–23 Therefore, these microorganisms should be ruled out and a definitive diagnosis of bacterial keratitis based on smear and culture or by confirming the response to anti-microbial therapy is suggested before topical corticosteroids.24
At the corneal clinic of our institution and hospital in a metropolitan area, which serves a population of 4 million, we sometimes encounter referred patients with severe corneal ulcers who have been treated with topical corticosteroids. The purpose of this study was to review the clinical features and the visual outcomes of these patients, and to elucidate the effect of the empirical use of topical corticosteroids on the clinical course of this condition and the background of steroid applications in such patients.
Patients and Methods
We retrospectively reviewed the medical records of patients who visited the Cornea Service at Fujita Health University Bantane Hospital and were treated for infectious keratitis from April 2016 to March 2020. The diagnosis of microbial infectious keratitis was confirmed by culture, but because the antibiotic therapy had already been started before the patients arrived at our institution, many of them were solely diagnosed based on the corneal findings and the clinical course.
Suspected infectious keratitis patients treated with topical corticosteroids before culture-proven diagnosis were retrospectively studied in terms of demographics, best-corrected visual acuity at arrival and at the last visit, clinical course after the initial visit, ocular history, and combination therapy by the previous ophthalmologist. We used this information to determine the influence of topical steroid therapy and to determine the factors that led to the steroid prescription.
This study was approved by the institutional review board of the Fujita Health University Faculty of Medicine (Approval number: C120-135). Informed consent was obtained from each patient for use in clinical records for future research.
Results
Patients’ Visits
Two hundred eyes of 197 patients were treated for microbial infectious keratitis in the investigation period. Among the 197 patients, 195 eyes of 192 patients were referred from a hospital or ophthalmic clinic. Almost all the referred patients had already been empirically treated with topical or systemic antibiotic therapy, and the reason for the referral was a poor response to the antibiotic therapy.
Among the referred patients, 14 eyes of 14 patients had been treated with corticosteroid eye drops before arrival (Table 1).Table 1 Patients in Whom Topical Corticosteroids Were Applied Before Culture: Demographics and Past Treatments Other Than Topical Antibiotics
Case No. Age (Years) Sex Laterality Onset-Arrival (Days) Steroid Eye Drops Prescribing Doctor Steroid Use (Days) CL User Ocular History Anti-HSV Drugs Diagnosis
1 32 Male L 7 Unknown Previous doctor 4 Yes BK
2 82 Male R 50 0.1% BM+Fra Referral doctor 30 DMR, Rubeotic gla BK susp
3 39 Male R 12 0.1% FLM Previous doctor 7 Yes ACV AK
4 24 Male R 30 0.1% BM+Fra Previous doctor 28 Yes Herpetic keratitis VACV AK
5 53 Female L 75 0.1% BM Previous doctor 60 Yes Herpetic keratitis AK
6 31 Male R 18 0.1% BM Previous doctor 10 Yes AK
7 56 Male L 14 0.1% BM Referral doctor 8 Yes ACV AK
8 33 Female L 240 Unknown Referral doctor 30 Herpetic keratitis AK
9 46 Female R 20 0.1% BM+Fra Previous doctor 15 Yes FK
10 48 Female R 21 0.1% FLM Referral doctor 7 ACV, VACV FK
11 44 Female L 14 0.1% BM Referral doctor 3 Yes Unknown
12 19 Female L 30 Unknown Previous doctor 21 Yes Unknown
13 51 Male R 14 0.1% BM Referral doctor 3 ACV, VACV Unknown
14 35 Male L 40 0.1% BM Previous doctor 28 Herpetic keratitis ACV Unknown
Abbreviations. No., number; CL, contact lenses; HSV, herpes simplex virus; R, right; L, left; FLM, fluorometholone; BM, betamethasone sodium phosphate; BM+Fra, combined betamethasone sodium sulfate and fradiomycin sulfate; AK, Acanthamoeba keratitis; BK, bacterial keratitis; FK, fungal keratitis; PDR, proliferative diabetic retinopathy; rubeotic gla, rubeotic glaucoma; ACV, acyclovir ocular ointment; VACV, valaciclovir tablets.
Use of Topical Corticosteroids
Corticosteroid eye drops were not used before keratitis occurred but were used to treat the corneal lesions. Out of the 14 patients, six patients were prescribed topical corticosteroids by the referring doctor, and eight patients were prescribed these drugs by another doctor (Table 1). The details of the medical practice, other than the referring doctor, at the previous doctor’s clinic were unknown, but the prescribed corticosteroid eye drops were 0.1% betamethasone sodium phosphate for nine patients, 0.1% fluorometholone for two patients, and unknown steroid eye drops for three patients. Among the nine patients who were treated with 0.1% betamethasone sodium phosphate, combined corticosteroid-antibiotic eye drops (betamethasone sodium sulfate/fradiomycin sulfate) were prescribed for at least three patients (Table 1).
All patients visited the ophthalmic clinic with a complaint of ocular pain, red eye, and visual disturbance. Nine patients were contact lens wearers (Table 1).
History of Herpetic Keratitis
The history of herpetic keratitis and treatment is described in Table 1. According to the referral letters, four patients (cases 4, 5, 8, and 14) had a past history of herpetic keratitis, but the details and the accuracy of the diagnosis were unknown. At least six of the 14 patients were treated with either acyclovir ocular ointment or valaciclovir tablets, along with topical corticosteroids (cases 3, 4, 7, 10, 13, 14). Although we could not exclude concurrent herpetic stromal keratitis because our institution did not have the facility to perform either the immune chromatography or the real-time polymerase chain reaction, the corneal findings and the clinical course of the patients’ eyes were not suggestive of herpetic necrotic keratitis.
Culture and Diagnosis
Corneal scraping and culture were performed for 13 patients (Table 2); however, because the cornea was already perforated and Acanthamoeba was proven by the referral doctor, culture was not performed for case 8. As listed in Table 2, based on the results of the cultures, we diagnosed keratitis as follows: bacterial keratitis in two patients including one suspected case, Acanthamoeba keratitis in six patients, fungal keratitis in two patients, and unknown cause in four patients. Case 2 had a corneal ulcer with a 3.0-mm diameter and hypopyon at the first visit, but the inflammation subsided within 3 weeks of topical antibiotic therapy, and we thus diagnosed the patient with bacterial keratitis even though the culture was negative. In four patients with unknown causes (cases 11−14), the diagnosis of microbial infectious keratitis was made from the clinical presentation at the first visit (Figure 1), but it was not possible to determine whether these were bacterial, fungal, or Acanthamoeba keratitis cases based on the clinical course.Table 2 Patients Topical Corticosteroids Were Applied Before Culture: Culture Results and Prognosis
Case No. BCVA at First Visit BCVA at Last Visit Weeks Taken to Settle Down Cultured Microorganisms Diagnosis Corneal Perforation
1 HM 0.3 3 Pseudomonas aeruginosa BK
2 NLP NLP 8 No growth BK susp
3 0.4 1.0 17 Amoeba, Staphylococcus epidermis, GM Pos bacilli AK
4 LP 0.4 22 Amoeba, Staphylococcus epidermis AK
5 CF HM 50 Amoeba AK
6 HM 0.9 15 Amoeba AK
7 0.3 0.9 19 Amoeba AK
8 LP LP 8 Amoeba at referring doctor AK Yes
9 HM NLP Evisceration Fusarium sp. FK Yes
10 LP NLP Evisceration Fusarium sp. FK Yes
11 0.03 0.8 3 No growth Unknown
12 CF 0.5 6 No growth Unknown
13 LP 0.05 25 No growth Unknown Yes
14 0.04 0.04 30 Staphylococcus epidermis (MRSE) Unknown
Abbreviations: BCVA, best-corrected visual acuity; HM, hand motion; NLP, no light perception; LP, light perception; CF, counting fingers; GM Pos bacilli, Gram-positive bacilli; AK, Acanthamoeba keratitis; BK, bacterial keratitis, FK, fungal keratitis; MRSE, methicillin-resistant Staphylococcus epidermis.
Figure 1 Cases of suspected infectious keratitis who were treated with topical corticosteroids without culture-proven diagnosis and before presentation to our clinic. (A) Case 11; Forty-four-year-old female. Although fungal keratitis was suspected based on corneal findings, it took only 3 weeks to cure the inflammation by a combination of topical antibiotics and anti-fungal therapy. (B) Case 12; Eighteen-year-old female. Early stage of Acanthamoeba keratitis was suspected based on the findings, but no organism could be cultured, even after co-culture with Escherichia coli. (C) Case 13; Fifty-one-year-old male. Despite treatment with a combination topical antibiotic and antifungal therapy, corneal perforation occurred 2 weeks after the first visit. (D) Case 14; Thirty-five-year-old male. Culture was attempted 3 times from the first visit, and at the second time of culture, 1 week after the intensive topical antibiotic therapy was started, methicillin-resistant Staphylococcus epidermis was detected by enrichment culture, but the significance of this result was unclear.
Prognosis
The prognosis is summarized in Table 2. The patients with bacterial keratitis (cases 1 and 2) responded well to the topical antibiotic therapy, and the corneal lesion healed as a scar after 3 weeks, after which corticosteroid eye drops were started again to settle the infiltration.
The prognosis for the vision of the two patients with Acanthamoeba keratitis (cases 5 and 8) whose anti-amoebic therapy was started more than 10 weeks after the onset was poor (Table 1). In patients with Acanthamoeba keratitis in whom appropriate anti-amoebic therapy was started at least within 2 weeks from the onset, the visual prognosis was good, even though topical corticosteroids were applied before the diagnosis (cases 3, 6, and 7).
Both patients with fungal keratitis visited the specialist clinic 3 weeks after the onset of the complaint (Table 1). The delay in the diagnosis and identification of the causative organism (Fusarium species), in addition to the use of topical corticosteroid before diagnosis, may have caused a corneal perforation and loss of sight in the affected eyes (cases 9 and 10).
In the five culture-negative cases, we could not determine the causative microorganism based on the corneal appearance and the clinical course in four cases (Figure 1). Favorable recovery of vision has still not been obtained in two of the cases (cases 13 and 14). This may be due to the difficulty in establishing a treatment plan because the empirical topical antibiotic and corticosteroid treatment has masked the appearance of the corneal lesion.
Discussion
Similar to the findings of the SCUT study, in our cases, the use of topical steroids along with antibiotics did not affect the vision prognoses in the eyes with bacterial keratitis; however, vision was lost in two eyes with fungal keratitis (Table 2). Even though this poor outcome may be attributed to the Fusarium sp. that was involved in two of our cases, topical corticosteroids should not be used for fungal keratitis.6,7,18 For the eyes with Acanthamoeba keratitis, topical corticosteroids are not contraindicated as long as appropriate anti-amoebic therapy is applied.19–21 However, two of the six Acanthamoeba keratitis eyes lost vision in our study (Table 2). In the Acanthamoeba keratitis patients (cases 5 and 8) as well as in two fungal keratitis patients (cases 9 and 10) and two unknown keratitis patients (cases 13 and 14), one of the reasons for the undesirable visual prognosis could be the delay in proper diagnosis (Table 1), caused by the masked clinical findings (Figure 1) and the reactions to the empirical use of topical antibiotics and corticosteroids.25,26
From the referral letter information, at least eight patients were assumed to be treated with topical corticosteroids after being diagnosed with stromal herpetic keratitis. Three of the six Acanthamoeba keratitis patients, one of the two fungal keratitis patients, and two of the four unknown keratitis patients were treated with acyclovir ointment or valaciclovir tablets (Table 1). In addition to these patients who were treated with anti-herpes virus drugs, two Acanthamoeba keratitis patients had a history of herpetic keratitis, according to the referral letter (Table 2). These facts show that we have to distinguish whether the keratitis is stromal keratitis related to herpes simplex virus or microbial infectious keratitis.
From the results of this study, we concluded that it is important to evaluate the patient for fungal keratitis and Acanthamoeba keratitis before deciding on the use of topical corticosteroids for the treatment of the keratitis. Because correct differentiation of bacterial or fungal keratitis by the clinical signs or findings is difficult even for a corneal specialist,27 it is important to make a biologically proven diagnosis by smear and culture before prescribing topical corticosteroids. In addition, it is important to stop the application of topical corticosteroids immediately when keratitis does not improve by these steroids.
A combination of 0.1% betamethasone sodium sulfate and fradiomycin sulfate was prescribed in at least three of the 14 cases. Along with the possibility of stromal herpetic keratitis, another possible reason for the immediate use of topical corticosteroids could be the commercial availability of corticosteroid-antibiotic combination eye drops. As O’Day DM pointed out,28 these preparations have the potential to violate the rule of combined corticosteroid–antibiotic therapy for infectious keratitis.
Accordingly, microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed when prescribing topical corticosteroids for the treatment of infectious keratitis. Although corticosteroid-antibiotic combination eye drops seem safe, they are meaningless or unsafe for treating infectious keratitis other than culture-proven bacterial keratitis.
In addition to its retrospective nature, the main limitation of this study was the single-center study design. As almost all the patients had already been treated empirically with topical antibiotics by the previous ophthalmologist, it was difficult to distinguish the causative microorganism by culture. Thus, we had to diagnose the keratitis as infectious keratitis, particularly bacterial keratitis, based on the corneal findings and clinical course. Additional information from other institutions is needed to clarify the merits and demerits, as well as the background for the empirical use of topical corticosteroids for suspected microbial infectious keratitis.
Conclusion
This study reported a series of severe infectious keratitis cases referred to a specialized medical institution, who were given an antibiotic-steroid combination treatment. Our findings show that it is harmful to apply topical corticosteroids for keratitis that does not respond to empirical antibiotic therapy, since Acanthamoeba keratitis or fungal keratitis are likely involved in these topical antibiotic-resistant cases.
The use of topical corticosteroids along with empirical antibiotic therapy make it difficult to distinguish the causative agent of the infection in suspected keratitis, either by culture or by the corneal findings and clinical course, and as a result, may delay the appropriate treatment and cause unfortunate outcomes. Therefore, we conclude that the use of topical corticosteroids, merely owing to ineffective empirical antibiotic therapy for keratitis, should be avoided. Microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed before prescribing topical corticosteroids for the treatment of suspected infectious keratitis.
Abbreviations
AK, Acanthamoeba keratitis; FK, fungal keratitis; SCUT, Steroids for Corneal Ulcers Trial.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Ethics Approval and Consent to Participate
Written informed consent was obtained from each patient. This study was approved by the Research Ethics Committee of Fujita Health University and was performed in accordance with the Declaration of Helsinki.
Consent for Publication
Written informed consent was obtained from the participants for publication of the research article and any accompanying images.
Author Contributions
KH followed all the patients in this study and wrote the manuscript. KH, HT, and KK analyzed and interpreted the data on the clinical features of the patients. KK and KA-S made critical comments on the manuscript and provided input regarding the clinical outcome of the series of patients with infectious keratitis in whom topical corticosteroids were used. All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agree to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for aspects of the work.
Disclosure
The authors report no conflicts of interest in this work. | ACYCLOVIR, BETAMETHASONE SODIUM PHOSPHATE, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33623362 | 19,087,364 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ocular discomfort'. | Topical Corticosteroids for Infectious Keratitis Before Culture-Proven Diagnosis.
In clinical practice we sometimes encounter patients with severe corneal ulcers who have been treated with topical corticosteroids. This study reviewed the clinical features and visual outcomes of these patients and investigated the background of the prescription of topical corticosteroids.
The medical records of patients who visited the Cornea Service at Fujita Health University Bantane Hospital and were treated for infectious keratitis from April 2016 to March 2020 were retrospectively reviewed. Patients treated with topical corticosteroids before a culture-proven diagnosis were studied in terms of demographics, best-corrected visual acuity at arrival and at last visit, the clinical course after visit, ocular history, and combination therapy by the previous ophthalmologist.
Out of the 200 eyes of 197 patients with infectious keratitis, 14 eyes of 14 patients were treated with topical corticosteroids before a culture-proven diagnosis. All 14 patients were referred, as they had severe keratitis that could not be cured with topical antibiotics and corticosteroids. Based on the culture results, we diagnosed Acanthamoeba keratitis (AK) in six patients, fungal keratitis (FK) in two patients, bacterial keratitis (including a suspected case) in two patients, and unknown cause in four patients. Two patients with AK, FK, and unknown keratitis had unfortunate clinical courses and poor visual outcomes. From the information in the referral letters, at least six of the 14 patients were treated with either acyclovir ocular ointment or valaciclovir tablets, along with topical corticosteroids.
Application of topical corticosteroids for keratitis that does not respond to empirical antibiotic therapy is harmful since AK or FK is likely involved in these topical antibiotic-resistant cases. Microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed when prescribing topical corticosteroid for the treatment of suspected infectious keratitis.
Plain Language Summary
In the corneal clinic of a university hospital in a metropolitan area, we sometimes encounter referred patients with severe corneal ulcers who have been treated with topical corticosteroids as well as antibiotic eye drops. Why were these topical corticosteroids prescribed? We retrospectively reviewed clinical records of patients with infectious keratitis treated with topical corticosteroids before a culture-proven diagnosis. During an investigative period of 4 years, 14 eyes of 14 patients were evaluated. All the patients were prescribed topical corticosteroids for the keratitis owing to unresponsive empirical antibiotic therapy, and at least six patients were treated for stromal keratitis due to herpes simplex virus.
Why did the corneal lesions of these patients worsen? Based on culture results, we diagnosed Acanthamoeba keratitis in six patients and fungal keratitis in two patients. Apart from bacterial keratitis, other microorganisms responsible for keratitis do not respond to antibiotic therapy, and the condition is worsened by the topical corticosteroids without appropriate anti-amoebic or anti-fungal therapy.
Application of topical corticosteroids for keratitis without microbiological evidence is harmful, and a differential diagnosis of herpetic stromal keratitis as well as fungal and Acanthamoeba keratitis is needed when using topical corticosteroid for the treatment of suspected infectious keratitis.
Introduction
The definitive diagnosis and specific therapy for microbial keratitis should only be determined by microbiological evaluation.1–3 Nevertheless, the application of empirical antibiotic therapy without the use of smears or cultures cannot be rejected, as topical fluoroquinolone is associated with of a high success rate; moreover, the time and cost involved in performing cultures and maintaining the necessary materials are reduced.4–6
During the treatment of microbial keratitis, adjunctive topical corticosteroids are used to reduce the inflammatory response and subsequent corneal scarring, to obtain better visual outcomes, despite the possible risk of enhanced microbial replication, corneal melting, and steroid glaucoma.6–8 The safety and efficacy of topical corticosteroids for microbial keratitis have been reported9–17 in the Steroids for Corneal Ulcers Trial (SCUT)9,10 and other randomized control studies.11,12 The consensus of these studies was that unlike the use of topical antibiotics, the empirical use of topical corticosteroids for suspected microbial keratitis is not recommended. According to the Bacterial Keratitis Preferred Practice Pattern® 2018, 24–48 hours after the causative organism has been identified and/or infection is responding to therapy, corticosteroids may be considered, and close follow-up by a corneal specialist is recommended. Corticosteroids should be avoided in bacterial keratitis caused by slow-cycling microbes such as Nocardia,10 and fungal keratitis,7,11,18 while in Acanthamoeba keratitis, maintaining adequate anti-amoebic therapy is needed if a topical corticosteroid is used.19–23 Therefore, these microorganisms should be ruled out and a definitive diagnosis of bacterial keratitis based on smear and culture or by confirming the response to anti-microbial therapy is suggested before topical corticosteroids.24
At the corneal clinic of our institution and hospital in a metropolitan area, which serves a population of 4 million, we sometimes encounter referred patients with severe corneal ulcers who have been treated with topical corticosteroids. The purpose of this study was to review the clinical features and the visual outcomes of these patients, and to elucidate the effect of the empirical use of topical corticosteroids on the clinical course of this condition and the background of steroid applications in such patients.
Patients and Methods
We retrospectively reviewed the medical records of patients who visited the Cornea Service at Fujita Health University Bantane Hospital and were treated for infectious keratitis from April 2016 to March 2020. The diagnosis of microbial infectious keratitis was confirmed by culture, but because the antibiotic therapy had already been started before the patients arrived at our institution, many of them were solely diagnosed based on the corneal findings and the clinical course.
Suspected infectious keratitis patients treated with topical corticosteroids before culture-proven diagnosis were retrospectively studied in terms of demographics, best-corrected visual acuity at arrival and at the last visit, clinical course after the initial visit, ocular history, and combination therapy by the previous ophthalmologist. We used this information to determine the influence of topical steroid therapy and to determine the factors that led to the steroid prescription.
This study was approved by the institutional review board of the Fujita Health University Faculty of Medicine (Approval number: C120-135). Informed consent was obtained from each patient for use in clinical records for future research.
Results
Patients’ Visits
Two hundred eyes of 197 patients were treated for microbial infectious keratitis in the investigation period. Among the 197 patients, 195 eyes of 192 patients were referred from a hospital or ophthalmic clinic. Almost all the referred patients had already been empirically treated with topical or systemic antibiotic therapy, and the reason for the referral was a poor response to the antibiotic therapy.
Among the referred patients, 14 eyes of 14 patients had been treated with corticosteroid eye drops before arrival (Table 1).Table 1 Patients in Whom Topical Corticosteroids Were Applied Before Culture: Demographics and Past Treatments Other Than Topical Antibiotics
Case No. Age (Years) Sex Laterality Onset-Arrival (Days) Steroid Eye Drops Prescribing Doctor Steroid Use (Days) CL User Ocular History Anti-HSV Drugs Diagnosis
1 32 Male L 7 Unknown Previous doctor 4 Yes BK
2 82 Male R 50 0.1% BM+Fra Referral doctor 30 DMR, Rubeotic gla BK susp
3 39 Male R 12 0.1% FLM Previous doctor 7 Yes ACV AK
4 24 Male R 30 0.1% BM+Fra Previous doctor 28 Yes Herpetic keratitis VACV AK
5 53 Female L 75 0.1% BM Previous doctor 60 Yes Herpetic keratitis AK
6 31 Male R 18 0.1% BM Previous doctor 10 Yes AK
7 56 Male L 14 0.1% BM Referral doctor 8 Yes ACV AK
8 33 Female L 240 Unknown Referral doctor 30 Herpetic keratitis AK
9 46 Female R 20 0.1% BM+Fra Previous doctor 15 Yes FK
10 48 Female R 21 0.1% FLM Referral doctor 7 ACV, VACV FK
11 44 Female L 14 0.1% BM Referral doctor 3 Yes Unknown
12 19 Female L 30 Unknown Previous doctor 21 Yes Unknown
13 51 Male R 14 0.1% BM Referral doctor 3 ACV, VACV Unknown
14 35 Male L 40 0.1% BM Previous doctor 28 Herpetic keratitis ACV Unknown
Abbreviations. No., number; CL, contact lenses; HSV, herpes simplex virus; R, right; L, left; FLM, fluorometholone; BM, betamethasone sodium phosphate; BM+Fra, combined betamethasone sodium sulfate and fradiomycin sulfate; AK, Acanthamoeba keratitis; BK, bacterial keratitis; FK, fungal keratitis; PDR, proliferative diabetic retinopathy; rubeotic gla, rubeotic glaucoma; ACV, acyclovir ocular ointment; VACV, valaciclovir tablets.
Use of Topical Corticosteroids
Corticosteroid eye drops were not used before keratitis occurred but were used to treat the corneal lesions. Out of the 14 patients, six patients were prescribed topical corticosteroids by the referring doctor, and eight patients were prescribed these drugs by another doctor (Table 1). The details of the medical practice, other than the referring doctor, at the previous doctor’s clinic were unknown, but the prescribed corticosteroid eye drops were 0.1% betamethasone sodium phosphate for nine patients, 0.1% fluorometholone for two patients, and unknown steroid eye drops for three patients. Among the nine patients who were treated with 0.1% betamethasone sodium phosphate, combined corticosteroid-antibiotic eye drops (betamethasone sodium sulfate/fradiomycin sulfate) were prescribed for at least three patients (Table 1).
All patients visited the ophthalmic clinic with a complaint of ocular pain, red eye, and visual disturbance. Nine patients were contact lens wearers (Table 1).
History of Herpetic Keratitis
The history of herpetic keratitis and treatment is described in Table 1. According to the referral letters, four patients (cases 4, 5, 8, and 14) had a past history of herpetic keratitis, but the details and the accuracy of the diagnosis were unknown. At least six of the 14 patients were treated with either acyclovir ocular ointment or valaciclovir tablets, along with topical corticosteroids (cases 3, 4, 7, 10, 13, 14). Although we could not exclude concurrent herpetic stromal keratitis because our institution did not have the facility to perform either the immune chromatography or the real-time polymerase chain reaction, the corneal findings and the clinical course of the patients’ eyes were not suggestive of herpetic necrotic keratitis.
Culture and Diagnosis
Corneal scraping and culture were performed for 13 patients (Table 2); however, because the cornea was already perforated and Acanthamoeba was proven by the referral doctor, culture was not performed for case 8. As listed in Table 2, based on the results of the cultures, we diagnosed keratitis as follows: bacterial keratitis in two patients including one suspected case, Acanthamoeba keratitis in six patients, fungal keratitis in two patients, and unknown cause in four patients. Case 2 had a corneal ulcer with a 3.0-mm diameter and hypopyon at the first visit, but the inflammation subsided within 3 weeks of topical antibiotic therapy, and we thus diagnosed the patient with bacterial keratitis even though the culture was negative. In four patients with unknown causes (cases 11−14), the diagnosis of microbial infectious keratitis was made from the clinical presentation at the first visit (Figure 1), but it was not possible to determine whether these were bacterial, fungal, or Acanthamoeba keratitis cases based on the clinical course.Table 2 Patients Topical Corticosteroids Were Applied Before Culture: Culture Results and Prognosis
Case No. BCVA at First Visit BCVA at Last Visit Weeks Taken to Settle Down Cultured Microorganisms Diagnosis Corneal Perforation
1 HM 0.3 3 Pseudomonas aeruginosa BK
2 NLP NLP 8 No growth BK susp
3 0.4 1.0 17 Amoeba, Staphylococcus epidermis, GM Pos bacilli AK
4 LP 0.4 22 Amoeba, Staphylococcus epidermis AK
5 CF HM 50 Amoeba AK
6 HM 0.9 15 Amoeba AK
7 0.3 0.9 19 Amoeba AK
8 LP LP 8 Amoeba at referring doctor AK Yes
9 HM NLP Evisceration Fusarium sp. FK Yes
10 LP NLP Evisceration Fusarium sp. FK Yes
11 0.03 0.8 3 No growth Unknown
12 CF 0.5 6 No growth Unknown
13 LP 0.05 25 No growth Unknown Yes
14 0.04 0.04 30 Staphylococcus epidermis (MRSE) Unknown
Abbreviations: BCVA, best-corrected visual acuity; HM, hand motion; NLP, no light perception; LP, light perception; CF, counting fingers; GM Pos bacilli, Gram-positive bacilli; AK, Acanthamoeba keratitis; BK, bacterial keratitis, FK, fungal keratitis; MRSE, methicillin-resistant Staphylococcus epidermis.
Figure 1 Cases of suspected infectious keratitis who were treated with topical corticosteroids without culture-proven diagnosis and before presentation to our clinic. (A) Case 11; Forty-four-year-old female. Although fungal keratitis was suspected based on corneal findings, it took only 3 weeks to cure the inflammation by a combination of topical antibiotics and anti-fungal therapy. (B) Case 12; Eighteen-year-old female. Early stage of Acanthamoeba keratitis was suspected based on the findings, but no organism could be cultured, even after co-culture with Escherichia coli. (C) Case 13; Fifty-one-year-old male. Despite treatment with a combination topical antibiotic and antifungal therapy, corneal perforation occurred 2 weeks after the first visit. (D) Case 14; Thirty-five-year-old male. Culture was attempted 3 times from the first visit, and at the second time of culture, 1 week after the intensive topical antibiotic therapy was started, methicillin-resistant Staphylococcus epidermis was detected by enrichment culture, but the significance of this result was unclear.
Prognosis
The prognosis is summarized in Table 2. The patients with bacterial keratitis (cases 1 and 2) responded well to the topical antibiotic therapy, and the corneal lesion healed as a scar after 3 weeks, after which corticosteroid eye drops were started again to settle the infiltration.
The prognosis for the vision of the two patients with Acanthamoeba keratitis (cases 5 and 8) whose anti-amoebic therapy was started more than 10 weeks after the onset was poor (Table 1). In patients with Acanthamoeba keratitis in whom appropriate anti-amoebic therapy was started at least within 2 weeks from the onset, the visual prognosis was good, even though topical corticosteroids were applied before the diagnosis (cases 3, 6, and 7).
Both patients with fungal keratitis visited the specialist clinic 3 weeks after the onset of the complaint (Table 1). The delay in the diagnosis and identification of the causative organism (Fusarium species), in addition to the use of topical corticosteroid before diagnosis, may have caused a corneal perforation and loss of sight in the affected eyes (cases 9 and 10).
In the five culture-negative cases, we could not determine the causative microorganism based on the corneal appearance and the clinical course in four cases (Figure 1). Favorable recovery of vision has still not been obtained in two of the cases (cases 13 and 14). This may be due to the difficulty in establishing a treatment plan because the empirical topical antibiotic and corticosteroid treatment has masked the appearance of the corneal lesion.
Discussion
Similar to the findings of the SCUT study, in our cases, the use of topical steroids along with antibiotics did not affect the vision prognoses in the eyes with bacterial keratitis; however, vision was lost in two eyes with fungal keratitis (Table 2). Even though this poor outcome may be attributed to the Fusarium sp. that was involved in two of our cases, topical corticosteroids should not be used for fungal keratitis.6,7,18 For the eyes with Acanthamoeba keratitis, topical corticosteroids are not contraindicated as long as appropriate anti-amoebic therapy is applied.19–21 However, two of the six Acanthamoeba keratitis eyes lost vision in our study (Table 2). In the Acanthamoeba keratitis patients (cases 5 and 8) as well as in two fungal keratitis patients (cases 9 and 10) and two unknown keratitis patients (cases 13 and 14), one of the reasons for the undesirable visual prognosis could be the delay in proper diagnosis (Table 1), caused by the masked clinical findings (Figure 1) and the reactions to the empirical use of topical antibiotics and corticosteroids.25,26
From the referral letter information, at least eight patients were assumed to be treated with topical corticosteroids after being diagnosed with stromal herpetic keratitis. Three of the six Acanthamoeba keratitis patients, one of the two fungal keratitis patients, and two of the four unknown keratitis patients were treated with acyclovir ointment or valaciclovir tablets (Table 1). In addition to these patients who were treated with anti-herpes virus drugs, two Acanthamoeba keratitis patients had a history of herpetic keratitis, according to the referral letter (Table 2). These facts show that we have to distinguish whether the keratitis is stromal keratitis related to herpes simplex virus or microbial infectious keratitis.
From the results of this study, we concluded that it is important to evaluate the patient for fungal keratitis and Acanthamoeba keratitis before deciding on the use of topical corticosteroids for the treatment of the keratitis. Because correct differentiation of bacterial or fungal keratitis by the clinical signs or findings is difficult even for a corneal specialist,27 it is important to make a biologically proven diagnosis by smear and culture before prescribing topical corticosteroids. In addition, it is important to stop the application of topical corticosteroids immediately when keratitis does not improve by these steroids.
A combination of 0.1% betamethasone sodium sulfate and fradiomycin sulfate was prescribed in at least three of the 14 cases. Along with the possibility of stromal herpetic keratitis, another possible reason for the immediate use of topical corticosteroids could be the commercial availability of corticosteroid-antibiotic combination eye drops. As O’Day DM pointed out,28 these preparations have the potential to violate the rule of combined corticosteroid–antibiotic therapy for infectious keratitis.
Accordingly, microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed when prescribing topical corticosteroids for the treatment of infectious keratitis. Although corticosteroid-antibiotic combination eye drops seem safe, they are meaningless or unsafe for treating infectious keratitis other than culture-proven bacterial keratitis.
In addition to its retrospective nature, the main limitation of this study was the single-center study design. As almost all the patients had already been treated empirically with topical antibiotics by the previous ophthalmologist, it was difficult to distinguish the causative microorganism by culture. Thus, we had to diagnose the keratitis as infectious keratitis, particularly bacterial keratitis, based on the corneal findings and clinical course. Additional information from other institutions is needed to clarify the merits and demerits, as well as the background for the empirical use of topical corticosteroids for suspected microbial infectious keratitis.
Conclusion
This study reported a series of severe infectious keratitis cases referred to a specialized medical institution, who were given an antibiotic-steroid combination treatment. Our findings show that it is harmful to apply topical corticosteroids for keratitis that does not respond to empirical antibiotic therapy, since Acanthamoeba keratitis or fungal keratitis are likely involved in these topical antibiotic-resistant cases.
The use of topical corticosteroids along with empirical antibiotic therapy make it difficult to distinguish the causative agent of the infection in suspected keratitis, either by culture or by the corneal findings and clinical course, and as a result, may delay the appropriate treatment and cause unfortunate outcomes. Therefore, we conclude that the use of topical corticosteroids, merely owing to ineffective empirical antibiotic therapy for keratitis, should be avoided. Microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed before prescribing topical corticosteroids for the treatment of suspected infectious keratitis.
Abbreviations
AK, Acanthamoeba keratitis; FK, fungal keratitis; SCUT, Steroids for Corneal Ulcers Trial.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Ethics Approval and Consent to Participate
Written informed consent was obtained from each patient. This study was approved by the Research Ethics Committee of Fujita Health University and was performed in accordance with the Declaration of Helsinki.
Consent for Publication
Written informed consent was obtained from the participants for publication of the research article and any accompanying images.
Author Contributions
KH followed all the patients in this study and wrote the manuscript. KH, HT, and KK analyzed and interpreted the data on the clinical features of the patients. KK and KA-S made critical comments on the manuscript and provided input regarding the clinical outcome of the series of patients with infectious keratitis in whom topical corticosteroids were used. All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agree to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for aspects of the work.
Disclosure
The authors report no conflicts of interest in this work. | ACYCLOVIR, BETAMETHASONE SODIUM PHOSPHATE, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33623362 | 19,087,364 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ocular hyperaemia'. | Topical Corticosteroids for Infectious Keratitis Before Culture-Proven Diagnosis.
In clinical practice we sometimes encounter patients with severe corneal ulcers who have been treated with topical corticosteroids. This study reviewed the clinical features and visual outcomes of these patients and investigated the background of the prescription of topical corticosteroids.
The medical records of patients who visited the Cornea Service at Fujita Health University Bantane Hospital and were treated for infectious keratitis from April 2016 to March 2020 were retrospectively reviewed. Patients treated with topical corticosteroids before a culture-proven diagnosis were studied in terms of demographics, best-corrected visual acuity at arrival and at last visit, the clinical course after visit, ocular history, and combination therapy by the previous ophthalmologist.
Out of the 200 eyes of 197 patients with infectious keratitis, 14 eyes of 14 patients were treated with topical corticosteroids before a culture-proven diagnosis. All 14 patients were referred, as they had severe keratitis that could not be cured with topical antibiotics and corticosteroids. Based on the culture results, we diagnosed Acanthamoeba keratitis (AK) in six patients, fungal keratitis (FK) in two patients, bacterial keratitis (including a suspected case) in two patients, and unknown cause in four patients. Two patients with AK, FK, and unknown keratitis had unfortunate clinical courses and poor visual outcomes. From the information in the referral letters, at least six of the 14 patients were treated with either acyclovir ocular ointment or valaciclovir tablets, along with topical corticosteroids.
Application of topical corticosteroids for keratitis that does not respond to empirical antibiotic therapy is harmful since AK or FK is likely involved in these topical antibiotic-resistant cases. Microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed when prescribing topical corticosteroid for the treatment of suspected infectious keratitis.
Plain Language Summary
In the corneal clinic of a university hospital in a metropolitan area, we sometimes encounter referred patients with severe corneal ulcers who have been treated with topical corticosteroids as well as antibiotic eye drops. Why were these topical corticosteroids prescribed? We retrospectively reviewed clinical records of patients with infectious keratitis treated with topical corticosteroids before a culture-proven diagnosis. During an investigative period of 4 years, 14 eyes of 14 patients were evaluated. All the patients were prescribed topical corticosteroids for the keratitis owing to unresponsive empirical antibiotic therapy, and at least six patients were treated for stromal keratitis due to herpes simplex virus.
Why did the corneal lesions of these patients worsen? Based on culture results, we diagnosed Acanthamoeba keratitis in six patients and fungal keratitis in two patients. Apart from bacterial keratitis, other microorganisms responsible for keratitis do not respond to antibiotic therapy, and the condition is worsened by the topical corticosteroids without appropriate anti-amoebic or anti-fungal therapy.
Application of topical corticosteroids for keratitis without microbiological evidence is harmful, and a differential diagnosis of herpetic stromal keratitis as well as fungal and Acanthamoeba keratitis is needed when using topical corticosteroid for the treatment of suspected infectious keratitis.
Introduction
The definitive diagnosis and specific therapy for microbial keratitis should only be determined by microbiological evaluation.1–3 Nevertheless, the application of empirical antibiotic therapy without the use of smears or cultures cannot be rejected, as topical fluoroquinolone is associated with of a high success rate; moreover, the time and cost involved in performing cultures and maintaining the necessary materials are reduced.4–6
During the treatment of microbial keratitis, adjunctive topical corticosteroids are used to reduce the inflammatory response and subsequent corneal scarring, to obtain better visual outcomes, despite the possible risk of enhanced microbial replication, corneal melting, and steroid glaucoma.6–8 The safety and efficacy of topical corticosteroids for microbial keratitis have been reported9–17 in the Steroids for Corneal Ulcers Trial (SCUT)9,10 and other randomized control studies.11,12 The consensus of these studies was that unlike the use of topical antibiotics, the empirical use of topical corticosteroids for suspected microbial keratitis is not recommended. According to the Bacterial Keratitis Preferred Practice Pattern® 2018, 24–48 hours after the causative organism has been identified and/or infection is responding to therapy, corticosteroids may be considered, and close follow-up by a corneal specialist is recommended. Corticosteroids should be avoided in bacterial keratitis caused by slow-cycling microbes such as Nocardia,10 and fungal keratitis,7,11,18 while in Acanthamoeba keratitis, maintaining adequate anti-amoebic therapy is needed if a topical corticosteroid is used.19–23 Therefore, these microorganisms should be ruled out and a definitive diagnosis of bacterial keratitis based on smear and culture or by confirming the response to anti-microbial therapy is suggested before topical corticosteroids.24
At the corneal clinic of our institution and hospital in a metropolitan area, which serves a population of 4 million, we sometimes encounter referred patients with severe corneal ulcers who have been treated with topical corticosteroids. The purpose of this study was to review the clinical features and the visual outcomes of these patients, and to elucidate the effect of the empirical use of topical corticosteroids on the clinical course of this condition and the background of steroid applications in such patients.
Patients and Methods
We retrospectively reviewed the medical records of patients who visited the Cornea Service at Fujita Health University Bantane Hospital and were treated for infectious keratitis from April 2016 to March 2020. The diagnosis of microbial infectious keratitis was confirmed by culture, but because the antibiotic therapy had already been started before the patients arrived at our institution, many of them were solely diagnosed based on the corneal findings and the clinical course.
Suspected infectious keratitis patients treated with topical corticosteroids before culture-proven diagnosis were retrospectively studied in terms of demographics, best-corrected visual acuity at arrival and at the last visit, clinical course after the initial visit, ocular history, and combination therapy by the previous ophthalmologist. We used this information to determine the influence of topical steroid therapy and to determine the factors that led to the steroid prescription.
This study was approved by the institutional review board of the Fujita Health University Faculty of Medicine (Approval number: C120-135). Informed consent was obtained from each patient for use in clinical records for future research.
Results
Patients’ Visits
Two hundred eyes of 197 patients were treated for microbial infectious keratitis in the investigation period. Among the 197 patients, 195 eyes of 192 patients were referred from a hospital or ophthalmic clinic. Almost all the referred patients had already been empirically treated with topical or systemic antibiotic therapy, and the reason for the referral was a poor response to the antibiotic therapy.
Among the referred patients, 14 eyes of 14 patients had been treated with corticosteroid eye drops before arrival (Table 1).Table 1 Patients in Whom Topical Corticosteroids Were Applied Before Culture: Demographics and Past Treatments Other Than Topical Antibiotics
Case No. Age (Years) Sex Laterality Onset-Arrival (Days) Steroid Eye Drops Prescribing Doctor Steroid Use (Days) CL User Ocular History Anti-HSV Drugs Diagnosis
1 32 Male L 7 Unknown Previous doctor 4 Yes BK
2 82 Male R 50 0.1% BM+Fra Referral doctor 30 DMR, Rubeotic gla BK susp
3 39 Male R 12 0.1% FLM Previous doctor 7 Yes ACV AK
4 24 Male R 30 0.1% BM+Fra Previous doctor 28 Yes Herpetic keratitis VACV AK
5 53 Female L 75 0.1% BM Previous doctor 60 Yes Herpetic keratitis AK
6 31 Male R 18 0.1% BM Previous doctor 10 Yes AK
7 56 Male L 14 0.1% BM Referral doctor 8 Yes ACV AK
8 33 Female L 240 Unknown Referral doctor 30 Herpetic keratitis AK
9 46 Female R 20 0.1% BM+Fra Previous doctor 15 Yes FK
10 48 Female R 21 0.1% FLM Referral doctor 7 ACV, VACV FK
11 44 Female L 14 0.1% BM Referral doctor 3 Yes Unknown
12 19 Female L 30 Unknown Previous doctor 21 Yes Unknown
13 51 Male R 14 0.1% BM Referral doctor 3 ACV, VACV Unknown
14 35 Male L 40 0.1% BM Previous doctor 28 Herpetic keratitis ACV Unknown
Abbreviations. No., number; CL, contact lenses; HSV, herpes simplex virus; R, right; L, left; FLM, fluorometholone; BM, betamethasone sodium phosphate; BM+Fra, combined betamethasone sodium sulfate and fradiomycin sulfate; AK, Acanthamoeba keratitis; BK, bacterial keratitis; FK, fungal keratitis; PDR, proliferative diabetic retinopathy; rubeotic gla, rubeotic glaucoma; ACV, acyclovir ocular ointment; VACV, valaciclovir tablets.
Use of Topical Corticosteroids
Corticosteroid eye drops were not used before keratitis occurred but were used to treat the corneal lesions. Out of the 14 patients, six patients were prescribed topical corticosteroids by the referring doctor, and eight patients were prescribed these drugs by another doctor (Table 1). The details of the medical practice, other than the referring doctor, at the previous doctor’s clinic were unknown, but the prescribed corticosteroid eye drops were 0.1% betamethasone sodium phosphate for nine patients, 0.1% fluorometholone for two patients, and unknown steroid eye drops for three patients. Among the nine patients who were treated with 0.1% betamethasone sodium phosphate, combined corticosteroid-antibiotic eye drops (betamethasone sodium sulfate/fradiomycin sulfate) were prescribed for at least three patients (Table 1).
All patients visited the ophthalmic clinic with a complaint of ocular pain, red eye, and visual disturbance. Nine patients were contact lens wearers (Table 1).
History of Herpetic Keratitis
The history of herpetic keratitis and treatment is described in Table 1. According to the referral letters, four patients (cases 4, 5, 8, and 14) had a past history of herpetic keratitis, but the details and the accuracy of the diagnosis were unknown. At least six of the 14 patients were treated with either acyclovir ocular ointment or valaciclovir tablets, along with topical corticosteroids (cases 3, 4, 7, 10, 13, 14). Although we could not exclude concurrent herpetic stromal keratitis because our institution did not have the facility to perform either the immune chromatography or the real-time polymerase chain reaction, the corneal findings and the clinical course of the patients’ eyes were not suggestive of herpetic necrotic keratitis.
Culture and Diagnosis
Corneal scraping and culture were performed for 13 patients (Table 2); however, because the cornea was already perforated and Acanthamoeba was proven by the referral doctor, culture was not performed for case 8. As listed in Table 2, based on the results of the cultures, we diagnosed keratitis as follows: bacterial keratitis in two patients including one suspected case, Acanthamoeba keratitis in six patients, fungal keratitis in two patients, and unknown cause in four patients. Case 2 had a corneal ulcer with a 3.0-mm diameter and hypopyon at the first visit, but the inflammation subsided within 3 weeks of topical antibiotic therapy, and we thus diagnosed the patient with bacterial keratitis even though the culture was negative. In four patients with unknown causes (cases 11−14), the diagnosis of microbial infectious keratitis was made from the clinical presentation at the first visit (Figure 1), but it was not possible to determine whether these were bacterial, fungal, or Acanthamoeba keratitis cases based on the clinical course.Table 2 Patients Topical Corticosteroids Were Applied Before Culture: Culture Results and Prognosis
Case No. BCVA at First Visit BCVA at Last Visit Weeks Taken to Settle Down Cultured Microorganisms Diagnosis Corneal Perforation
1 HM 0.3 3 Pseudomonas aeruginosa BK
2 NLP NLP 8 No growth BK susp
3 0.4 1.0 17 Amoeba, Staphylococcus epidermis, GM Pos bacilli AK
4 LP 0.4 22 Amoeba, Staphylococcus epidermis AK
5 CF HM 50 Amoeba AK
6 HM 0.9 15 Amoeba AK
7 0.3 0.9 19 Amoeba AK
8 LP LP 8 Amoeba at referring doctor AK Yes
9 HM NLP Evisceration Fusarium sp. FK Yes
10 LP NLP Evisceration Fusarium sp. FK Yes
11 0.03 0.8 3 No growth Unknown
12 CF 0.5 6 No growth Unknown
13 LP 0.05 25 No growth Unknown Yes
14 0.04 0.04 30 Staphylococcus epidermis (MRSE) Unknown
Abbreviations: BCVA, best-corrected visual acuity; HM, hand motion; NLP, no light perception; LP, light perception; CF, counting fingers; GM Pos bacilli, Gram-positive bacilli; AK, Acanthamoeba keratitis; BK, bacterial keratitis, FK, fungal keratitis; MRSE, methicillin-resistant Staphylococcus epidermis.
Figure 1 Cases of suspected infectious keratitis who were treated with topical corticosteroids without culture-proven diagnosis and before presentation to our clinic. (A) Case 11; Forty-four-year-old female. Although fungal keratitis was suspected based on corneal findings, it took only 3 weeks to cure the inflammation by a combination of topical antibiotics and anti-fungal therapy. (B) Case 12; Eighteen-year-old female. Early stage of Acanthamoeba keratitis was suspected based on the findings, but no organism could be cultured, even after co-culture with Escherichia coli. (C) Case 13; Fifty-one-year-old male. Despite treatment with a combination topical antibiotic and antifungal therapy, corneal perforation occurred 2 weeks after the first visit. (D) Case 14; Thirty-five-year-old male. Culture was attempted 3 times from the first visit, and at the second time of culture, 1 week after the intensive topical antibiotic therapy was started, methicillin-resistant Staphylococcus epidermis was detected by enrichment culture, but the significance of this result was unclear.
Prognosis
The prognosis is summarized in Table 2. The patients with bacterial keratitis (cases 1 and 2) responded well to the topical antibiotic therapy, and the corneal lesion healed as a scar after 3 weeks, after which corticosteroid eye drops were started again to settle the infiltration.
The prognosis for the vision of the two patients with Acanthamoeba keratitis (cases 5 and 8) whose anti-amoebic therapy was started more than 10 weeks after the onset was poor (Table 1). In patients with Acanthamoeba keratitis in whom appropriate anti-amoebic therapy was started at least within 2 weeks from the onset, the visual prognosis was good, even though topical corticosteroids were applied before the diagnosis (cases 3, 6, and 7).
Both patients with fungal keratitis visited the specialist clinic 3 weeks after the onset of the complaint (Table 1). The delay in the diagnosis and identification of the causative organism (Fusarium species), in addition to the use of topical corticosteroid before diagnosis, may have caused a corneal perforation and loss of sight in the affected eyes (cases 9 and 10).
In the five culture-negative cases, we could not determine the causative microorganism based on the corneal appearance and the clinical course in four cases (Figure 1). Favorable recovery of vision has still not been obtained in two of the cases (cases 13 and 14). This may be due to the difficulty in establishing a treatment plan because the empirical topical antibiotic and corticosteroid treatment has masked the appearance of the corneal lesion.
Discussion
Similar to the findings of the SCUT study, in our cases, the use of topical steroids along with antibiotics did not affect the vision prognoses in the eyes with bacterial keratitis; however, vision was lost in two eyes with fungal keratitis (Table 2). Even though this poor outcome may be attributed to the Fusarium sp. that was involved in two of our cases, topical corticosteroids should not be used for fungal keratitis.6,7,18 For the eyes with Acanthamoeba keratitis, topical corticosteroids are not contraindicated as long as appropriate anti-amoebic therapy is applied.19–21 However, two of the six Acanthamoeba keratitis eyes lost vision in our study (Table 2). In the Acanthamoeba keratitis patients (cases 5 and 8) as well as in two fungal keratitis patients (cases 9 and 10) and two unknown keratitis patients (cases 13 and 14), one of the reasons for the undesirable visual prognosis could be the delay in proper diagnosis (Table 1), caused by the masked clinical findings (Figure 1) and the reactions to the empirical use of topical antibiotics and corticosteroids.25,26
From the referral letter information, at least eight patients were assumed to be treated with topical corticosteroids after being diagnosed with stromal herpetic keratitis. Three of the six Acanthamoeba keratitis patients, one of the two fungal keratitis patients, and two of the four unknown keratitis patients were treated with acyclovir ointment or valaciclovir tablets (Table 1). In addition to these patients who were treated with anti-herpes virus drugs, two Acanthamoeba keratitis patients had a history of herpetic keratitis, according to the referral letter (Table 2). These facts show that we have to distinguish whether the keratitis is stromal keratitis related to herpes simplex virus or microbial infectious keratitis.
From the results of this study, we concluded that it is important to evaluate the patient for fungal keratitis and Acanthamoeba keratitis before deciding on the use of topical corticosteroids for the treatment of the keratitis. Because correct differentiation of bacterial or fungal keratitis by the clinical signs or findings is difficult even for a corneal specialist,27 it is important to make a biologically proven diagnosis by smear and culture before prescribing topical corticosteroids. In addition, it is important to stop the application of topical corticosteroids immediately when keratitis does not improve by these steroids.
A combination of 0.1% betamethasone sodium sulfate and fradiomycin sulfate was prescribed in at least three of the 14 cases. Along with the possibility of stromal herpetic keratitis, another possible reason for the immediate use of topical corticosteroids could be the commercial availability of corticosteroid-antibiotic combination eye drops. As O’Day DM pointed out,28 these preparations have the potential to violate the rule of combined corticosteroid–antibiotic therapy for infectious keratitis.
Accordingly, microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed when prescribing topical corticosteroids for the treatment of infectious keratitis. Although corticosteroid-antibiotic combination eye drops seem safe, they are meaningless or unsafe for treating infectious keratitis other than culture-proven bacterial keratitis.
In addition to its retrospective nature, the main limitation of this study was the single-center study design. As almost all the patients had already been treated empirically with topical antibiotics by the previous ophthalmologist, it was difficult to distinguish the causative microorganism by culture. Thus, we had to diagnose the keratitis as infectious keratitis, particularly bacterial keratitis, based on the corneal findings and clinical course. Additional information from other institutions is needed to clarify the merits and demerits, as well as the background for the empirical use of topical corticosteroids for suspected microbial infectious keratitis.
Conclusion
This study reported a series of severe infectious keratitis cases referred to a specialized medical institution, who were given an antibiotic-steroid combination treatment. Our findings show that it is harmful to apply topical corticosteroids for keratitis that does not respond to empirical antibiotic therapy, since Acanthamoeba keratitis or fungal keratitis are likely involved in these topical antibiotic-resistant cases.
The use of topical corticosteroids along with empirical antibiotic therapy make it difficult to distinguish the causative agent of the infection in suspected keratitis, either by culture or by the corneal findings and clinical course, and as a result, may delay the appropriate treatment and cause unfortunate outcomes. Therefore, we conclude that the use of topical corticosteroids, merely owing to ineffective empirical antibiotic therapy for keratitis, should be avoided. Microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed before prescribing topical corticosteroids for the treatment of suspected infectious keratitis.
Abbreviations
AK, Acanthamoeba keratitis; FK, fungal keratitis; SCUT, Steroids for Corneal Ulcers Trial.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Ethics Approval and Consent to Participate
Written informed consent was obtained from each patient. This study was approved by the Research Ethics Committee of Fujita Health University and was performed in accordance with the Declaration of Helsinki.
Consent for Publication
Written informed consent was obtained from the participants for publication of the research article and any accompanying images.
Author Contributions
KH followed all the patients in this study and wrote the manuscript. KH, HT, and KK analyzed and interpreted the data on the clinical features of the patients. KK and KA-S made critical comments on the manuscript and provided input regarding the clinical outcome of the series of patients with infectious keratitis in whom topical corticosteroids were used. All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agree to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for aspects of the work.
Disclosure
The authors report no conflicts of interest in this work. | ACYCLOVIR, BETAMETHASONE SODIUM PHOSPHATE, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33623362 | 19,087,364 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Visual impairment'. | Topical Corticosteroids for Infectious Keratitis Before Culture-Proven Diagnosis.
In clinical practice we sometimes encounter patients with severe corneal ulcers who have been treated with topical corticosteroids. This study reviewed the clinical features and visual outcomes of these patients and investigated the background of the prescription of topical corticosteroids.
The medical records of patients who visited the Cornea Service at Fujita Health University Bantane Hospital and were treated for infectious keratitis from April 2016 to March 2020 were retrospectively reviewed. Patients treated with topical corticosteroids before a culture-proven diagnosis were studied in terms of demographics, best-corrected visual acuity at arrival and at last visit, the clinical course after visit, ocular history, and combination therapy by the previous ophthalmologist.
Out of the 200 eyes of 197 patients with infectious keratitis, 14 eyes of 14 patients were treated with topical corticosteroids before a culture-proven diagnosis. All 14 patients were referred, as they had severe keratitis that could not be cured with topical antibiotics and corticosteroids. Based on the culture results, we diagnosed Acanthamoeba keratitis (AK) in six patients, fungal keratitis (FK) in two patients, bacterial keratitis (including a suspected case) in two patients, and unknown cause in four patients. Two patients with AK, FK, and unknown keratitis had unfortunate clinical courses and poor visual outcomes. From the information in the referral letters, at least six of the 14 patients were treated with either acyclovir ocular ointment or valaciclovir tablets, along with topical corticosteroids.
Application of topical corticosteroids for keratitis that does not respond to empirical antibiotic therapy is harmful since AK or FK is likely involved in these topical antibiotic-resistant cases. Microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed when prescribing topical corticosteroid for the treatment of suspected infectious keratitis.
Plain Language Summary
In the corneal clinic of a university hospital in a metropolitan area, we sometimes encounter referred patients with severe corneal ulcers who have been treated with topical corticosteroids as well as antibiotic eye drops. Why were these topical corticosteroids prescribed? We retrospectively reviewed clinical records of patients with infectious keratitis treated with topical corticosteroids before a culture-proven diagnosis. During an investigative period of 4 years, 14 eyes of 14 patients were evaluated. All the patients were prescribed topical corticosteroids for the keratitis owing to unresponsive empirical antibiotic therapy, and at least six patients were treated for stromal keratitis due to herpes simplex virus.
Why did the corneal lesions of these patients worsen? Based on culture results, we diagnosed Acanthamoeba keratitis in six patients and fungal keratitis in two patients. Apart from bacterial keratitis, other microorganisms responsible for keratitis do not respond to antibiotic therapy, and the condition is worsened by the topical corticosteroids without appropriate anti-amoebic or anti-fungal therapy.
Application of topical corticosteroids for keratitis without microbiological evidence is harmful, and a differential diagnosis of herpetic stromal keratitis as well as fungal and Acanthamoeba keratitis is needed when using topical corticosteroid for the treatment of suspected infectious keratitis.
Introduction
The definitive diagnosis and specific therapy for microbial keratitis should only be determined by microbiological evaluation.1–3 Nevertheless, the application of empirical antibiotic therapy without the use of smears or cultures cannot be rejected, as topical fluoroquinolone is associated with of a high success rate; moreover, the time and cost involved in performing cultures and maintaining the necessary materials are reduced.4–6
During the treatment of microbial keratitis, adjunctive topical corticosteroids are used to reduce the inflammatory response and subsequent corneal scarring, to obtain better visual outcomes, despite the possible risk of enhanced microbial replication, corneal melting, and steroid glaucoma.6–8 The safety and efficacy of topical corticosteroids for microbial keratitis have been reported9–17 in the Steroids for Corneal Ulcers Trial (SCUT)9,10 and other randomized control studies.11,12 The consensus of these studies was that unlike the use of topical antibiotics, the empirical use of topical corticosteroids for suspected microbial keratitis is not recommended. According to the Bacterial Keratitis Preferred Practice Pattern® 2018, 24–48 hours after the causative organism has been identified and/or infection is responding to therapy, corticosteroids may be considered, and close follow-up by a corneal specialist is recommended. Corticosteroids should be avoided in bacterial keratitis caused by slow-cycling microbes such as Nocardia,10 and fungal keratitis,7,11,18 while in Acanthamoeba keratitis, maintaining adequate anti-amoebic therapy is needed if a topical corticosteroid is used.19–23 Therefore, these microorganisms should be ruled out and a definitive diagnosis of bacterial keratitis based on smear and culture or by confirming the response to anti-microbial therapy is suggested before topical corticosteroids.24
At the corneal clinic of our institution and hospital in a metropolitan area, which serves a population of 4 million, we sometimes encounter referred patients with severe corneal ulcers who have been treated with topical corticosteroids. The purpose of this study was to review the clinical features and the visual outcomes of these patients, and to elucidate the effect of the empirical use of topical corticosteroids on the clinical course of this condition and the background of steroid applications in such patients.
Patients and Methods
We retrospectively reviewed the medical records of patients who visited the Cornea Service at Fujita Health University Bantane Hospital and were treated for infectious keratitis from April 2016 to March 2020. The diagnosis of microbial infectious keratitis was confirmed by culture, but because the antibiotic therapy had already been started before the patients arrived at our institution, many of them were solely diagnosed based on the corneal findings and the clinical course.
Suspected infectious keratitis patients treated with topical corticosteroids before culture-proven diagnosis were retrospectively studied in terms of demographics, best-corrected visual acuity at arrival and at the last visit, clinical course after the initial visit, ocular history, and combination therapy by the previous ophthalmologist. We used this information to determine the influence of topical steroid therapy and to determine the factors that led to the steroid prescription.
This study was approved by the institutional review board of the Fujita Health University Faculty of Medicine (Approval number: C120-135). Informed consent was obtained from each patient for use in clinical records for future research.
Results
Patients’ Visits
Two hundred eyes of 197 patients were treated for microbial infectious keratitis in the investigation period. Among the 197 patients, 195 eyes of 192 patients were referred from a hospital or ophthalmic clinic. Almost all the referred patients had already been empirically treated with topical or systemic antibiotic therapy, and the reason for the referral was a poor response to the antibiotic therapy.
Among the referred patients, 14 eyes of 14 patients had been treated with corticosteroid eye drops before arrival (Table 1).Table 1 Patients in Whom Topical Corticosteroids Were Applied Before Culture: Demographics and Past Treatments Other Than Topical Antibiotics
Case No. Age (Years) Sex Laterality Onset-Arrival (Days) Steroid Eye Drops Prescribing Doctor Steroid Use (Days) CL User Ocular History Anti-HSV Drugs Diagnosis
1 32 Male L 7 Unknown Previous doctor 4 Yes BK
2 82 Male R 50 0.1% BM+Fra Referral doctor 30 DMR, Rubeotic gla BK susp
3 39 Male R 12 0.1% FLM Previous doctor 7 Yes ACV AK
4 24 Male R 30 0.1% BM+Fra Previous doctor 28 Yes Herpetic keratitis VACV AK
5 53 Female L 75 0.1% BM Previous doctor 60 Yes Herpetic keratitis AK
6 31 Male R 18 0.1% BM Previous doctor 10 Yes AK
7 56 Male L 14 0.1% BM Referral doctor 8 Yes ACV AK
8 33 Female L 240 Unknown Referral doctor 30 Herpetic keratitis AK
9 46 Female R 20 0.1% BM+Fra Previous doctor 15 Yes FK
10 48 Female R 21 0.1% FLM Referral doctor 7 ACV, VACV FK
11 44 Female L 14 0.1% BM Referral doctor 3 Yes Unknown
12 19 Female L 30 Unknown Previous doctor 21 Yes Unknown
13 51 Male R 14 0.1% BM Referral doctor 3 ACV, VACV Unknown
14 35 Male L 40 0.1% BM Previous doctor 28 Herpetic keratitis ACV Unknown
Abbreviations. No., number; CL, contact lenses; HSV, herpes simplex virus; R, right; L, left; FLM, fluorometholone; BM, betamethasone sodium phosphate; BM+Fra, combined betamethasone sodium sulfate and fradiomycin sulfate; AK, Acanthamoeba keratitis; BK, bacterial keratitis; FK, fungal keratitis; PDR, proliferative diabetic retinopathy; rubeotic gla, rubeotic glaucoma; ACV, acyclovir ocular ointment; VACV, valaciclovir tablets.
Use of Topical Corticosteroids
Corticosteroid eye drops were not used before keratitis occurred but were used to treat the corneal lesions. Out of the 14 patients, six patients were prescribed topical corticosteroids by the referring doctor, and eight patients were prescribed these drugs by another doctor (Table 1). The details of the medical practice, other than the referring doctor, at the previous doctor’s clinic were unknown, but the prescribed corticosteroid eye drops were 0.1% betamethasone sodium phosphate for nine patients, 0.1% fluorometholone for two patients, and unknown steroid eye drops for three patients. Among the nine patients who were treated with 0.1% betamethasone sodium phosphate, combined corticosteroid-antibiotic eye drops (betamethasone sodium sulfate/fradiomycin sulfate) were prescribed for at least three patients (Table 1).
All patients visited the ophthalmic clinic with a complaint of ocular pain, red eye, and visual disturbance. Nine patients were contact lens wearers (Table 1).
History of Herpetic Keratitis
The history of herpetic keratitis and treatment is described in Table 1. According to the referral letters, four patients (cases 4, 5, 8, and 14) had a past history of herpetic keratitis, but the details and the accuracy of the diagnosis were unknown. At least six of the 14 patients were treated with either acyclovir ocular ointment or valaciclovir tablets, along with topical corticosteroids (cases 3, 4, 7, 10, 13, 14). Although we could not exclude concurrent herpetic stromal keratitis because our institution did not have the facility to perform either the immune chromatography or the real-time polymerase chain reaction, the corneal findings and the clinical course of the patients’ eyes were not suggestive of herpetic necrotic keratitis.
Culture and Diagnosis
Corneal scraping and culture were performed for 13 patients (Table 2); however, because the cornea was already perforated and Acanthamoeba was proven by the referral doctor, culture was not performed for case 8. As listed in Table 2, based on the results of the cultures, we diagnosed keratitis as follows: bacterial keratitis in two patients including one suspected case, Acanthamoeba keratitis in six patients, fungal keratitis in two patients, and unknown cause in four patients. Case 2 had a corneal ulcer with a 3.0-mm diameter and hypopyon at the first visit, but the inflammation subsided within 3 weeks of topical antibiotic therapy, and we thus diagnosed the patient with bacterial keratitis even though the culture was negative. In four patients with unknown causes (cases 11−14), the diagnosis of microbial infectious keratitis was made from the clinical presentation at the first visit (Figure 1), but it was not possible to determine whether these were bacterial, fungal, or Acanthamoeba keratitis cases based on the clinical course.Table 2 Patients Topical Corticosteroids Were Applied Before Culture: Culture Results and Prognosis
Case No. BCVA at First Visit BCVA at Last Visit Weeks Taken to Settle Down Cultured Microorganisms Diagnosis Corneal Perforation
1 HM 0.3 3 Pseudomonas aeruginosa BK
2 NLP NLP 8 No growth BK susp
3 0.4 1.0 17 Amoeba, Staphylococcus epidermis, GM Pos bacilli AK
4 LP 0.4 22 Amoeba, Staphylococcus epidermis AK
5 CF HM 50 Amoeba AK
6 HM 0.9 15 Amoeba AK
7 0.3 0.9 19 Amoeba AK
8 LP LP 8 Amoeba at referring doctor AK Yes
9 HM NLP Evisceration Fusarium sp. FK Yes
10 LP NLP Evisceration Fusarium sp. FK Yes
11 0.03 0.8 3 No growth Unknown
12 CF 0.5 6 No growth Unknown
13 LP 0.05 25 No growth Unknown Yes
14 0.04 0.04 30 Staphylococcus epidermis (MRSE) Unknown
Abbreviations: BCVA, best-corrected visual acuity; HM, hand motion; NLP, no light perception; LP, light perception; CF, counting fingers; GM Pos bacilli, Gram-positive bacilli; AK, Acanthamoeba keratitis; BK, bacterial keratitis, FK, fungal keratitis; MRSE, methicillin-resistant Staphylococcus epidermis.
Figure 1 Cases of suspected infectious keratitis who were treated with topical corticosteroids without culture-proven diagnosis and before presentation to our clinic. (A) Case 11; Forty-four-year-old female. Although fungal keratitis was suspected based on corneal findings, it took only 3 weeks to cure the inflammation by a combination of topical antibiotics and anti-fungal therapy. (B) Case 12; Eighteen-year-old female. Early stage of Acanthamoeba keratitis was suspected based on the findings, but no organism could be cultured, even after co-culture with Escherichia coli. (C) Case 13; Fifty-one-year-old male. Despite treatment with a combination topical antibiotic and antifungal therapy, corneal perforation occurred 2 weeks after the first visit. (D) Case 14; Thirty-five-year-old male. Culture was attempted 3 times from the first visit, and at the second time of culture, 1 week after the intensive topical antibiotic therapy was started, methicillin-resistant Staphylococcus epidermis was detected by enrichment culture, but the significance of this result was unclear.
Prognosis
The prognosis is summarized in Table 2. The patients with bacterial keratitis (cases 1 and 2) responded well to the topical antibiotic therapy, and the corneal lesion healed as a scar after 3 weeks, after which corticosteroid eye drops were started again to settle the infiltration.
The prognosis for the vision of the two patients with Acanthamoeba keratitis (cases 5 and 8) whose anti-amoebic therapy was started more than 10 weeks after the onset was poor (Table 1). In patients with Acanthamoeba keratitis in whom appropriate anti-amoebic therapy was started at least within 2 weeks from the onset, the visual prognosis was good, even though topical corticosteroids were applied before the diagnosis (cases 3, 6, and 7).
Both patients with fungal keratitis visited the specialist clinic 3 weeks after the onset of the complaint (Table 1). The delay in the diagnosis and identification of the causative organism (Fusarium species), in addition to the use of topical corticosteroid before diagnosis, may have caused a corneal perforation and loss of sight in the affected eyes (cases 9 and 10).
In the five culture-negative cases, we could not determine the causative microorganism based on the corneal appearance and the clinical course in four cases (Figure 1). Favorable recovery of vision has still not been obtained in two of the cases (cases 13 and 14). This may be due to the difficulty in establishing a treatment plan because the empirical topical antibiotic and corticosteroid treatment has masked the appearance of the corneal lesion.
Discussion
Similar to the findings of the SCUT study, in our cases, the use of topical steroids along with antibiotics did not affect the vision prognoses in the eyes with bacterial keratitis; however, vision was lost in two eyes with fungal keratitis (Table 2). Even though this poor outcome may be attributed to the Fusarium sp. that was involved in two of our cases, topical corticosteroids should not be used for fungal keratitis.6,7,18 For the eyes with Acanthamoeba keratitis, topical corticosteroids are not contraindicated as long as appropriate anti-amoebic therapy is applied.19–21 However, two of the six Acanthamoeba keratitis eyes lost vision in our study (Table 2). In the Acanthamoeba keratitis patients (cases 5 and 8) as well as in two fungal keratitis patients (cases 9 and 10) and two unknown keratitis patients (cases 13 and 14), one of the reasons for the undesirable visual prognosis could be the delay in proper diagnosis (Table 1), caused by the masked clinical findings (Figure 1) and the reactions to the empirical use of topical antibiotics and corticosteroids.25,26
From the referral letter information, at least eight patients were assumed to be treated with topical corticosteroids after being diagnosed with stromal herpetic keratitis. Three of the six Acanthamoeba keratitis patients, one of the two fungal keratitis patients, and two of the four unknown keratitis patients were treated with acyclovir ointment or valaciclovir tablets (Table 1). In addition to these patients who were treated with anti-herpes virus drugs, two Acanthamoeba keratitis patients had a history of herpetic keratitis, according to the referral letter (Table 2). These facts show that we have to distinguish whether the keratitis is stromal keratitis related to herpes simplex virus or microbial infectious keratitis.
From the results of this study, we concluded that it is important to evaluate the patient for fungal keratitis and Acanthamoeba keratitis before deciding on the use of topical corticosteroids for the treatment of the keratitis. Because correct differentiation of bacterial or fungal keratitis by the clinical signs or findings is difficult even for a corneal specialist,27 it is important to make a biologically proven diagnosis by smear and culture before prescribing topical corticosteroids. In addition, it is important to stop the application of topical corticosteroids immediately when keratitis does not improve by these steroids.
A combination of 0.1% betamethasone sodium sulfate and fradiomycin sulfate was prescribed in at least three of the 14 cases. Along with the possibility of stromal herpetic keratitis, another possible reason for the immediate use of topical corticosteroids could be the commercial availability of corticosteroid-antibiotic combination eye drops. As O’Day DM pointed out,28 these preparations have the potential to violate the rule of combined corticosteroid–antibiotic therapy for infectious keratitis.
Accordingly, microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed when prescribing topical corticosteroids for the treatment of infectious keratitis. Although corticosteroid-antibiotic combination eye drops seem safe, they are meaningless or unsafe for treating infectious keratitis other than culture-proven bacterial keratitis.
In addition to its retrospective nature, the main limitation of this study was the single-center study design. As almost all the patients had already been treated empirically with topical antibiotics by the previous ophthalmologist, it was difficult to distinguish the causative microorganism by culture. Thus, we had to diagnose the keratitis as infectious keratitis, particularly bacterial keratitis, based on the corneal findings and clinical course. Additional information from other institutions is needed to clarify the merits and demerits, as well as the background for the empirical use of topical corticosteroids for suspected microbial infectious keratitis.
Conclusion
This study reported a series of severe infectious keratitis cases referred to a specialized medical institution, who were given an antibiotic-steroid combination treatment. Our findings show that it is harmful to apply topical corticosteroids for keratitis that does not respond to empirical antibiotic therapy, since Acanthamoeba keratitis or fungal keratitis are likely involved in these topical antibiotic-resistant cases.
The use of topical corticosteroids along with empirical antibiotic therapy make it difficult to distinguish the causative agent of the infection in suspected keratitis, either by culture or by the corneal findings and clinical course, and as a result, may delay the appropriate treatment and cause unfortunate outcomes. Therefore, we conclude that the use of topical corticosteroids, merely owing to ineffective empirical antibiotic therapy for keratitis, should be avoided. Microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed before prescribing topical corticosteroids for the treatment of suspected infectious keratitis.
Abbreviations
AK, Acanthamoeba keratitis; FK, fungal keratitis; SCUT, Steroids for Corneal Ulcers Trial.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Ethics Approval and Consent to Participate
Written informed consent was obtained from each patient. This study was approved by the Research Ethics Committee of Fujita Health University and was performed in accordance with the Declaration of Helsinki.
Consent for Publication
Written informed consent was obtained from the participants for publication of the research article and any accompanying images.
Author Contributions
KH followed all the patients in this study and wrote the manuscript. KH, HT, and KK analyzed and interpreted the data on the clinical features of the patients. KK and KA-S made critical comments on the manuscript and provided input regarding the clinical outcome of the series of patients with infectious keratitis in whom topical corticosteroids were used. All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agree to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for aspects of the work.
Disclosure
The authors report no conflicts of interest in this work. | ACYCLOVIR, BETAMETHASONE SODIUM PHOSPHATE, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33623362 | 19,087,364 | 2021 |
What was the administration route of drug 'ACYCLOVIR'? | Topical Corticosteroids for Infectious Keratitis Before Culture-Proven Diagnosis.
In clinical practice we sometimes encounter patients with severe corneal ulcers who have been treated with topical corticosteroids. This study reviewed the clinical features and visual outcomes of these patients and investigated the background of the prescription of topical corticosteroids.
The medical records of patients who visited the Cornea Service at Fujita Health University Bantane Hospital and were treated for infectious keratitis from April 2016 to March 2020 were retrospectively reviewed. Patients treated with topical corticosteroids before a culture-proven diagnosis were studied in terms of demographics, best-corrected visual acuity at arrival and at last visit, the clinical course after visit, ocular history, and combination therapy by the previous ophthalmologist.
Out of the 200 eyes of 197 patients with infectious keratitis, 14 eyes of 14 patients were treated with topical corticosteroids before a culture-proven diagnosis. All 14 patients were referred, as they had severe keratitis that could not be cured with topical antibiotics and corticosteroids. Based on the culture results, we diagnosed Acanthamoeba keratitis (AK) in six patients, fungal keratitis (FK) in two patients, bacterial keratitis (including a suspected case) in two patients, and unknown cause in four patients. Two patients with AK, FK, and unknown keratitis had unfortunate clinical courses and poor visual outcomes. From the information in the referral letters, at least six of the 14 patients were treated with either acyclovir ocular ointment or valaciclovir tablets, along with topical corticosteroids.
Application of topical corticosteroids for keratitis that does not respond to empirical antibiotic therapy is harmful since AK or FK is likely involved in these topical antibiotic-resistant cases. Microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed when prescribing topical corticosteroid for the treatment of suspected infectious keratitis.
Plain Language Summary
In the corneal clinic of a university hospital in a metropolitan area, we sometimes encounter referred patients with severe corneal ulcers who have been treated with topical corticosteroids as well as antibiotic eye drops. Why were these topical corticosteroids prescribed? We retrospectively reviewed clinical records of patients with infectious keratitis treated with topical corticosteroids before a culture-proven diagnosis. During an investigative period of 4 years, 14 eyes of 14 patients were evaluated. All the patients were prescribed topical corticosteroids for the keratitis owing to unresponsive empirical antibiotic therapy, and at least six patients were treated for stromal keratitis due to herpes simplex virus.
Why did the corneal lesions of these patients worsen? Based on culture results, we diagnosed Acanthamoeba keratitis in six patients and fungal keratitis in two patients. Apart from bacterial keratitis, other microorganisms responsible for keratitis do not respond to antibiotic therapy, and the condition is worsened by the topical corticosteroids without appropriate anti-amoebic or anti-fungal therapy.
Application of topical corticosteroids for keratitis without microbiological evidence is harmful, and a differential diagnosis of herpetic stromal keratitis as well as fungal and Acanthamoeba keratitis is needed when using topical corticosteroid for the treatment of suspected infectious keratitis.
Introduction
The definitive diagnosis and specific therapy for microbial keratitis should only be determined by microbiological evaluation.1–3 Nevertheless, the application of empirical antibiotic therapy without the use of smears or cultures cannot be rejected, as topical fluoroquinolone is associated with of a high success rate; moreover, the time and cost involved in performing cultures and maintaining the necessary materials are reduced.4–6
During the treatment of microbial keratitis, adjunctive topical corticosteroids are used to reduce the inflammatory response and subsequent corneal scarring, to obtain better visual outcomes, despite the possible risk of enhanced microbial replication, corneal melting, and steroid glaucoma.6–8 The safety and efficacy of topical corticosteroids for microbial keratitis have been reported9–17 in the Steroids for Corneal Ulcers Trial (SCUT)9,10 and other randomized control studies.11,12 The consensus of these studies was that unlike the use of topical antibiotics, the empirical use of topical corticosteroids for suspected microbial keratitis is not recommended. According to the Bacterial Keratitis Preferred Practice Pattern® 2018, 24–48 hours after the causative organism has been identified and/or infection is responding to therapy, corticosteroids may be considered, and close follow-up by a corneal specialist is recommended. Corticosteroids should be avoided in bacterial keratitis caused by slow-cycling microbes such as Nocardia,10 and fungal keratitis,7,11,18 while in Acanthamoeba keratitis, maintaining adequate anti-amoebic therapy is needed if a topical corticosteroid is used.19–23 Therefore, these microorganisms should be ruled out and a definitive diagnosis of bacterial keratitis based on smear and culture or by confirming the response to anti-microbial therapy is suggested before topical corticosteroids.24
At the corneal clinic of our institution and hospital in a metropolitan area, which serves a population of 4 million, we sometimes encounter referred patients with severe corneal ulcers who have been treated with topical corticosteroids. The purpose of this study was to review the clinical features and the visual outcomes of these patients, and to elucidate the effect of the empirical use of topical corticosteroids on the clinical course of this condition and the background of steroid applications in such patients.
Patients and Methods
We retrospectively reviewed the medical records of patients who visited the Cornea Service at Fujita Health University Bantane Hospital and were treated for infectious keratitis from April 2016 to March 2020. The diagnosis of microbial infectious keratitis was confirmed by culture, but because the antibiotic therapy had already been started before the patients arrived at our institution, many of them were solely diagnosed based on the corneal findings and the clinical course.
Suspected infectious keratitis patients treated with topical corticosteroids before culture-proven diagnosis were retrospectively studied in terms of demographics, best-corrected visual acuity at arrival and at the last visit, clinical course after the initial visit, ocular history, and combination therapy by the previous ophthalmologist. We used this information to determine the influence of topical steroid therapy and to determine the factors that led to the steroid prescription.
This study was approved by the institutional review board of the Fujita Health University Faculty of Medicine (Approval number: C120-135). Informed consent was obtained from each patient for use in clinical records for future research.
Results
Patients’ Visits
Two hundred eyes of 197 patients were treated for microbial infectious keratitis in the investigation period. Among the 197 patients, 195 eyes of 192 patients were referred from a hospital or ophthalmic clinic. Almost all the referred patients had already been empirically treated with topical or systemic antibiotic therapy, and the reason for the referral was a poor response to the antibiotic therapy.
Among the referred patients, 14 eyes of 14 patients had been treated with corticosteroid eye drops before arrival (Table 1).Table 1 Patients in Whom Topical Corticosteroids Were Applied Before Culture: Demographics and Past Treatments Other Than Topical Antibiotics
Case No. Age (Years) Sex Laterality Onset-Arrival (Days) Steroid Eye Drops Prescribing Doctor Steroid Use (Days) CL User Ocular History Anti-HSV Drugs Diagnosis
1 32 Male L 7 Unknown Previous doctor 4 Yes BK
2 82 Male R 50 0.1% BM+Fra Referral doctor 30 DMR, Rubeotic gla BK susp
3 39 Male R 12 0.1% FLM Previous doctor 7 Yes ACV AK
4 24 Male R 30 0.1% BM+Fra Previous doctor 28 Yes Herpetic keratitis VACV AK
5 53 Female L 75 0.1% BM Previous doctor 60 Yes Herpetic keratitis AK
6 31 Male R 18 0.1% BM Previous doctor 10 Yes AK
7 56 Male L 14 0.1% BM Referral doctor 8 Yes ACV AK
8 33 Female L 240 Unknown Referral doctor 30 Herpetic keratitis AK
9 46 Female R 20 0.1% BM+Fra Previous doctor 15 Yes FK
10 48 Female R 21 0.1% FLM Referral doctor 7 ACV, VACV FK
11 44 Female L 14 0.1% BM Referral doctor 3 Yes Unknown
12 19 Female L 30 Unknown Previous doctor 21 Yes Unknown
13 51 Male R 14 0.1% BM Referral doctor 3 ACV, VACV Unknown
14 35 Male L 40 0.1% BM Previous doctor 28 Herpetic keratitis ACV Unknown
Abbreviations. No., number; CL, contact lenses; HSV, herpes simplex virus; R, right; L, left; FLM, fluorometholone; BM, betamethasone sodium phosphate; BM+Fra, combined betamethasone sodium sulfate and fradiomycin sulfate; AK, Acanthamoeba keratitis; BK, bacterial keratitis; FK, fungal keratitis; PDR, proliferative diabetic retinopathy; rubeotic gla, rubeotic glaucoma; ACV, acyclovir ocular ointment; VACV, valaciclovir tablets.
Use of Topical Corticosteroids
Corticosteroid eye drops were not used before keratitis occurred but were used to treat the corneal lesions. Out of the 14 patients, six patients were prescribed topical corticosteroids by the referring doctor, and eight patients were prescribed these drugs by another doctor (Table 1). The details of the medical practice, other than the referring doctor, at the previous doctor’s clinic were unknown, but the prescribed corticosteroid eye drops were 0.1% betamethasone sodium phosphate for nine patients, 0.1% fluorometholone for two patients, and unknown steroid eye drops for three patients. Among the nine patients who were treated with 0.1% betamethasone sodium phosphate, combined corticosteroid-antibiotic eye drops (betamethasone sodium sulfate/fradiomycin sulfate) were prescribed for at least three patients (Table 1).
All patients visited the ophthalmic clinic with a complaint of ocular pain, red eye, and visual disturbance. Nine patients were contact lens wearers (Table 1).
History of Herpetic Keratitis
The history of herpetic keratitis and treatment is described in Table 1. According to the referral letters, four patients (cases 4, 5, 8, and 14) had a past history of herpetic keratitis, but the details and the accuracy of the diagnosis were unknown. At least six of the 14 patients were treated with either acyclovir ocular ointment or valaciclovir tablets, along with topical corticosteroids (cases 3, 4, 7, 10, 13, 14). Although we could not exclude concurrent herpetic stromal keratitis because our institution did not have the facility to perform either the immune chromatography or the real-time polymerase chain reaction, the corneal findings and the clinical course of the patients’ eyes were not suggestive of herpetic necrotic keratitis.
Culture and Diagnosis
Corneal scraping and culture were performed for 13 patients (Table 2); however, because the cornea was already perforated and Acanthamoeba was proven by the referral doctor, culture was not performed for case 8. As listed in Table 2, based on the results of the cultures, we diagnosed keratitis as follows: bacterial keratitis in two patients including one suspected case, Acanthamoeba keratitis in six patients, fungal keratitis in two patients, and unknown cause in four patients. Case 2 had a corneal ulcer with a 3.0-mm diameter and hypopyon at the first visit, but the inflammation subsided within 3 weeks of topical antibiotic therapy, and we thus diagnosed the patient with bacterial keratitis even though the culture was negative. In four patients with unknown causes (cases 11−14), the diagnosis of microbial infectious keratitis was made from the clinical presentation at the first visit (Figure 1), but it was not possible to determine whether these were bacterial, fungal, or Acanthamoeba keratitis cases based on the clinical course.Table 2 Patients Topical Corticosteroids Were Applied Before Culture: Culture Results and Prognosis
Case No. BCVA at First Visit BCVA at Last Visit Weeks Taken to Settle Down Cultured Microorganisms Diagnosis Corneal Perforation
1 HM 0.3 3 Pseudomonas aeruginosa BK
2 NLP NLP 8 No growth BK susp
3 0.4 1.0 17 Amoeba, Staphylococcus epidermis, GM Pos bacilli AK
4 LP 0.4 22 Amoeba, Staphylococcus epidermis AK
5 CF HM 50 Amoeba AK
6 HM 0.9 15 Amoeba AK
7 0.3 0.9 19 Amoeba AK
8 LP LP 8 Amoeba at referring doctor AK Yes
9 HM NLP Evisceration Fusarium sp. FK Yes
10 LP NLP Evisceration Fusarium sp. FK Yes
11 0.03 0.8 3 No growth Unknown
12 CF 0.5 6 No growth Unknown
13 LP 0.05 25 No growth Unknown Yes
14 0.04 0.04 30 Staphylococcus epidermis (MRSE) Unknown
Abbreviations: BCVA, best-corrected visual acuity; HM, hand motion; NLP, no light perception; LP, light perception; CF, counting fingers; GM Pos bacilli, Gram-positive bacilli; AK, Acanthamoeba keratitis; BK, bacterial keratitis, FK, fungal keratitis; MRSE, methicillin-resistant Staphylococcus epidermis.
Figure 1 Cases of suspected infectious keratitis who were treated with topical corticosteroids without culture-proven diagnosis and before presentation to our clinic. (A) Case 11; Forty-four-year-old female. Although fungal keratitis was suspected based on corneal findings, it took only 3 weeks to cure the inflammation by a combination of topical antibiotics and anti-fungal therapy. (B) Case 12; Eighteen-year-old female. Early stage of Acanthamoeba keratitis was suspected based on the findings, but no organism could be cultured, even after co-culture with Escherichia coli. (C) Case 13; Fifty-one-year-old male. Despite treatment with a combination topical antibiotic and antifungal therapy, corneal perforation occurred 2 weeks after the first visit. (D) Case 14; Thirty-five-year-old male. Culture was attempted 3 times from the first visit, and at the second time of culture, 1 week after the intensive topical antibiotic therapy was started, methicillin-resistant Staphylococcus epidermis was detected by enrichment culture, but the significance of this result was unclear.
Prognosis
The prognosis is summarized in Table 2. The patients with bacterial keratitis (cases 1 and 2) responded well to the topical antibiotic therapy, and the corneal lesion healed as a scar after 3 weeks, after which corticosteroid eye drops were started again to settle the infiltration.
The prognosis for the vision of the two patients with Acanthamoeba keratitis (cases 5 and 8) whose anti-amoebic therapy was started more than 10 weeks after the onset was poor (Table 1). In patients with Acanthamoeba keratitis in whom appropriate anti-amoebic therapy was started at least within 2 weeks from the onset, the visual prognosis was good, even though topical corticosteroids were applied before the diagnosis (cases 3, 6, and 7).
Both patients with fungal keratitis visited the specialist clinic 3 weeks after the onset of the complaint (Table 1). The delay in the diagnosis and identification of the causative organism (Fusarium species), in addition to the use of topical corticosteroid before diagnosis, may have caused a corneal perforation and loss of sight in the affected eyes (cases 9 and 10).
In the five culture-negative cases, we could not determine the causative microorganism based on the corneal appearance and the clinical course in four cases (Figure 1). Favorable recovery of vision has still not been obtained in two of the cases (cases 13 and 14). This may be due to the difficulty in establishing a treatment plan because the empirical topical antibiotic and corticosteroid treatment has masked the appearance of the corneal lesion.
Discussion
Similar to the findings of the SCUT study, in our cases, the use of topical steroids along with antibiotics did not affect the vision prognoses in the eyes with bacterial keratitis; however, vision was lost in two eyes with fungal keratitis (Table 2). Even though this poor outcome may be attributed to the Fusarium sp. that was involved in two of our cases, topical corticosteroids should not be used for fungal keratitis.6,7,18 For the eyes with Acanthamoeba keratitis, topical corticosteroids are not contraindicated as long as appropriate anti-amoebic therapy is applied.19–21 However, two of the six Acanthamoeba keratitis eyes lost vision in our study (Table 2). In the Acanthamoeba keratitis patients (cases 5 and 8) as well as in two fungal keratitis patients (cases 9 and 10) and two unknown keratitis patients (cases 13 and 14), one of the reasons for the undesirable visual prognosis could be the delay in proper diagnosis (Table 1), caused by the masked clinical findings (Figure 1) and the reactions to the empirical use of topical antibiotics and corticosteroids.25,26
From the referral letter information, at least eight patients were assumed to be treated with topical corticosteroids after being diagnosed with stromal herpetic keratitis. Three of the six Acanthamoeba keratitis patients, one of the two fungal keratitis patients, and two of the four unknown keratitis patients were treated with acyclovir ointment or valaciclovir tablets (Table 1). In addition to these patients who were treated with anti-herpes virus drugs, two Acanthamoeba keratitis patients had a history of herpetic keratitis, according to the referral letter (Table 2). These facts show that we have to distinguish whether the keratitis is stromal keratitis related to herpes simplex virus or microbial infectious keratitis.
From the results of this study, we concluded that it is important to evaluate the patient for fungal keratitis and Acanthamoeba keratitis before deciding on the use of topical corticosteroids for the treatment of the keratitis. Because correct differentiation of bacterial or fungal keratitis by the clinical signs or findings is difficult even for a corneal specialist,27 it is important to make a biologically proven diagnosis by smear and culture before prescribing topical corticosteroids. In addition, it is important to stop the application of topical corticosteroids immediately when keratitis does not improve by these steroids.
A combination of 0.1% betamethasone sodium sulfate and fradiomycin sulfate was prescribed in at least three of the 14 cases. Along with the possibility of stromal herpetic keratitis, another possible reason for the immediate use of topical corticosteroids could be the commercial availability of corticosteroid-antibiotic combination eye drops. As O’Day DM pointed out,28 these preparations have the potential to violate the rule of combined corticosteroid–antibiotic therapy for infectious keratitis.
Accordingly, microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed when prescribing topical corticosteroids for the treatment of infectious keratitis. Although corticosteroid-antibiotic combination eye drops seem safe, they are meaningless or unsafe for treating infectious keratitis other than culture-proven bacterial keratitis.
In addition to its retrospective nature, the main limitation of this study was the single-center study design. As almost all the patients had already been treated empirically with topical antibiotics by the previous ophthalmologist, it was difficult to distinguish the causative microorganism by culture. Thus, we had to diagnose the keratitis as infectious keratitis, particularly bacterial keratitis, based on the corneal findings and clinical course. Additional information from other institutions is needed to clarify the merits and demerits, as well as the background for the empirical use of topical corticosteroids for suspected microbial infectious keratitis.
Conclusion
This study reported a series of severe infectious keratitis cases referred to a specialized medical institution, who were given an antibiotic-steroid combination treatment. Our findings show that it is harmful to apply topical corticosteroids for keratitis that does not respond to empirical antibiotic therapy, since Acanthamoeba keratitis or fungal keratitis are likely involved in these topical antibiotic-resistant cases.
The use of topical corticosteroids along with empirical antibiotic therapy make it difficult to distinguish the causative agent of the infection in suspected keratitis, either by culture or by the corneal findings and clinical course, and as a result, may delay the appropriate treatment and cause unfortunate outcomes. Therefore, we conclude that the use of topical corticosteroids, merely owing to ineffective empirical antibiotic therapy for keratitis, should be avoided. Microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed before prescribing topical corticosteroids for the treatment of suspected infectious keratitis.
Abbreviations
AK, Acanthamoeba keratitis; FK, fungal keratitis; SCUT, Steroids for Corneal Ulcers Trial.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Ethics Approval and Consent to Participate
Written informed consent was obtained from each patient. This study was approved by the Research Ethics Committee of Fujita Health University and was performed in accordance with the Declaration of Helsinki.
Consent for Publication
Written informed consent was obtained from the participants for publication of the research article and any accompanying images.
Author Contributions
KH followed all the patients in this study and wrote the manuscript. KH, HT, and KK analyzed and interpreted the data on the clinical features of the patients. KK and KA-S made critical comments on the manuscript and provided input regarding the clinical outcome of the series of patients with infectious keratitis in whom topical corticosteroids were used. All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agree to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for aspects of the work.
Disclosure
The authors report no conflicts of interest in this work. | Other | DrugAdministrationRoute | CC BY-NC | 33623362 | 19,087,364 | 2021 |
What was the administration route of drug 'BETAMETHASONE SODIUM PHOSPHATE'? | Topical Corticosteroids for Infectious Keratitis Before Culture-Proven Diagnosis.
In clinical practice we sometimes encounter patients with severe corneal ulcers who have been treated with topical corticosteroids. This study reviewed the clinical features and visual outcomes of these patients and investigated the background of the prescription of topical corticosteroids.
The medical records of patients who visited the Cornea Service at Fujita Health University Bantane Hospital and were treated for infectious keratitis from April 2016 to March 2020 were retrospectively reviewed. Patients treated with topical corticosteroids before a culture-proven diagnosis were studied in terms of demographics, best-corrected visual acuity at arrival and at last visit, the clinical course after visit, ocular history, and combination therapy by the previous ophthalmologist.
Out of the 200 eyes of 197 patients with infectious keratitis, 14 eyes of 14 patients were treated with topical corticosteroids before a culture-proven diagnosis. All 14 patients were referred, as they had severe keratitis that could not be cured with topical antibiotics and corticosteroids. Based on the culture results, we diagnosed Acanthamoeba keratitis (AK) in six patients, fungal keratitis (FK) in two patients, bacterial keratitis (including a suspected case) in two patients, and unknown cause in four patients. Two patients with AK, FK, and unknown keratitis had unfortunate clinical courses and poor visual outcomes. From the information in the referral letters, at least six of the 14 patients were treated with either acyclovir ocular ointment or valaciclovir tablets, along with topical corticosteroids.
Application of topical corticosteroids for keratitis that does not respond to empirical antibiotic therapy is harmful since AK or FK is likely involved in these topical antibiotic-resistant cases. Microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed when prescribing topical corticosteroid for the treatment of suspected infectious keratitis.
Plain Language Summary
In the corneal clinic of a university hospital in a metropolitan area, we sometimes encounter referred patients with severe corneal ulcers who have been treated with topical corticosteroids as well as antibiotic eye drops. Why were these topical corticosteroids prescribed? We retrospectively reviewed clinical records of patients with infectious keratitis treated with topical corticosteroids before a culture-proven diagnosis. During an investigative period of 4 years, 14 eyes of 14 patients were evaluated. All the patients were prescribed topical corticosteroids for the keratitis owing to unresponsive empirical antibiotic therapy, and at least six patients were treated for stromal keratitis due to herpes simplex virus.
Why did the corneal lesions of these patients worsen? Based on culture results, we diagnosed Acanthamoeba keratitis in six patients and fungal keratitis in two patients. Apart from bacterial keratitis, other microorganisms responsible for keratitis do not respond to antibiotic therapy, and the condition is worsened by the topical corticosteroids without appropriate anti-amoebic or anti-fungal therapy.
Application of topical corticosteroids for keratitis without microbiological evidence is harmful, and a differential diagnosis of herpetic stromal keratitis as well as fungal and Acanthamoeba keratitis is needed when using topical corticosteroid for the treatment of suspected infectious keratitis.
Introduction
The definitive diagnosis and specific therapy for microbial keratitis should only be determined by microbiological evaluation.1–3 Nevertheless, the application of empirical antibiotic therapy without the use of smears or cultures cannot be rejected, as topical fluoroquinolone is associated with of a high success rate; moreover, the time and cost involved in performing cultures and maintaining the necessary materials are reduced.4–6
During the treatment of microbial keratitis, adjunctive topical corticosteroids are used to reduce the inflammatory response and subsequent corneal scarring, to obtain better visual outcomes, despite the possible risk of enhanced microbial replication, corneal melting, and steroid glaucoma.6–8 The safety and efficacy of topical corticosteroids for microbial keratitis have been reported9–17 in the Steroids for Corneal Ulcers Trial (SCUT)9,10 and other randomized control studies.11,12 The consensus of these studies was that unlike the use of topical antibiotics, the empirical use of topical corticosteroids for suspected microbial keratitis is not recommended. According to the Bacterial Keratitis Preferred Practice Pattern® 2018, 24–48 hours after the causative organism has been identified and/or infection is responding to therapy, corticosteroids may be considered, and close follow-up by a corneal specialist is recommended. Corticosteroids should be avoided in bacterial keratitis caused by slow-cycling microbes such as Nocardia,10 and fungal keratitis,7,11,18 while in Acanthamoeba keratitis, maintaining adequate anti-amoebic therapy is needed if a topical corticosteroid is used.19–23 Therefore, these microorganisms should be ruled out and a definitive diagnosis of bacterial keratitis based on smear and culture or by confirming the response to anti-microbial therapy is suggested before topical corticosteroids.24
At the corneal clinic of our institution and hospital in a metropolitan area, which serves a population of 4 million, we sometimes encounter referred patients with severe corneal ulcers who have been treated with topical corticosteroids. The purpose of this study was to review the clinical features and the visual outcomes of these patients, and to elucidate the effect of the empirical use of topical corticosteroids on the clinical course of this condition and the background of steroid applications in such patients.
Patients and Methods
We retrospectively reviewed the medical records of patients who visited the Cornea Service at Fujita Health University Bantane Hospital and were treated for infectious keratitis from April 2016 to March 2020. The diagnosis of microbial infectious keratitis was confirmed by culture, but because the antibiotic therapy had already been started before the patients arrived at our institution, many of them were solely diagnosed based on the corneal findings and the clinical course.
Suspected infectious keratitis patients treated with topical corticosteroids before culture-proven diagnosis were retrospectively studied in terms of demographics, best-corrected visual acuity at arrival and at the last visit, clinical course after the initial visit, ocular history, and combination therapy by the previous ophthalmologist. We used this information to determine the influence of topical steroid therapy and to determine the factors that led to the steroid prescription.
This study was approved by the institutional review board of the Fujita Health University Faculty of Medicine (Approval number: C120-135). Informed consent was obtained from each patient for use in clinical records for future research.
Results
Patients’ Visits
Two hundred eyes of 197 patients were treated for microbial infectious keratitis in the investigation period. Among the 197 patients, 195 eyes of 192 patients were referred from a hospital or ophthalmic clinic. Almost all the referred patients had already been empirically treated with topical or systemic antibiotic therapy, and the reason for the referral was a poor response to the antibiotic therapy.
Among the referred patients, 14 eyes of 14 patients had been treated with corticosteroid eye drops before arrival (Table 1).Table 1 Patients in Whom Topical Corticosteroids Were Applied Before Culture: Demographics and Past Treatments Other Than Topical Antibiotics
Case No. Age (Years) Sex Laterality Onset-Arrival (Days) Steroid Eye Drops Prescribing Doctor Steroid Use (Days) CL User Ocular History Anti-HSV Drugs Diagnosis
1 32 Male L 7 Unknown Previous doctor 4 Yes BK
2 82 Male R 50 0.1% BM+Fra Referral doctor 30 DMR, Rubeotic gla BK susp
3 39 Male R 12 0.1% FLM Previous doctor 7 Yes ACV AK
4 24 Male R 30 0.1% BM+Fra Previous doctor 28 Yes Herpetic keratitis VACV AK
5 53 Female L 75 0.1% BM Previous doctor 60 Yes Herpetic keratitis AK
6 31 Male R 18 0.1% BM Previous doctor 10 Yes AK
7 56 Male L 14 0.1% BM Referral doctor 8 Yes ACV AK
8 33 Female L 240 Unknown Referral doctor 30 Herpetic keratitis AK
9 46 Female R 20 0.1% BM+Fra Previous doctor 15 Yes FK
10 48 Female R 21 0.1% FLM Referral doctor 7 ACV, VACV FK
11 44 Female L 14 0.1% BM Referral doctor 3 Yes Unknown
12 19 Female L 30 Unknown Previous doctor 21 Yes Unknown
13 51 Male R 14 0.1% BM Referral doctor 3 ACV, VACV Unknown
14 35 Male L 40 0.1% BM Previous doctor 28 Herpetic keratitis ACV Unknown
Abbreviations. No., number; CL, contact lenses; HSV, herpes simplex virus; R, right; L, left; FLM, fluorometholone; BM, betamethasone sodium phosphate; BM+Fra, combined betamethasone sodium sulfate and fradiomycin sulfate; AK, Acanthamoeba keratitis; BK, bacterial keratitis; FK, fungal keratitis; PDR, proliferative diabetic retinopathy; rubeotic gla, rubeotic glaucoma; ACV, acyclovir ocular ointment; VACV, valaciclovir tablets.
Use of Topical Corticosteroids
Corticosteroid eye drops were not used before keratitis occurred but were used to treat the corneal lesions. Out of the 14 patients, six patients were prescribed topical corticosteroids by the referring doctor, and eight patients were prescribed these drugs by another doctor (Table 1). The details of the medical practice, other than the referring doctor, at the previous doctor’s clinic were unknown, but the prescribed corticosteroid eye drops were 0.1% betamethasone sodium phosphate for nine patients, 0.1% fluorometholone for two patients, and unknown steroid eye drops for three patients. Among the nine patients who were treated with 0.1% betamethasone sodium phosphate, combined corticosteroid-antibiotic eye drops (betamethasone sodium sulfate/fradiomycin sulfate) were prescribed for at least three patients (Table 1).
All patients visited the ophthalmic clinic with a complaint of ocular pain, red eye, and visual disturbance. Nine patients were contact lens wearers (Table 1).
History of Herpetic Keratitis
The history of herpetic keratitis and treatment is described in Table 1. According to the referral letters, four patients (cases 4, 5, 8, and 14) had a past history of herpetic keratitis, but the details and the accuracy of the diagnosis were unknown. At least six of the 14 patients were treated with either acyclovir ocular ointment or valaciclovir tablets, along with topical corticosteroids (cases 3, 4, 7, 10, 13, 14). Although we could not exclude concurrent herpetic stromal keratitis because our institution did not have the facility to perform either the immune chromatography or the real-time polymerase chain reaction, the corneal findings and the clinical course of the patients’ eyes were not suggestive of herpetic necrotic keratitis.
Culture and Diagnosis
Corneal scraping and culture were performed for 13 patients (Table 2); however, because the cornea was already perforated and Acanthamoeba was proven by the referral doctor, culture was not performed for case 8. As listed in Table 2, based on the results of the cultures, we diagnosed keratitis as follows: bacterial keratitis in two patients including one suspected case, Acanthamoeba keratitis in six patients, fungal keratitis in two patients, and unknown cause in four patients. Case 2 had a corneal ulcer with a 3.0-mm diameter and hypopyon at the first visit, but the inflammation subsided within 3 weeks of topical antibiotic therapy, and we thus diagnosed the patient with bacterial keratitis even though the culture was negative. In four patients with unknown causes (cases 11−14), the diagnosis of microbial infectious keratitis was made from the clinical presentation at the first visit (Figure 1), but it was not possible to determine whether these were bacterial, fungal, or Acanthamoeba keratitis cases based on the clinical course.Table 2 Patients Topical Corticosteroids Were Applied Before Culture: Culture Results and Prognosis
Case No. BCVA at First Visit BCVA at Last Visit Weeks Taken to Settle Down Cultured Microorganisms Diagnosis Corneal Perforation
1 HM 0.3 3 Pseudomonas aeruginosa BK
2 NLP NLP 8 No growth BK susp
3 0.4 1.0 17 Amoeba, Staphylococcus epidermis, GM Pos bacilli AK
4 LP 0.4 22 Amoeba, Staphylococcus epidermis AK
5 CF HM 50 Amoeba AK
6 HM 0.9 15 Amoeba AK
7 0.3 0.9 19 Amoeba AK
8 LP LP 8 Amoeba at referring doctor AK Yes
9 HM NLP Evisceration Fusarium sp. FK Yes
10 LP NLP Evisceration Fusarium sp. FK Yes
11 0.03 0.8 3 No growth Unknown
12 CF 0.5 6 No growth Unknown
13 LP 0.05 25 No growth Unknown Yes
14 0.04 0.04 30 Staphylococcus epidermis (MRSE) Unknown
Abbreviations: BCVA, best-corrected visual acuity; HM, hand motion; NLP, no light perception; LP, light perception; CF, counting fingers; GM Pos bacilli, Gram-positive bacilli; AK, Acanthamoeba keratitis; BK, bacterial keratitis, FK, fungal keratitis; MRSE, methicillin-resistant Staphylococcus epidermis.
Figure 1 Cases of suspected infectious keratitis who were treated with topical corticosteroids without culture-proven diagnosis and before presentation to our clinic. (A) Case 11; Forty-four-year-old female. Although fungal keratitis was suspected based on corneal findings, it took only 3 weeks to cure the inflammation by a combination of topical antibiotics and anti-fungal therapy. (B) Case 12; Eighteen-year-old female. Early stage of Acanthamoeba keratitis was suspected based on the findings, but no organism could be cultured, even after co-culture with Escherichia coli. (C) Case 13; Fifty-one-year-old male. Despite treatment with a combination topical antibiotic and antifungal therapy, corneal perforation occurred 2 weeks after the first visit. (D) Case 14; Thirty-five-year-old male. Culture was attempted 3 times from the first visit, and at the second time of culture, 1 week after the intensive topical antibiotic therapy was started, methicillin-resistant Staphylococcus epidermis was detected by enrichment culture, but the significance of this result was unclear.
Prognosis
The prognosis is summarized in Table 2. The patients with bacterial keratitis (cases 1 and 2) responded well to the topical antibiotic therapy, and the corneal lesion healed as a scar after 3 weeks, after which corticosteroid eye drops were started again to settle the infiltration.
The prognosis for the vision of the two patients with Acanthamoeba keratitis (cases 5 and 8) whose anti-amoebic therapy was started more than 10 weeks after the onset was poor (Table 1). In patients with Acanthamoeba keratitis in whom appropriate anti-amoebic therapy was started at least within 2 weeks from the onset, the visual prognosis was good, even though topical corticosteroids were applied before the diagnosis (cases 3, 6, and 7).
Both patients with fungal keratitis visited the specialist clinic 3 weeks after the onset of the complaint (Table 1). The delay in the diagnosis and identification of the causative organism (Fusarium species), in addition to the use of topical corticosteroid before diagnosis, may have caused a corneal perforation and loss of sight in the affected eyes (cases 9 and 10).
In the five culture-negative cases, we could not determine the causative microorganism based on the corneal appearance and the clinical course in four cases (Figure 1). Favorable recovery of vision has still not been obtained in two of the cases (cases 13 and 14). This may be due to the difficulty in establishing a treatment plan because the empirical topical antibiotic and corticosteroid treatment has masked the appearance of the corneal lesion.
Discussion
Similar to the findings of the SCUT study, in our cases, the use of topical steroids along with antibiotics did not affect the vision prognoses in the eyes with bacterial keratitis; however, vision was lost in two eyes with fungal keratitis (Table 2). Even though this poor outcome may be attributed to the Fusarium sp. that was involved in two of our cases, topical corticosteroids should not be used for fungal keratitis.6,7,18 For the eyes with Acanthamoeba keratitis, topical corticosteroids are not contraindicated as long as appropriate anti-amoebic therapy is applied.19–21 However, two of the six Acanthamoeba keratitis eyes lost vision in our study (Table 2). In the Acanthamoeba keratitis patients (cases 5 and 8) as well as in two fungal keratitis patients (cases 9 and 10) and two unknown keratitis patients (cases 13 and 14), one of the reasons for the undesirable visual prognosis could be the delay in proper diagnosis (Table 1), caused by the masked clinical findings (Figure 1) and the reactions to the empirical use of topical antibiotics and corticosteroids.25,26
From the referral letter information, at least eight patients were assumed to be treated with topical corticosteroids after being diagnosed with stromal herpetic keratitis. Three of the six Acanthamoeba keratitis patients, one of the two fungal keratitis patients, and two of the four unknown keratitis patients were treated with acyclovir ointment or valaciclovir tablets (Table 1). In addition to these patients who were treated with anti-herpes virus drugs, two Acanthamoeba keratitis patients had a history of herpetic keratitis, according to the referral letter (Table 2). These facts show that we have to distinguish whether the keratitis is stromal keratitis related to herpes simplex virus or microbial infectious keratitis.
From the results of this study, we concluded that it is important to evaluate the patient for fungal keratitis and Acanthamoeba keratitis before deciding on the use of topical corticosteroids for the treatment of the keratitis. Because correct differentiation of bacterial or fungal keratitis by the clinical signs or findings is difficult even for a corneal specialist,27 it is important to make a biologically proven diagnosis by smear and culture before prescribing topical corticosteroids. In addition, it is important to stop the application of topical corticosteroids immediately when keratitis does not improve by these steroids.
A combination of 0.1% betamethasone sodium sulfate and fradiomycin sulfate was prescribed in at least three of the 14 cases. Along with the possibility of stromal herpetic keratitis, another possible reason for the immediate use of topical corticosteroids could be the commercial availability of corticosteroid-antibiotic combination eye drops. As O’Day DM pointed out,28 these preparations have the potential to violate the rule of combined corticosteroid–antibiotic therapy for infectious keratitis.
Accordingly, microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed when prescribing topical corticosteroids for the treatment of infectious keratitis. Although corticosteroid-antibiotic combination eye drops seem safe, they are meaningless or unsafe for treating infectious keratitis other than culture-proven bacterial keratitis.
In addition to its retrospective nature, the main limitation of this study was the single-center study design. As almost all the patients had already been treated empirically with topical antibiotics by the previous ophthalmologist, it was difficult to distinguish the causative microorganism by culture. Thus, we had to diagnose the keratitis as infectious keratitis, particularly bacterial keratitis, based on the corneal findings and clinical course. Additional information from other institutions is needed to clarify the merits and demerits, as well as the background for the empirical use of topical corticosteroids for suspected microbial infectious keratitis.
Conclusion
This study reported a series of severe infectious keratitis cases referred to a specialized medical institution, who were given an antibiotic-steroid combination treatment. Our findings show that it is harmful to apply topical corticosteroids for keratitis that does not respond to empirical antibiotic therapy, since Acanthamoeba keratitis or fungal keratitis are likely involved in these topical antibiotic-resistant cases.
The use of topical corticosteroids along with empirical antibiotic therapy make it difficult to distinguish the causative agent of the infection in suspected keratitis, either by culture or by the corneal findings and clinical course, and as a result, may delay the appropriate treatment and cause unfortunate outcomes. Therefore, we conclude that the use of topical corticosteroids, merely owing to ineffective empirical antibiotic therapy for keratitis, should be avoided. Microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed before prescribing topical corticosteroids for the treatment of suspected infectious keratitis.
Abbreviations
AK, Acanthamoeba keratitis; FK, fungal keratitis; SCUT, Steroids for Corneal Ulcers Trial.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Ethics Approval and Consent to Participate
Written informed consent was obtained from each patient. This study was approved by the Research Ethics Committee of Fujita Health University and was performed in accordance with the Declaration of Helsinki.
Consent for Publication
Written informed consent was obtained from the participants for publication of the research article and any accompanying images.
Author Contributions
KH followed all the patients in this study and wrote the manuscript. KH, HT, and KK analyzed and interpreted the data on the clinical features of the patients. KK and KA-S made critical comments on the manuscript and provided input regarding the clinical outcome of the series of patients with infectious keratitis in whom topical corticosteroids were used. All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agree to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for aspects of the work.
Disclosure
The authors report no conflicts of interest in this work. | Topical | DrugAdministrationRoute | CC BY-NC | 33623362 | 19,087,364 | 2021 |
What was the dosage of drug 'BETAMETHASONE SODIUM PHOSPHATE'? | Topical Corticosteroids for Infectious Keratitis Before Culture-Proven Diagnosis.
In clinical practice we sometimes encounter patients with severe corneal ulcers who have been treated with topical corticosteroids. This study reviewed the clinical features and visual outcomes of these patients and investigated the background of the prescription of topical corticosteroids.
The medical records of patients who visited the Cornea Service at Fujita Health University Bantane Hospital and were treated for infectious keratitis from April 2016 to March 2020 were retrospectively reviewed. Patients treated with topical corticosteroids before a culture-proven diagnosis were studied in terms of demographics, best-corrected visual acuity at arrival and at last visit, the clinical course after visit, ocular history, and combination therapy by the previous ophthalmologist.
Out of the 200 eyes of 197 patients with infectious keratitis, 14 eyes of 14 patients were treated with topical corticosteroids before a culture-proven diagnosis. All 14 patients were referred, as they had severe keratitis that could not be cured with topical antibiotics and corticosteroids. Based on the culture results, we diagnosed Acanthamoeba keratitis (AK) in six patients, fungal keratitis (FK) in two patients, bacterial keratitis (including a suspected case) in two patients, and unknown cause in four patients. Two patients with AK, FK, and unknown keratitis had unfortunate clinical courses and poor visual outcomes. From the information in the referral letters, at least six of the 14 patients were treated with either acyclovir ocular ointment or valaciclovir tablets, along with topical corticosteroids.
Application of topical corticosteroids for keratitis that does not respond to empirical antibiotic therapy is harmful since AK or FK is likely involved in these topical antibiotic-resistant cases. Microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed when prescribing topical corticosteroid for the treatment of suspected infectious keratitis.
Plain Language Summary
In the corneal clinic of a university hospital in a metropolitan area, we sometimes encounter referred patients with severe corneal ulcers who have been treated with topical corticosteroids as well as antibiotic eye drops. Why were these topical corticosteroids prescribed? We retrospectively reviewed clinical records of patients with infectious keratitis treated with topical corticosteroids before a culture-proven diagnosis. During an investigative period of 4 years, 14 eyes of 14 patients were evaluated. All the patients were prescribed topical corticosteroids for the keratitis owing to unresponsive empirical antibiotic therapy, and at least six patients were treated for stromal keratitis due to herpes simplex virus.
Why did the corneal lesions of these patients worsen? Based on culture results, we diagnosed Acanthamoeba keratitis in six patients and fungal keratitis in two patients. Apart from bacterial keratitis, other microorganisms responsible for keratitis do not respond to antibiotic therapy, and the condition is worsened by the topical corticosteroids without appropriate anti-amoebic or anti-fungal therapy.
Application of topical corticosteroids for keratitis without microbiological evidence is harmful, and a differential diagnosis of herpetic stromal keratitis as well as fungal and Acanthamoeba keratitis is needed when using topical corticosteroid for the treatment of suspected infectious keratitis.
Introduction
The definitive diagnosis and specific therapy for microbial keratitis should only be determined by microbiological evaluation.1–3 Nevertheless, the application of empirical antibiotic therapy without the use of smears or cultures cannot be rejected, as topical fluoroquinolone is associated with of a high success rate; moreover, the time and cost involved in performing cultures and maintaining the necessary materials are reduced.4–6
During the treatment of microbial keratitis, adjunctive topical corticosteroids are used to reduce the inflammatory response and subsequent corneal scarring, to obtain better visual outcomes, despite the possible risk of enhanced microbial replication, corneal melting, and steroid glaucoma.6–8 The safety and efficacy of topical corticosteroids for microbial keratitis have been reported9–17 in the Steroids for Corneal Ulcers Trial (SCUT)9,10 and other randomized control studies.11,12 The consensus of these studies was that unlike the use of topical antibiotics, the empirical use of topical corticosteroids for suspected microbial keratitis is not recommended. According to the Bacterial Keratitis Preferred Practice Pattern® 2018, 24–48 hours after the causative organism has been identified and/or infection is responding to therapy, corticosteroids may be considered, and close follow-up by a corneal specialist is recommended. Corticosteroids should be avoided in bacterial keratitis caused by slow-cycling microbes such as Nocardia,10 and fungal keratitis,7,11,18 while in Acanthamoeba keratitis, maintaining adequate anti-amoebic therapy is needed if a topical corticosteroid is used.19–23 Therefore, these microorganisms should be ruled out and a definitive diagnosis of bacterial keratitis based on smear and culture or by confirming the response to anti-microbial therapy is suggested before topical corticosteroids.24
At the corneal clinic of our institution and hospital in a metropolitan area, which serves a population of 4 million, we sometimes encounter referred patients with severe corneal ulcers who have been treated with topical corticosteroids. The purpose of this study was to review the clinical features and the visual outcomes of these patients, and to elucidate the effect of the empirical use of topical corticosteroids on the clinical course of this condition and the background of steroid applications in such patients.
Patients and Methods
We retrospectively reviewed the medical records of patients who visited the Cornea Service at Fujita Health University Bantane Hospital and were treated for infectious keratitis from April 2016 to March 2020. The diagnosis of microbial infectious keratitis was confirmed by culture, but because the antibiotic therapy had already been started before the patients arrived at our institution, many of them were solely diagnosed based on the corneal findings and the clinical course.
Suspected infectious keratitis patients treated with topical corticosteroids before culture-proven diagnosis were retrospectively studied in terms of demographics, best-corrected visual acuity at arrival and at the last visit, clinical course after the initial visit, ocular history, and combination therapy by the previous ophthalmologist. We used this information to determine the influence of topical steroid therapy and to determine the factors that led to the steroid prescription.
This study was approved by the institutional review board of the Fujita Health University Faculty of Medicine (Approval number: C120-135). Informed consent was obtained from each patient for use in clinical records for future research.
Results
Patients’ Visits
Two hundred eyes of 197 patients were treated for microbial infectious keratitis in the investigation period. Among the 197 patients, 195 eyes of 192 patients were referred from a hospital or ophthalmic clinic. Almost all the referred patients had already been empirically treated with topical or systemic antibiotic therapy, and the reason for the referral was a poor response to the antibiotic therapy.
Among the referred patients, 14 eyes of 14 patients had been treated with corticosteroid eye drops before arrival (Table 1).Table 1 Patients in Whom Topical Corticosteroids Were Applied Before Culture: Demographics and Past Treatments Other Than Topical Antibiotics
Case No. Age (Years) Sex Laterality Onset-Arrival (Days) Steroid Eye Drops Prescribing Doctor Steroid Use (Days) CL User Ocular History Anti-HSV Drugs Diagnosis
1 32 Male L 7 Unknown Previous doctor 4 Yes BK
2 82 Male R 50 0.1% BM+Fra Referral doctor 30 DMR, Rubeotic gla BK susp
3 39 Male R 12 0.1% FLM Previous doctor 7 Yes ACV AK
4 24 Male R 30 0.1% BM+Fra Previous doctor 28 Yes Herpetic keratitis VACV AK
5 53 Female L 75 0.1% BM Previous doctor 60 Yes Herpetic keratitis AK
6 31 Male R 18 0.1% BM Previous doctor 10 Yes AK
7 56 Male L 14 0.1% BM Referral doctor 8 Yes ACV AK
8 33 Female L 240 Unknown Referral doctor 30 Herpetic keratitis AK
9 46 Female R 20 0.1% BM+Fra Previous doctor 15 Yes FK
10 48 Female R 21 0.1% FLM Referral doctor 7 ACV, VACV FK
11 44 Female L 14 0.1% BM Referral doctor 3 Yes Unknown
12 19 Female L 30 Unknown Previous doctor 21 Yes Unknown
13 51 Male R 14 0.1% BM Referral doctor 3 ACV, VACV Unknown
14 35 Male L 40 0.1% BM Previous doctor 28 Herpetic keratitis ACV Unknown
Abbreviations. No., number; CL, contact lenses; HSV, herpes simplex virus; R, right; L, left; FLM, fluorometholone; BM, betamethasone sodium phosphate; BM+Fra, combined betamethasone sodium sulfate and fradiomycin sulfate; AK, Acanthamoeba keratitis; BK, bacterial keratitis; FK, fungal keratitis; PDR, proliferative diabetic retinopathy; rubeotic gla, rubeotic glaucoma; ACV, acyclovir ocular ointment; VACV, valaciclovir tablets.
Use of Topical Corticosteroids
Corticosteroid eye drops were not used before keratitis occurred but were used to treat the corneal lesions. Out of the 14 patients, six patients were prescribed topical corticosteroids by the referring doctor, and eight patients were prescribed these drugs by another doctor (Table 1). The details of the medical practice, other than the referring doctor, at the previous doctor’s clinic were unknown, but the prescribed corticosteroid eye drops were 0.1% betamethasone sodium phosphate for nine patients, 0.1% fluorometholone for two patients, and unknown steroid eye drops for three patients. Among the nine patients who were treated with 0.1% betamethasone sodium phosphate, combined corticosteroid-antibiotic eye drops (betamethasone sodium sulfate/fradiomycin sulfate) were prescribed for at least three patients (Table 1).
All patients visited the ophthalmic clinic with a complaint of ocular pain, red eye, and visual disturbance. Nine patients were contact lens wearers (Table 1).
History of Herpetic Keratitis
The history of herpetic keratitis and treatment is described in Table 1. According to the referral letters, four patients (cases 4, 5, 8, and 14) had a past history of herpetic keratitis, but the details and the accuracy of the diagnosis were unknown. At least six of the 14 patients were treated with either acyclovir ocular ointment or valaciclovir tablets, along with topical corticosteroids (cases 3, 4, 7, 10, 13, 14). Although we could not exclude concurrent herpetic stromal keratitis because our institution did not have the facility to perform either the immune chromatography or the real-time polymerase chain reaction, the corneal findings and the clinical course of the patients’ eyes were not suggestive of herpetic necrotic keratitis.
Culture and Diagnosis
Corneal scraping and culture were performed for 13 patients (Table 2); however, because the cornea was already perforated and Acanthamoeba was proven by the referral doctor, culture was not performed for case 8. As listed in Table 2, based on the results of the cultures, we diagnosed keratitis as follows: bacterial keratitis in two patients including one suspected case, Acanthamoeba keratitis in six patients, fungal keratitis in two patients, and unknown cause in four patients. Case 2 had a corneal ulcer with a 3.0-mm diameter and hypopyon at the first visit, but the inflammation subsided within 3 weeks of topical antibiotic therapy, and we thus diagnosed the patient with bacterial keratitis even though the culture was negative. In four patients with unknown causes (cases 11−14), the diagnosis of microbial infectious keratitis was made from the clinical presentation at the first visit (Figure 1), but it was not possible to determine whether these were bacterial, fungal, or Acanthamoeba keratitis cases based on the clinical course.Table 2 Patients Topical Corticosteroids Were Applied Before Culture: Culture Results and Prognosis
Case No. BCVA at First Visit BCVA at Last Visit Weeks Taken to Settle Down Cultured Microorganisms Diagnosis Corneal Perforation
1 HM 0.3 3 Pseudomonas aeruginosa BK
2 NLP NLP 8 No growth BK susp
3 0.4 1.0 17 Amoeba, Staphylococcus epidermis, GM Pos bacilli AK
4 LP 0.4 22 Amoeba, Staphylococcus epidermis AK
5 CF HM 50 Amoeba AK
6 HM 0.9 15 Amoeba AK
7 0.3 0.9 19 Amoeba AK
8 LP LP 8 Amoeba at referring doctor AK Yes
9 HM NLP Evisceration Fusarium sp. FK Yes
10 LP NLP Evisceration Fusarium sp. FK Yes
11 0.03 0.8 3 No growth Unknown
12 CF 0.5 6 No growth Unknown
13 LP 0.05 25 No growth Unknown Yes
14 0.04 0.04 30 Staphylococcus epidermis (MRSE) Unknown
Abbreviations: BCVA, best-corrected visual acuity; HM, hand motion; NLP, no light perception; LP, light perception; CF, counting fingers; GM Pos bacilli, Gram-positive bacilli; AK, Acanthamoeba keratitis; BK, bacterial keratitis, FK, fungal keratitis; MRSE, methicillin-resistant Staphylococcus epidermis.
Figure 1 Cases of suspected infectious keratitis who were treated with topical corticosteroids without culture-proven diagnosis and before presentation to our clinic. (A) Case 11; Forty-four-year-old female. Although fungal keratitis was suspected based on corneal findings, it took only 3 weeks to cure the inflammation by a combination of topical antibiotics and anti-fungal therapy. (B) Case 12; Eighteen-year-old female. Early stage of Acanthamoeba keratitis was suspected based on the findings, but no organism could be cultured, even after co-culture with Escherichia coli. (C) Case 13; Fifty-one-year-old male. Despite treatment with a combination topical antibiotic and antifungal therapy, corneal perforation occurred 2 weeks after the first visit. (D) Case 14; Thirty-five-year-old male. Culture was attempted 3 times from the first visit, and at the second time of culture, 1 week after the intensive topical antibiotic therapy was started, methicillin-resistant Staphylococcus epidermis was detected by enrichment culture, but the significance of this result was unclear.
Prognosis
The prognosis is summarized in Table 2. The patients with bacterial keratitis (cases 1 and 2) responded well to the topical antibiotic therapy, and the corneal lesion healed as a scar after 3 weeks, after which corticosteroid eye drops were started again to settle the infiltration.
The prognosis for the vision of the two patients with Acanthamoeba keratitis (cases 5 and 8) whose anti-amoebic therapy was started more than 10 weeks after the onset was poor (Table 1). In patients with Acanthamoeba keratitis in whom appropriate anti-amoebic therapy was started at least within 2 weeks from the onset, the visual prognosis was good, even though topical corticosteroids were applied before the diagnosis (cases 3, 6, and 7).
Both patients with fungal keratitis visited the specialist clinic 3 weeks after the onset of the complaint (Table 1). The delay in the diagnosis and identification of the causative organism (Fusarium species), in addition to the use of topical corticosteroid before diagnosis, may have caused a corneal perforation and loss of sight in the affected eyes (cases 9 and 10).
In the five culture-negative cases, we could not determine the causative microorganism based on the corneal appearance and the clinical course in four cases (Figure 1). Favorable recovery of vision has still not been obtained in two of the cases (cases 13 and 14). This may be due to the difficulty in establishing a treatment plan because the empirical topical antibiotic and corticosteroid treatment has masked the appearance of the corneal lesion.
Discussion
Similar to the findings of the SCUT study, in our cases, the use of topical steroids along with antibiotics did not affect the vision prognoses in the eyes with bacterial keratitis; however, vision was lost in two eyes with fungal keratitis (Table 2). Even though this poor outcome may be attributed to the Fusarium sp. that was involved in two of our cases, topical corticosteroids should not be used for fungal keratitis.6,7,18 For the eyes with Acanthamoeba keratitis, topical corticosteroids are not contraindicated as long as appropriate anti-amoebic therapy is applied.19–21 However, two of the six Acanthamoeba keratitis eyes lost vision in our study (Table 2). In the Acanthamoeba keratitis patients (cases 5 and 8) as well as in two fungal keratitis patients (cases 9 and 10) and two unknown keratitis patients (cases 13 and 14), one of the reasons for the undesirable visual prognosis could be the delay in proper diagnosis (Table 1), caused by the masked clinical findings (Figure 1) and the reactions to the empirical use of topical antibiotics and corticosteroids.25,26
From the referral letter information, at least eight patients were assumed to be treated with topical corticosteroids after being diagnosed with stromal herpetic keratitis. Three of the six Acanthamoeba keratitis patients, one of the two fungal keratitis patients, and two of the four unknown keratitis patients were treated with acyclovir ointment or valaciclovir tablets (Table 1). In addition to these patients who were treated with anti-herpes virus drugs, two Acanthamoeba keratitis patients had a history of herpetic keratitis, according to the referral letter (Table 2). These facts show that we have to distinguish whether the keratitis is stromal keratitis related to herpes simplex virus or microbial infectious keratitis.
From the results of this study, we concluded that it is important to evaluate the patient for fungal keratitis and Acanthamoeba keratitis before deciding on the use of topical corticosteroids for the treatment of the keratitis. Because correct differentiation of bacterial or fungal keratitis by the clinical signs or findings is difficult even for a corneal specialist,27 it is important to make a biologically proven diagnosis by smear and culture before prescribing topical corticosteroids. In addition, it is important to stop the application of topical corticosteroids immediately when keratitis does not improve by these steroids.
A combination of 0.1% betamethasone sodium sulfate and fradiomycin sulfate was prescribed in at least three of the 14 cases. Along with the possibility of stromal herpetic keratitis, another possible reason for the immediate use of topical corticosteroids could be the commercial availability of corticosteroid-antibiotic combination eye drops. As O’Day DM pointed out,28 these preparations have the potential to violate the rule of combined corticosteroid–antibiotic therapy for infectious keratitis.
Accordingly, microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed when prescribing topical corticosteroids for the treatment of infectious keratitis. Although corticosteroid-antibiotic combination eye drops seem safe, they are meaningless or unsafe for treating infectious keratitis other than culture-proven bacterial keratitis.
In addition to its retrospective nature, the main limitation of this study was the single-center study design. As almost all the patients had already been treated empirically with topical antibiotics by the previous ophthalmologist, it was difficult to distinguish the causative microorganism by culture. Thus, we had to diagnose the keratitis as infectious keratitis, particularly bacterial keratitis, based on the corneal findings and clinical course. Additional information from other institutions is needed to clarify the merits and demerits, as well as the background for the empirical use of topical corticosteroids for suspected microbial infectious keratitis.
Conclusion
This study reported a series of severe infectious keratitis cases referred to a specialized medical institution, who were given an antibiotic-steroid combination treatment. Our findings show that it is harmful to apply topical corticosteroids for keratitis that does not respond to empirical antibiotic therapy, since Acanthamoeba keratitis or fungal keratitis are likely involved in these topical antibiotic-resistant cases.
The use of topical corticosteroids along with empirical antibiotic therapy make it difficult to distinguish the causative agent of the infection in suspected keratitis, either by culture or by the corneal findings and clinical course, and as a result, may delay the appropriate treatment and cause unfortunate outcomes. Therefore, we conclude that the use of topical corticosteroids, merely owing to ineffective empirical antibiotic therapy for keratitis, should be avoided. Microbiological evidence, as well as a differential diagnosis of herpetic stromal keratitis, is needed before prescribing topical corticosteroids for the treatment of suspected infectious keratitis.
Abbreviations
AK, Acanthamoeba keratitis; FK, fungal keratitis; SCUT, Steroids for Corneal Ulcers Trial.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Ethics Approval and Consent to Participate
Written informed consent was obtained from each patient. This study was approved by the Research Ethics Committee of Fujita Health University and was performed in accordance with the Declaration of Helsinki.
Consent for Publication
Written informed consent was obtained from the participants for publication of the research article and any accompanying images.
Author Contributions
KH followed all the patients in this study and wrote the manuscript. KH, HT, and KK analyzed and interpreted the data on the clinical features of the patients. KK and KA-S made critical comments on the manuscript and provided input regarding the clinical outcome of the series of patients with infectious keratitis in whom topical corticosteroids were used. All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agree to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for aspects of the work.
Disclosure
The authors report no conflicts of interest in this work. | 0.1 % | DrugDosageText | CC BY-NC | 33623362 | 19,087,364 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'No adverse event'. | Real-World Patterns of Utilization and Costs Associated with Second-Generation Oral Antipsychotic Medication for the Treatment of Bipolar Disorder: A Literature Review.
Treatment with second-generation antipsychotics (SGAs) for bipolar disorder, including bipolar I disorder (BD-I), is common. This review evaluated real-world utilization patterns with oral SGAs in the United States (US) for bipolar disorder (and BD-I specifically when reported) and economic burden associated with these patterns.
Structured, systematic searches of MEDLINE®, EMBASE®, and National Health Service Economic Evaluation Database identified primary research studies (published 2008-2018) describing real-world SGA use in adults with bipolar disorder/BD-I.
Among 769 studies screened, 39 met inclusion criteria. Most studies (72%) were analyses of commercial or Medicare/Medicaid claims databases. Patient-related (eg, demographic, comorbidities) and disease-related (eg, mania, psychosis) factors were associated with prescribed SGA. Suboptimal utilization patterns (ie, nonadherence, nonpersistence, treatment gaps, medication switching, and discontinuation) were common for patients treated with SGAs. Also common were SGAs prescribed with another psychotropic medication and SGA combination treatment (use of ≥2 SGAs concurrently). Suboptimal adherence and SGA combination treatment were both associated with increased health care resource use (HCRU); suboptimal adherence was associated with higher total direct medical and indirect costs.
Different definitions for populations and concepts limited between-study comparisons. Focusing on SGAs limits contextualizing findings within the broader treatment landscape (eg, lithium, anticonvulsants). Given the nature of claims data, prescribing rationale (eg, acute episodes vs maintenance) and factors influencing observed utilization patterns could not be fully derived.
Despite increased use of SGAs to treat bipolar disorder over the last decade, reports of suboptimal utilization patterns of SGAs (eg, nonadherence, nonpersistence) were common as was combination treatment. Patterns of SGA use associated with additional HCRU and/or costs were suboptimal adherence and SGA combination treatment; economic consequences associated with other utilization patterns (eg, nonpersistence) were unclear. Strategies to improve SGA treatment continuity, particularly adherence, may improve clinical and economic outcomes among people living with bipolar disorder.
Introduction
Bipolar disorder is a complex and severe mental health disorder that encompasses a variety of subtypes marked by extreme shifts in mood and energy that can lead to cognitive, functional, and social impairment.1,2 The bipolar I disorder (BD-I) subtype, defined as having ≥1 lifetime manic episode,3 accounts for approximately one-quarter of bipolar disorder cases in the United States (US).4 BD-I has a lifetime prevalence of 2.1% and the average age of onset of BD-I is 22 years in the US.2 It is debilitating disorder associated with significant medical and psychiatric comorbidities, as well as high rates of premature mortality resulting from both medical comorbidities and suicide.2,3
Over 90% of those with BD-I who experience a single manic episode transition to having recurrent mood episodes,3 necessitating long-term clinical management involving pharmacologic treatment.1,5,6 A variety of medications are approved to treat or prevent manic episodes, such as “traditional” mood stabilizers (eg, lithium, anticonvulsants including valproate, lamotrigine, and carbamazepine) and antipsychotics. Medication prescribed to resolve an acute episode is generally continued longer-term to prevent new mood episodes and improve patients’ overall functioning.1,7 Guidelines recommend that choice of medication is individualized, informed by response to previous medication(s), patient preferences, the rapidity of response required (combination regimens tend to work more quickly than monotherapy), severity of mania, concerns with adherence, and safety and tolerability profiles.
There are multiple second-generation antipsychotics (SGAs) that are first-line options for initial mood-stabilizing treatment in patients with BD-I, either as monotherapy or in combination with “traditional” mood stabilizers. As of May 2020, seven oral SGAs (aripiprazole, asenapine, cariprazine, olanzapine, quetiapine, risperidone, and ziprasidone) have been approved by the US Food and Drug Administration (FDA) to treat BD-I acute manic/mixed episodes or as BD-I maintenance therapy.8 The first regulatory approvals for SGAs to treat BD-I were granted 20 years ago, and over the period since, the volume of outpatient prescriptions for SGAs has outpaced those for “traditional” mood-stabilizing medications.9–11 From 2013 to 2016, the proportion of outpatient visits that included an SGA prescription was 52.7% compared to 26.4% for those prescribed any mood stabilizer.9
BD-I is associated with considerable disease and economic burden, as well as reduced quality of life, relative to other subtypes of bipolar disorder.2,3,12,13 To better understand real-world use of SGAs to treat patients with mania or predominately manic symptoms in the US, this review was conducted to: 1) characterize real-world utilization patterns with oral SGAs in patients with BD-I [or bipolar disorder in general where BD-I estimates were not available]; and 2) report the relationship between these patterns and HCRU and/or associated medical costs.
Materials and Methods
MEDLINE®, MEDLINE® in-process, EMBASE®, and the National Health Service Economic Evaluation Database (NHS EED) were searched for primary research studies published between 1 January 2008 and 9 July 2018, and abstracts from relevant conferences published between 1 January 2015 and 9 July 2018. Systematic, database-specific search strategies were created using terms related to disease, intervention, and outcomes, and were limited to English-language publications. Structured searches utilized the following Medical Subject Heading terms along with keyword equivalents: bipolar and related disorders, antipsychotic agents, costs and cost analyses, drug prescriptions, drug utilization, and medication adherence. The full search strategy is reported in the Supplementary Material.
The search period for published articles was selected for multiple reasons. First, it captured a decade of published literature on the use of SGAs for the treatment of bipolar disorder at the time the review was conducted. Secondly, since SGAs were first approved in 2001 in the US for the treatment of bipolar disorder, identified papers were likely to describe utilization patterns of SGAs when they were available as an approved treatment for bipolar disorder. Thirdly, most included papers were published after the passage of two federal laws (Mental Health Parity and Addictions Equity Act [MHPAEA] in 2008 and Affordable Care Act [ACA] in 2010, respectively) that changed the insurance landscape and substantially improved mental health pharmacy benefits for patients in the US.14 Finally, a search of conference abstracts from 2015 and 2018 was included to discover any relevant data that may not have been published as a manuscript.
Studies were included if 1) the population of interest was adults with BD-I, mixed subtypes of bipolar disorder including BD-I, or bipolar disorder generally; and 2) the study evaluated choice and dosing of SGAs, patterns of SGA use (eg, adherence, persistence), treatment-specific outcomes (eg, side effects), HCRU, and costs. Papers reporting HCRU or costs were included in this review. Scoping searches informed the broader criterion for study population that included general/mixed bipolar disorders in addition to BD-I, as few studies in pilot searches reported data specific to BD-I patients. Additionally, inclusion in this review was limited to studies conducted in real-world settings (ie, not randomized controlled trials or economic evaluations of specific agents) describing cohorts of at least 100 patients in the US over a period of at least six months. Studies were excluded if they focused on narrow or transient bipolar subtypes (eg, bipolar depression, postpartum bipolar disorder). Review articles were not included, but their reference lists were searched for studies that met inclusion criteria but were not captured via the systematic search.
Article titles and abstracts were screened by a single reviewer. In cases of uncertainty, a second reviewer evaluated the title and abstract to confirm inclusion for full-text review. Full-text review was also performed by a single reviewer, with queries resolved through discussion with a second reviewer. Data from included studies were extracted by one researcher into a structured spreadsheet, which was then validated by a second researcher against source publications. Disagreements on the extracted data were flagged and resolved by discussion between the two researchers. Data specific to BD-I were extracted separately where possible.
Costs were converted to 2018 US dollars (USD), using the Consumer Price Index (CPI) for Medical Care, to facilitate descriptive comparisons across studies reporting similar outcomes.15 If cost-year was not reported, the cost-year was assumed to be the last year of the reported observation period.
Results
A total of 2041 citations were identified across all database searches; all records were combined, and duplicate records and excluded publication types were flagged electronically and removed. The titles and abstracts of the remaining 769 abstracts were screened to determine inclusion. After screening and full-text review, 39 studies met inclusion criteria. Of these, 28 studies (72%) were analyses of commercial or Medicare/Medicaid claims databases and six studies (15%) reported data specific to patients with BD-I. Thirty-seven studies reported the period of data collection (1998–2014); most of these studies (92%) evaluated data collected prior to 2011. Figure 1 presents a PRISMA diagram showing the search and selection process.Figure 1 Search Results and Study Selection.
Note: Articles retrieved from other sources refer to papers identified from bibliographic review of relevant published systematic reviews. PRISMA figure adapted from Liberati A, Altman D, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of clinical epidemiology. 2009;62(10). Creative Commons.57Abbreviation: NHS EED, National Health Service Economic Evaluation Database.
Twenty-two studies (56%) reported HCRU or costs of treatment with oral SGAs. Of these, the most frequently studied SGA agent was quetiapine (73%), followed by risperidone (68%), olanzapine (64%), aripiprazole (59%), ziprasidone (50%), and lurasidone (5%). Since most papers were retrospective studies of health care claims, papers did not document whether SGA prescriptions represented treatment for an acute episode or maintenance. Several studies reported aggregated evidence pertaining to SGAs but did not specify the route of administration (ie, oral vs injection), and the route could not be inferred contextually. A list of FDA-approved SGAs for the treatment of BD-I and the chronology of their approvals are included in the Supplementary Material.
Trends in SGA Use and Dosing
Trends in SGA Use
Results of studies suggest that SGA use increased rapidly from 1998 to 2011. In an analysis of Department of Veterans Affairs (VA) health care claims data between 2003 and 2010, SGAs replaced lithium, valproate, and carbamazepine/oxcarbazepine as the most commonly initiated mood-stabilizing treatments for bipolar disorder by 2007.11 A study of commercial health care claims for outpatient visits for bipolar disorder reported SGA prescribing grew from 18% to 49% between 1998 and 2009. This trend began with off-label use, most commonly with olanzapine and risperidone, prior to the first FDA approvals of SGAs in BD-I.10
Another study examined trends in the mix of SGAs prescribed at a bipolar disorder specialty clinic over a 12-year period (2000–2011). During this interval, use of quetiapine and aripiprazole more than doubled, while use of olanzapine and risperidone decreased by more than half. It was suggested that these trends may have been driven by differences in tolerability (eg, fewer side effects associated with aripiprazole, weight gain observed with olanzapine, and extrapyramidal symptoms associated with risperidone), and by improved efficacy observed with quetiapine in bipolar depression.16
SGA Dosing
Eight studies described dosing patterns for aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone (Table 1). Seven papers reported daily doses for quetiapine that fell below the recommended dose range specified in the product label.17–23 Due to its sedating properties, three studies suggested low dose quetiapine may have been prescribed to treat insomnia and/or anxiety; however, the prescribing rationale for subtherapeutic dose ranges reported could not be confirmed.18,20,24 Daily doses reported for the other four SGAs generally corresponded to the lower end of the recommended dose range in product labels,17–23 with two separate analyses suggesting that dosing at the lower end of therapeutic ranges may be associated with attempts to manage side effects and improve tolerability.20,22 Another study of Medicaid patients with bipolar disorder for whom oral SGAs were prescribed (study period 2000 to 2008) found that fewer than half (45%) received clinically recommended doses after two months of treatment. The proportion of patients receiving doses lower than recommended varied by SGA; the majority of patients receiving quetiapine (72%) received doses below the clinically recommended range, followed by risperidone (45%), olanzapine and ziprasidone (both 35%), and aripiprazole (20%).24 A prospective naturalistic study (reporting period 1998–2005) reporting on the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) found that average daily doses of some SGAs were higher in patients treated with more than one SGA compared to those on SGA monotherapy.18 In a separate analysis from STEP-BD, SGA dosing varied by patient age: younger (vs older) patients were prescribed higher doses for four out of five SGA agents studied.17Table 1 SGA Dosing
Study Data Source [Study Period] Sample Dose Findings Reported Dose, mg [Current Recommended Range]
Aripiprazole [10–30mg] Olanzapine [5–20mg] Quetiapine [400–800mg] Risperidone [1–6mg] Ziprasidone [80–160mg]
Al Jurdi et al, 200817 STEP-BD study
[1998–2005]
n=3615 (67.6% BD-I) Mean daily dose, overall sample 15.99 9.2 224.79 1.37 90.16
Brooks et al, 201118 STEP-BD study
[1998–2005]
n=1958 (72% BD-I) Mean daily dose, SGA monotherapy 16 10 269 2 92
Gianfrancesco et al, 200819 Commercial claims
[1999–2004]
n=8750 Tx episodes* (70% M/M) Mean daily dose in any 3-month segment (M/M group), minimum/maximum 13/16.4 9.0/9.7 172.8/239.7 1.7/2.0 76.8/88.7
Jing et al, 200921 and Kim et al, 200923 Commercial claims
[2003–2006]
n=6162 (BD) ** Mean daily dose, starting/maximum 11.2/12.4 9.3/10.2 147/169.8 1.6/1.8 90.3/100.2
Jing et al, 201120 Medicaid claims
[2003–2008]
n=22,479 (BD) Mean daily dose, starting/maximum 11.8/13.7 8.2/9.6 149/194 1.4/1.7 80.4/94.4
Kim et al, 201122 Commercial claims
[2003–2006]
n=7169 (BD) Mean daily dose, starting/maximum 11.8/13.4 7.8/8.7 140.3/172.2 1.6 83.2/95.5
Rascati et al, 201124 Medicaid claims
[2002–2008]
n=2446 (BD) Mean daily dose for patients with clinically recommended doses 16 13 450 3 126
Notes: Current recommended ranges listed are sourced from product package inserts. *A treatment episode was defined as period consisting of ≥2 sequential antipsychotic prescriptions. **This is one dataset that was published in two different analyses.
Abbreviations: BD, bipolar disorder; BD-I, bipolar I disorder; M/M, manic/mixed; SGA, second-generation antipsychotic; STEP-BD, Systematic Treatment Enhancement Program for Bipolar Disorder; Tx, treatment.
Choice of SGA
Prescribing patterns described in the literature suggest patient-related (age, gender, race, comorbidities, and treatment history) and disease-related factors (clinical symptoms, eg, presence of mania or psychosis) may influence prescribers’ choice of SGA. Younger patients (age 25–34 years) were less likely to receive risperidone (vs olanzapine), while older patients (age 45–64 years) were less likely to receive quetiapine (vs olanzapine). Compared with olanzapine, African-American patients were more likely to receive risperidone and women were more likely to receive quetiapine.25 Other patient-related factors associated with prescribers’ choice of SGA were the presence of comorbid metabolic conditions (eg, diabetes, obesity); for example, selecting a regimen less likely to induce additional weight gain.11,25,26 Another study found patients who received treatment with lithium were less likely to be prescribed SGA medications.27
Disease-related factors associated with initiating SGA treatment included having a complex clinical profile,26 presence of psychosis,11,27 mania, or receiving treatment in an inpatient (vs outpatient) setting.27 Additionally, patients’ pre-existing risks for adverse events (AEs) can limit the choice of SGA prescribed. A retrospective analysis estimated the prevalence of pre-existing risk factors for AEs and potential drug–drug interactions for a cohort of bipolar patients newly initiating SGA treatment. After comparing patients’ comorbid conditions and concomitant medications against the warnings and precautions from product package inserts, the prevalence of pre-existing AE risk factors was estimated to range from 25% to 88% by individual SGA (aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone).28
Utilization Patterns with Oral SGA Medication
Twenty-three studies described real-world utilization patterns observed with oral SGAs including adherence, persistence, treatment gaps, medication switching, discontinuation, and combination treatment (use of ≥2 concurrent psychotropic medications). Suboptimal treatment outcomes reported in association with these patterns are described in the sections that follow, noting authors’ definitions for these measures.
Adherence
Studies reporting on adherence are shown in Table 2. Some studies reported on adherence to bipolar disorder medication aggregated across several drug classes where SGA-specific adherence data were not available.Table 2 Adherence with SGAs and BD Medications (Multiple Classes Including SGAs)
Study Data Source
[Study Period] Sample Adherence Findings
Bagalman et al, 201029 Commercial claims
[2001–2004] n=1258 (BD)
Employed patients receiving psychotropic medication(30.6% index oral SGA) At 1 year, mean MPR was 0.58.
Only 35.3% of employees were adherent (MPR ≥0.8) with their BD medication after 1 year.
Baldessarini et al, 200835 Cross-sectional study
[2001–2005] n=429 (79.0% BD-I)
Patients recruited by their prescribing physician for a survey(61.3% receiving an antipsychotic) Self-report of missing ≥1 dose of BD medication was 33.8% over a 10-day recall period.
Chen et al, 201330 Commercial, Medicare, and Medicaid claims
[2005] n=16,807 (BD-I) Patients newly initiating SGA monotherapy At 1 year, mean MPR was 0.19 (overall).
Adherence (MPR ≥0.8) was 8.3% to index SGA after 1 year.
Gianfrancesco et al, 200819 Commercial claims
[1999–2004] n=8750 treatment episodes* (70% M/M)
Patients receiving SGA or FGA monotherapy (95% SGA) In any 3-month period, mean MPR ranged from 0.8 to 1.02 (M/M cohort) over the 15-month evaluation period.
Gianfrancesco et al, 200832 Commercial claims
[1999–2004] n=8770 treatment episodes* (70% M/M)
Patients receiving SGA or FGA monotherapy (95% SGA) In any 3-month period, mean MPR ranged from 0.87 to 0.96 (M/M cohort) over the 15-month evaluation period.
Gianfrancesco et al, 200833 Commercial claims
[1999–2005] n=5531 treatment episodes* (69% M/M)
Patients initiated on quetiapine or risperidone, alone and in various MS+ADT combinations Over a 150-day period, mean MPR was 0.94 (quetiapine) and 0.91 (risperidone) in the monotherapy groups and ranged from 0.86 to 1.00 in the combination treatment groups.
Hassan and Lage, 200940 Commercial claims
[2000–2006] n=1973 (BD)
Hospital discharges with an SGA/FGA prescription(98% SGA) At 1 year, mean MPR was 0.4565.
The proportion of patients with MPR ≥0.75 was 26.76%.
Lage and Hassan, 200939 Commercial claims
[2000–2006] n=7769 (BD)
Patients with ≥1 SGA/FGA claim(95% SGA) At 1 year, mean MPR was 0.417.
The proportion of patients with MPR ≥0.75 was 21.3%.
Lang et al, 201131 Medicaid claims
[2004–2006] n=9410 (BD-I)
Patients with ≥1 SGA/FGA claim(83.1% oral SGA) Among patients receiving oral SGA, mean MPR was 0.63 and only 38.9% were adherent (MPR ≥0.8) at 1 year.
Perlis et al, 201034 Prospective longitudinal cohort study
[1998–2005] n=3640 (BD)
Patients receiving ≥1 psychotropic medication Across all study visits, 46.4% of patients reported adherence with BD medication.
Qiu et al, 200925 Medicaid claims
[2000–2005] n=838 (BD)
Patients receiving monotherapy with olanzapine, risperidone, or quetiapine Adherence with index SGA, as measured by CMA and CMG, was similar across treatment groups at 1 year. CMA ranged from 70% to 76% and CMG ranged from 35% to 38%.
Rascati et al, 201124 Medicaid claims
[2002–2008] n=2446 (BD)
Patients initially prescribed SGA therapy At 1 year, 58% of patients prescribed a clinically recommended dose of an index SGA were adherent (MPR ≥0.8).
Seabury et al, 201436 Medicaid claims
[2001–2008] n=170,596 (BD)
Patients newly initiated on SGA therapy At 1 year, the mean proportion of days covered over 12 months for patients with BD was 72%.
Notes: *A treatment episode was defined as period consisting of ≥2 sequential antipsychotic prescriptions. CMA calculated as the sum of days’ supply of all SGA prescriptions in the 12-month treatment period after the index date divided by total days between the date of the first fill to the date of last refill. CMG was calculated as the ratio of total days without treatment divided by total days between the first fill and last refill date.
Abbreviations: ADT, antidepressant therapy; BD, bipolar disorder; BD-I, bipolar I disorder; CMA, cumulative medication acquisition; CMG, cumulative medication gap; FGA, first-generation antipsychotic (also known as typical antipsychotics); M/M, manic/mixed; MPR, medication possession ratio; MS, traditional mood stabilizer medication; SGA, second-generation antipsychotic.
Medication possession ratio (MPR) was the most common measure of adherence, and many analyses of health care claims defined adherence as an MPR of ≥0.8.24,29–31 Utilizing this definition, fewer than 39% of patients with BD-I were adherent with their oral SGA medication at one year in two separate studies.30 A study of bipolar disorder patients taking SGAs, first-generation antipsychotics (FGAs), or mood stabilizer medications found about one-third (35.3%) were adherent with their regimen over a year of follow-up.29 There were three analyses that reported relatively high adherence rates for patients prescribed antipsychotics (MPRs ranged from 0.80 to 1.02);19,32,33 however, these adherence rates may have been due to assessing MPR over treatment episodes (defined as period of ≥2 sequential antipsychotic prescriptions), rather than over a discrete evaluation period (eg, 1 year).
Other studies collected data on medication adherence via self-report from patients, and reported adherence estimates that are similar to those calculated using MPR. During 48,287 follow-up visits among 3640 patients, fewer than half (46.4%) self-reported being adherent with their bipolar disorder medications, which was defined as having missed fewer than 25% of total doses of any one medication.34 In another patient survey, 33.8% self-reported missing at least one dose of bipolar disorder medications in the prior 10 days.35
Less frequently utilized metrics of adherence included cumulative medication acquisition (CMA), cumulative medication gap (CMG), and proportion of days covered (PDC). A cost analysis of Medicaid claims for bipolar disorder patients newly started on SGA monotherapy with olanzapine, risperidone, or quetiapine reported adherence over a 1-year period as measured by CMA and CMG.25 Across the three treatment cohorts, similar rates were reported for CMA (70% to 76%) and CMG (35% to 38%), respectively. An analysis of multi-state Medicaid claims for bipolar disorder patients newly prescribed SGA therapy reported a PDC of 72% over 1 year of follow-up.36
Four analyses evaluated sociodemographic, clinical, and/or treatment-related characteristics associated with suboptimal adherence with oral SGA therapy, which included comorbid substance use disorder,19,31 a history of suicide attempts,24 and older age (Table 3).19,24,33 Two studies examined adherence by prescribed SGA dose. An analysis of commercial health care claims reported those with predominately manic/mixed symptoms who received risperidone, olanzapine, and FGAs had reduced adherence (MPR) with higher doses in every 3-month treatment segment over a 15-month period, an effect that was not observed among those receiving aripiprazole, quetiapine, or ziprasidone.19 In a cohort of Medicaid bipolar patients for whom SGAs were prescribed, only 45% had clinically recommended doses after two months of treatment, and of these, only 58% were adherent (MPR ≥0.8). Level of adherence was not reported for the 55% of patients who received either subtherapeutic or high doses of the index SGA treatment, nor were reasons for prescriptions that fell outside of the clinically recommended dose range described.24Table 3 Factors Associated with Suboptimal Adherence with SGA Regimen in Analyses of Health Care Claims
Patient Characteristic Factors Associated with Suboptimal Adherence to SGA Regimen
Commercial Claims, BD (predominately M/M) Medicaid Claims, BD-I Medicaid Claims, BD
Gianfrancesco et al., 200819 Gianfrancesco et al., 200933 Lang et al., 201131 Rascati et al., 201124
Sociodemographic Characteristics Age (younger, ≤30 years) ●
Age (older, range not specified) ● ● ●
Race (African American vs. Caucasian) ●
Clinical Characteristics History of suicide attempt ●
Current (or history) of comorbid substance use disorder ● ●
Baseline psychiatric hospitalization ●
Treatment-Related Characteristics Newly initiated SGA ●
Higher SGA dose (olanzapine, risperidone) ●
Baseline antidepressant use ●
Prior or concomitant use of mood stabilizers ● ●
Concomitant use of SGA with other psychotropic medication ●
Hyperprolactinemia as a pre-existing antipsychotic-related side effect ●
Abbreviations: BD, bipolar disorder; BD-I, bipolar I disorder; M/M, manic/mixed symptoms; SGA, second-generation antipsychotic.
One study surveyed patients about factors that contributed to suboptimal adherence with their bipolar disorder medications, such as missing doses or stopping treatment. Patients cited two frustrations that negatively impacted medication adherence: having to take medicine daily (51.1%) and side effects associated with mood-stabilizing psychotropic medications (40.2%). Patients who self-reported suboptimal adherence pointed to adverse effects of bipolar disorder medications such as weight gain (58.5%), excessive sedation (54.2%), and physical awkwardness or tremor (33.1%) to explain their incomplete adherence with prescribed therapies.35
Persistence, Treatment Gaps, Switching, and Discontinuation
Studies reporting on treatment persistence and duration of treatment/treatment gaps are summarized in Tables 4 and 5. Although definitions of persistence varied across studies, regardless of the assessment criteria used, persistence with treatment was generally low. An analysis of Medicaid health care claims found that only 18% of patients who were prescribed SGAs at clinically recommended doses were persistent with therapy defined as no gap (>30 days between refills) over a 1-year period. Median time to SGA-nonpersistence (30-day gap in treatment) was approximately three months (96 days), with modest variation depending on the prescribed SGA (low of 72 days with olanzapine; high of 117 with ziprasidone).24 An analysis of commercial health care claims for employees with bipolar disorder found greater persistence among adherent (MPR ≥0.8) patients; although, over 1 year of follow-up these patients had more treatment gaps (3.62 vs 2.60) for shorter periods (15.57 vs 58.89 days) than those with a MPR <0.8.29 In evaluating dosing regularity, drug holidays (missing ≥3 consecutive days of medication, found in 35.8% of analysis periods), single-day omissions (present in 64.7% of periods) and self-directed changes in daily dosing (86.7% of periods) were common.37Table 4 Persistence with Oral SGAs or BD Medication
Study Data Source
[Study Period] Sample Persistence Findings
Bagalman et al, 201029 Commercial claims
[2001–2004] n=1258 (BD)
Employed patients receiving psychotropic medication
(30.6% index oral SGA) At 1 year, mean persistence with BD medication was 0.77 (overall, measure for persistence was not defined).
Adherent (vs MPR <0.8) patients had greater persistence at 1 year (0.99 vs 0.64).
Chen et al, 201330 Commercial, Medicare, and Medicaid claims
[2005] n=16,807 (BD-I) Patients newly initiating SGA monotherapy At 1 year, 10.5% of patients were persistent to SGA therapy (no gaps >15 days between refills and no continuous concomitant treatment with another SGA ≥30 days).
Lang et al, 201131 Medicaid claims
[2004–2006] n=9410 (BD-I)
Patients with ≥1 SGA/FGA claim
(83.1% oral SGA) At 1 year, mean persistence was 0.84 (±0.26) (defined as the number of days between the first and last day receiving an oral SGA divided by the number of days remaining in the period after the first oral SGA was dispensed).
Rascati et al, 201124 Medicaid claims
[2002–2008] n=2446 (BD)
Patients initially prescribed SGA therapy At 1 year, 18% of patients prescribed SGA at clinically recommended doses were persistent (no gap >30 days between SGA refills).
The median time-to-SGA-nonpersistence was 96 days with modest variation depending on the index SGA (range: 72 for olanzapine to 117 days for ziprasidone).
Abbreviations: BD, bipolar disorder; BD-I, bipolar I disorder; FGA, first-generation antipsychotic (also known as typical antipsychotics); MPR, medication possession ratio; SGA, second-generation antipsychotic.
Table 5 Duration of Therapy and Treatment Gaps with SGAs
Study Data Source
[Study Period] Sample Treatment Gap and/or Duration of Therapy Findings
Bagalman et al, 201029 Commercial claims
[2001–2004] n=1258 (BD)
Employed patients receiving psychotropic medication
(30.6% index oral SGA) Over 1 year, adherent patients (vs MPR <0.8) had more gaps in therapy (3.62 vs 2.60), but these gaps occurred for shorter durations (15.57 vs 58.89 days).
Chen et al, 201330 Commercial, Medicare, and Medicaid claims
[2005] n=16,807 (BD-I)
Patients newly initiating SGA monotherapy Average time to first non-compliance was approximately 90 days (defined as gaps between index SGA refills >15 days but <30 days and no evidence of adding or switching to another SGA medication).
Over 1 year, most patients (63.4%) discontinued initial SGA therapy (gap of ≥30 days for index SGA with no evidence of antipsychotic augmentation or switch). The average time to discontinuation was 66 days.
Many (69.7%) did not restart any type of antipsychotic therapy during the remainder of the 1-year follow-up period; one-third resumed antipsychotic therapy after 3 to 6 months.
Kim et al, 201122 Commercial claims
[2003–2006] n=7169 (BD)
Patients with ≥1 SGA claim Over 1 year, rates of discontinuation (>15 days’ gap in coverage) were high (67% [ziprasidone] to 83% [aripiprazole]).
Fewer than 5% of patients completed a full year of follow-up taking their index SGA medication.
The duration of therapy with SGA was comparable across all treatment groups (median of 30 days across all index SGA treatment groups).
Lang et al, 201131 Medicaid claims
[2004–2006] n=9410 (BD-I)
Patients with ≥1 SGA/FGA claim
(83.1% oral SGA) The mean maximum consecutive gap in treatment was 49.3 days for the oral SGA group over a 1-year period.
Gianfrancesco et al, 200819 Commercial claims
[1999–2004] n=8750 treatment episodes* (70% M/M)
Patients receiving SGA or FGA monotherapy (95% SGA) In the M/M cohort, treatment duration ranged from 7.6 months (aripiprazole) to 9.6 months (risperidone).
For all risperidone- or quetiapine-treated individuals, higher doses were associated with longer duration of treatment among patients with predominantly M/M symptoms.
Gianfrancesco et al, 200933 Commercial claims
[1999–2005] n=5531 treatment episodes* (69% M/M)
Patients initiated on quetiapine or risperidone, alone and in various MS/ADT combinations Mean treatment duration for both quetiapine and risperidone monotherapy was 12.4 months.
The mean treatment duration for combination therapies (ADT and/or MS) with quetiapine or risperidone ranged from 11.1 to 13.3 months. Comparisons of MPRs for quetiapine/risperidone combinations vs monotherapy showed no clear relationship to treatment duration.
Pilhatsch et al, 201837 Prospective study
[NR – 100-day periods] n=241
Outpatients recruited from a university mood clinic and private practice.
(50% SGA) Patients took drugs on 84.4% of days.
Irregular daily dosing was frequently reported, mostly due to single-day omissions (64.7% of analysis period) or patients’ self-directed dosage changes (86.7% of analysis periods).
Drug holidays (missing ≥3 consecutive days of medication) were found in 35.8% of analysis periods.
Note: *Treatment episode was defined as period consisting of ≥2 sequential antipsychotic prescriptions.
Abbreviations: ADT, antidepressant therapy; BD, bipolar disorder; FGA, first-generation antipsychotic (also known as typical antipsychotics); M/M, manic/mixed; MPR, medication possession ratio; MS, traditional mood stabilizers; NR, not reported; SGA, second-generation antipsychotic.
Of the studies describing utilization patterns for patients newly initiated on SGAs, only one study reported rates of switching treatment and two studies described rates of discontinuation with the index SGA medication. A study of utilization patterns for BD-I patients newly prescribed SGA treatment over a 1-year period reported 8.4% of patients switched treatment (changing from index SGA to another) and most (63.4%) discontinued their index SGA medication. The average time to discontinuation was approximately 2 months, with only one-third of patients who discontinued their index SGA resuming any type of antipsychotic medication within the remaining 1-year evaluation period.30 A second retrospective study reported that discontinuation rates varied by individual SGA (67% for ziprasidone to 83% for aripiprazole) and fewer than 5% of patients completed a full year of taking their index SGA medication.22
Combination Treatment
Fourteen studies reported use of concomitant psychotropic medications in patients prescribed SGAs (Table 6), including SGA combination treatment (use of ≥2 SGAs concurrently) and concomitant use of SGAs with other psychotropic medications (eg, antidepressants, traditional mood stabilizers). The prevalence of SGA combination treatment ranged from 1% in a sample of patients newly initiated on SGAs to 23% of SGA-treated patients insured by a large commercial health plan.26,30 In the STEP-BD study, SGA combination treatment (vs monotherapy) was associated with no improvement in clinical status and slightly poorer global functioning, although the effect size was small. In addition, there was no association between use of combination treatment and illness severity based on number of comorbid diagnoses, duration of illness, number of manic or depressive episodes, or clinical measures collected at baseline.18Table 6 Prevalence of Combination Treatment
Study Data Source
[Study Period]
Sample SGA Combination Treatment (Use of ≥2 SGAs Concurrently) Combination Treatment (Use of ≥2 Psychotropics Concurrently) Notes
Aparasu et al, 200953 Cross-sectional study
[2003–3004]
N=2860 (multiple diagnoses) 10.3% – Proportion of treatment visits for BD in which concurrent SGA use was documented
Baldessarini et al, 200854 Commercial claims
[2001–2005]
N=7406 (55.4% BD-I) – 48% to 49% (SGA + any psychotropic) Range for initial and final treatment over 1 year
Baldessarini et al, 200835 Cross-sectional study
[2005]
N=429 (79.0% BD-I) – 76.2% (any combination ≥2 psychotropics)
20.0% (>3 psychotropics)
11.2% (antipsychotic + MS) Combination treatment reported at study baseline
Brooks et al, 201118 STEP-BD study
[1998–2005]
n=1958 (72% BD-I) 8.3% – Calculated (162/1958 [patients prescribed >1 SGA/patients prescribed ≥1 SGA during the study])
Chen et al, 201330 Commercial, Medicare and Medicaid claims
[2002–2008]
N=16,807 (BD-I) 1% (baseline)
4.2% (during the study) –
Goldberg et al, 200938 STEP-BD study
[1998–2005]
n=4035 (66% BD-I) – 38% (SGA + ≥3 any psychotropic) Study refers to the use of ≥4 psychotropic medications as a “complex regimen”
Guo et al, 200855 Commercial claims
[1998–2002]
N=67,862 (BD) – 25.3% (SGA +MS)
Jing et al, 201120 Medicaid claims
[2003–2008]
n=22,479 (BD) 4% to 6% 59% to 68% (SGA + ADT)
17% to 31% (SGA +MS) Rates varied by individual SGA treatment group
Kim et al, 201122 Commercial claims
[2003–2006]
n=7169 (BD) – 67.6% to 77.9% (SGA + MS) Rates varied by individual SGA treatment group
Lang et al, 201131 Medicaid claims
[2004–2006]
n=9410 (BD-I) – 78% (SGA + ADT)
68% (SGA + MS)
53.6% (SGA + anxiolytic) Data reported for the oral SGA treatment group only
Qiu et al, 200925 Medicaid claims
[2000–2005]
N=838 (BD) 2% to 5% – Rates of SGA augmentation over the 1-year evaluation period
Qiu et al, 201056 Medicaid claims
[2000–2005]
N=3328 (BD) – 43.4% (SGA + MS)
Rascati et al, 201124 Medicaid claims
[2002–2008]
n=2446 (BD) – 57% (SGA + MS)
Tohen et al, 201726 Commercial claims
[2012–2014]
n=3329 (BD) 6.7% to 23% 5% to 7.7% (SGA + MS) Rates varied by individual SGA treatment group
Abbreviations: ADT, antidepressant therapy (any); BD, bipolar disorder; BD-I, bipolar I disorder; MS, mood stabilizer therapy; SGA, second-generation antipsychotic; STEP-BD, Systematic Treatment Enhancement Program for Bipolar Disorder.
Combination treatment with SGAs and another class of psychotropic medication was reported more frequently than SGA combination treatment, with rates that ranged from 5% to 78%. Different sample characteristics and inclusion criteria associated with concomitant treatments at baseline contributed to the wide range reported.22,26 Complex combination treatment (ie, four or more bipolar disorder-related psychotropic medications concomitantly) was reported among 38% of patients receiving a SGA regimen in the STEP-BD study.38
HCRU and Costs Associated with Utilization Patterns
Studies reporting the effects of the utilization patterns observed with SGAs on HCRU and costs are summarized in Table 7. Generally, patients with lower antipsychotic adherence were at greater risk of hospitalizations and emergency room visits;31,39 conversely, those who had higher rates of adherence had lower risks of hospitalization39,40 and lower outpatient psychiatric care expenditures.32 Having an MPR ≥0.75 after a year of treatment was associated with lower risk of all-cause (OR=0.730) and psychiatric-related rehospitalizations (OR= 0.759). Additionally, improvements in MPR above the 75% threshold further decreased odds of both types of rehospitalization.40 Similarly, bipolar disorder patients with greater adherence to antipsychotic medication also had lower subsequent total and outpatient psychiatric care expenditures driven by decreased risk of requiring acute mental health care (ie, hospitalization, ER visit). Among patients with predominately manic/mixed symptoms followed over 15 months, a single-point increase in MPR was significantly associated with a $192-$686 quarterly reduction in total expenditures and a $112-$583 quarterly reduction in outpatient psychiatric care over every 3-month period of treatment (2018 USD). This inverse relationship between MPR and mental health care expenditures (total and outpatient) was also observed for patients with predominantly depressive symptoms; however, this association was significant in only one of the 3-month treatment periods (months 10 to 12).32 In addition, in a study of Medicaid patients receiving oral or injectable antipsychotic medications over a 1-year period, those with suboptimal adherence (MPR<0.8) were more likely than adherent patients to have an all-cause ER visit (73% vs 57%) or hospitalization (42% vs 37%), respectively.31Table 7 Utilization Patterns with SGAs Associated with Increased HCRU or Costs
Study Data Source
[Study Period] Sample HCRU/Cost Findings
Bagalman et al, 201029 Commercial claims from the MarketScan research database [2001–2004] n=1258
Employees with BD who had ≥1 claim for mood stabilizer or SGA therapy (oral SGA was the index BD medication for 30.6% of the sample) Employees receiving BD medication who had a MPR <0.8 had incrementally higher adjusted indirect costs over 1 year for increased claims due to absence from work (+$1156), short-term disability (+$427), and workers’ compensation (+$541) compared to those with those who were adherent (MPR ≥0.8).
Brooks et al, 201118 STEP-BD study
[1998–2005] n=1958
Longitudinal cohort of BD patients (72% BD-I) who were prescribed ≥1 SGA medication Over 21 months, patients receiving ≥2 SGA concurrently reported greater use of medical and mental health related HCRU compared to those receiving SGA monotherapy.
BD-I patients receiving ≥2 SGAs had 80% more general medical HCRU (3.6 v. 2.0) and more than twice the mental health-related HCRU (6.4 vs 2.1) than patients taking SGA monotherapy.
Gianfrancesco et al, 200832 Commercial claims from the PharMetrics database
[1999–2004] n=8770 treatment episodes* (70% predominately manic/mixed symptoms)
Patients with BD or manic disorder receiving SGA or FGA monotherapy, evaluated in 3-month segments The risk of acute mental health care (hospitalization or ER visit) at the end of treatment was reduced by 2.6% in the M/M cohort for each additional month of antipsychotic treatment.
In M/M individuals, a 1-point increase in MPR (over 3 months) was associated with a $192 to $686 quarterly reduction in total expenditures and a $112 to $583 quarterly reduction in outpatient mental health care over subsequent quarters of treatment.
Hassan and Lage, 200940 Commercial claims from the PharMetrics database
[2000–2006] n=1973
BD patients who received outpatient antipsychotic prescription within 2 weeks of hospital discharge Discharged patients prescribed antipsychotics who had higher MPR, had lower risk of rehospitalization over 1 year.
Patients who achieved MPR ≥0.75 had significantly decreased odds of rehospitalization for any cause (OR=0.730), and significantly decreased odds of mental health-related rehospitalization (OR=0.759).
Lage and Hassan, 200939 Commercial claims from the PharMetrics database
[2000–2006] n=7769
BD patients with ≥1 claim for antipsychotic medication Over 1 year, higher antipsychotic MPR was associated with lower risk of hospitalization and ER visit.
Patients who achieved MPR ≥0.75 had significantly lower odds of all-cause hospitalization (OR=0.85) and those with MPR ≥0.8 had a significant reduction in the odds of a psychiatric-related hospitalization (OR=0.82).
Lang et al, 201131 Medicaid claims from the MarketScan research database [2004–2006] n=9410
Patients with BD-I who received ≥1 antipsychotic prescription for oral or injectable SGA or FGA Over 1 year of follow-up, patients with suboptimal adherence (vs MPR ≥0.8) had higher rates of acute HCRU (ER visits and hospitalizations).
ER visits, all-cause: 72.5% vs 57.4%ER visits, psychiatric: 30.0% vs 23.5%Hospitalization, all-cause: 38.8% vs 33.5%Hospitalization, psychiatric: 35.5% vs 30.9%
Notes: *Treatment episode was defined as period consisting of ≥2 sequential antipsychotic prescriptions.
Abbreviations: BD, bipolar disorder; BD-I, bipolar I disorder; ER, emergency room; FGA, first-generation antipsychotic (also known as typical antipsychotics; HCRU, health care resource use; MPR, medication possession ratio; OR, odds ratio; SGA, second-generation antipsychotic; STEP-BD, Systematic Treatment Enhancement Program for Bipolar Disorder.
Increased use of both general medical and psychiatric services was reported for patients receiving SGA combination treatment (use of ≥2 SGAs concurrently) compared to SGA monotherapy in a longitudinal cohort study over a mean follow-up duration of 21 months. BD-I patients with SGA combination treatment had 80% more general medical service visits (3.6 vs 2.0 visits) and more than twice the psychiatric treatment visits (6.4 vs 2.1 visits) than patients receiving SGA monotherapy. Regression analyses that included factors considered proxies for illness severity (eg, age, illness duration, and use of other psychotropic medications) confirmed there was an independent association between SGA combination treatment and medical and psychiatric HCRU.18
Discussion
Since 2000, expanded approval of SGAs to treat bipolar disorder has led to their increased use in the clinical management of manic and mixed acute episodes, and as a maintenance treatment, relative to traditional mood stabilizers. Prescribing trends reported in this review10,11,16 align with a recent US analysis of National Ambulatory Medical Care Survey (NAMCS) data that found SGA prescriptions in the outpatient setting grew from 12.4% to 51.4% over the periods from 1997 to 2000 and 2013 to 2016, respectively. Meanwhile, during these same 4-year periods, use of traditional mood stabilizers, such as lithium, valproate, and carbamazepine/oxcarbazepine, declined substantially from 62.3% to 26.4%.9
A greater proportion of outpatient visits may include prescriptions for SGA treatment than traditional mood stabilizers; yet, treatment prevalence rates for bipolar disorder in the US remain low.41 In a recent epidemiological study for example, the 12-month treatment rate for BD-I was 46%.2 Among those who do receive any type of oral medication, adherence (MPR ≥80%) is achieved by roughly 60% of patients.41 This review of real-world studies reported rates of adherence to SGA treatment that were lower still, ranging from 38.9% to as low as 8.3%.30,31 Other notable suboptimal patterns described included use of SGAs outside of, or at the lower end of, therapeutic recommended ranges;24 low rates of persistence,24,30 and long treatment gaps (eg, >30 days).24,31 The majority of these findings were drawn from retrospective analyses of health care claims (72% of studies in this review), which shed little light on reasons for these trends, or the degree to which factors associated with SGA medication (eg, efficacy or tolerability) or other factors (eg, patient or clinical status) may have influenced these findings. This review also highlights a large gap in the knowledge base, underscoring the need for more prospective, real-world research that incorporates input from patients and clinicians to help illuminate what factors may be influencing utilization patterns observed with SGA treatment, as well as their economic impact on patients and health systems.
A common reason for nonadherence to bipolar medication cited in the extant literature is patients’ experience of side effects. Studies exploring factors associated with nonadherence to mood-stabilizing treatment (including antipsychotics) have found that patients’ negative attitudes toward medications,42–44 worry about medication,45 and adverse effects of medication (eg, weight gain, cognitive effects, sedation) contribute to nonadherence.44,46 In a recent study of BD-I patients taking oral antipsychotics, experience of medication side effects was cited as a reason for stopping medication nearly half of the time. When participants were asked to describe the adverse effects of antipsychotics they wanted to avoid most in a new medication, the most common answers were medication-induced anxiety (50%), weight gain (48%), and “feeling like a zombie” (47%).47 Similar findings were reported in this review, with 40% of patients (in a survey) attributing their nonadherence with mood-stabilizing psychotropic medications to side effects, suggesting a need for treatments with better benefit/risk profiles to improve patients’ adherence with medication.
The association between treatment nonadherence and poor clinical/economic outcomes, coupled with evidence that modest improvements in adherence can significantly reduce HCRU and/or costs associated with inadequate symptom control,32,39, call for increased efforts to support patients in maintaining continuous pharmacotherapy. In a 2018 retrospective study, published outside the date range for this review, analyses showed patients newly initiated on antipsychotic medication who were fully adherent (PDC ≥80%) for ≥6 months had significantly lower adjusted rates of psychiatric hospitalization (6.0%) compared to those who were partially adherent (8.3%, PDC ≥40% and <80%) or nonadherent (8.8%, PDC <40%).48 To this end, building upon interventions targeted to other factors associated with nonadherence, such as simplifying medication regimens,38,49,50 programming medication reminders,44,51 and programs to strengthen the patient-clinician therapeutic alliance5,6,44 need to be a research priority as well as part of ongoing clinical management of patients.
This review has several limitations. It considered only studies published between 2008 and 2018, in English, describing US data. Most studies (92%) evaluated data collected prior to 2011; these older data may not reflect contemporary practice patterns. Most studies used pre-DSM-5 definitions of bipolar disorder subtypes. Because DSM-5 criteria broaden the definition of bipolar disorder,52 outcomes reported from studies using earlier DSM criteria may not be representative of current clinical experience. In addition, publications were excluded if they considered fewer than 6 months of treatment, which may have excluded relevant publications. Wherever possible, the primary focus of investigation was BD-I. However, in the absence of relevant research for BD-I populations, evidence related to general bipolar disorder populations was described. Including findings based on individuals across bipolar disorder subtypes could conceivably mischaracterize results as applied to BD-I patients.
There are many treatment options for bipolar disorder; focusing on SGA therapy may limit the degree to which these findings may be applied within the broader treatment landscape. Some of the real-world studies did not break results out by drug class or by SGA agent. This led to some additional limitations. For example, it was not always possible to separate out the effects of individual drug classes on adherence or persistence. Most real-world papers were retrospective analyses of health care claims data; it is well established that data collected for reimbursement are subject to coding errors and sampling issues that can limit the generalizability of the patterns observed. Further, claims provide no direct information from clinicians or patients describing the reasons for initiating/stopping treatment with SGAs (eg, treatment for acute episodes vs maintenance), the planned duration of treatment, choice of dose, or choice to prescribe combination regimens in the real-world setting. Few analyses considered disease severity or complexity; thus, the degree to which severity of bipolar symptoms or medical comorbidities may have influenced the associated data reported are unknown. Finally, although the terminology used to describe adherence and persistence was similar across studies, operational definitions varied, potentially influencing the comparability of findings, as well as the interpretability of reported results. However, the overall focus on real-world evidence was a strength of this review in terms of understanding current clinical practice, its effects on outcomes, and barriers to improved SGA treatment.
Conclusion
SGA treatment is routinely prescribed to treat bipolar disorder, yet reports of suboptimal utilization patterns (ie, nonadherence, nonpersistence, treatment gaps, medication switching, and discontinuation) with SGAs are common. Also common were SGAs prescribed with another psychotropic medication and SGA combination treatment. Of the utilization patterns described in this review, two (suboptimal adherence, SGA combination treatment) were found to have a likely economic impact for patients and the health care system. Both suboptimal adherence and SGA combination treatment were associated with increased HCRU. Additionally, increased direct and indirect medical costs were observed in SGA-treated cohorts with suboptimal adherence. Other utilization patterns with the potential to affect HCRU or costs included nonpersistence, treatment gaps (ie, treatment episodes with one or more periods of no SGA treatment), switching, and early discontinuation of SGA medication; however, cost estimates associated with these patterns were not reported in the identified literature. Strategies to improve treatment continuity, particularly adherence with SGA medications, as well as to reduce the need for combination treatments may improve clinical and economic outcomes among people living with bipolar disorder.
Acknowledgments
The authors thank Nancy Neil, PhD (Worldwide Clinical Trials, Inc., USA), who assisted in the planning and conduct of the literature searches and analyses. Medical writing and editorial support for the preparation of the manuscript, under the direction of the authors, was provided by Jo Whelan, MSc (Textpharm Limited, UK) and was funded by Alkermes, Inc. In October of 2019, data included in this manuscript were presented as a poster at the Academy of Managed Care Pharmacy (AMCP) NEXUS 2019 annual meeting in National Harbor, Maryland. The poster’s abstract was published in “Meeting Abstracts” in Journal of Managed Care & Specialty Pharmacy, Supplement Vol 25(10-a): https://www.jmcp.org/doi/pdf/10.18553/jmcp.2019.25.10-a.s1.
Author Contributions
All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.
Disclosure
Leona Bessonova, Michael J. Doane, and Amy K. O’Sullivan are employees of Alkermes, Inc.; Leona Bessonova and Amy K. O’Sullivan may own stock/options in the company and Michael J. Doane owns Alkermes, Inc stock. Kristine Ogden is an employee of Worldwide Clinical Trials, Inc., which has received consulting fees from Alkermes, Inc. for conducting this study. Leona Bessonova reports personal fees from Alkermes Inc., outside the submitted work. Mauricio Tohen was an employee of Lilly (1997 to 2008) and has received honoraria from or consulted for Abbott, AstraZeneca, Alkermes, Allergan, Bristol-Myers Squibb, GlaxoSmithKline, Intracellular Therapies, Lilly, Johnson & Johnson, Otsuka, Merck, Gedeon Richter Plc, Sunovion, Forest, Roche, Elan, Lundbeck, Teva, Pamlab, Minerva, Neurocrine, Pfizer, Wyeth and Wiley Publishing; his spouse was a full time employee at Lilly (1998–2013). | ARIPIPRAZOLE | DrugsGivenReaction | CC BY-NC | 33623386 | 19,918,294 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypersensitivity'. | Labor Epidural in a Patient Who is Allergic to Lidocaine: A Case Series.
Continuous epidural anesthesia is considered the best modality for pain relief during labor, local anesthetic allergy is an uncommon occurrence but if a patient has an allergy to bupivacaine or lidocaine owing to its cross-reactivity with bupivacaine then it becomes very challenging to manage labor analgesia. A direct challenge test to rule out actual hypersensitivity was not considered a viable option given the risks involved if a severe allergic reaction occurred with the test dose. Using IV opioid-based analgesia has harmful effects for both mother and the baby in addition to decreasing participation of mothers in the birthing process owing to its sedative properties. We report two cases where the mother had a history of lidocaine allergy, so labor analgesia was managed using chloroprocaine patient-controlled epidural analgesia (PCEA).
Introduction
Local anesthetics are very commonly used drugs. Lidocaine after being first manufactured in 1943 is still extensively used with a good safety record if given in prescribed dose. Hypersensitivity reaction to local anesthetics are rare and many adverse reactions are mislabeled as an allergic reaction.3 Local anesthetics are primarily of two types amino amides and amino esters. Both lidocaine and bupivacaine are amino amides and share some cross-reactivity concerning allergic reactions.3 Our patients had an allergic reaction to the amino amide class of local anesthetic namely lidocaine, so we decided to use an amino ester local anesthetic chloroprocaine instead. The use of chloroprocaine in PCEA is not a widely accepted practice and is mostly documented in case reports or small series. Mention of chloroprocaine safe usage in literature may prompt its wider usage.
Case 1
A 25-year-old G2P1 parturient with no major co-morbidity except for the history of lidocaine allergy in childhood presented to our hospital with 37 weeks’ gestation in an active phase of labor. She did not remember the exact details of allergic reaction as it “occurred in childhood”. Her airway exam was reassuring. Though direct challenge can be tried with non-proven local anesthetic allergy,4 or skin testing, it was not planned considering the risk for the mother and the baby in case of anaphylaxis. We discussed at length the possible pain relief modalities including the risk and benefits of chloroprocaine PCEA and remifentanil intravenous (IV) patient-controlled analgesia (PCA). The patient opted for chloroprocaine PCEA after understanding the risks and the benefits. Standard ASA monitors were applied, an 18G IV was placed, and the patient was prepared for the procedure with the code cart in the labor room. The obstetric team was made aware to be on standby if anaphylaxis occurred and stat delivery of the fetus was necessary. We performed skin testing with 0.1 mL of chloroprocaine subcutaneously, followed by 0.5mL and 1 mL of the same, no allergic reactions were noted, and the vital signs were stable 2 mL of chloroprocaine 1.5% (Nescaine MPF) was used to numb the skin. The epidural catheter placement was performed easily, and 8 mL of chloroprocaine 1.5% was used as a loading dose. A pump for patient-controlled epidural analgesia (PCEA) at a basal rate of 12 mL/hr of chloroprocaine 1.5%+ fentanyl 2mcg/mL with optional boluses of 5 mL every 20 minutes was started. She was closely monitored for any symptoms of allergic reactions. She was comfortable, with no symptoms of allergic reactions, and had a spontaneous vaginal delivery, after eight hours without issues. Mother and baby were discharged home on the third postpartum day. Our patient was advised to visit an allergist six months post-delivery.
Case 2
A 36-year-old G2P1 parturient with a history of gastroesophageal reflux disease with the fetus in a cephalic presentation in an active phase of labor requested labor analgesia. She reported a history of swelling of the throat on lidocaine gargle years prior. She had reassuring airway, cardiac, liver, lung, and kidney functions. The patient decided to proceed with the epidural analgesia using chloroprocaine for pain relief, after discussing the options available. The code cart was kept in the room, and the obstetric team was made aware. The epidural catheter placement was done and a pump for patient-controlled epidural analgesia (PCEA) at a basal rate of 12 mL/hr of chloroprocaine 1.5%+ fentanyl 2mcg/mL with optional boluses of 5 mL every 20 minutes was started. However, the patient reported severe back spasm, which she described as burning pain deep in the muscles and was not willing for the continuation of epidural boluses of chloroprocaine. After a total of 30 mL was infused PCEA was discontinued. After an hour, the Ob team treated her with intermittent doses of Stadol (nalbuphine). The patient was comfortable with the intermittent boluses of nalbuphine, and she delivered a healthy baby after ten hours.
Discussion
Epidural anesthesia is considered the best modality for labor analgesia.1,2 With intravenous opioid-based analgesia marred with lesser pain relief and a higher rate of adverse effects.4–7 True allergy to local anesthetic is not common.8 Allergic reaction is commonly triggered by preservative methylparaben, para-aminobenzoic acid which is a metabolite of the amide group of local anesthetics, or ester or amide component.9–11
If allergy to local anesthetic is reported it is very important to evaluate it further pre-conception or early in pregnancy. First is a careful history as symptoms like palpitations, vasovagal attacks, and anxiety during the IV injections can be mistaken for allergic reactions by the patient.8 A detailed history should be elicited for true allergic reactions like rashes, bronchospasm, urticarial, angioedema, and cardiovascular collapse.8 If allergy to lidocaine is true, bupivacaine cannot be used as it is also an amide group local anesthetic and has cross-reactivity with lidocaine2 though the exact rate is not known. Skin testing or challenge dose of local anesthetic can be used4 and would have been ideal if this patient was reviewed pre-conception or in the second trimester.
Chloroprocaine is a fast-acting local anesthetic with a short duration of action and belongs to the ester group with no cross-reactivity to lidocaine which is an amide. It is rapidly hydrolyzed by plasma esterases. Chloroprocaine is very rarely used in labor epidural anesthesia possibly due to the possibility of cauda equina syndrome and arachnoiditis with unintentional intrathecal administration.12 Now the preservative-free chloroprocaine is being used as a spinal anesthetic without complications.13
The dosing of chloroprocaine has not been standardized yet and we used the dose used by Lee14 though lower dosing has been recommended by Coffman et al.15 As a conclusion, we would say that local anesthetic allergy is reported it should be evaluated early and in pregnancy and chloroprocaine, epidural analgesia is an underutilized modality of pain relief. We would also agree with Coffman et al to decrease the dosing needed to further increase the safety profile and think that it should be further evaluated to standardize the dosing regimen. The downside of the chloroprocaine is the back muscle spasms as in our case 2 and the unintended motor blockade which could be uncomfortable for the patient. Muscle spasms are more common with chloroprocaine containing EDTA as a preservative with doses of more than 40mL. In our patient, a total of 30mL was used before it was discontinued.
Conclusion
Appropriate alternative medications can be used only if we understand the basic pharmacology of the medications. It is crucial to elicit a detailed history regarding the allergic reaction as we can rule out the side effects of the medications which could be misinterpreted as an allergic reaction by the patients. Clinicians should be aware of the necessity of the proper evaluation of the patients who report a local anesthetic allergy to an allergist and an anesthesiologist early in pregnancy.
Acknowledgment
We appreciate the input of Dr. Minal Joshi.
Consent Statement
Both the patient’s informed consent was obtained for the publication of the report. Study was approved for publication by New York-Presbyterian Brooklyn Methodist Hospital institutional review committee.
Disclosure
None of the authors have any conflicts of interest to disclose. | LIDOCAINE | DrugsGivenReaction | CC BY-NC | 33623428 | 19,810,909 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pharyngeal swelling'. | Labor Epidural in a Patient Who is Allergic to Lidocaine: A Case Series.
Continuous epidural anesthesia is considered the best modality for pain relief during labor, local anesthetic allergy is an uncommon occurrence but if a patient has an allergy to bupivacaine or lidocaine owing to its cross-reactivity with bupivacaine then it becomes very challenging to manage labor analgesia. A direct challenge test to rule out actual hypersensitivity was not considered a viable option given the risks involved if a severe allergic reaction occurred with the test dose. Using IV opioid-based analgesia has harmful effects for both mother and the baby in addition to decreasing participation of mothers in the birthing process owing to its sedative properties. We report two cases where the mother had a history of lidocaine allergy, so labor analgesia was managed using chloroprocaine patient-controlled epidural analgesia (PCEA).
Introduction
Local anesthetics are very commonly used drugs. Lidocaine after being first manufactured in 1943 is still extensively used with a good safety record if given in prescribed dose. Hypersensitivity reaction to local anesthetics are rare and many adverse reactions are mislabeled as an allergic reaction.3 Local anesthetics are primarily of two types amino amides and amino esters. Both lidocaine and bupivacaine are amino amides and share some cross-reactivity concerning allergic reactions.3 Our patients had an allergic reaction to the amino amide class of local anesthetic namely lidocaine, so we decided to use an amino ester local anesthetic chloroprocaine instead. The use of chloroprocaine in PCEA is not a widely accepted practice and is mostly documented in case reports or small series. Mention of chloroprocaine safe usage in literature may prompt its wider usage.
Case 1
A 25-year-old G2P1 parturient with no major co-morbidity except for the history of lidocaine allergy in childhood presented to our hospital with 37 weeks’ gestation in an active phase of labor. She did not remember the exact details of allergic reaction as it “occurred in childhood”. Her airway exam was reassuring. Though direct challenge can be tried with non-proven local anesthetic allergy,4 or skin testing, it was not planned considering the risk for the mother and the baby in case of anaphylaxis. We discussed at length the possible pain relief modalities including the risk and benefits of chloroprocaine PCEA and remifentanil intravenous (IV) patient-controlled analgesia (PCA). The patient opted for chloroprocaine PCEA after understanding the risks and the benefits. Standard ASA monitors were applied, an 18G IV was placed, and the patient was prepared for the procedure with the code cart in the labor room. The obstetric team was made aware to be on standby if anaphylaxis occurred and stat delivery of the fetus was necessary. We performed skin testing with 0.1 mL of chloroprocaine subcutaneously, followed by 0.5mL and 1 mL of the same, no allergic reactions were noted, and the vital signs were stable 2 mL of chloroprocaine 1.5% (Nescaine MPF) was used to numb the skin. The epidural catheter placement was performed easily, and 8 mL of chloroprocaine 1.5% was used as a loading dose. A pump for patient-controlled epidural analgesia (PCEA) at a basal rate of 12 mL/hr of chloroprocaine 1.5%+ fentanyl 2mcg/mL with optional boluses of 5 mL every 20 minutes was started. She was closely monitored for any symptoms of allergic reactions. She was comfortable, with no symptoms of allergic reactions, and had a spontaneous vaginal delivery, after eight hours without issues. Mother and baby were discharged home on the third postpartum day. Our patient was advised to visit an allergist six months post-delivery.
Case 2
A 36-year-old G2P1 parturient with a history of gastroesophageal reflux disease with the fetus in a cephalic presentation in an active phase of labor requested labor analgesia. She reported a history of swelling of the throat on lidocaine gargle years prior. She had reassuring airway, cardiac, liver, lung, and kidney functions. The patient decided to proceed with the epidural analgesia using chloroprocaine for pain relief, after discussing the options available. The code cart was kept in the room, and the obstetric team was made aware. The epidural catheter placement was done and a pump for patient-controlled epidural analgesia (PCEA) at a basal rate of 12 mL/hr of chloroprocaine 1.5%+ fentanyl 2mcg/mL with optional boluses of 5 mL every 20 minutes was started. However, the patient reported severe back spasm, which she described as burning pain deep in the muscles and was not willing for the continuation of epidural boluses of chloroprocaine. After a total of 30 mL was infused PCEA was discontinued. After an hour, the Ob team treated her with intermittent doses of Stadol (nalbuphine). The patient was comfortable with the intermittent boluses of nalbuphine, and she delivered a healthy baby after ten hours.
Discussion
Epidural anesthesia is considered the best modality for labor analgesia.1,2 With intravenous opioid-based analgesia marred with lesser pain relief and a higher rate of adverse effects.4–7 True allergy to local anesthetic is not common.8 Allergic reaction is commonly triggered by preservative methylparaben, para-aminobenzoic acid which is a metabolite of the amide group of local anesthetics, or ester or amide component.9–11
If allergy to local anesthetic is reported it is very important to evaluate it further pre-conception or early in pregnancy. First is a careful history as symptoms like palpitations, vasovagal attacks, and anxiety during the IV injections can be mistaken for allergic reactions by the patient.8 A detailed history should be elicited for true allergic reactions like rashes, bronchospasm, urticarial, angioedema, and cardiovascular collapse.8 If allergy to lidocaine is true, bupivacaine cannot be used as it is also an amide group local anesthetic and has cross-reactivity with lidocaine2 though the exact rate is not known. Skin testing or challenge dose of local anesthetic can be used4 and would have been ideal if this patient was reviewed pre-conception or in the second trimester.
Chloroprocaine is a fast-acting local anesthetic with a short duration of action and belongs to the ester group with no cross-reactivity to lidocaine which is an amide. It is rapidly hydrolyzed by plasma esterases. Chloroprocaine is very rarely used in labor epidural anesthesia possibly due to the possibility of cauda equina syndrome and arachnoiditis with unintentional intrathecal administration.12 Now the preservative-free chloroprocaine is being used as a spinal anesthetic without complications.13
The dosing of chloroprocaine has not been standardized yet and we used the dose used by Lee14 though lower dosing has been recommended by Coffman et al.15 As a conclusion, we would say that local anesthetic allergy is reported it should be evaluated early and in pregnancy and chloroprocaine, epidural analgesia is an underutilized modality of pain relief. We would also agree with Coffman et al to decrease the dosing needed to further increase the safety profile and think that it should be further evaluated to standardize the dosing regimen. The downside of the chloroprocaine is the back muscle spasms as in our case 2 and the unintended motor blockade which could be uncomfortable for the patient. Muscle spasms are more common with chloroprocaine containing EDTA as a preservative with doses of more than 40mL. In our patient, a total of 30mL was used before it was discontinued.
Conclusion
Appropriate alternative medications can be used only if we understand the basic pharmacology of the medications. It is crucial to elicit a detailed history regarding the allergic reaction as we can rule out the side effects of the medications which could be misinterpreted as an allergic reaction by the patients. Clinicians should be aware of the necessity of the proper evaluation of the patients who report a local anesthetic allergy to an allergist and an anesthesiologist early in pregnancy.
Acknowledgment
We appreciate the input of Dr. Minal Joshi.
Consent Statement
Both the patient’s informed consent was obtained for the publication of the report. Study was approved for publication by New York-Presbyterian Brooklyn Methodist Hospital institutional review committee.
Disclosure
None of the authors have any conflicts of interest to disclose. | LIDOCAINE | DrugsGivenReaction | CC BY-NC | 33623428 | 19,831,955 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anaemia'. | Effect of Cisplatin Arterial Infusion (CAI) on Primary Nonmetastatic Pelvic Osteosarcoma: A Preliminary Study.
The critical role of arterial infusion chemotherapy in the multimodal treatment of extremity bone cancer has been investigated extensively, but few studies have focused on pelvic osteosarcoma. Therefore, we attempted to evaluate the clinical significance of arterial infusion chemotherapy in the treatment of pelvic osteosarcoma.
We combined a cisplatin arterial infusion regimen with multidrug systematic chemotherapy as a neoadjuvant protocol for the treatment of pelvic osteosarcoma. The course number and dosage of cisplatin arterial infusion were adjusted to achieve a maximal tumor response evaluated by contrast-enhanced MRI per RECIST 1.1. Good responders received the same systematic combination for postoperative chemotherapy, and poor responders received second-line therapy. Twelve patients with nonmetastatic high-grade pelvic osteosarcoma were included. Survival, chemotherapy response and adverse events data were analyzed.
The mean follow-up period was 56.1 months. Four patients died of refractory tumor progression, and 1 patient with local recurrence had no evidence of disease for 27 months after receiving secondary amputation and resection. Kaplan-Meier survival analysis demonstrated a 57.8% overall survival and 52.5% event-free survival rate at 5 years. Eight of 12 patients had a >90% tumor necrosis rate according to histopathologic examinations. The rates of local adverse events were lower than those reported for extremity osteosarcoma.
Our study initially indicated that the cisplatin arterial infusion regimen was a potential therapy with good tolerance in the treatment of pelvic osteosarcoma.
Introduction
Osteosarcoma is the most common solid malignant tumor of bone with a highly aggressive behavior.1 The most susceptible age of osteosarcoma is bimodal, which is characterized by one peak at 10-to-20 years and another at over 60 years.2,3 Although this disease endangers the health of both adolescent and aged populations, limited progress has been made to improve survival and functional prognosis, especially in patients with pelvic osteosarcoma.4–6 Osteosarcoma patients treated with mere immediate surgical resection register a recurrence rate up to 60–90%.7 (Since 1980s, traditional adjuvant intravenous (IV) systematic chemotherapy produces an improved five-year event-free survival (EFS) rate of 61%.8 In the early 2000s, the propagation of a multidrug neoadjuvant chemotherapy regimen elevated this rate to 60% and above.9,10) Henceforth, numerous explorations have been conducted to optimize the category, dosage, combination and duration of chemotherapy drug administration. The most recent studies of EURAMOS revealed a 5-year EFS of 65–70% for localized osteosarcoma treated by multidrug neoadjuvant chemotherapy. However, there are few studies focusing on arterial infusion as an improved method and its clinical outcome in the treatment of pelvic osteosarcoma.
Osteosarcoma in pelvic bone is more notorious than that in extremities. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate than those with extremity lesions, which may be associated with a poor chemotherapy response and an inability to achieve adequate surgical resection.11 Therefore, more challenges are faced in the management of pelvic osteosarcoma.
Platinum complexes, such as cis-diamine-dichloro platinum (cisplatin, CDDP), have been proven to be cell cycle-nonspecific agents and to have multiple broad-spectrum antitumor effects.12 Several clinical trials reported that employing an arterial infusion technique to deliver CDDP, in combination with an IV systematic chemotherapy regimen or not, can elevate the local drug concentration to fivefold that of IV administration and can produce better survival in the treatment of extremity osteosarcoma.13–15 Therefore, the arterial infusion of CDDP might have potential in the treatment of pelvic osteosarcoma.
The histopathologic response of surgically removed tumors has been shown to be one of most critical indicators of chemotherapeutic effectiveness and survival prognosis.16,17 However, preoperative examination is more valuable to predict tumor response and allow individualized neoadjuvant chemotherapy. Response evaluation criteria in solid tumors version 1.1 (RECIST 1.1), which was commonly adopted for the tumor-response evaluation of a variety of cancers, affirmed the value of sectional radiological imaging measurement.18–20 Therefore, preoperative contrast-enhanced MRI (CE-MRI) evaluation based on RECIST 1.1 is expected to guide the adjustment of treatment for optimal surgical timing in pelvic osteosarcoma.
Given all these findings, we combined CDDP arterial infusion (CAI) with individualized multidrug systematic chemotherapy (MSC) and surgery (S) to treat nonmetastatic pelvic osteosarcoma and attempted to investigate (1) the chemotherapy response and survival yielded from this protocol, (2) the individualized adjustment of the neoadjuvant MSC regimen necessary to achieve the maximal tumor response according to RECIST-1.1-based CE-MRI reassessment, and (3) the potential adverse effects caused by the arterial infusion technique and the multidrug systematic chemotherapy regimen.
Patients and Methods
Study Design and Consent
This is a retrospective cohort study (Level III evidence) in which subjects received a protocol comprising multidrug systematic chemotherapy, cisplatin arterial infusion and resection surgery (CAI + MSC + S). The study design conformed with the Declaration of Helsinki, and the treatment protocol was approved by the hospital institutional review board. All patients provided written informed consent for receiving this treatment protocol. All data used in the present study were obtained from the electronic medical records of our hospital and treated with strict confidentiality; therefore, the requirement of obtaining specific informed consent for this retrospective study was waived.
Patients
Inclusion criteria for subjects included (1) histopathologically defined primary osteosarcoma of pelvic bone; (2) no metastatic foci; (3) no past history of cancer treatment; and (4) normal cardiac, hepatic and renal function. All patients were confirmed to have high-grade osteosarcoma morbidity via biopsy. Pretreatment baseline safety indexes were determined with routine blood tests, hepatic and renal function tests, and Doppler echocardiography. A peripherally inserted central catheter was placed in each patient for the IV administration of neoadjuvant chemotherapy agents.
From January 2010 to June 2015, 21 patients were consecutively diagnosed with osteosarcoma of the pelvic bones in our work unit. A total of 4 patients were excluded for the following reasons: 2 patients had evidence of distant metastasis, and 2 tumors involved the femur or lumbar vertebra. Among the eligible people, 2 refused to take CAI + MSC + S treatment: 1 had hemophilia with severely impaired coagulation function; 1 intended to transfer to another hospital after being definitively diagnosed via biopsy. Subsequently, 15 patients took the CAI + MSC + S treatment, but 1 of them stopped midway (because of intolerance to vomiting as the adverse effect in the first two rounds of IV multidrug therapy) and turned to other treatment. Two patients were lost to follow-up after surgical resection. Eventually, 12 patients finished the treatment protocol and yielded analyzable data for survival, chemotherapy response and toxicity assessment.
The data of these 12 patients are listed in Table 1. The study population consisted of 7 (58.3%) males and 5 (41.7%) females with an average age of 28.8 years (11 to 69 years). The morbid sites included the pubis (n = 2), ilium (n = 4), ischium (n = 1), sacrum (n = 1) and unclear sites (n = 4).Table 1 Patient Data
Case No. Age (y) Sex Tumor Size (cm) Morbid Site MRI Tumor Response Before Surgery Surgical Margins Histopathologic Response Diagnosis Date Surgery Type Follow-Up (Month) First Relapse Status
1 62 F <8 Unclear +27.4%, PD R0 <90% 5/19/2010 1 42 CDF
2 19 M <8 Ilium −35.1%, PR R0 >90% 10/4/2010 2 46 Jan. 2014 DOD
3 14 M <8 Unclear +14.6%, SD R0 95% 7/23/2011 2 52 CDF
4 53 F >8 Sacrum −7.3%, SD R1 <90% 6/30/2012 4 57 Feb. 2015 NED
5 15 M <8 Ilium −32.7%, PR R0 >90% 10/28/2012 2 93 CDF
6 21 F 7 Ilium +25.9%, PD R0 >90% 4/24/2013 2 87 CDF
7 16 M >8 Unclear +8.6%, SD R1 <90% 9/22/2013 2 37 Aug. 2015 DOD
8 36 F 9 Pubis −24.1%, SD R0 >90% 4/14/2014 2 76 CDF
9 69 M 12 Ischium +43.7% PD R1 <90% 5/17/2014 3 15 Jan. 2015 DOD
10 12 F <8 Unclear −37.4%, PR R0 99% 8/21/2014 2 72 CDF
11 41 M <8 Pubis +33.5%, PR R0 >90% 3/6/2015 2 34 CDF
12 47 M <8 Ilium +16.6%, SD R0 95% 6/30/2015 2 62 Dec. 2019 DOD
Notes: Surgical type = 1) primary lower limb amputation; 2) lower limb salvage surgery; 3) secondary amputation and reresection due to local recurrence; 4) revision surgery due to periprosthetic infection.
Abbreviations: CAI, cisplatin arterial infusion; PR, partial response; PD, progressive disease; SD, stable disease; CAP, cisplatin arterial perfusion; CDF, continuously disease free; NED, no evidence of disease; DOD, died of disease.
Description of the Study Treatments and Outcome Measures
The adopted CAI + MSC + S treatment protocol is depicted in Figure 1. In general, MSCs usually consist of high-dose methotrexate (MTX), vincristine (VCR), adriamycin (ADM), CDDP and ifosfamide (IFO). Specifically, the routine CAI + MSC regimen was initiated with 24-hour continuous IV dripping of high-dose MTX at 10 g/m2 followed by 2 mg IV VCR the next day for the first group at Week 0; in Week 2, 120 mg/m2 CDDP AI over 3 to 6 hours and following 30 mg/m2/d IV ADM for 2 days were given to the second group; these 2 groups were repeated in Weeks 3 and 4; then, the resection surgery was performed 2 weeks after the neoadjuvant chemotherapy was finished. Notably, 160 mg/m2 was determined as the enhanced dosage of CDDP for tumors with the longest diameter over 8 cm in CE-MRI slices. In addition, IV IFO at 2 g/m2/d for 5 days was given in Week 5 for tumors over 8 cm after the 4-week routine regimen was completed. Central venous catheterization for MSC administration was performed under inhalation anesthesia if necessary. Before each CAI regimen, percutaneous punctuation of the femoral artery was performed using the Seldinger technique, and the catheter was inserted from the femoral artery of the contralateral side to the beginning of the artery trunk supplying the tumor with the assistance of CT-guided positioning.21 Then, CT arterial angiography was conducted. Each course of MSC and CAI was accompanied by IV hydration, diuretics, rescue and protecting drugs. The CDDP was perfused via the catheter with chemotherapy pumps (LimLess Infusion Pump; PFM Medical Inc, Cologne, Germany) in a pulsed manner (Bolus dose administrator; PFM Medical Inc, Cologne, Germany). The patients were asked to have strict bed rest under multiparameter monitoring. Routine blood tests for electrolytes and hepatic and renal function were performed on the first day after drug administration and every 3 days thereafter.Figure 1 The individualized pelvic osteosarcoma treatment protocol combined cisplatin arterial infusion, multidrug systematic chemotherapy and resection surgery (CAI + MSC + S).
To evaluate the therapeutic response, primary plain X-ray (Figure 2A) and physical examination parameters of the tumor, including pre- and postchemotherapy size, tenderness, pain and inflammation, were collected. More importantly, CE-MRI was performed to monitor the tumor chemotherapy response before and after routine neoadjuvant CAI + MSC administration. (Figure 2B–E) According to the RECIST 1.1 guidelines, tumor size was calculated in gadolinium-enhancing T1-weighted fat‐saturated coronal images using the following criteria: complete response (CR), complete elimination of target lesion; partial response (PR), ≥30% decrease in the diameter of target lesion compared to baseline); progressive disease (PD), ≥20% increase in the diameter of target lesion compared to baseline or new metastatic lesion); and stable disease (SD) or observed changes in the diameter of the target lesion between 30% decrease and 20% increase compared to baseline. Each tumor lesion was assessed by orthopedic oncologists and interventional radiologists who were blinded to the treatment allocation and clinical outcome data. For patients who achieved PD after the routine neoadjuvant regimen was finished, surgery was performed immediately. For patients who demonstrated CR or PR, surgery was performed 2 weeks after the neoadjuvant regimen as usual. For patients who presented SD, the same IFO course as that mentioned in the adjustment for large tumors was added to maximize the tumor response of the neoadjuvant regimen. Then, a multidisciplinary consultation was conducted to identify the achievement of maximal tumor response. If any uncertainty of maximal response achievement was left, one more course of IFO could be given, and patients received resection surgery no later than 9 weeks after the first diagnosis.Figure 2 (A) Pelvis X-ray of a 36-year-old female with an osteosarcoma in the pubis. (B) and (C) Fat-saturated T1- and T2-weighted coronal slices of contrast-enhanced MRI showing the maximum diameter of the tumor at the first diagnosis, which showed heterogeneous enhancement, thick septa and obscure boundaries of the tumor. (D) and (E) MRI reevaluation after completion of the neoadjuvant CAI + MSC regimen, showing thin septa, clear boundaries and stable disease according to RECIST 1.1 with a decrease in the tumor diameter. (F) Pelvis plain X-ray of this patient. (The identifiable captions in these images are occluded.).
A chest CT scan, a full-body bone scan and a pelvic CE-MRI scan (Figure 2D and E) were repeated before surgery. The tumor response per RECIST 1.1 measured in the last CE-MRI examination was compared with the baseline level. Surgical excision extension was determined by the involved scope of the tumor and the tumor response category according to the CE-MRI assessment per RECIST 1.1. The pelvic reconstruction project depended on the morbidity site, excision extension, bone mineral density and functional requirements.
In case of uncontrollable hemorrhage during the resection surgery, a temporary balloon blocking technique for the abdominal aorta was performed under the guidance of CTA 4 hours before resection surgery. A balloon compatible in size to the abdominal aortic diameter was placed intraarterially at the level of 2 to 3 cm above the bifurcation of the common iliac arteries. The injection of saline with 0.1% heparin inflated the balloon, consequently blocking blood perfusion of the surgical site. Angiography was performed to confirm the satisfactory blockage of the iliac arteries and unobstruction of the renal arteries. Then, the balloon was deflated until the surgery began. Each deflation was performed with an interval of 60 min during the resection surgery before satisfactory hemostasis was achieved.
Histopathologic examination was conducted using the method reported by Huvos et al to quantify the necrosis ratio of the tumor after removal.22 Patients with a ≥90% tumor necrosis rate (TNR) (Grade III and IV) were classified as good responders. The other (Grade Ⅰ and Ⅱ) were deemed poor responders.
The postoperative IV chemotherapy cycle was repeated every 3 weeks. The recovery of hematopoietic function in patients was required before each course, which was defined as a white blood cell count over 1×104/mm3 and a platelet count over 5×106/mm3 for 3 successive days without hematopoietic stimulants. For good responders, the duration of postoperative MSC was usually 3 courses, which could be extended to the maximum of 6 courses accompanied by the existence of high-risk factors, including SD or PD in the CE-MRI per RECIST 1.1 before surgery or histology-proven tumor involvement in the surgical margin (R1 resection). For poor responders, IFO at 2 g/m2/d for 5 days and etoposide (ETOP) at 100 mg/m2/d for 5 days were given sequentially as one cycle repeated every 3 weeks for 6 cycles.23
After the planned treatment was finished, the discontinuation of chemotherapy was allowed by the orthopedic oncologist if X-ray (Figure 2F) and CE-MRI of the primary morbidity site along with chest X-ray every 2 months, chest CT scanning every 6 months in the first year off the treatment prove no local recurrence or lung metastasis. Routine blood tests and hepatic and renal function tests were deployed every week until the recovery of hematopoietic function.
Statistical Analysis
We used the Kaplan-Meier method to analyze the overall survival (OS) and EFS, which were calculated from the day the preoperative MSC + CAI regimen began. The events were defined as local recurrence, distant metastasis or death from the disease. Additionally, the OS and EFS in groups with different histopathologic chemotherapy responses or tumor sizes were calculated. All statistical analyses were conducted with SPSS software packages (SPSS Inc., Chicago, IL, USA).
Results
Chemotherapy Response
Significant improvement in physical examination parameters was observed in 10 of 12 patients after the neoadjuvant regimen, including alleviation of pain. In terms of tumor response measurement per RECIST 1.1, 4 patients had PR and 5 had SD after routine neoadjuvant CAI + MSC administration. Three patients had to undergo resection surgery ahead of schedule because of PD, as shown by CE-MRI after neoadjuvant CAI + MSC administration. No patient demonstrated CR.
According to the histopathologic assessment, 66.7% (8 of 12) of patients demonstrated TNR over 90%. One of the 3 patients with PD according to the CE-MRI assessment turned out to be good responders with Grade III histopathologic results.
Surgery
Three patients underwent local radical excision and lower limb amputation because of neurovascular bundle involvement. The remaining 9 patients received limb salvage surgery followed by pelvic reconstruction using a modular prosthesis (Lidakang Inc., Beijing, China), tumor bone devitalization and replantation, or just bone fusion. As a result, 1 patient who underwent primary limb salvage surgery developed local recurrence and underwent secondary amputation and local reresection. Two patients had surgical site infections but were cured 2 months after surgery. One patient who developed a periprosthetic infection underwent a secondary amputation.
Survival
A total of 58.3% of patients (7 of 12) remained continuously disease free in an average follow-up period of 65.1 months (range, 34–93 months). One patient who developed local recurrence was proven alive with no evidence of disease for 31 months after receiving a secondary amputation and resection. Four patients (3 lung metastases and 1 local recurrence) died of refractory disease progression. Kaplan-Meier survival analysis suggested an OS rate of 57.8% and an EFS of 52.5% at 5 years (Figure 3). For patients with a good chemotherapy response, the 5-year OS and EFS rates were 68.6%, both of which showed significant differences (P = 0.04 for OS and 0.01 for EFS) compared with the corresponding measures for poor responders (Table 2). The comparison of patients with tumor sizes greater (n = 4) or less (n = 8) than 8 cm did not yield statistical significance (P = 0.32 and 0.13, respectively). As shown in the pathological report, 75% (9 of 12) patients received R0 resection and 25% (3 of 12) had R1 resection. There was no significant difference in the OS but in the EFS between patient group with R0 or R1 surgical resection (P = 0.15 and 0.05, respectively). The confidence interval of all OS and EFS are 95%.Table 2 Overall Survival (OS) and Event-Free Survival (EFS) Rate
Variables 1 y 5 y
All patients – OS 91.7% 57.8%
All patients – EFS 91.7% 52.5%
Good responders – OS 100.0% 68.6%
Good responders – EFS 100.0% 68.6%
Poor responders – OS 75.0% 50.0%
Poor responders – EFS 75.0% 25.0%
Patients with tumor size ≥8 cm – OS 75.0% 50.0%
Patients with tumor size ≥8 cm – EFS 75.0% 25.0%
Patients with tumor size<8 cm – OS 100.0% 62.5%
Patients with tumor size<8 cm – EFS 100.0% 64.3%
R0 resection – OS 85.7% 70.0%
R0 resection – EFS 88.9% 71.1%
R1 resection – OS 66.7% 33.3%
R1 resection – EFS 66.7% 33.3%
Note: Confidence Interval = 95%
Figure 3 The Kaplan-Meier survival curve for overall survival (OS) and event-free survival (EFS) rates of 12 pelvic osteosarcoma patients treated with the CAI + MSC + S protocol.
Chemotherapy Toxicity
We recorded the adverse effects referred to in the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.24 The statistics of CAI-related adverse events are summarized in Table 3. Three of 12 patients had local adverse events, including grade 1 to 2 skin pelvic soft tissue necrosis in muscle and hyperpigmentation, which exhibited no effect on the surgical method choice or wound healing. Nausea and vomiting were the most common systematic adverse events, with 41.7% of patients developing grade 3 events. A 36-year-old female received a reduced dosage of MTX (7 g/m2) due to intolerable vomiting after the first MTX course. Four of 12 patients developed grade 1 infusion-related reactions.Table 3 Statistics of CAI-Related Adverse Events
Adverse Events No. of Courses Percentage of Patients with Grade 3–4 Adverse Events
Skin hyperpigmentation 12.5% (3/24) 0% (0/12)
Pelvic soft tissue necrosis (muscle) 4.2% (1/24) 0% (0/12)
Pelvic pain 16.7% (4/24) 8.3% (1/12)
Nausea and vomiting 75.0% (18/24) 41.7% (5/12)
Anemia 8.3% (2/24) 8.3% (1/12)
Increase in creatinine level 8.3% (2/24) 0% (0/12)
Increase in aminotransferase level 4.2% (1/24) 0% (0/12)
Infusion related reaction 29.2% (7/24) 0% (0/12)
During the postoperative MSC period, one 12-year-old child complained of grade 1 palpitations and chest pain. Therefore, we replaced ADM with ETOP, and the complaint disappeared with no evidence reported in Doppler echocardiography. Three patients out of 12 developed grade 1 to 2 increases in alanine/aspartate aminotransferase levels.
Three children developed oral mucositis at grade 2 to 3, 2 of whom were under IV nutrition, and one used a mouth rinse with metronidazole to treat thrush. All patients eventually resumed normal oral food intake.
Blood system disorders were commonly noted in patients after the second cycle of postoperative MSC administration. Three patients developed febrile neutropenia and were treated by injection of recombinant human granulocyte stimulating factor.
Discussion
Conventional IV adjuvant chemotherapy and neoadjuvant chemotherapy have been applied extensively in multimodal osteosarcoma treatment for over 45 years.25 Though changes in drug combination, dosage, and administration duration were made to optimize the regimen, no significant improvement was achieved based on the approximately 50% to 70% 5-year OS and EFS rates in the past decade.26–28 As a modified approach to augment the potential of chemotherapy drugs, the AI technique combined with MSCs has been studied for years.13,29,30 In the present study, we attempted to investigate the therapeutic effect of the CAI + MSC + S protocol in osteosarcoma treatment. The 5-year OS and EFS rates were 57.8% and 52.5%, respectively.
The CAI regimen and its outcome measurements were first documented by Jaffe et al in 1983.31 Then, a series of studies concerning CAI-facilitated multidrug chemotherapy followed.13,30,32–37 Information on all 9 studies, including the present study, is listed in Table 4.Table 4 Synopsis of IA CDDP Information Reported in the Literature
Authors Type of Study No. of Patients Ages (y) Sites Metastases Preoperative CDDP Courses No. >90% TN OS EFS
Winkler et al and Fuchs et al30,34 Nonrandomized, 2 arms 50 <40 All Included 2 68% 67% at 10 y 63% at 10 y
Ferrari et al33 Single arm 164 <40 Extremity Excluded 2 NA 72% at 8 y 63% at 8 y
Ferrari et al33 Randomized, 2 arms 59 <40 Extremity Excluded 2 64% 61% at 8 y 54% at 8 y
Rha et al35 Single arm 37 8~41 Extremity ? 3 75% 78% at 3 y 55% at 3 y
Bacci et al32 Randomized, 2 arms 40 <40 Extremity Included 2 77% NA 26% at 5 y
Bacci et al32 Randomized, 2 arms 72 <40 Extremity Included 2 80% NA 61% at 5 y
Wilkins et al37 Single arm 47 <21 Extremity Excluded 3–5 (response dependent) 87% 92% at 10 y 84% at 10 y
Wilkins et al36 Single arm 62 <22 Extremity Excluded 3–5 (response dependent) 87% 93% at 10 y 86% at 10 y
Xie et al13 Nonrandomized, 2 arms 48 NA Extremity Included 3 63% 64% at 5 y 60% at 5 y
Hu et al (Current study) Single arm 12 11~69 Pelvis Excluded 2 66.7% 57.8% at 5 y 52.5% at 5 y
Abbreviations: IA, intraarterial; CDDP, cisplatin; TN, tumor necrosis; OS, overall survival; EFS, event-free survival.
Among these 9 studies, 8 used CAI and systematic chemotherapy sequentially before surgery, and 5 studies scheduled a 2-course preoperative regimen. Six of 9 studies suggested a higher chemotherapy response rate and/or survival rate in the CAI group compared with the IV CDDP group; 2 of these investigations were 2-arm randomized cohort studies and reported a statistically significant improvement in the good-response ratio (21% and 31%, respectively). In the third randomized cohort study reported by Rha et al, the improvement was not statistically significant, probably because the limited sample size was insufficient to test the 9% difference between the two groups.35 In the multicenter study reported by Winkler et al and Fuchs et al in the 1990s, no difference in chemotherapy response was observed between the intraarterial and IV CDDP groups.30,34 Similarly, Xie et al also proved a superior histological response rate but equivalent survival in the CAI group versus the IV group in 2019.13 However, the reliability of the conclusions in the 2 studies may be impaired by the nonrandomized grouping design conducted at the researchers’ discretion, which could be affected by the severity of disease. Although CAI may bring benefits to chemotherapy response augmentation and survival rates in limb osteosarcoma patients, how pelvic osteosarcoma reacts to CAI-facilitated multidrug chemotherapy remains elusive.
Pelvic tumor resection surgeries such as hemipelvectomy are notoriously known as one of the most destructive operations in modern orthopedic surgery.38 Due to the adjacency of the vascular network, nerves and viscera in the pelvis, surgeons have to weigh tumor eradication against functional preservation in the determination of the extent of surgical excision. This dilemma makes the treatment more challenging. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate compared with the extremity-morbidity population, which could be explained by the higher rate of not only failure of surgical remission but also advanced age, large tumor size, primary metastasis, prolonged latency periods and poor chemotherapy responses.11,39 Thus, it is critical to maximize the chemotherapy response and achieve better survival outcomes in pelvic osteosarcoma patients.
The combination of agents in our MSC protocol was determined by reference to NCCN guidelines for bone cancer and the study reported by Xie et al.13 Although the agent numbers and categories differed, all of the above-reviewed studies and the present study deployed a multidrug protocol to treat tumor cells in different phases of the cell cycle. Unfortunately, insufficient data are available to appropriately compare the therapeutic effect of CAI alone or in various combinations with MTX, VCR, ADM and IFO because of great heterogeneity. In the present study, we used high-dose MTX at 10 g/m2 and CAI at 120 mg/m2 in 2 doses as routine preoperative treatment. For patients with tumors over 8 cm, we employed an enhanced dose of CAI at 160 mg/m2. Additionally, additional IFO courses were given to slow responders. This individualized regimen directly yielded a 66.7% prevalence of good histopathologic responders and contributed to the 5-year survival rate of 57.8% in pelvic osteosarcoma. Both of the two figures were seemingly improved when compared to those from conventional systematic chemotherapy.11
The cumulative dosage of CDDP was 780 mg/m2 for a good responder with a tumor size ≤ 8 cm in the present study. Wilkins et al reported the highest accumulated dose of CDDP at 960 mg/m2 and a single dose at 160 mg/m2 over 24 h as an enhanced regimen for patients with tumors over 10 cm versus 120 mg/m2 over 6 h as routine, which consequently yielded the highest 10-year OS and EFS rates (93% and 86%, respectively) among all reviewed studies. Notably, Ferrari et al and Xie et al investigated CDDP administration at equivalent doses to those in the present study but yielded poorer survival outcomes seemingly.13,33 This may be because 120 mg/m2 CDDP was given intraarterially in 72 h in the first study, which is too long to achieve a high enough blood concentration; patients with tumor metastases at the initial diagnosis were included in the second study so that the survival rate would be reduced. We used relatively high-dose CDDP administered over 3 to 6 h combined with 4 other drugs, including ETOP, and made individualized adjustments to the protocol for patients with high-risk factors. This may have contributed to the 57.8% OS and 52.5% EFS rate at 5 years, which is favorable for pelvic osteosarcoma. Moreover, we discovered that the OS and EFS rates in the population with tumors ≤ or >8 cm showed insignificant differences. Patients who received R0 resection also shared equivalent OS but higher EFS with R1 patients. These finding suggest that this protocol with risk-dependent adjustment in the drug dosage and combination could be beneficial to bridge the gap in survival rate between patients with large or small tumors, and those who received R0 or R1 resection.
We noticed that 3 of 5 cases developing SD turned out to demonstrate TNR >90%, which probably means that good response of osteosarcoma is not necessarily accompanied with tumor size decrease. This may be attributed to the formation of tumor bone generated by subtypes like osteoblastic osteosarcoma, which could prevent tumors from shrinkage.40
Only 4 poor responders were observed, 3 of whom developed tumor relapses. Two of the 3 patients died of metastasis during postoperative MSC; another showed no evidence of disease after receiving secondary amputation and resection for local recurrence. This protocol seemed to provide limited benefit to the poor responders. However, the present data are so limited that few tenable conclusions can be drawn from it to guide salvage treatment for poor responders.
Although the AI technique and additional courses were given in this protocol, no patients received an overdose of chemotherapy drugs compared with previous studies using similar drug combinations. No AI-relative grade 4 or 5 adverse events were observed. Although systematic adverse events, including nausea, vomiting, anemia and an increase in creatinine/aminotransferase levels, shared equivalent incidence rates and severities with the study reported by Xie et al, local skin hyperpigmentation and pelvic soft tissue necrosis in muscle occurred after only 3 and 1 of 24 CAI events (12.5% and 4.2%, respectively), which is more favorable than the situation reported in the most reviewed studies concerning extremity osteosarcoma.13,30,33 This finding could be explained by the shorter local drug-retention time since the pelvis has a more sufficient blood supply and drainage.
In terms of the postoperative MSC regimen for poor responders, we determined the IFO + ETOP regimen by reference to the second-line chemotherapy recommended in NCCN guidelines for bone cancer, which is supported by the study reported by Goorin et al and Miser et al.23,41 These two studies were conducted in patients with initial metastasis or recurrence of osteosarcoma, and the former one used IFO + ETOP as an induction regimen accompanied by surgical resection and continuation MSC of MTX + ADM + ETOP + IFO. Therefore, we adopted the regimen similar as the one reported by Miser et al However, the study of EURAMOS reported by Marina et al suggested that treatment with MTX + ADM + CDDP + IFO + ETOP resulted in similar EFS to MTX + ADM + CDDP and increased toxicity. In the present study, we found it hard for patients to accept 12 cycles of second-line therapy in 3 years in view of the high expenditure and physical discomfort. Therefore, the number of cycles was reduced to 6 for poor responders, which is equivalent to a half of the regimen of Miser et al in accumulative dosage and duration time. During the postoperative MSC period, there was no early death. The reported cardiac irritation, increase in creatinine/aminotransferase, oral mucosa inflammation and hematologic system abnormality were acceptable. In summary, our chemotherapy regimen seems to be well tolerated.
To monitor the chemotherapy response, several methods have been reported in previous studies. In the studies reported by Winkler et al and Fuch et al, plain X-ray, local CT and emission CT of bone were used to monitor the TNR before the surgery.30,34 Bacci et al, Wilkins et al and Xie et al deployed CT arterial angiography, which yielded sensitivity and specificity over 90% and 50%, respectively.13,32,36,37 Nevertheless, a repeated CT arterial angiography assessment is difficult to be accepted by patients because it requires multiple invasive operations and high expenditure. RECIST-1.1-based MRI remains one of the most commonly used approaches in tumor response evaluation.42,43 In the present study, we used CE-MRI to detect the tumor response and guide the adjustment of treatment for each patient. Although the results did not seem to suggest that this method is highly predictive of the histopathologic chemotherapy response, the equivalent survival rate between patients with large and small tumors may reflect the effectiveness of the individualized treatment.
There were several limitations in our investigation. First, the design was restricted to a small-sample-size single-arm clinical study due to the rarity of pelvis osteosarcoma morbidity, therefore reducing the reliability of the conclusions. Second, several previous studies reported that pathological subtypes of osteosarcoma, such as chondroblastic and telangiectatic osteosarcoma, respond differently to chemotherapy.39,44 However, the pathological subtype of each patient was not analyzed as an independent prognostic factor in our study. Heterogeneity of the osteosarcoma subtype constitution could distort chemotherapy response and survival outcomes. Third, we used CE-MRI per RECIST 1.1 to monitor the tumor response before surgery and guide the individualized adjustment of the treatment protocol. However, CE-MRI evaluation was not the gold standard for TNR prediction. Multiple innovative approaches for TNR prediction in osteosarcoma have been researched in the past 30 years, such as dynamic CE-MRI with sensitivity and specificity over 70% and 80%, respectively, according to previous studies.45–47 We would attempt to deploy approaches with higher accuracy to evaluate viable tumors in hope of providing more precise guidance for individualized pelvic osteosarcoma treatment in further studies.
Conclusions
In the present study, we employed CAI in the multimodal treatment of pelvic osteosarcoma patients. Our findings suggest that the CAI-facilitated chemotherapy regimen demonstrated great potential for improving the survival of patients with pelvic osteosarcoma. This treatment protocol yielded high tolerance with acceptable adverse effects. However, further randomized controlled trials with large sample sizes are required to elucidate the findings of this preliminary study.
Acknowledgments
We would like to thank all patients for their devotion to taking unidentified risks in this clinical trial. We are also grateful to the participating orthopedic oncologists and interventional radiologists for their prudence and patience in the therapeutic effect evaluation and the multidisciplinary consultation.
Abbreviations
ADM, adriamycin; CAI, effect of cisplatin arterial infusion; CDDP, cis-diamine-dichloro platinum; CE-MRI, contrast-enhanced MRI; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; EFS, event-free survival; ETOP, etoposide; IFO, ifosfamide; IV, intravenous; MSC, multidrug systematic chemotherapy; MTX, methotrexate; OS, overall survival; PD, progressive disease; PR, partial response; RECIST, response evaluation criteria in solid tumors version; S, surgery; SD, stable disease; TNR, tumor necrosis rate; VCR, vincristine.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics Approval and Informed Consent
This study was approved by the ethics committees and the institutional review board of the Second Xiangya Hospital. All patients provided written informed consent for receiving this treatment protocol. The requirement of obtaining specific informed consent for this retrospective study was waived for the reason mentioned before.
Consent for Publication
This study conforms to Declaration of Helsinki. The requirement of obtaining specific informed consent from the patients for the publication of the case presentation and any accompanying images.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
No commercial sponsorship was involved in any part of this study. The authors report no conflicts of interest related to this work. | CISPLATIN, DOXORUBICIN HYDROCHLORIDE, METHOTREXATE SODIUM, VINCRISTINE | DrugsGivenReaction | CC BY-NC | 33623429 | 19,827,868 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Chest pain'. | Effect of Cisplatin Arterial Infusion (CAI) on Primary Nonmetastatic Pelvic Osteosarcoma: A Preliminary Study.
The critical role of arterial infusion chemotherapy in the multimodal treatment of extremity bone cancer has been investigated extensively, but few studies have focused on pelvic osteosarcoma. Therefore, we attempted to evaluate the clinical significance of arterial infusion chemotherapy in the treatment of pelvic osteosarcoma.
We combined a cisplatin arterial infusion regimen with multidrug systematic chemotherapy as a neoadjuvant protocol for the treatment of pelvic osteosarcoma. The course number and dosage of cisplatin arterial infusion were adjusted to achieve a maximal tumor response evaluated by contrast-enhanced MRI per RECIST 1.1. Good responders received the same systematic combination for postoperative chemotherapy, and poor responders received second-line therapy. Twelve patients with nonmetastatic high-grade pelvic osteosarcoma were included. Survival, chemotherapy response and adverse events data were analyzed.
The mean follow-up period was 56.1 months. Four patients died of refractory tumor progression, and 1 patient with local recurrence had no evidence of disease for 27 months after receiving secondary amputation and resection. Kaplan-Meier survival analysis demonstrated a 57.8% overall survival and 52.5% event-free survival rate at 5 years. Eight of 12 patients had a >90% tumor necrosis rate according to histopathologic examinations. The rates of local adverse events were lower than those reported for extremity osteosarcoma.
Our study initially indicated that the cisplatin arterial infusion regimen was a potential therapy with good tolerance in the treatment of pelvic osteosarcoma.
Introduction
Osteosarcoma is the most common solid malignant tumor of bone with a highly aggressive behavior.1 The most susceptible age of osteosarcoma is bimodal, which is characterized by one peak at 10-to-20 years and another at over 60 years.2,3 Although this disease endangers the health of both adolescent and aged populations, limited progress has been made to improve survival and functional prognosis, especially in patients with pelvic osteosarcoma.4–6 Osteosarcoma patients treated with mere immediate surgical resection register a recurrence rate up to 60–90%.7 (Since 1980s, traditional adjuvant intravenous (IV) systematic chemotherapy produces an improved five-year event-free survival (EFS) rate of 61%.8 In the early 2000s, the propagation of a multidrug neoadjuvant chemotherapy regimen elevated this rate to 60% and above.9,10) Henceforth, numerous explorations have been conducted to optimize the category, dosage, combination and duration of chemotherapy drug administration. The most recent studies of EURAMOS revealed a 5-year EFS of 65–70% for localized osteosarcoma treated by multidrug neoadjuvant chemotherapy. However, there are few studies focusing on arterial infusion as an improved method and its clinical outcome in the treatment of pelvic osteosarcoma.
Osteosarcoma in pelvic bone is more notorious than that in extremities. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate than those with extremity lesions, which may be associated with a poor chemotherapy response and an inability to achieve adequate surgical resection.11 Therefore, more challenges are faced in the management of pelvic osteosarcoma.
Platinum complexes, such as cis-diamine-dichloro platinum (cisplatin, CDDP), have been proven to be cell cycle-nonspecific agents and to have multiple broad-spectrum antitumor effects.12 Several clinical trials reported that employing an arterial infusion technique to deliver CDDP, in combination with an IV systematic chemotherapy regimen or not, can elevate the local drug concentration to fivefold that of IV administration and can produce better survival in the treatment of extremity osteosarcoma.13–15 Therefore, the arterial infusion of CDDP might have potential in the treatment of pelvic osteosarcoma.
The histopathologic response of surgically removed tumors has been shown to be one of most critical indicators of chemotherapeutic effectiveness and survival prognosis.16,17 However, preoperative examination is more valuable to predict tumor response and allow individualized neoadjuvant chemotherapy. Response evaluation criteria in solid tumors version 1.1 (RECIST 1.1), which was commonly adopted for the tumor-response evaluation of a variety of cancers, affirmed the value of sectional radiological imaging measurement.18–20 Therefore, preoperative contrast-enhanced MRI (CE-MRI) evaluation based on RECIST 1.1 is expected to guide the adjustment of treatment for optimal surgical timing in pelvic osteosarcoma.
Given all these findings, we combined CDDP arterial infusion (CAI) with individualized multidrug systematic chemotherapy (MSC) and surgery (S) to treat nonmetastatic pelvic osteosarcoma and attempted to investigate (1) the chemotherapy response and survival yielded from this protocol, (2) the individualized adjustment of the neoadjuvant MSC regimen necessary to achieve the maximal tumor response according to RECIST-1.1-based CE-MRI reassessment, and (3) the potential adverse effects caused by the arterial infusion technique and the multidrug systematic chemotherapy regimen.
Patients and Methods
Study Design and Consent
This is a retrospective cohort study (Level III evidence) in which subjects received a protocol comprising multidrug systematic chemotherapy, cisplatin arterial infusion and resection surgery (CAI + MSC + S). The study design conformed with the Declaration of Helsinki, and the treatment protocol was approved by the hospital institutional review board. All patients provided written informed consent for receiving this treatment protocol. All data used in the present study were obtained from the electronic medical records of our hospital and treated with strict confidentiality; therefore, the requirement of obtaining specific informed consent for this retrospective study was waived.
Patients
Inclusion criteria for subjects included (1) histopathologically defined primary osteosarcoma of pelvic bone; (2) no metastatic foci; (3) no past history of cancer treatment; and (4) normal cardiac, hepatic and renal function. All patients were confirmed to have high-grade osteosarcoma morbidity via biopsy. Pretreatment baseline safety indexes were determined with routine blood tests, hepatic and renal function tests, and Doppler echocardiography. A peripherally inserted central catheter was placed in each patient for the IV administration of neoadjuvant chemotherapy agents.
From January 2010 to June 2015, 21 patients were consecutively diagnosed with osteosarcoma of the pelvic bones in our work unit. A total of 4 patients were excluded for the following reasons: 2 patients had evidence of distant metastasis, and 2 tumors involved the femur or lumbar vertebra. Among the eligible people, 2 refused to take CAI + MSC + S treatment: 1 had hemophilia with severely impaired coagulation function; 1 intended to transfer to another hospital after being definitively diagnosed via biopsy. Subsequently, 15 patients took the CAI + MSC + S treatment, but 1 of them stopped midway (because of intolerance to vomiting as the adverse effect in the first two rounds of IV multidrug therapy) and turned to other treatment. Two patients were lost to follow-up after surgical resection. Eventually, 12 patients finished the treatment protocol and yielded analyzable data for survival, chemotherapy response and toxicity assessment.
The data of these 12 patients are listed in Table 1. The study population consisted of 7 (58.3%) males and 5 (41.7%) females with an average age of 28.8 years (11 to 69 years). The morbid sites included the pubis (n = 2), ilium (n = 4), ischium (n = 1), sacrum (n = 1) and unclear sites (n = 4).Table 1 Patient Data
Case No. Age (y) Sex Tumor Size (cm) Morbid Site MRI Tumor Response Before Surgery Surgical Margins Histopathologic Response Diagnosis Date Surgery Type Follow-Up (Month) First Relapse Status
1 62 F <8 Unclear +27.4%, PD R0 <90% 5/19/2010 1 42 CDF
2 19 M <8 Ilium −35.1%, PR R0 >90% 10/4/2010 2 46 Jan. 2014 DOD
3 14 M <8 Unclear +14.6%, SD R0 95% 7/23/2011 2 52 CDF
4 53 F >8 Sacrum −7.3%, SD R1 <90% 6/30/2012 4 57 Feb. 2015 NED
5 15 M <8 Ilium −32.7%, PR R0 >90% 10/28/2012 2 93 CDF
6 21 F 7 Ilium +25.9%, PD R0 >90% 4/24/2013 2 87 CDF
7 16 M >8 Unclear +8.6%, SD R1 <90% 9/22/2013 2 37 Aug. 2015 DOD
8 36 F 9 Pubis −24.1%, SD R0 >90% 4/14/2014 2 76 CDF
9 69 M 12 Ischium +43.7% PD R1 <90% 5/17/2014 3 15 Jan. 2015 DOD
10 12 F <8 Unclear −37.4%, PR R0 99% 8/21/2014 2 72 CDF
11 41 M <8 Pubis +33.5%, PR R0 >90% 3/6/2015 2 34 CDF
12 47 M <8 Ilium +16.6%, SD R0 95% 6/30/2015 2 62 Dec. 2019 DOD
Notes: Surgical type = 1) primary lower limb amputation; 2) lower limb salvage surgery; 3) secondary amputation and reresection due to local recurrence; 4) revision surgery due to periprosthetic infection.
Abbreviations: CAI, cisplatin arterial infusion; PR, partial response; PD, progressive disease; SD, stable disease; CAP, cisplatin arterial perfusion; CDF, continuously disease free; NED, no evidence of disease; DOD, died of disease.
Description of the Study Treatments and Outcome Measures
The adopted CAI + MSC + S treatment protocol is depicted in Figure 1. In general, MSCs usually consist of high-dose methotrexate (MTX), vincristine (VCR), adriamycin (ADM), CDDP and ifosfamide (IFO). Specifically, the routine CAI + MSC regimen was initiated with 24-hour continuous IV dripping of high-dose MTX at 10 g/m2 followed by 2 mg IV VCR the next day for the first group at Week 0; in Week 2, 120 mg/m2 CDDP AI over 3 to 6 hours and following 30 mg/m2/d IV ADM for 2 days were given to the second group; these 2 groups were repeated in Weeks 3 and 4; then, the resection surgery was performed 2 weeks after the neoadjuvant chemotherapy was finished. Notably, 160 mg/m2 was determined as the enhanced dosage of CDDP for tumors with the longest diameter over 8 cm in CE-MRI slices. In addition, IV IFO at 2 g/m2/d for 5 days was given in Week 5 for tumors over 8 cm after the 4-week routine regimen was completed. Central venous catheterization for MSC administration was performed under inhalation anesthesia if necessary. Before each CAI regimen, percutaneous punctuation of the femoral artery was performed using the Seldinger technique, and the catheter was inserted from the femoral artery of the contralateral side to the beginning of the artery trunk supplying the tumor with the assistance of CT-guided positioning.21 Then, CT arterial angiography was conducted. Each course of MSC and CAI was accompanied by IV hydration, diuretics, rescue and protecting drugs. The CDDP was perfused via the catheter with chemotherapy pumps (LimLess Infusion Pump; PFM Medical Inc, Cologne, Germany) in a pulsed manner (Bolus dose administrator; PFM Medical Inc, Cologne, Germany). The patients were asked to have strict bed rest under multiparameter monitoring. Routine blood tests for electrolytes and hepatic and renal function were performed on the first day after drug administration and every 3 days thereafter.Figure 1 The individualized pelvic osteosarcoma treatment protocol combined cisplatin arterial infusion, multidrug systematic chemotherapy and resection surgery (CAI + MSC + S).
To evaluate the therapeutic response, primary plain X-ray (Figure 2A) and physical examination parameters of the tumor, including pre- and postchemotherapy size, tenderness, pain and inflammation, were collected. More importantly, CE-MRI was performed to monitor the tumor chemotherapy response before and after routine neoadjuvant CAI + MSC administration. (Figure 2B–E) According to the RECIST 1.1 guidelines, tumor size was calculated in gadolinium-enhancing T1-weighted fat‐saturated coronal images using the following criteria: complete response (CR), complete elimination of target lesion; partial response (PR), ≥30% decrease in the diameter of target lesion compared to baseline); progressive disease (PD), ≥20% increase in the diameter of target lesion compared to baseline or new metastatic lesion); and stable disease (SD) or observed changes in the diameter of the target lesion between 30% decrease and 20% increase compared to baseline. Each tumor lesion was assessed by orthopedic oncologists and interventional radiologists who were blinded to the treatment allocation and clinical outcome data. For patients who achieved PD after the routine neoadjuvant regimen was finished, surgery was performed immediately. For patients who demonstrated CR or PR, surgery was performed 2 weeks after the neoadjuvant regimen as usual. For patients who presented SD, the same IFO course as that mentioned in the adjustment for large tumors was added to maximize the tumor response of the neoadjuvant regimen. Then, a multidisciplinary consultation was conducted to identify the achievement of maximal tumor response. If any uncertainty of maximal response achievement was left, one more course of IFO could be given, and patients received resection surgery no later than 9 weeks after the first diagnosis.Figure 2 (A) Pelvis X-ray of a 36-year-old female with an osteosarcoma in the pubis. (B) and (C) Fat-saturated T1- and T2-weighted coronal slices of contrast-enhanced MRI showing the maximum diameter of the tumor at the first diagnosis, which showed heterogeneous enhancement, thick septa and obscure boundaries of the tumor. (D) and (E) MRI reevaluation after completion of the neoadjuvant CAI + MSC regimen, showing thin septa, clear boundaries and stable disease according to RECIST 1.1 with a decrease in the tumor diameter. (F) Pelvis plain X-ray of this patient. (The identifiable captions in these images are occluded.).
A chest CT scan, a full-body bone scan and a pelvic CE-MRI scan (Figure 2D and E) were repeated before surgery. The tumor response per RECIST 1.1 measured in the last CE-MRI examination was compared with the baseline level. Surgical excision extension was determined by the involved scope of the tumor and the tumor response category according to the CE-MRI assessment per RECIST 1.1. The pelvic reconstruction project depended on the morbidity site, excision extension, bone mineral density and functional requirements.
In case of uncontrollable hemorrhage during the resection surgery, a temporary balloon blocking technique for the abdominal aorta was performed under the guidance of CTA 4 hours before resection surgery. A balloon compatible in size to the abdominal aortic diameter was placed intraarterially at the level of 2 to 3 cm above the bifurcation of the common iliac arteries. The injection of saline with 0.1% heparin inflated the balloon, consequently blocking blood perfusion of the surgical site. Angiography was performed to confirm the satisfactory blockage of the iliac arteries and unobstruction of the renal arteries. Then, the balloon was deflated until the surgery began. Each deflation was performed with an interval of 60 min during the resection surgery before satisfactory hemostasis was achieved.
Histopathologic examination was conducted using the method reported by Huvos et al to quantify the necrosis ratio of the tumor after removal.22 Patients with a ≥90% tumor necrosis rate (TNR) (Grade III and IV) were classified as good responders. The other (Grade Ⅰ and Ⅱ) were deemed poor responders.
The postoperative IV chemotherapy cycle was repeated every 3 weeks. The recovery of hematopoietic function in patients was required before each course, which was defined as a white blood cell count over 1×104/mm3 and a platelet count over 5×106/mm3 for 3 successive days without hematopoietic stimulants. For good responders, the duration of postoperative MSC was usually 3 courses, which could be extended to the maximum of 6 courses accompanied by the existence of high-risk factors, including SD or PD in the CE-MRI per RECIST 1.1 before surgery or histology-proven tumor involvement in the surgical margin (R1 resection). For poor responders, IFO at 2 g/m2/d for 5 days and etoposide (ETOP) at 100 mg/m2/d for 5 days were given sequentially as one cycle repeated every 3 weeks for 6 cycles.23
After the planned treatment was finished, the discontinuation of chemotherapy was allowed by the orthopedic oncologist if X-ray (Figure 2F) and CE-MRI of the primary morbidity site along with chest X-ray every 2 months, chest CT scanning every 6 months in the first year off the treatment prove no local recurrence or lung metastasis. Routine blood tests and hepatic and renal function tests were deployed every week until the recovery of hematopoietic function.
Statistical Analysis
We used the Kaplan-Meier method to analyze the overall survival (OS) and EFS, which were calculated from the day the preoperative MSC + CAI regimen began. The events were defined as local recurrence, distant metastasis or death from the disease. Additionally, the OS and EFS in groups with different histopathologic chemotherapy responses or tumor sizes were calculated. All statistical analyses were conducted with SPSS software packages (SPSS Inc., Chicago, IL, USA).
Results
Chemotherapy Response
Significant improvement in physical examination parameters was observed in 10 of 12 patients after the neoadjuvant regimen, including alleviation of pain. In terms of tumor response measurement per RECIST 1.1, 4 patients had PR and 5 had SD after routine neoadjuvant CAI + MSC administration. Three patients had to undergo resection surgery ahead of schedule because of PD, as shown by CE-MRI after neoadjuvant CAI + MSC administration. No patient demonstrated CR.
According to the histopathologic assessment, 66.7% (8 of 12) of patients demonstrated TNR over 90%. One of the 3 patients with PD according to the CE-MRI assessment turned out to be good responders with Grade III histopathologic results.
Surgery
Three patients underwent local radical excision and lower limb amputation because of neurovascular bundle involvement. The remaining 9 patients received limb salvage surgery followed by pelvic reconstruction using a modular prosthesis (Lidakang Inc., Beijing, China), tumor bone devitalization and replantation, or just bone fusion. As a result, 1 patient who underwent primary limb salvage surgery developed local recurrence and underwent secondary amputation and local reresection. Two patients had surgical site infections but were cured 2 months after surgery. One patient who developed a periprosthetic infection underwent a secondary amputation.
Survival
A total of 58.3% of patients (7 of 12) remained continuously disease free in an average follow-up period of 65.1 months (range, 34–93 months). One patient who developed local recurrence was proven alive with no evidence of disease for 31 months after receiving a secondary amputation and resection. Four patients (3 lung metastases and 1 local recurrence) died of refractory disease progression. Kaplan-Meier survival analysis suggested an OS rate of 57.8% and an EFS of 52.5% at 5 years (Figure 3). For patients with a good chemotherapy response, the 5-year OS and EFS rates were 68.6%, both of which showed significant differences (P = 0.04 for OS and 0.01 for EFS) compared with the corresponding measures for poor responders (Table 2). The comparison of patients with tumor sizes greater (n = 4) or less (n = 8) than 8 cm did not yield statistical significance (P = 0.32 and 0.13, respectively). As shown in the pathological report, 75% (9 of 12) patients received R0 resection and 25% (3 of 12) had R1 resection. There was no significant difference in the OS but in the EFS between patient group with R0 or R1 surgical resection (P = 0.15 and 0.05, respectively). The confidence interval of all OS and EFS are 95%.Table 2 Overall Survival (OS) and Event-Free Survival (EFS) Rate
Variables 1 y 5 y
All patients – OS 91.7% 57.8%
All patients – EFS 91.7% 52.5%
Good responders – OS 100.0% 68.6%
Good responders – EFS 100.0% 68.6%
Poor responders – OS 75.0% 50.0%
Poor responders – EFS 75.0% 25.0%
Patients with tumor size ≥8 cm – OS 75.0% 50.0%
Patients with tumor size ≥8 cm – EFS 75.0% 25.0%
Patients with tumor size<8 cm – OS 100.0% 62.5%
Patients with tumor size<8 cm – EFS 100.0% 64.3%
R0 resection – OS 85.7% 70.0%
R0 resection – EFS 88.9% 71.1%
R1 resection – OS 66.7% 33.3%
R1 resection – EFS 66.7% 33.3%
Note: Confidence Interval = 95%
Figure 3 The Kaplan-Meier survival curve for overall survival (OS) and event-free survival (EFS) rates of 12 pelvic osteosarcoma patients treated with the CAI + MSC + S protocol.
Chemotherapy Toxicity
We recorded the adverse effects referred to in the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.24 The statistics of CAI-related adverse events are summarized in Table 3. Three of 12 patients had local adverse events, including grade 1 to 2 skin pelvic soft tissue necrosis in muscle and hyperpigmentation, which exhibited no effect on the surgical method choice or wound healing. Nausea and vomiting were the most common systematic adverse events, with 41.7% of patients developing grade 3 events. A 36-year-old female received a reduced dosage of MTX (7 g/m2) due to intolerable vomiting after the first MTX course. Four of 12 patients developed grade 1 infusion-related reactions.Table 3 Statistics of CAI-Related Adverse Events
Adverse Events No. of Courses Percentage of Patients with Grade 3–4 Adverse Events
Skin hyperpigmentation 12.5% (3/24) 0% (0/12)
Pelvic soft tissue necrosis (muscle) 4.2% (1/24) 0% (0/12)
Pelvic pain 16.7% (4/24) 8.3% (1/12)
Nausea and vomiting 75.0% (18/24) 41.7% (5/12)
Anemia 8.3% (2/24) 8.3% (1/12)
Increase in creatinine level 8.3% (2/24) 0% (0/12)
Increase in aminotransferase level 4.2% (1/24) 0% (0/12)
Infusion related reaction 29.2% (7/24) 0% (0/12)
During the postoperative MSC period, one 12-year-old child complained of grade 1 palpitations and chest pain. Therefore, we replaced ADM with ETOP, and the complaint disappeared with no evidence reported in Doppler echocardiography. Three patients out of 12 developed grade 1 to 2 increases in alanine/aspartate aminotransferase levels.
Three children developed oral mucositis at grade 2 to 3, 2 of whom were under IV nutrition, and one used a mouth rinse with metronidazole to treat thrush. All patients eventually resumed normal oral food intake.
Blood system disorders were commonly noted in patients after the second cycle of postoperative MSC administration. Three patients developed febrile neutropenia and were treated by injection of recombinant human granulocyte stimulating factor.
Discussion
Conventional IV adjuvant chemotherapy and neoadjuvant chemotherapy have been applied extensively in multimodal osteosarcoma treatment for over 45 years.25 Though changes in drug combination, dosage, and administration duration were made to optimize the regimen, no significant improvement was achieved based on the approximately 50% to 70% 5-year OS and EFS rates in the past decade.26–28 As a modified approach to augment the potential of chemotherapy drugs, the AI technique combined with MSCs has been studied for years.13,29,30 In the present study, we attempted to investigate the therapeutic effect of the CAI + MSC + S protocol in osteosarcoma treatment. The 5-year OS and EFS rates were 57.8% and 52.5%, respectively.
The CAI regimen and its outcome measurements were first documented by Jaffe et al in 1983.31 Then, a series of studies concerning CAI-facilitated multidrug chemotherapy followed.13,30,32–37 Information on all 9 studies, including the present study, is listed in Table 4.Table 4 Synopsis of IA CDDP Information Reported in the Literature
Authors Type of Study No. of Patients Ages (y) Sites Metastases Preoperative CDDP Courses No. >90% TN OS EFS
Winkler et al and Fuchs et al30,34 Nonrandomized, 2 arms 50 <40 All Included 2 68% 67% at 10 y 63% at 10 y
Ferrari et al33 Single arm 164 <40 Extremity Excluded 2 NA 72% at 8 y 63% at 8 y
Ferrari et al33 Randomized, 2 arms 59 <40 Extremity Excluded 2 64% 61% at 8 y 54% at 8 y
Rha et al35 Single arm 37 8~41 Extremity ? 3 75% 78% at 3 y 55% at 3 y
Bacci et al32 Randomized, 2 arms 40 <40 Extremity Included 2 77% NA 26% at 5 y
Bacci et al32 Randomized, 2 arms 72 <40 Extremity Included 2 80% NA 61% at 5 y
Wilkins et al37 Single arm 47 <21 Extremity Excluded 3–5 (response dependent) 87% 92% at 10 y 84% at 10 y
Wilkins et al36 Single arm 62 <22 Extremity Excluded 3–5 (response dependent) 87% 93% at 10 y 86% at 10 y
Xie et al13 Nonrandomized, 2 arms 48 NA Extremity Included 3 63% 64% at 5 y 60% at 5 y
Hu et al (Current study) Single arm 12 11~69 Pelvis Excluded 2 66.7% 57.8% at 5 y 52.5% at 5 y
Abbreviations: IA, intraarterial; CDDP, cisplatin; TN, tumor necrosis; OS, overall survival; EFS, event-free survival.
Among these 9 studies, 8 used CAI and systematic chemotherapy sequentially before surgery, and 5 studies scheduled a 2-course preoperative regimen. Six of 9 studies suggested a higher chemotherapy response rate and/or survival rate in the CAI group compared with the IV CDDP group; 2 of these investigations were 2-arm randomized cohort studies and reported a statistically significant improvement in the good-response ratio (21% and 31%, respectively). In the third randomized cohort study reported by Rha et al, the improvement was not statistically significant, probably because the limited sample size was insufficient to test the 9% difference between the two groups.35 In the multicenter study reported by Winkler et al and Fuchs et al in the 1990s, no difference in chemotherapy response was observed between the intraarterial and IV CDDP groups.30,34 Similarly, Xie et al also proved a superior histological response rate but equivalent survival in the CAI group versus the IV group in 2019.13 However, the reliability of the conclusions in the 2 studies may be impaired by the nonrandomized grouping design conducted at the researchers’ discretion, which could be affected by the severity of disease. Although CAI may bring benefits to chemotherapy response augmentation and survival rates in limb osteosarcoma patients, how pelvic osteosarcoma reacts to CAI-facilitated multidrug chemotherapy remains elusive.
Pelvic tumor resection surgeries such as hemipelvectomy are notoriously known as one of the most destructive operations in modern orthopedic surgery.38 Due to the adjacency of the vascular network, nerves and viscera in the pelvis, surgeons have to weigh tumor eradication against functional preservation in the determination of the extent of surgical excision. This dilemma makes the treatment more challenging. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate compared with the extremity-morbidity population, which could be explained by the higher rate of not only failure of surgical remission but also advanced age, large tumor size, primary metastasis, prolonged latency periods and poor chemotherapy responses.11,39 Thus, it is critical to maximize the chemotherapy response and achieve better survival outcomes in pelvic osteosarcoma patients.
The combination of agents in our MSC protocol was determined by reference to NCCN guidelines for bone cancer and the study reported by Xie et al.13 Although the agent numbers and categories differed, all of the above-reviewed studies and the present study deployed a multidrug protocol to treat tumor cells in different phases of the cell cycle. Unfortunately, insufficient data are available to appropriately compare the therapeutic effect of CAI alone or in various combinations with MTX, VCR, ADM and IFO because of great heterogeneity. In the present study, we used high-dose MTX at 10 g/m2 and CAI at 120 mg/m2 in 2 doses as routine preoperative treatment. For patients with tumors over 8 cm, we employed an enhanced dose of CAI at 160 mg/m2. Additionally, additional IFO courses were given to slow responders. This individualized regimen directly yielded a 66.7% prevalence of good histopathologic responders and contributed to the 5-year survival rate of 57.8% in pelvic osteosarcoma. Both of the two figures were seemingly improved when compared to those from conventional systematic chemotherapy.11
The cumulative dosage of CDDP was 780 mg/m2 for a good responder with a tumor size ≤ 8 cm in the present study. Wilkins et al reported the highest accumulated dose of CDDP at 960 mg/m2 and a single dose at 160 mg/m2 over 24 h as an enhanced regimen for patients with tumors over 10 cm versus 120 mg/m2 over 6 h as routine, which consequently yielded the highest 10-year OS and EFS rates (93% and 86%, respectively) among all reviewed studies. Notably, Ferrari et al and Xie et al investigated CDDP administration at equivalent doses to those in the present study but yielded poorer survival outcomes seemingly.13,33 This may be because 120 mg/m2 CDDP was given intraarterially in 72 h in the first study, which is too long to achieve a high enough blood concentration; patients with tumor metastases at the initial diagnosis were included in the second study so that the survival rate would be reduced. We used relatively high-dose CDDP administered over 3 to 6 h combined with 4 other drugs, including ETOP, and made individualized adjustments to the protocol for patients with high-risk factors. This may have contributed to the 57.8% OS and 52.5% EFS rate at 5 years, which is favorable for pelvic osteosarcoma. Moreover, we discovered that the OS and EFS rates in the population with tumors ≤ or >8 cm showed insignificant differences. Patients who received R0 resection also shared equivalent OS but higher EFS with R1 patients. These finding suggest that this protocol with risk-dependent adjustment in the drug dosage and combination could be beneficial to bridge the gap in survival rate between patients with large or small tumors, and those who received R0 or R1 resection.
We noticed that 3 of 5 cases developing SD turned out to demonstrate TNR >90%, which probably means that good response of osteosarcoma is not necessarily accompanied with tumor size decrease. This may be attributed to the formation of tumor bone generated by subtypes like osteoblastic osteosarcoma, which could prevent tumors from shrinkage.40
Only 4 poor responders were observed, 3 of whom developed tumor relapses. Two of the 3 patients died of metastasis during postoperative MSC; another showed no evidence of disease after receiving secondary amputation and resection for local recurrence. This protocol seemed to provide limited benefit to the poor responders. However, the present data are so limited that few tenable conclusions can be drawn from it to guide salvage treatment for poor responders.
Although the AI technique and additional courses were given in this protocol, no patients received an overdose of chemotherapy drugs compared with previous studies using similar drug combinations. No AI-relative grade 4 or 5 adverse events were observed. Although systematic adverse events, including nausea, vomiting, anemia and an increase in creatinine/aminotransferase levels, shared equivalent incidence rates and severities with the study reported by Xie et al, local skin hyperpigmentation and pelvic soft tissue necrosis in muscle occurred after only 3 and 1 of 24 CAI events (12.5% and 4.2%, respectively), which is more favorable than the situation reported in the most reviewed studies concerning extremity osteosarcoma.13,30,33 This finding could be explained by the shorter local drug-retention time since the pelvis has a more sufficient blood supply and drainage.
In terms of the postoperative MSC regimen for poor responders, we determined the IFO + ETOP regimen by reference to the second-line chemotherapy recommended in NCCN guidelines for bone cancer, which is supported by the study reported by Goorin et al and Miser et al.23,41 These two studies were conducted in patients with initial metastasis or recurrence of osteosarcoma, and the former one used IFO + ETOP as an induction regimen accompanied by surgical resection and continuation MSC of MTX + ADM + ETOP + IFO. Therefore, we adopted the regimen similar as the one reported by Miser et al However, the study of EURAMOS reported by Marina et al suggested that treatment with MTX + ADM + CDDP + IFO + ETOP resulted in similar EFS to MTX + ADM + CDDP and increased toxicity. In the present study, we found it hard for patients to accept 12 cycles of second-line therapy in 3 years in view of the high expenditure and physical discomfort. Therefore, the number of cycles was reduced to 6 for poor responders, which is equivalent to a half of the regimen of Miser et al in accumulative dosage and duration time. During the postoperative MSC period, there was no early death. The reported cardiac irritation, increase in creatinine/aminotransferase, oral mucosa inflammation and hematologic system abnormality were acceptable. In summary, our chemotherapy regimen seems to be well tolerated.
To monitor the chemotherapy response, several methods have been reported in previous studies. In the studies reported by Winkler et al and Fuch et al, plain X-ray, local CT and emission CT of bone were used to monitor the TNR before the surgery.30,34 Bacci et al, Wilkins et al and Xie et al deployed CT arterial angiography, which yielded sensitivity and specificity over 90% and 50%, respectively.13,32,36,37 Nevertheless, a repeated CT arterial angiography assessment is difficult to be accepted by patients because it requires multiple invasive operations and high expenditure. RECIST-1.1-based MRI remains one of the most commonly used approaches in tumor response evaluation.42,43 In the present study, we used CE-MRI to detect the tumor response and guide the adjustment of treatment for each patient. Although the results did not seem to suggest that this method is highly predictive of the histopathologic chemotherapy response, the equivalent survival rate between patients with large and small tumors may reflect the effectiveness of the individualized treatment.
There were several limitations in our investigation. First, the design was restricted to a small-sample-size single-arm clinical study due to the rarity of pelvis osteosarcoma morbidity, therefore reducing the reliability of the conclusions. Second, several previous studies reported that pathological subtypes of osteosarcoma, such as chondroblastic and telangiectatic osteosarcoma, respond differently to chemotherapy.39,44 However, the pathological subtype of each patient was not analyzed as an independent prognostic factor in our study. Heterogeneity of the osteosarcoma subtype constitution could distort chemotherapy response and survival outcomes. Third, we used CE-MRI per RECIST 1.1 to monitor the tumor response before surgery and guide the individualized adjustment of the treatment protocol. However, CE-MRI evaluation was not the gold standard for TNR prediction. Multiple innovative approaches for TNR prediction in osteosarcoma have been researched in the past 30 years, such as dynamic CE-MRI with sensitivity and specificity over 70% and 80%, respectively, according to previous studies.45–47 We would attempt to deploy approaches with higher accuracy to evaluate viable tumors in hope of providing more precise guidance for individualized pelvic osteosarcoma treatment in further studies.
Conclusions
In the present study, we employed CAI in the multimodal treatment of pelvic osteosarcoma patients. Our findings suggest that the CAI-facilitated chemotherapy regimen demonstrated great potential for improving the survival of patients with pelvic osteosarcoma. This treatment protocol yielded high tolerance with acceptable adverse effects. However, further randomized controlled trials with large sample sizes are required to elucidate the findings of this preliminary study.
Acknowledgments
We would like to thank all patients for their devotion to taking unidentified risks in this clinical trial. We are also grateful to the participating orthopedic oncologists and interventional radiologists for their prudence and patience in the therapeutic effect evaluation and the multidisciplinary consultation.
Abbreviations
ADM, adriamycin; CAI, effect of cisplatin arterial infusion; CDDP, cis-diamine-dichloro platinum; CE-MRI, contrast-enhanced MRI; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; EFS, event-free survival; ETOP, etoposide; IFO, ifosfamide; IV, intravenous; MSC, multidrug systematic chemotherapy; MTX, methotrexate; OS, overall survival; PD, progressive disease; PR, partial response; RECIST, response evaluation criteria in solid tumors version; S, surgery; SD, stable disease; TNR, tumor necrosis rate; VCR, vincristine.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics Approval and Informed Consent
This study was approved by the ethics committees and the institutional review board of the Second Xiangya Hospital. All patients provided written informed consent for receiving this treatment protocol. The requirement of obtaining specific informed consent for this retrospective study was waived for the reason mentioned before.
Consent for Publication
This study conforms to Declaration of Helsinki. The requirement of obtaining specific informed consent from the patients for the publication of the case presentation and any accompanying images.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
No commercial sponsorship was involved in any part of this study. The authors report no conflicts of interest related to this work. | CISPLATIN, DOXORUBICIN HYDROCHLORIDE, METHOTREXATE SODIUM, VINCRISTINE | DrugsGivenReaction | CC BY-NC | 33623429 | 19,834,550 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Palpitations'. | Effect of Cisplatin Arterial Infusion (CAI) on Primary Nonmetastatic Pelvic Osteosarcoma: A Preliminary Study.
The critical role of arterial infusion chemotherapy in the multimodal treatment of extremity bone cancer has been investigated extensively, but few studies have focused on pelvic osteosarcoma. Therefore, we attempted to evaluate the clinical significance of arterial infusion chemotherapy in the treatment of pelvic osteosarcoma.
We combined a cisplatin arterial infusion regimen with multidrug systematic chemotherapy as a neoadjuvant protocol for the treatment of pelvic osteosarcoma. The course number and dosage of cisplatin arterial infusion were adjusted to achieve a maximal tumor response evaluated by contrast-enhanced MRI per RECIST 1.1. Good responders received the same systematic combination for postoperative chemotherapy, and poor responders received second-line therapy. Twelve patients with nonmetastatic high-grade pelvic osteosarcoma were included. Survival, chemotherapy response and adverse events data were analyzed.
The mean follow-up period was 56.1 months. Four patients died of refractory tumor progression, and 1 patient with local recurrence had no evidence of disease for 27 months after receiving secondary amputation and resection. Kaplan-Meier survival analysis demonstrated a 57.8% overall survival and 52.5% event-free survival rate at 5 years. Eight of 12 patients had a >90% tumor necrosis rate according to histopathologic examinations. The rates of local adverse events were lower than those reported for extremity osteosarcoma.
Our study initially indicated that the cisplatin arterial infusion regimen was a potential therapy with good tolerance in the treatment of pelvic osteosarcoma.
Introduction
Osteosarcoma is the most common solid malignant tumor of bone with a highly aggressive behavior.1 The most susceptible age of osteosarcoma is bimodal, which is characterized by one peak at 10-to-20 years and another at over 60 years.2,3 Although this disease endangers the health of both adolescent and aged populations, limited progress has been made to improve survival and functional prognosis, especially in patients with pelvic osteosarcoma.4–6 Osteosarcoma patients treated with mere immediate surgical resection register a recurrence rate up to 60–90%.7 (Since 1980s, traditional adjuvant intravenous (IV) systematic chemotherapy produces an improved five-year event-free survival (EFS) rate of 61%.8 In the early 2000s, the propagation of a multidrug neoadjuvant chemotherapy regimen elevated this rate to 60% and above.9,10) Henceforth, numerous explorations have been conducted to optimize the category, dosage, combination and duration of chemotherapy drug administration. The most recent studies of EURAMOS revealed a 5-year EFS of 65–70% for localized osteosarcoma treated by multidrug neoadjuvant chemotherapy. However, there are few studies focusing on arterial infusion as an improved method and its clinical outcome in the treatment of pelvic osteosarcoma.
Osteosarcoma in pelvic bone is more notorious than that in extremities. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate than those with extremity lesions, which may be associated with a poor chemotherapy response and an inability to achieve adequate surgical resection.11 Therefore, more challenges are faced in the management of pelvic osteosarcoma.
Platinum complexes, such as cis-diamine-dichloro platinum (cisplatin, CDDP), have been proven to be cell cycle-nonspecific agents and to have multiple broad-spectrum antitumor effects.12 Several clinical trials reported that employing an arterial infusion technique to deliver CDDP, in combination with an IV systematic chemotherapy regimen or not, can elevate the local drug concentration to fivefold that of IV administration and can produce better survival in the treatment of extremity osteosarcoma.13–15 Therefore, the arterial infusion of CDDP might have potential in the treatment of pelvic osteosarcoma.
The histopathologic response of surgically removed tumors has been shown to be one of most critical indicators of chemotherapeutic effectiveness and survival prognosis.16,17 However, preoperative examination is more valuable to predict tumor response and allow individualized neoadjuvant chemotherapy. Response evaluation criteria in solid tumors version 1.1 (RECIST 1.1), which was commonly adopted for the tumor-response evaluation of a variety of cancers, affirmed the value of sectional radiological imaging measurement.18–20 Therefore, preoperative contrast-enhanced MRI (CE-MRI) evaluation based on RECIST 1.1 is expected to guide the adjustment of treatment for optimal surgical timing in pelvic osteosarcoma.
Given all these findings, we combined CDDP arterial infusion (CAI) with individualized multidrug systematic chemotherapy (MSC) and surgery (S) to treat nonmetastatic pelvic osteosarcoma and attempted to investigate (1) the chemotherapy response and survival yielded from this protocol, (2) the individualized adjustment of the neoadjuvant MSC regimen necessary to achieve the maximal tumor response according to RECIST-1.1-based CE-MRI reassessment, and (3) the potential adverse effects caused by the arterial infusion technique and the multidrug systematic chemotherapy regimen.
Patients and Methods
Study Design and Consent
This is a retrospective cohort study (Level III evidence) in which subjects received a protocol comprising multidrug systematic chemotherapy, cisplatin arterial infusion and resection surgery (CAI + MSC + S). The study design conformed with the Declaration of Helsinki, and the treatment protocol was approved by the hospital institutional review board. All patients provided written informed consent for receiving this treatment protocol. All data used in the present study were obtained from the electronic medical records of our hospital and treated with strict confidentiality; therefore, the requirement of obtaining specific informed consent for this retrospective study was waived.
Patients
Inclusion criteria for subjects included (1) histopathologically defined primary osteosarcoma of pelvic bone; (2) no metastatic foci; (3) no past history of cancer treatment; and (4) normal cardiac, hepatic and renal function. All patients were confirmed to have high-grade osteosarcoma morbidity via biopsy. Pretreatment baseline safety indexes were determined with routine blood tests, hepatic and renal function tests, and Doppler echocardiography. A peripherally inserted central catheter was placed in each patient for the IV administration of neoadjuvant chemotherapy agents.
From January 2010 to June 2015, 21 patients were consecutively diagnosed with osteosarcoma of the pelvic bones in our work unit. A total of 4 patients were excluded for the following reasons: 2 patients had evidence of distant metastasis, and 2 tumors involved the femur or lumbar vertebra. Among the eligible people, 2 refused to take CAI + MSC + S treatment: 1 had hemophilia with severely impaired coagulation function; 1 intended to transfer to another hospital after being definitively diagnosed via biopsy. Subsequently, 15 patients took the CAI + MSC + S treatment, but 1 of them stopped midway (because of intolerance to vomiting as the adverse effect in the first two rounds of IV multidrug therapy) and turned to other treatment. Two patients were lost to follow-up after surgical resection. Eventually, 12 patients finished the treatment protocol and yielded analyzable data for survival, chemotherapy response and toxicity assessment.
The data of these 12 patients are listed in Table 1. The study population consisted of 7 (58.3%) males and 5 (41.7%) females with an average age of 28.8 years (11 to 69 years). The morbid sites included the pubis (n = 2), ilium (n = 4), ischium (n = 1), sacrum (n = 1) and unclear sites (n = 4).Table 1 Patient Data
Case No. Age (y) Sex Tumor Size (cm) Morbid Site MRI Tumor Response Before Surgery Surgical Margins Histopathologic Response Diagnosis Date Surgery Type Follow-Up (Month) First Relapse Status
1 62 F <8 Unclear +27.4%, PD R0 <90% 5/19/2010 1 42 CDF
2 19 M <8 Ilium −35.1%, PR R0 >90% 10/4/2010 2 46 Jan. 2014 DOD
3 14 M <8 Unclear +14.6%, SD R0 95% 7/23/2011 2 52 CDF
4 53 F >8 Sacrum −7.3%, SD R1 <90% 6/30/2012 4 57 Feb. 2015 NED
5 15 M <8 Ilium −32.7%, PR R0 >90% 10/28/2012 2 93 CDF
6 21 F 7 Ilium +25.9%, PD R0 >90% 4/24/2013 2 87 CDF
7 16 M >8 Unclear +8.6%, SD R1 <90% 9/22/2013 2 37 Aug. 2015 DOD
8 36 F 9 Pubis −24.1%, SD R0 >90% 4/14/2014 2 76 CDF
9 69 M 12 Ischium +43.7% PD R1 <90% 5/17/2014 3 15 Jan. 2015 DOD
10 12 F <8 Unclear −37.4%, PR R0 99% 8/21/2014 2 72 CDF
11 41 M <8 Pubis +33.5%, PR R0 >90% 3/6/2015 2 34 CDF
12 47 M <8 Ilium +16.6%, SD R0 95% 6/30/2015 2 62 Dec. 2019 DOD
Notes: Surgical type = 1) primary lower limb amputation; 2) lower limb salvage surgery; 3) secondary amputation and reresection due to local recurrence; 4) revision surgery due to periprosthetic infection.
Abbreviations: CAI, cisplatin arterial infusion; PR, partial response; PD, progressive disease; SD, stable disease; CAP, cisplatin arterial perfusion; CDF, continuously disease free; NED, no evidence of disease; DOD, died of disease.
Description of the Study Treatments and Outcome Measures
The adopted CAI + MSC + S treatment protocol is depicted in Figure 1. In general, MSCs usually consist of high-dose methotrexate (MTX), vincristine (VCR), adriamycin (ADM), CDDP and ifosfamide (IFO). Specifically, the routine CAI + MSC regimen was initiated with 24-hour continuous IV dripping of high-dose MTX at 10 g/m2 followed by 2 mg IV VCR the next day for the first group at Week 0; in Week 2, 120 mg/m2 CDDP AI over 3 to 6 hours and following 30 mg/m2/d IV ADM for 2 days were given to the second group; these 2 groups were repeated in Weeks 3 and 4; then, the resection surgery was performed 2 weeks after the neoadjuvant chemotherapy was finished. Notably, 160 mg/m2 was determined as the enhanced dosage of CDDP for tumors with the longest diameter over 8 cm in CE-MRI slices. In addition, IV IFO at 2 g/m2/d for 5 days was given in Week 5 for tumors over 8 cm after the 4-week routine regimen was completed. Central venous catheterization for MSC administration was performed under inhalation anesthesia if necessary. Before each CAI regimen, percutaneous punctuation of the femoral artery was performed using the Seldinger technique, and the catheter was inserted from the femoral artery of the contralateral side to the beginning of the artery trunk supplying the tumor with the assistance of CT-guided positioning.21 Then, CT arterial angiography was conducted. Each course of MSC and CAI was accompanied by IV hydration, diuretics, rescue and protecting drugs. The CDDP was perfused via the catheter with chemotherapy pumps (LimLess Infusion Pump; PFM Medical Inc, Cologne, Germany) in a pulsed manner (Bolus dose administrator; PFM Medical Inc, Cologne, Germany). The patients were asked to have strict bed rest under multiparameter monitoring. Routine blood tests for electrolytes and hepatic and renal function were performed on the first day after drug administration and every 3 days thereafter.Figure 1 The individualized pelvic osteosarcoma treatment protocol combined cisplatin arterial infusion, multidrug systematic chemotherapy and resection surgery (CAI + MSC + S).
To evaluate the therapeutic response, primary plain X-ray (Figure 2A) and physical examination parameters of the tumor, including pre- and postchemotherapy size, tenderness, pain and inflammation, were collected. More importantly, CE-MRI was performed to monitor the tumor chemotherapy response before and after routine neoadjuvant CAI + MSC administration. (Figure 2B–E) According to the RECIST 1.1 guidelines, tumor size was calculated in gadolinium-enhancing T1-weighted fat‐saturated coronal images using the following criteria: complete response (CR), complete elimination of target lesion; partial response (PR), ≥30% decrease in the diameter of target lesion compared to baseline); progressive disease (PD), ≥20% increase in the diameter of target lesion compared to baseline or new metastatic lesion); and stable disease (SD) or observed changes in the diameter of the target lesion between 30% decrease and 20% increase compared to baseline. Each tumor lesion was assessed by orthopedic oncologists and interventional radiologists who were blinded to the treatment allocation and clinical outcome data. For patients who achieved PD after the routine neoadjuvant regimen was finished, surgery was performed immediately. For patients who demonstrated CR or PR, surgery was performed 2 weeks after the neoadjuvant regimen as usual. For patients who presented SD, the same IFO course as that mentioned in the adjustment for large tumors was added to maximize the tumor response of the neoadjuvant regimen. Then, a multidisciplinary consultation was conducted to identify the achievement of maximal tumor response. If any uncertainty of maximal response achievement was left, one more course of IFO could be given, and patients received resection surgery no later than 9 weeks after the first diagnosis.Figure 2 (A) Pelvis X-ray of a 36-year-old female with an osteosarcoma in the pubis. (B) and (C) Fat-saturated T1- and T2-weighted coronal slices of contrast-enhanced MRI showing the maximum diameter of the tumor at the first diagnosis, which showed heterogeneous enhancement, thick septa and obscure boundaries of the tumor. (D) and (E) MRI reevaluation after completion of the neoadjuvant CAI + MSC regimen, showing thin septa, clear boundaries and stable disease according to RECIST 1.1 with a decrease in the tumor diameter. (F) Pelvis plain X-ray of this patient. (The identifiable captions in these images are occluded.).
A chest CT scan, a full-body bone scan and a pelvic CE-MRI scan (Figure 2D and E) were repeated before surgery. The tumor response per RECIST 1.1 measured in the last CE-MRI examination was compared with the baseline level. Surgical excision extension was determined by the involved scope of the tumor and the tumor response category according to the CE-MRI assessment per RECIST 1.1. The pelvic reconstruction project depended on the morbidity site, excision extension, bone mineral density and functional requirements.
In case of uncontrollable hemorrhage during the resection surgery, a temporary balloon blocking technique for the abdominal aorta was performed under the guidance of CTA 4 hours before resection surgery. A balloon compatible in size to the abdominal aortic diameter was placed intraarterially at the level of 2 to 3 cm above the bifurcation of the common iliac arteries. The injection of saline with 0.1% heparin inflated the balloon, consequently blocking blood perfusion of the surgical site. Angiography was performed to confirm the satisfactory blockage of the iliac arteries and unobstruction of the renal arteries. Then, the balloon was deflated until the surgery began. Each deflation was performed with an interval of 60 min during the resection surgery before satisfactory hemostasis was achieved.
Histopathologic examination was conducted using the method reported by Huvos et al to quantify the necrosis ratio of the tumor after removal.22 Patients with a ≥90% tumor necrosis rate (TNR) (Grade III and IV) were classified as good responders. The other (Grade Ⅰ and Ⅱ) were deemed poor responders.
The postoperative IV chemotherapy cycle was repeated every 3 weeks. The recovery of hematopoietic function in patients was required before each course, which was defined as a white blood cell count over 1×104/mm3 and a platelet count over 5×106/mm3 for 3 successive days without hematopoietic stimulants. For good responders, the duration of postoperative MSC was usually 3 courses, which could be extended to the maximum of 6 courses accompanied by the existence of high-risk factors, including SD or PD in the CE-MRI per RECIST 1.1 before surgery or histology-proven tumor involvement in the surgical margin (R1 resection). For poor responders, IFO at 2 g/m2/d for 5 days and etoposide (ETOP) at 100 mg/m2/d for 5 days were given sequentially as one cycle repeated every 3 weeks for 6 cycles.23
After the planned treatment was finished, the discontinuation of chemotherapy was allowed by the orthopedic oncologist if X-ray (Figure 2F) and CE-MRI of the primary morbidity site along with chest X-ray every 2 months, chest CT scanning every 6 months in the first year off the treatment prove no local recurrence or lung metastasis. Routine blood tests and hepatic and renal function tests were deployed every week until the recovery of hematopoietic function.
Statistical Analysis
We used the Kaplan-Meier method to analyze the overall survival (OS) and EFS, which were calculated from the day the preoperative MSC + CAI regimen began. The events were defined as local recurrence, distant metastasis or death from the disease. Additionally, the OS and EFS in groups with different histopathologic chemotherapy responses or tumor sizes were calculated. All statistical analyses were conducted with SPSS software packages (SPSS Inc., Chicago, IL, USA).
Results
Chemotherapy Response
Significant improvement in physical examination parameters was observed in 10 of 12 patients after the neoadjuvant regimen, including alleviation of pain. In terms of tumor response measurement per RECIST 1.1, 4 patients had PR and 5 had SD after routine neoadjuvant CAI + MSC administration. Three patients had to undergo resection surgery ahead of schedule because of PD, as shown by CE-MRI after neoadjuvant CAI + MSC administration. No patient demonstrated CR.
According to the histopathologic assessment, 66.7% (8 of 12) of patients demonstrated TNR over 90%. One of the 3 patients with PD according to the CE-MRI assessment turned out to be good responders with Grade III histopathologic results.
Surgery
Three patients underwent local radical excision and lower limb amputation because of neurovascular bundle involvement. The remaining 9 patients received limb salvage surgery followed by pelvic reconstruction using a modular prosthesis (Lidakang Inc., Beijing, China), tumor bone devitalization and replantation, or just bone fusion. As a result, 1 patient who underwent primary limb salvage surgery developed local recurrence and underwent secondary amputation and local reresection. Two patients had surgical site infections but were cured 2 months after surgery. One patient who developed a periprosthetic infection underwent a secondary amputation.
Survival
A total of 58.3% of patients (7 of 12) remained continuously disease free in an average follow-up period of 65.1 months (range, 34–93 months). One patient who developed local recurrence was proven alive with no evidence of disease for 31 months after receiving a secondary amputation and resection. Four patients (3 lung metastases and 1 local recurrence) died of refractory disease progression. Kaplan-Meier survival analysis suggested an OS rate of 57.8% and an EFS of 52.5% at 5 years (Figure 3). For patients with a good chemotherapy response, the 5-year OS and EFS rates were 68.6%, both of which showed significant differences (P = 0.04 for OS and 0.01 for EFS) compared with the corresponding measures for poor responders (Table 2). The comparison of patients with tumor sizes greater (n = 4) or less (n = 8) than 8 cm did not yield statistical significance (P = 0.32 and 0.13, respectively). As shown in the pathological report, 75% (9 of 12) patients received R0 resection and 25% (3 of 12) had R1 resection. There was no significant difference in the OS but in the EFS between patient group with R0 or R1 surgical resection (P = 0.15 and 0.05, respectively). The confidence interval of all OS and EFS are 95%.Table 2 Overall Survival (OS) and Event-Free Survival (EFS) Rate
Variables 1 y 5 y
All patients – OS 91.7% 57.8%
All patients – EFS 91.7% 52.5%
Good responders – OS 100.0% 68.6%
Good responders – EFS 100.0% 68.6%
Poor responders – OS 75.0% 50.0%
Poor responders – EFS 75.0% 25.0%
Patients with tumor size ≥8 cm – OS 75.0% 50.0%
Patients with tumor size ≥8 cm – EFS 75.0% 25.0%
Patients with tumor size<8 cm – OS 100.0% 62.5%
Patients with tumor size<8 cm – EFS 100.0% 64.3%
R0 resection – OS 85.7% 70.0%
R0 resection – EFS 88.9% 71.1%
R1 resection – OS 66.7% 33.3%
R1 resection – EFS 66.7% 33.3%
Note: Confidence Interval = 95%
Figure 3 The Kaplan-Meier survival curve for overall survival (OS) and event-free survival (EFS) rates of 12 pelvic osteosarcoma patients treated with the CAI + MSC + S protocol.
Chemotherapy Toxicity
We recorded the adverse effects referred to in the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.24 The statistics of CAI-related adverse events are summarized in Table 3. Three of 12 patients had local adverse events, including grade 1 to 2 skin pelvic soft tissue necrosis in muscle and hyperpigmentation, which exhibited no effect on the surgical method choice or wound healing. Nausea and vomiting were the most common systematic adverse events, with 41.7% of patients developing grade 3 events. A 36-year-old female received a reduced dosage of MTX (7 g/m2) due to intolerable vomiting after the first MTX course. Four of 12 patients developed grade 1 infusion-related reactions.Table 3 Statistics of CAI-Related Adverse Events
Adverse Events No. of Courses Percentage of Patients with Grade 3–4 Adverse Events
Skin hyperpigmentation 12.5% (3/24) 0% (0/12)
Pelvic soft tissue necrosis (muscle) 4.2% (1/24) 0% (0/12)
Pelvic pain 16.7% (4/24) 8.3% (1/12)
Nausea and vomiting 75.0% (18/24) 41.7% (5/12)
Anemia 8.3% (2/24) 8.3% (1/12)
Increase in creatinine level 8.3% (2/24) 0% (0/12)
Increase in aminotransferase level 4.2% (1/24) 0% (0/12)
Infusion related reaction 29.2% (7/24) 0% (0/12)
During the postoperative MSC period, one 12-year-old child complained of grade 1 palpitations and chest pain. Therefore, we replaced ADM with ETOP, and the complaint disappeared with no evidence reported in Doppler echocardiography. Three patients out of 12 developed grade 1 to 2 increases in alanine/aspartate aminotransferase levels.
Three children developed oral mucositis at grade 2 to 3, 2 of whom were under IV nutrition, and one used a mouth rinse with metronidazole to treat thrush. All patients eventually resumed normal oral food intake.
Blood system disorders were commonly noted in patients after the second cycle of postoperative MSC administration. Three patients developed febrile neutropenia and were treated by injection of recombinant human granulocyte stimulating factor.
Discussion
Conventional IV adjuvant chemotherapy and neoadjuvant chemotherapy have been applied extensively in multimodal osteosarcoma treatment for over 45 years.25 Though changes in drug combination, dosage, and administration duration were made to optimize the regimen, no significant improvement was achieved based on the approximately 50% to 70% 5-year OS and EFS rates in the past decade.26–28 As a modified approach to augment the potential of chemotherapy drugs, the AI technique combined with MSCs has been studied for years.13,29,30 In the present study, we attempted to investigate the therapeutic effect of the CAI + MSC + S protocol in osteosarcoma treatment. The 5-year OS and EFS rates were 57.8% and 52.5%, respectively.
The CAI regimen and its outcome measurements were first documented by Jaffe et al in 1983.31 Then, a series of studies concerning CAI-facilitated multidrug chemotherapy followed.13,30,32–37 Information on all 9 studies, including the present study, is listed in Table 4.Table 4 Synopsis of IA CDDP Information Reported in the Literature
Authors Type of Study No. of Patients Ages (y) Sites Metastases Preoperative CDDP Courses No. >90% TN OS EFS
Winkler et al and Fuchs et al30,34 Nonrandomized, 2 arms 50 <40 All Included 2 68% 67% at 10 y 63% at 10 y
Ferrari et al33 Single arm 164 <40 Extremity Excluded 2 NA 72% at 8 y 63% at 8 y
Ferrari et al33 Randomized, 2 arms 59 <40 Extremity Excluded 2 64% 61% at 8 y 54% at 8 y
Rha et al35 Single arm 37 8~41 Extremity ? 3 75% 78% at 3 y 55% at 3 y
Bacci et al32 Randomized, 2 arms 40 <40 Extremity Included 2 77% NA 26% at 5 y
Bacci et al32 Randomized, 2 arms 72 <40 Extremity Included 2 80% NA 61% at 5 y
Wilkins et al37 Single arm 47 <21 Extremity Excluded 3–5 (response dependent) 87% 92% at 10 y 84% at 10 y
Wilkins et al36 Single arm 62 <22 Extremity Excluded 3–5 (response dependent) 87% 93% at 10 y 86% at 10 y
Xie et al13 Nonrandomized, 2 arms 48 NA Extremity Included 3 63% 64% at 5 y 60% at 5 y
Hu et al (Current study) Single arm 12 11~69 Pelvis Excluded 2 66.7% 57.8% at 5 y 52.5% at 5 y
Abbreviations: IA, intraarterial; CDDP, cisplatin; TN, tumor necrosis; OS, overall survival; EFS, event-free survival.
Among these 9 studies, 8 used CAI and systematic chemotherapy sequentially before surgery, and 5 studies scheduled a 2-course preoperative regimen. Six of 9 studies suggested a higher chemotherapy response rate and/or survival rate in the CAI group compared with the IV CDDP group; 2 of these investigations were 2-arm randomized cohort studies and reported a statistically significant improvement in the good-response ratio (21% and 31%, respectively). In the third randomized cohort study reported by Rha et al, the improvement was not statistically significant, probably because the limited sample size was insufficient to test the 9% difference between the two groups.35 In the multicenter study reported by Winkler et al and Fuchs et al in the 1990s, no difference in chemotherapy response was observed between the intraarterial and IV CDDP groups.30,34 Similarly, Xie et al also proved a superior histological response rate but equivalent survival in the CAI group versus the IV group in 2019.13 However, the reliability of the conclusions in the 2 studies may be impaired by the nonrandomized grouping design conducted at the researchers’ discretion, which could be affected by the severity of disease. Although CAI may bring benefits to chemotherapy response augmentation and survival rates in limb osteosarcoma patients, how pelvic osteosarcoma reacts to CAI-facilitated multidrug chemotherapy remains elusive.
Pelvic tumor resection surgeries such as hemipelvectomy are notoriously known as one of the most destructive operations in modern orthopedic surgery.38 Due to the adjacency of the vascular network, nerves and viscera in the pelvis, surgeons have to weigh tumor eradication against functional preservation in the determination of the extent of surgical excision. This dilemma makes the treatment more challenging. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate compared with the extremity-morbidity population, which could be explained by the higher rate of not only failure of surgical remission but also advanced age, large tumor size, primary metastasis, prolonged latency periods and poor chemotherapy responses.11,39 Thus, it is critical to maximize the chemotherapy response and achieve better survival outcomes in pelvic osteosarcoma patients.
The combination of agents in our MSC protocol was determined by reference to NCCN guidelines for bone cancer and the study reported by Xie et al.13 Although the agent numbers and categories differed, all of the above-reviewed studies and the present study deployed a multidrug protocol to treat tumor cells in different phases of the cell cycle. Unfortunately, insufficient data are available to appropriately compare the therapeutic effect of CAI alone or in various combinations with MTX, VCR, ADM and IFO because of great heterogeneity. In the present study, we used high-dose MTX at 10 g/m2 and CAI at 120 mg/m2 in 2 doses as routine preoperative treatment. For patients with tumors over 8 cm, we employed an enhanced dose of CAI at 160 mg/m2. Additionally, additional IFO courses were given to slow responders. This individualized regimen directly yielded a 66.7% prevalence of good histopathologic responders and contributed to the 5-year survival rate of 57.8% in pelvic osteosarcoma. Both of the two figures were seemingly improved when compared to those from conventional systematic chemotherapy.11
The cumulative dosage of CDDP was 780 mg/m2 for a good responder with a tumor size ≤ 8 cm in the present study. Wilkins et al reported the highest accumulated dose of CDDP at 960 mg/m2 and a single dose at 160 mg/m2 over 24 h as an enhanced regimen for patients with tumors over 10 cm versus 120 mg/m2 over 6 h as routine, which consequently yielded the highest 10-year OS and EFS rates (93% and 86%, respectively) among all reviewed studies. Notably, Ferrari et al and Xie et al investigated CDDP administration at equivalent doses to those in the present study but yielded poorer survival outcomes seemingly.13,33 This may be because 120 mg/m2 CDDP was given intraarterially in 72 h in the first study, which is too long to achieve a high enough blood concentration; patients with tumor metastases at the initial diagnosis were included in the second study so that the survival rate would be reduced. We used relatively high-dose CDDP administered over 3 to 6 h combined with 4 other drugs, including ETOP, and made individualized adjustments to the protocol for patients with high-risk factors. This may have contributed to the 57.8% OS and 52.5% EFS rate at 5 years, which is favorable for pelvic osteosarcoma. Moreover, we discovered that the OS and EFS rates in the population with tumors ≤ or >8 cm showed insignificant differences. Patients who received R0 resection also shared equivalent OS but higher EFS with R1 patients. These finding suggest that this protocol with risk-dependent adjustment in the drug dosage and combination could be beneficial to bridge the gap in survival rate between patients with large or small tumors, and those who received R0 or R1 resection.
We noticed that 3 of 5 cases developing SD turned out to demonstrate TNR >90%, which probably means that good response of osteosarcoma is not necessarily accompanied with tumor size decrease. This may be attributed to the formation of tumor bone generated by subtypes like osteoblastic osteosarcoma, which could prevent tumors from shrinkage.40
Only 4 poor responders were observed, 3 of whom developed tumor relapses. Two of the 3 patients died of metastasis during postoperative MSC; another showed no evidence of disease after receiving secondary amputation and resection for local recurrence. This protocol seemed to provide limited benefit to the poor responders. However, the present data are so limited that few tenable conclusions can be drawn from it to guide salvage treatment for poor responders.
Although the AI technique and additional courses were given in this protocol, no patients received an overdose of chemotherapy drugs compared with previous studies using similar drug combinations. No AI-relative grade 4 or 5 adverse events were observed. Although systematic adverse events, including nausea, vomiting, anemia and an increase in creatinine/aminotransferase levels, shared equivalent incidence rates and severities with the study reported by Xie et al, local skin hyperpigmentation and pelvic soft tissue necrosis in muscle occurred after only 3 and 1 of 24 CAI events (12.5% and 4.2%, respectively), which is more favorable than the situation reported in the most reviewed studies concerning extremity osteosarcoma.13,30,33 This finding could be explained by the shorter local drug-retention time since the pelvis has a more sufficient blood supply and drainage.
In terms of the postoperative MSC regimen for poor responders, we determined the IFO + ETOP regimen by reference to the second-line chemotherapy recommended in NCCN guidelines for bone cancer, which is supported by the study reported by Goorin et al and Miser et al.23,41 These two studies were conducted in patients with initial metastasis or recurrence of osteosarcoma, and the former one used IFO + ETOP as an induction regimen accompanied by surgical resection and continuation MSC of MTX + ADM + ETOP + IFO. Therefore, we adopted the regimen similar as the one reported by Miser et al However, the study of EURAMOS reported by Marina et al suggested that treatment with MTX + ADM + CDDP + IFO + ETOP resulted in similar EFS to MTX + ADM + CDDP and increased toxicity. In the present study, we found it hard for patients to accept 12 cycles of second-line therapy in 3 years in view of the high expenditure and physical discomfort. Therefore, the number of cycles was reduced to 6 for poor responders, which is equivalent to a half of the regimen of Miser et al in accumulative dosage and duration time. During the postoperative MSC period, there was no early death. The reported cardiac irritation, increase in creatinine/aminotransferase, oral mucosa inflammation and hematologic system abnormality were acceptable. In summary, our chemotherapy regimen seems to be well tolerated.
To monitor the chemotherapy response, several methods have been reported in previous studies. In the studies reported by Winkler et al and Fuch et al, plain X-ray, local CT and emission CT of bone were used to monitor the TNR before the surgery.30,34 Bacci et al, Wilkins et al and Xie et al deployed CT arterial angiography, which yielded sensitivity and specificity over 90% and 50%, respectively.13,32,36,37 Nevertheless, a repeated CT arterial angiography assessment is difficult to be accepted by patients because it requires multiple invasive operations and high expenditure. RECIST-1.1-based MRI remains one of the most commonly used approaches in tumor response evaluation.42,43 In the present study, we used CE-MRI to detect the tumor response and guide the adjustment of treatment for each patient. Although the results did not seem to suggest that this method is highly predictive of the histopathologic chemotherapy response, the equivalent survival rate between patients with large and small tumors may reflect the effectiveness of the individualized treatment.
There were several limitations in our investigation. First, the design was restricted to a small-sample-size single-arm clinical study due to the rarity of pelvis osteosarcoma morbidity, therefore reducing the reliability of the conclusions. Second, several previous studies reported that pathological subtypes of osteosarcoma, such as chondroblastic and telangiectatic osteosarcoma, respond differently to chemotherapy.39,44 However, the pathological subtype of each patient was not analyzed as an independent prognostic factor in our study. Heterogeneity of the osteosarcoma subtype constitution could distort chemotherapy response and survival outcomes. Third, we used CE-MRI per RECIST 1.1 to monitor the tumor response before surgery and guide the individualized adjustment of the treatment protocol. However, CE-MRI evaluation was not the gold standard for TNR prediction. Multiple innovative approaches for TNR prediction in osteosarcoma have been researched in the past 30 years, such as dynamic CE-MRI with sensitivity and specificity over 70% and 80%, respectively, according to previous studies.45–47 We would attempt to deploy approaches with higher accuracy to evaluate viable tumors in hope of providing more precise guidance for individualized pelvic osteosarcoma treatment in further studies.
Conclusions
In the present study, we employed CAI in the multimodal treatment of pelvic osteosarcoma patients. Our findings suggest that the CAI-facilitated chemotherapy regimen demonstrated great potential for improving the survival of patients with pelvic osteosarcoma. This treatment protocol yielded high tolerance with acceptable adverse effects. However, further randomized controlled trials with large sample sizes are required to elucidate the findings of this preliminary study.
Acknowledgments
We would like to thank all patients for their devotion to taking unidentified risks in this clinical trial. We are also grateful to the participating orthopedic oncologists and interventional radiologists for their prudence and patience in the therapeutic effect evaluation and the multidisciplinary consultation.
Abbreviations
ADM, adriamycin; CAI, effect of cisplatin arterial infusion; CDDP, cis-diamine-dichloro platinum; CE-MRI, contrast-enhanced MRI; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; EFS, event-free survival; ETOP, etoposide; IFO, ifosfamide; IV, intravenous; MSC, multidrug systematic chemotherapy; MTX, methotrexate; OS, overall survival; PD, progressive disease; PR, partial response; RECIST, response evaluation criteria in solid tumors version; S, surgery; SD, stable disease; TNR, tumor necrosis rate; VCR, vincristine.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics Approval and Informed Consent
This study was approved by the ethics committees and the institutional review board of the Second Xiangya Hospital. All patients provided written informed consent for receiving this treatment protocol. The requirement of obtaining specific informed consent for this retrospective study was waived for the reason mentioned before.
Consent for Publication
This study conforms to Declaration of Helsinki. The requirement of obtaining specific informed consent from the patients for the publication of the case presentation and any accompanying images.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
No commercial sponsorship was involved in any part of this study. The authors report no conflicts of interest related to this work. | CISPLATIN, DOXORUBICIN HYDROCHLORIDE, METHOTREXATE SODIUM, VINCRISTINE | DrugsGivenReaction | CC BY-NC | 33623429 | 19,834,550 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pelvic pain'. | Effect of Cisplatin Arterial Infusion (CAI) on Primary Nonmetastatic Pelvic Osteosarcoma: A Preliminary Study.
The critical role of arterial infusion chemotherapy in the multimodal treatment of extremity bone cancer has been investigated extensively, but few studies have focused on pelvic osteosarcoma. Therefore, we attempted to evaluate the clinical significance of arterial infusion chemotherapy in the treatment of pelvic osteosarcoma.
We combined a cisplatin arterial infusion regimen with multidrug systematic chemotherapy as a neoadjuvant protocol for the treatment of pelvic osteosarcoma. The course number and dosage of cisplatin arterial infusion were adjusted to achieve a maximal tumor response evaluated by contrast-enhanced MRI per RECIST 1.1. Good responders received the same systematic combination for postoperative chemotherapy, and poor responders received second-line therapy. Twelve patients with nonmetastatic high-grade pelvic osteosarcoma were included. Survival, chemotherapy response and adverse events data were analyzed.
The mean follow-up period was 56.1 months. Four patients died of refractory tumor progression, and 1 patient with local recurrence had no evidence of disease for 27 months after receiving secondary amputation and resection. Kaplan-Meier survival analysis demonstrated a 57.8% overall survival and 52.5% event-free survival rate at 5 years. Eight of 12 patients had a >90% tumor necrosis rate according to histopathologic examinations. The rates of local adverse events were lower than those reported for extremity osteosarcoma.
Our study initially indicated that the cisplatin arterial infusion regimen was a potential therapy with good tolerance in the treatment of pelvic osteosarcoma.
Introduction
Osteosarcoma is the most common solid malignant tumor of bone with a highly aggressive behavior.1 The most susceptible age of osteosarcoma is bimodal, which is characterized by one peak at 10-to-20 years and another at over 60 years.2,3 Although this disease endangers the health of both adolescent and aged populations, limited progress has been made to improve survival and functional prognosis, especially in patients with pelvic osteosarcoma.4–6 Osteosarcoma patients treated with mere immediate surgical resection register a recurrence rate up to 60–90%.7 (Since 1980s, traditional adjuvant intravenous (IV) systematic chemotherapy produces an improved five-year event-free survival (EFS) rate of 61%.8 In the early 2000s, the propagation of a multidrug neoadjuvant chemotherapy regimen elevated this rate to 60% and above.9,10) Henceforth, numerous explorations have been conducted to optimize the category, dosage, combination and duration of chemotherapy drug administration. The most recent studies of EURAMOS revealed a 5-year EFS of 65–70% for localized osteosarcoma treated by multidrug neoadjuvant chemotherapy. However, there are few studies focusing on arterial infusion as an improved method and its clinical outcome in the treatment of pelvic osteosarcoma.
Osteosarcoma in pelvic bone is more notorious than that in extremities. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate than those with extremity lesions, which may be associated with a poor chemotherapy response and an inability to achieve adequate surgical resection.11 Therefore, more challenges are faced in the management of pelvic osteosarcoma.
Platinum complexes, such as cis-diamine-dichloro platinum (cisplatin, CDDP), have been proven to be cell cycle-nonspecific agents and to have multiple broad-spectrum antitumor effects.12 Several clinical trials reported that employing an arterial infusion technique to deliver CDDP, in combination with an IV systematic chemotherapy regimen or not, can elevate the local drug concentration to fivefold that of IV administration and can produce better survival in the treatment of extremity osteosarcoma.13–15 Therefore, the arterial infusion of CDDP might have potential in the treatment of pelvic osteosarcoma.
The histopathologic response of surgically removed tumors has been shown to be one of most critical indicators of chemotherapeutic effectiveness and survival prognosis.16,17 However, preoperative examination is more valuable to predict tumor response and allow individualized neoadjuvant chemotherapy. Response evaluation criteria in solid tumors version 1.1 (RECIST 1.1), which was commonly adopted for the tumor-response evaluation of a variety of cancers, affirmed the value of sectional radiological imaging measurement.18–20 Therefore, preoperative contrast-enhanced MRI (CE-MRI) evaluation based on RECIST 1.1 is expected to guide the adjustment of treatment for optimal surgical timing in pelvic osteosarcoma.
Given all these findings, we combined CDDP arterial infusion (CAI) with individualized multidrug systematic chemotherapy (MSC) and surgery (S) to treat nonmetastatic pelvic osteosarcoma and attempted to investigate (1) the chemotherapy response and survival yielded from this protocol, (2) the individualized adjustment of the neoadjuvant MSC regimen necessary to achieve the maximal tumor response according to RECIST-1.1-based CE-MRI reassessment, and (3) the potential adverse effects caused by the arterial infusion technique and the multidrug systematic chemotherapy regimen.
Patients and Methods
Study Design and Consent
This is a retrospective cohort study (Level III evidence) in which subjects received a protocol comprising multidrug systematic chemotherapy, cisplatin arterial infusion and resection surgery (CAI + MSC + S). The study design conformed with the Declaration of Helsinki, and the treatment protocol was approved by the hospital institutional review board. All patients provided written informed consent for receiving this treatment protocol. All data used in the present study were obtained from the electronic medical records of our hospital and treated with strict confidentiality; therefore, the requirement of obtaining specific informed consent for this retrospective study was waived.
Patients
Inclusion criteria for subjects included (1) histopathologically defined primary osteosarcoma of pelvic bone; (2) no metastatic foci; (3) no past history of cancer treatment; and (4) normal cardiac, hepatic and renal function. All patients were confirmed to have high-grade osteosarcoma morbidity via biopsy. Pretreatment baseline safety indexes were determined with routine blood tests, hepatic and renal function tests, and Doppler echocardiography. A peripherally inserted central catheter was placed in each patient for the IV administration of neoadjuvant chemotherapy agents.
From January 2010 to June 2015, 21 patients were consecutively diagnosed with osteosarcoma of the pelvic bones in our work unit. A total of 4 patients were excluded for the following reasons: 2 patients had evidence of distant metastasis, and 2 tumors involved the femur or lumbar vertebra. Among the eligible people, 2 refused to take CAI + MSC + S treatment: 1 had hemophilia with severely impaired coagulation function; 1 intended to transfer to another hospital after being definitively diagnosed via biopsy. Subsequently, 15 patients took the CAI + MSC + S treatment, but 1 of them stopped midway (because of intolerance to vomiting as the adverse effect in the first two rounds of IV multidrug therapy) and turned to other treatment. Two patients were lost to follow-up after surgical resection. Eventually, 12 patients finished the treatment protocol and yielded analyzable data for survival, chemotherapy response and toxicity assessment.
The data of these 12 patients are listed in Table 1. The study population consisted of 7 (58.3%) males and 5 (41.7%) females with an average age of 28.8 years (11 to 69 years). The morbid sites included the pubis (n = 2), ilium (n = 4), ischium (n = 1), sacrum (n = 1) and unclear sites (n = 4).Table 1 Patient Data
Case No. Age (y) Sex Tumor Size (cm) Morbid Site MRI Tumor Response Before Surgery Surgical Margins Histopathologic Response Diagnosis Date Surgery Type Follow-Up (Month) First Relapse Status
1 62 F <8 Unclear +27.4%, PD R0 <90% 5/19/2010 1 42 CDF
2 19 M <8 Ilium −35.1%, PR R0 >90% 10/4/2010 2 46 Jan. 2014 DOD
3 14 M <8 Unclear +14.6%, SD R0 95% 7/23/2011 2 52 CDF
4 53 F >8 Sacrum −7.3%, SD R1 <90% 6/30/2012 4 57 Feb. 2015 NED
5 15 M <8 Ilium −32.7%, PR R0 >90% 10/28/2012 2 93 CDF
6 21 F 7 Ilium +25.9%, PD R0 >90% 4/24/2013 2 87 CDF
7 16 M >8 Unclear +8.6%, SD R1 <90% 9/22/2013 2 37 Aug. 2015 DOD
8 36 F 9 Pubis −24.1%, SD R0 >90% 4/14/2014 2 76 CDF
9 69 M 12 Ischium +43.7% PD R1 <90% 5/17/2014 3 15 Jan. 2015 DOD
10 12 F <8 Unclear −37.4%, PR R0 99% 8/21/2014 2 72 CDF
11 41 M <8 Pubis +33.5%, PR R0 >90% 3/6/2015 2 34 CDF
12 47 M <8 Ilium +16.6%, SD R0 95% 6/30/2015 2 62 Dec. 2019 DOD
Notes: Surgical type = 1) primary lower limb amputation; 2) lower limb salvage surgery; 3) secondary amputation and reresection due to local recurrence; 4) revision surgery due to periprosthetic infection.
Abbreviations: CAI, cisplatin arterial infusion; PR, partial response; PD, progressive disease; SD, stable disease; CAP, cisplatin arterial perfusion; CDF, continuously disease free; NED, no evidence of disease; DOD, died of disease.
Description of the Study Treatments and Outcome Measures
The adopted CAI + MSC + S treatment protocol is depicted in Figure 1. In general, MSCs usually consist of high-dose methotrexate (MTX), vincristine (VCR), adriamycin (ADM), CDDP and ifosfamide (IFO). Specifically, the routine CAI + MSC regimen was initiated with 24-hour continuous IV dripping of high-dose MTX at 10 g/m2 followed by 2 mg IV VCR the next day for the first group at Week 0; in Week 2, 120 mg/m2 CDDP AI over 3 to 6 hours and following 30 mg/m2/d IV ADM for 2 days were given to the second group; these 2 groups were repeated in Weeks 3 and 4; then, the resection surgery was performed 2 weeks after the neoadjuvant chemotherapy was finished. Notably, 160 mg/m2 was determined as the enhanced dosage of CDDP for tumors with the longest diameter over 8 cm in CE-MRI slices. In addition, IV IFO at 2 g/m2/d for 5 days was given in Week 5 for tumors over 8 cm after the 4-week routine regimen was completed. Central venous catheterization for MSC administration was performed under inhalation anesthesia if necessary. Before each CAI regimen, percutaneous punctuation of the femoral artery was performed using the Seldinger technique, and the catheter was inserted from the femoral artery of the contralateral side to the beginning of the artery trunk supplying the tumor with the assistance of CT-guided positioning.21 Then, CT arterial angiography was conducted. Each course of MSC and CAI was accompanied by IV hydration, diuretics, rescue and protecting drugs. The CDDP was perfused via the catheter with chemotherapy pumps (LimLess Infusion Pump; PFM Medical Inc, Cologne, Germany) in a pulsed manner (Bolus dose administrator; PFM Medical Inc, Cologne, Germany). The patients were asked to have strict bed rest under multiparameter monitoring. Routine blood tests for electrolytes and hepatic and renal function were performed on the first day after drug administration and every 3 days thereafter.Figure 1 The individualized pelvic osteosarcoma treatment protocol combined cisplatin arterial infusion, multidrug systematic chemotherapy and resection surgery (CAI + MSC + S).
To evaluate the therapeutic response, primary plain X-ray (Figure 2A) and physical examination parameters of the tumor, including pre- and postchemotherapy size, tenderness, pain and inflammation, were collected. More importantly, CE-MRI was performed to monitor the tumor chemotherapy response before and after routine neoadjuvant CAI + MSC administration. (Figure 2B–E) According to the RECIST 1.1 guidelines, tumor size was calculated in gadolinium-enhancing T1-weighted fat‐saturated coronal images using the following criteria: complete response (CR), complete elimination of target lesion; partial response (PR), ≥30% decrease in the diameter of target lesion compared to baseline); progressive disease (PD), ≥20% increase in the diameter of target lesion compared to baseline or new metastatic lesion); and stable disease (SD) or observed changes in the diameter of the target lesion between 30% decrease and 20% increase compared to baseline. Each tumor lesion was assessed by orthopedic oncologists and interventional radiologists who were blinded to the treatment allocation and clinical outcome data. For patients who achieved PD after the routine neoadjuvant regimen was finished, surgery was performed immediately. For patients who demonstrated CR or PR, surgery was performed 2 weeks after the neoadjuvant regimen as usual. For patients who presented SD, the same IFO course as that mentioned in the adjustment for large tumors was added to maximize the tumor response of the neoadjuvant regimen. Then, a multidisciplinary consultation was conducted to identify the achievement of maximal tumor response. If any uncertainty of maximal response achievement was left, one more course of IFO could be given, and patients received resection surgery no later than 9 weeks after the first diagnosis.Figure 2 (A) Pelvis X-ray of a 36-year-old female with an osteosarcoma in the pubis. (B) and (C) Fat-saturated T1- and T2-weighted coronal slices of contrast-enhanced MRI showing the maximum diameter of the tumor at the first diagnosis, which showed heterogeneous enhancement, thick septa and obscure boundaries of the tumor. (D) and (E) MRI reevaluation after completion of the neoadjuvant CAI + MSC regimen, showing thin septa, clear boundaries and stable disease according to RECIST 1.1 with a decrease in the tumor diameter. (F) Pelvis plain X-ray of this patient. (The identifiable captions in these images are occluded.).
A chest CT scan, a full-body bone scan and a pelvic CE-MRI scan (Figure 2D and E) were repeated before surgery. The tumor response per RECIST 1.1 measured in the last CE-MRI examination was compared with the baseline level. Surgical excision extension was determined by the involved scope of the tumor and the tumor response category according to the CE-MRI assessment per RECIST 1.1. The pelvic reconstruction project depended on the morbidity site, excision extension, bone mineral density and functional requirements.
In case of uncontrollable hemorrhage during the resection surgery, a temporary balloon blocking technique for the abdominal aorta was performed under the guidance of CTA 4 hours before resection surgery. A balloon compatible in size to the abdominal aortic diameter was placed intraarterially at the level of 2 to 3 cm above the bifurcation of the common iliac arteries. The injection of saline with 0.1% heparin inflated the balloon, consequently blocking blood perfusion of the surgical site. Angiography was performed to confirm the satisfactory blockage of the iliac arteries and unobstruction of the renal arteries. Then, the balloon was deflated until the surgery began. Each deflation was performed with an interval of 60 min during the resection surgery before satisfactory hemostasis was achieved.
Histopathologic examination was conducted using the method reported by Huvos et al to quantify the necrosis ratio of the tumor after removal.22 Patients with a ≥90% tumor necrosis rate (TNR) (Grade III and IV) were classified as good responders. The other (Grade Ⅰ and Ⅱ) were deemed poor responders.
The postoperative IV chemotherapy cycle was repeated every 3 weeks. The recovery of hematopoietic function in patients was required before each course, which was defined as a white blood cell count over 1×104/mm3 and a platelet count over 5×106/mm3 for 3 successive days without hematopoietic stimulants. For good responders, the duration of postoperative MSC was usually 3 courses, which could be extended to the maximum of 6 courses accompanied by the existence of high-risk factors, including SD or PD in the CE-MRI per RECIST 1.1 before surgery or histology-proven tumor involvement in the surgical margin (R1 resection). For poor responders, IFO at 2 g/m2/d for 5 days and etoposide (ETOP) at 100 mg/m2/d for 5 days were given sequentially as one cycle repeated every 3 weeks for 6 cycles.23
After the planned treatment was finished, the discontinuation of chemotherapy was allowed by the orthopedic oncologist if X-ray (Figure 2F) and CE-MRI of the primary morbidity site along with chest X-ray every 2 months, chest CT scanning every 6 months in the first year off the treatment prove no local recurrence or lung metastasis. Routine blood tests and hepatic and renal function tests were deployed every week until the recovery of hematopoietic function.
Statistical Analysis
We used the Kaplan-Meier method to analyze the overall survival (OS) and EFS, which were calculated from the day the preoperative MSC + CAI regimen began. The events were defined as local recurrence, distant metastasis or death from the disease. Additionally, the OS and EFS in groups with different histopathologic chemotherapy responses or tumor sizes were calculated. All statistical analyses were conducted with SPSS software packages (SPSS Inc., Chicago, IL, USA).
Results
Chemotherapy Response
Significant improvement in physical examination parameters was observed in 10 of 12 patients after the neoadjuvant regimen, including alleviation of pain. In terms of tumor response measurement per RECIST 1.1, 4 patients had PR and 5 had SD after routine neoadjuvant CAI + MSC administration. Three patients had to undergo resection surgery ahead of schedule because of PD, as shown by CE-MRI after neoadjuvant CAI + MSC administration. No patient demonstrated CR.
According to the histopathologic assessment, 66.7% (8 of 12) of patients demonstrated TNR over 90%. One of the 3 patients with PD according to the CE-MRI assessment turned out to be good responders with Grade III histopathologic results.
Surgery
Three patients underwent local radical excision and lower limb amputation because of neurovascular bundle involvement. The remaining 9 patients received limb salvage surgery followed by pelvic reconstruction using a modular prosthesis (Lidakang Inc., Beijing, China), tumor bone devitalization and replantation, or just bone fusion. As a result, 1 patient who underwent primary limb salvage surgery developed local recurrence and underwent secondary amputation and local reresection. Two patients had surgical site infections but were cured 2 months after surgery. One patient who developed a periprosthetic infection underwent a secondary amputation.
Survival
A total of 58.3% of patients (7 of 12) remained continuously disease free in an average follow-up period of 65.1 months (range, 34–93 months). One patient who developed local recurrence was proven alive with no evidence of disease for 31 months after receiving a secondary amputation and resection. Four patients (3 lung metastases and 1 local recurrence) died of refractory disease progression. Kaplan-Meier survival analysis suggested an OS rate of 57.8% and an EFS of 52.5% at 5 years (Figure 3). For patients with a good chemotherapy response, the 5-year OS and EFS rates were 68.6%, both of which showed significant differences (P = 0.04 for OS and 0.01 for EFS) compared with the corresponding measures for poor responders (Table 2). The comparison of patients with tumor sizes greater (n = 4) or less (n = 8) than 8 cm did not yield statistical significance (P = 0.32 and 0.13, respectively). As shown in the pathological report, 75% (9 of 12) patients received R0 resection and 25% (3 of 12) had R1 resection. There was no significant difference in the OS but in the EFS between patient group with R0 or R1 surgical resection (P = 0.15 and 0.05, respectively). The confidence interval of all OS and EFS are 95%.Table 2 Overall Survival (OS) and Event-Free Survival (EFS) Rate
Variables 1 y 5 y
All patients – OS 91.7% 57.8%
All patients – EFS 91.7% 52.5%
Good responders – OS 100.0% 68.6%
Good responders – EFS 100.0% 68.6%
Poor responders – OS 75.0% 50.0%
Poor responders – EFS 75.0% 25.0%
Patients with tumor size ≥8 cm – OS 75.0% 50.0%
Patients with tumor size ≥8 cm – EFS 75.0% 25.0%
Patients with tumor size<8 cm – OS 100.0% 62.5%
Patients with tumor size<8 cm – EFS 100.0% 64.3%
R0 resection – OS 85.7% 70.0%
R0 resection – EFS 88.9% 71.1%
R1 resection – OS 66.7% 33.3%
R1 resection – EFS 66.7% 33.3%
Note: Confidence Interval = 95%
Figure 3 The Kaplan-Meier survival curve for overall survival (OS) and event-free survival (EFS) rates of 12 pelvic osteosarcoma patients treated with the CAI + MSC + S protocol.
Chemotherapy Toxicity
We recorded the adverse effects referred to in the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.24 The statistics of CAI-related adverse events are summarized in Table 3. Three of 12 patients had local adverse events, including grade 1 to 2 skin pelvic soft tissue necrosis in muscle and hyperpigmentation, which exhibited no effect on the surgical method choice or wound healing. Nausea and vomiting were the most common systematic adverse events, with 41.7% of patients developing grade 3 events. A 36-year-old female received a reduced dosage of MTX (7 g/m2) due to intolerable vomiting after the first MTX course. Four of 12 patients developed grade 1 infusion-related reactions.Table 3 Statistics of CAI-Related Adverse Events
Adverse Events No. of Courses Percentage of Patients with Grade 3–4 Adverse Events
Skin hyperpigmentation 12.5% (3/24) 0% (0/12)
Pelvic soft tissue necrosis (muscle) 4.2% (1/24) 0% (0/12)
Pelvic pain 16.7% (4/24) 8.3% (1/12)
Nausea and vomiting 75.0% (18/24) 41.7% (5/12)
Anemia 8.3% (2/24) 8.3% (1/12)
Increase in creatinine level 8.3% (2/24) 0% (0/12)
Increase in aminotransferase level 4.2% (1/24) 0% (0/12)
Infusion related reaction 29.2% (7/24) 0% (0/12)
During the postoperative MSC period, one 12-year-old child complained of grade 1 palpitations and chest pain. Therefore, we replaced ADM with ETOP, and the complaint disappeared with no evidence reported in Doppler echocardiography. Three patients out of 12 developed grade 1 to 2 increases in alanine/aspartate aminotransferase levels.
Three children developed oral mucositis at grade 2 to 3, 2 of whom were under IV nutrition, and one used a mouth rinse with metronidazole to treat thrush. All patients eventually resumed normal oral food intake.
Blood system disorders were commonly noted in patients after the second cycle of postoperative MSC administration. Three patients developed febrile neutropenia and were treated by injection of recombinant human granulocyte stimulating factor.
Discussion
Conventional IV adjuvant chemotherapy and neoadjuvant chemotherapy have been applied extensively in multimodal osteosarcoma treatment for over 45 years.25 Though changes in drug combination, dosage, and administration duration were made to optimize the regimen, no significant improvement was achieved based on the approximately 50% to 70% 5-year OS and EFS rates in the past decade.26–28 As a modified approach to augment the potential of chemotherapy drugs, the AI technique combined with MSCs has been studied for years.13,29,30 In the present study, we attempted to investigate the therapeutic effect of the CAI + MSC + S protocol in osteosarcoma treatment. The 5-year OS and EFS rates were 57.8% and 52.5%, respectively.
The CAI regimen and its outcome measurements were first documented by Jaffe et al in 1983.31 Then, a series of studies concerning CAI-facilitated multidrug chemotherapy followed.13,30,32–37 Information on all 9 studies, including the present study, is listed in Table 4.Table 4 Synopsis of IA CDDP Information Reported in the Literature
Authors Type of Study No. of Patients Ages (y) Sites Metastases Preoperative CDDP Courses No. >90% TN OS EFS
Winkler et al and Fuchs et al30,34 Nonrandomized, 2 arms 50 <40 All Included 2 68% 67% at 10 y 63% at 10 y
Ferrari et al33 Single arm 164 <40 Extremity Excluded 2 NA 72% at 8 y 63% at 8 y
Ferrari et al33 Randomized, 2 arms 59 <40 Extremity Excluded 2 64% 61% at 8 y 54% at 8 y
Rha et al35 Single arm 37 8~41 Extremity ? 3 75% 78% at 3 y 55% at 3 y
Bacci et al32 Randomized, 2 arms 40 <40 Extremity Included 2 77% NA 26% at 5 y
Bacci et al32 Randomized, 2 arms 72 <40 Extremity Included 2 80% NA 61% at 5 y
Wilkins et al37 Single arm 47 <21 Extremity Excluded 3–5 (response dependent) 87% 92% at 10 y 84% at 10 y
Wilkins et al36 Single arm 62 <22 Extremity Excluded 3–5 (response dependent) 87% 93% at 10 y 86% at 10 y
Xie et al13 Nonrandomized, 2 arms 48 NA Extremity Included 3 63% 64% at 5 y 60% at 5 y
Hu et al (Current study) Single arm 12 11~69 Pelvis Excluded 2 66.7% 57.8% at 5 y 52.5% at 5 y
Abbreviations: IA, intraarterial; CDDP, cisplatin; TN, tumor necrosis; OS, overall survival; EFS, event-free survival.
Among these 9 studies, 8 used CAI and systematic chemotherapy sequentially before surgery, and 5 studies scheduled a 2-course preoperative regimen. Six of 9 studies suggested a higher chemotherapy response rate and/or survival rate in the CAI group compared with the IV CDDP group; 2 of these investigations were 2-arm randomized cohort studies and reported a statistically significant improvement in the good-response ratio (21% and 31%, respectively). In the third randomized cohort study reported by Rha et al, the improvement was not statistically significant, probably because the limited sample size was insufficient to test the 9% difference between the two groups.35 In the multicenter study reported by Winkler et al and Fuchs et al in the 1990s, no difference in chemotherapy response was observed between the intraarterial and IV CDDP groups.30,34 Similarly, Xie et al also proved a superior histological response rate but equivalent survival in the CAI group versus the IV group in 2019.13 However, the reliability of the conclusions in the 2 studies may be impaired by the nonrandomized grouping design conducted at the researchers’ discretion, which could be affected by the severity of disease. Although CAI may bring benefits to chemotherapy response augmentation and survival rates in limb osteosarcoma patients, how pelvic osteosarcoma reacts to CAI-facilitated multidrug chemotherapy remains elusive.
Pelvic tumor resection surgeries such as hemipelvectomy are notoriously known as one of the most destructive operations in modern orthopedic surgery.38 Due to the adjacency of the vascular network, nerves and viscera in the pelvis, surgeons have to weigh tumor eradication against functional preservation in the determination of the extent of surgical excision. This dilemma makes the treatment more challenging. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate compared with the extremity-morbidity population, which could be explained by the higher rate of not only failure of surgical remission but also advanced age, large tumor size, primary metastasis, prolonged latency periods and poor chemotherapy responses.11,39 Thus, it is critical to maximize the chemotherapy response and achieve better survival outcomes in pelvic osteosarcoma patients.
The combination of agents in our MSC protocol was determined by reference to NCCN guidelines for bone cancer and the study reported by Xie et al.13 Although the agent numbers and categories differed, all of the above-reviewed studies and the present study deployed a multidrug protocol to treat tumor cells in different phases of the cell cycle. Unfortunately, insufficient data are available to appropriately compare the therapeutic effect of CAI alone or in various combinations with MTX, VCR, ADM and IFO because of great heterogeneity. In the present study, we used high-dose MTX at 10 g/m2 and CAI at 120 mg/m2 in 2 doses as routine preoperative treatment. For patients with tumors over 8 cm, we employed an enhanced dose of CAI at 160 mg/m2. Additionally, additional IFO courses were given to slow responders. This individualized regimen directly yielded a 66.7% prevalence of good histopathologic responders and contributed to the 5-year survival rate of 57.8% in pelvic osteosarcoma. Both of the two figures were seemingly improved when compared to those from conventional systematic chemotherapy.11
The cumulative dosage of CDDP was 780 mg/m2 for a good responder with a tumor size ≤ 8 cm in the present study. Wilkins et al reported the highest accumulated dose of CDDP at 960 mg/m2 and a single dose at 160 mg/m2 over 24 h as an enhanced regimen for patients with tumors over 10 cm versus 120 mg/m2 over 6 h as routine, which consequently yielded the highest 10-year OS and EFS rates (93% and 86%, respectively) among all reviewed studies. Notably, Ferrari et al and Xie et al investigated CDDP administration at equivalent doses to those in the present study but yielded poorer survival outcomes seemingly.13,33 This may be because 120 mg/m2 CDDP was given intraarterially in 72 h in the first study, which is too long to achieve a high enough blood concentration; patients with tumor metastases at the initial diagnosis were included in the second study so that the survival rate would be reduced. We used relatively high-dose CDDP administered over 3 to 6 h combined with 4 other drugs, including ETOP, and made individualized adjustments to the protocol for patients with high-risk factors. This may have contributed to the 57.8% OS and 52.5% EFS rate at 5 years, which is favorable for pelvic osteosarcoma. Moreover, we discovered that the OS and EFS rates in the population with tumors ≤ or >8 cm showed insignificant differences. Patients who received R0 resection also shared equivalent OS but higher EFS with R1 patients. These finding suggest that this protocol with risk-dependent adjustment in the drug dosage and combination could be beneficial to bridge the gap in survival rate between patients with large or small tumors, and those who received R0 or R1 resection.
We noticed that 3 of 5 cases developing SD turned out to demonstrate TNR >90%, which probably means that good response of osteosarcoma is not necessarily accompanied with tumor size decrease. This may be attributed to the formation of tumor bone generated by subtypes like osteoblastic osteosarcoma, which could prevent tumors from shrinkage.40
Only 4 poor responders were observed, 3 of whom developed tumor relapses. Two of the 3 patients died of metastasis during postoperative MSC; another showed no evidence of disease after receiving secondary amputation and resection for local recurrence. This protocol seemed to provide limited benefit to the poor responders. However, the present data are so limited that few tenable conclusions can be drawn from it to guide salvage treatment for poor responders.
Although the AI technique and additional courses were given in this protocol, no patients received an overdose of chemotherapy drugs compared with previous studies using similar drug combinations. No AI-relative grade 4 or 5 adverse events were observed. Although systematic adverse events, including nausea, vomiting, anemia and an increase in creatinine/aminotransferase levels, shared equivalent incidence rates and severities with the study reported by Xie et al, local skin hyperpigmentation and pelvic soft tissue necrosis in muscle occurred after only 3 and 1 of 24 CAI events (12.5% and 4.2%, respectively), which is more favorable than the situation reported in the most reviewed studies concerning extremity osteosarcoma.13,30,33 This finding could be explained by the shorter local drug-retention time since the pelvis has a more sufficient blood supply and drainage.
In terms of the postoperative MSC regimen for poor responders, we determined the IFO + ETOP regimen by reference to the second-line chemotherapy recommended in NCCN guidelines for bone cancer, which is supported by the study reported by Goorin et al and Miser et al.23,41 These two studies were conducted in patients with initial metastasis or recurrence of osteosarcoma, and the former one used IFO + ETOP as an induction regimen accompanied by surgical resection and continuation MSC of MTX + ADM + ETOP + IFO. Therefore, we adopted the regimen similar as the one reported by Miser et al However, the study of EURAMOS reported by Marina et al suggested that treatment with MTX + ADM + CDDP + IFO + ETOP resulted in similar EFS to MTX + ADM + CDDP and increased toxicity. In the present study, we found it hard for patients to accept 12 cycles of second-line therapy in 3 years in view of the high expenditure and physical discomfort. Therefore, the number of cycles was reduced to 6 for poor responders, which is equivalent to a half of the regimen of Miser et al in accumulative dosage and duration time. During the postoperative MSC period, there was no early death. The reported cardiac irritation, increase in creatinine/aminotransferase, oral mucosa inflammation and hematologic system abnormality were acceptable. In summary, our chemotherapy regimen seems to be well tolerated.
To monitor the chemotherapy response, several methods have been reported in previous studies. In the studies reported by Winkler et al and Fuch et al, plain X-ray, local CT and emission CT of bone were used to monitor the TNR before the surgery.30,34 Bacci et al, Wilkins et al and Xie et al deployed CT arterial angiography, which yielded sensitivity and specificity over 90% and 50%, respectively.13,32,36,37 Nevertheless, a repeated CT arterial angiography assessment is difficult to be accepted by patients because it requires multiple invasive operations and high expenditure. RECIST-1.1-based MRI remains one of the most commonly used approaches in tumor response evaluation.42,43 In the present study, we used CE-MRI to detect the tumor response and guide the adjustment of treatment for each patient. Although the results did not seem to suggest that this method is highly predictive of the histopathologic chemotherapy response, the equivalent survival rate between patients with large and small tumors may reflect the effectiveness of the individualized treatment.
There were several limitations in our investigation. First, the design was restricted to a small-sample-size single-arm clinical study due to the rarity of pelvis osteosarcoma morbidity, therefore reducing the reliability of the conclusions. Second, several previous studies reported that pathological subtypes of osteosarcoma, such as chondroblastic and telangiectatic osteosarcoma, respond differently to chemotherapy.39,44 However, the pathological subtype of each patient was not analyzed as an independent prognostic factor in our study. Heterogeneity of the osteosarcoma subtype constitution could distort chemotherapy response and survival outcomes. Third, we used CE-MRI per RECIST 1.1 to monitor the tumor response before surgery and guide the individualized adjustment of the treatment protocol. However, CE-MRI evaluation was not the gold standard for TNR prediction. Multiple innovative approaches for TNR prediction in osteosarcoma have been researched in the past 30 years, such as dynamic CE-MRI with sensitivity and specificity over 70% and 80%, respectively, according to previous studies.45–47 We would attempt to deploy approaches with higher accuracy to evaluate viable tumors in hope of providing more precise guidance for individualized pelvic osteosarcoma treatment in further studies.
Conclusions
In the present study, we employed CAI in the multimodal treatment of pelvic osteosarcoma patients. Our findings suggest that the CAI-facilitated chemotherapy regimen demonstrated great potential for improving the survival of patients with pelvic osteosarcoma. This treatment protocol yielded high tolerance with acceptable adverse effects. However, further randomized controlled trials with large sample sizes are required to elucidate the findings of this preliminary study.
Acknowledgments
We would like to thank all patients for their devotion to taking unidentified risks in this clinical trial. We are also grateful to the participating orthopedic oncologists and interventional radiologists for their prudence and patience in the therapeutic effect evaluation and the multidisciplinary consultation.
Abbreviations
ADM, adriamycin; CAI, effect of cisplatin arterial infusion; CDDP, cis-diamine-dichloro platinum; CE-MRI, contrast-enhanced MRI; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; EFS, event-free survival; ETOP, etoposide; IFO, ifosfamide; IV, intravenous; MSC, multidrug systematic chemotherapy; MTX, methotrexate; OS, overall survival; PD, progressive disease; PR, partial response; RECIST, response evaluation criteria in solid tumors version; S, surgery; SD, stable disease; TNR, tumor necrosis rate; VCR, vincristine.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics Approval and Informed Consent
This study was approved by the ethics committees and the institutional review board of the Second Xiangya Hospital. All patients provided written informed consent for receiving this treatment protocol. The requirement of obtaining specific informed consent for this retrospective study was waived for the reason mentioned before.
Consent for Publication
This study conforms to Declaration of Helsinki. The requirement of obtaining specific informed consent from the patients for the publication of the case presentation and any accompanying images.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
No commercial sponsorship was involved in any part of this study. The authors report no conflicts of interest related to this work. | CISPLATIN, DOXORUBICIN HYDROCHLORIDE, METHOTREXATE SODIUM, VINCRISTINE | DrugsGivenReaction | CC BY-NC | 33623429 | 19,834,554 | 2021 |
What was the administration route of drug 'DOXORUBICIN HYDROCHLORIDE'? | Effect of Cisplatin Arterial Infusion (CAI) on Primary Nonmetastatic Pelvic Osteosarcoma: A Preliminary Study.
The critical role of arterial infusion chemotherapy in the multimodal treatment of extremity bone cancer has been investigated extensively, but few studies have focused on pelvic osteosarcoma. Therefore, we attempted to evaluate the clinical significance of arterial infusion chemotherapy in the treatment of pelvic osteosarcoma.
We combined a cisplatin arterial infusion regimen with multidrug systematic chemotherapy as a neoadjuvant protocol for the treatment of pelvic osteosarcoma. The course number and dosage of cisplatin arterial infusion were adjusted to achieve a maximal tumor response evaluated by contrast-enhanced MRI per RECIST 1.1. Good responders received the same systematic combination for postoperative chemotherapy, and poor responders received second-line therapy. Twelve patients with nonmetastatic high-grade pelvic osteosarcoma were included. Survival, chemotherapy response and adverse events data were analyzed.
The mean follow-up period was 56.1 months. Four patients died of refractory tumor progression, and 1 patient with local recurrence had no evidence of disease for 27 months after receiving secondary amputation and resection. Kaplan-Meier survival analysis demonstrated a 57.8% overall survival and 52.5% event-free survival rate at 5 years. Eight of 12 patients had a >90% tumor necrosis rate according to histopathologic examinations. The rates of local adverse events were lower than those reported for extremity osteosarcoma.
Our study initially indicated that the cisplatin arterial infusion regimen was a potential therapy with good tolerance in the treatment of pelvic osteosarcoma.
Introduction
Osteosarcoma is the most common solid malignant tumor of bone with a highly aggressive behavior.1 The most susceptible age of osteosarcoma is bimodal, which is characterized by one peak at 10-to-20 years and another at over 60 years.2,3 Although this disease endangers the health of both adolescent and aged populations, limited progress has been made to improve survival and functional prognosis, especially in patients with pelvic osteosarcoma.4–6 Osteosarcoma patients treated with mere immediate surgical resection register a recurrence rate up to 60–90%.7 (Since 1980s, traditional adjuvant intravenous (IV) systematic chemotherapy produces an improved five-year event-free survival (EFS) rate of 61%.8 In the early 2000s, the propagation of a multidrug neoadjuvant chemotherapy regimen elevated this rate to 60% and above.9,10) Henceforth, numerous explorations have been conducted to optimize the category, dosage, combination and duration of chemotherapy drug administration. The most recent studies of EURAMOS revealed a 5-year EFS of 65–70% for localized osteosarcoma treated by multidrug neoadjuvant chemotherapy. However, there are few studies focusing on arterial infusion as an improved method and its clinical outcome in the treatment of pelvic osteosarcoma.
Osteosarcoma in pelvic bone is more notorious than that in extremities. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate than those with extremity lesions, which may be associated with a poor chemotherapy response and an inability to achieve adequate surgical resection.11 Therefore, more challenges are faced in the management of pelvic osteosarcoma.
Platinum complexes, such as cis-diamine-dichloro platinum (cisplatin, CDDP), have been proven to be cell cycle-nonspecific agents and to have multiple broad-spectrum antitumor effects.12 Several clinical trials reported that employing an arterial infusion technique to deliver CDDP, in combination with an IV systematic chemotherapy regimen or not, can elevate the local drug concentration to fivefold that of IV administration and can produce better survival in the treatment of extremity osteosarcoma.13–15 Therefore, the arterial infusion of CDDP might have potential in the treatment of pelvic osteosarcoma.
The histopathologic response of surgically removed tumors has been shown to be one of most critical indicators of chemotherapeutic effectiveness and survival prognosis.16,17 However, preoperative examination is more valuable to predict tumor response and allow individualized neoadjuvant chemotherapy. Response evaluation criteria in solid tumors version 1.1 (RECIST 1.1), which was commonly adopted for the tumor-response evaluation of a variety of cancers, affirmed the value of sectional radiological imaging measurement.18–20 Therefore, preoperative contrast-enhanced MRI (CE-MRI) evaluation based on RECIST 1.1 is expected to guide the adjustment of treatment for optimal surgical timing in pelvic osteosarcoma.
Given all these findings, we combined CDDP arterial infusion (CAI) with individualized multidrug systematic chemotherapy (MSC) and surgery (S) to treat nonmetastatic pelvic osteosarcoma and attempted to investigate (1) the chemotherapy response and survival yielded from this protocol, (2) the individualized adjustment of the neoadjuvant MSC regimen necessary to achieve the maximal tumor response according to RECIST-1.1-based CE-MRI reassessment, and (3) the potential adverse effects caused by the arterial infusion technique and the multidrug systematic chemotherapy regimen.
Patients and Methods
Study Design and Consent
This is a retrospective cohort study (Level III evidence) in which subjects received a protocol comprising multidrug systematic chemotherapy, cisplatin arterial infusion and resection surgery (CAI + MSC + S). The study design conformed with the Declaration of Helsinki, and the treatment protocol was approved by the hospital institutional review board. All patients provided written informed consent for receiving this treatment protocol. All data used in the present study were obtained from the electronic medical records of our hospital and treated with strict confidentiality; therefore, the requirement of obtaining specific informed consent for this retrospective study was waived.
Patients
Inclusion criteria for subjects included (1) histopathologically defined primary osteosarcoma of pelvic bone; (2) no metastatic foci; (3) no past history of cancer treatment; and (4) normal cardiac, hepatic and renal function. All patients were confirmed to have high-grade osteosarcoma morbidity via biopsy. Pretreatment baseline safety indexes were determined with routine blood tests, hepatic and renal function tests, and Doppler echocardiography. A peripherally inserted central catheter was placed in each patient for the IV administration of neoadjuvant chemotherapy agents.
From January 2010 to June 2015, 21 patients were consecutively diagnosed with osteosarcoma of the pelvic bones in our work unit. A total of 4 patients were excluded for the following reasons: 2 patients had evidence of distant metastasis, and 2 tumors involved the femur or lumbar vertebra. Among the eligible people, 2 refused to take CAI + MSC + S treatment: 1 had hemophilia with severely impaired coagulation function; 1 intended to transfer to another hospital after being definitively diagnosed via biopsy. Subsequently, 15 patients took the CAI + MSC + S treatment, but 1 of them stopped midway (because of intolerance to vomiting as the adverse effect in the first two rounds of IV multidrug therapy) and turned to other treatment. Two patients were lost to follow-up after surgical resection. Eventually, 12 patients finished the treatment protocol and yielded analyzable data for survival, chemotherapy response and toxicity assessment.
The data of these 12 patients are listed in Table 1. The study population consisted of 7 (58.3%) males and 5 (41.7%) females with an average age of 28.8 years (11 to 69 years). The morbid sites included the pubis (n = 2), ilium (n = 4), ischium (n = 1), sacrum (n = 1) and unclear sites (n = 4).Table 1 Patient Data
Case No. Age (y) Sex Tumor Size (cm) Morbid Site MRI Tumor Response Before Surgery Surgical Margins Histopathologic Response Diagnosis Date Surgery Type Follow-Up (Month) First Relapse Status
1 62 F <8 Unclear +27.4%, PD R0 <90% 5/19/2010 1 42 CDF
2 19 M <8 Ilium −35.1%, PR R0 >90% 10/4/2010 2 46 Jan. 2014 DOD
3 14 M <8 Unclear +14.6%, SD R0 95% 7/23/2011 2 52 CDF
4 53 F >8 Sacrum −7.3%, SD R1 <90% 6/30/2012 4 57 Feb. 2015 NED
5 15 M <8 Ilium −32.7%, PR R0 >90% 10/28/2012 2 93 CDF
6 21 F 7 Ilium +25.9%, PD R0 >90% 4/24/2013 2 87 CDF
7 16 M >8 Unclear +8.6%, SD R1 <90% 9/22/2013 2 37 Aug. 2015 DOD
8 36 F 9 Pubis −24.1%, SD R0 >90% 4/14/2014 2 76 CDF
9 69 M 12 Ischium +43.7% PD R1 <90% 5/17/2014 3 15 Jan. 2015 DOD
10 12 F <8 Unclear −37.4%, PR R0 99% 8/21/2014 2 72 CDF
11 41 M <8 Pubis +33.5%, PR R0 >90% 3/6/2015 2 34 CDF
12 47 M <8 Ilium +16.6%, SD R0 95% 6/30/2015 2 62 Dec. 2019 DOD
Notes: Surgical type = 1) primary lower limb amputation; 2) lower limb salvage surgery; 3) secondary amputation and reresection due to local recurrence; 4) revision surgery due to periprosthetic infection.
Abbreviations: CAI, cisplatin arterial infusion; PR, partial response; PD, progressive disease; SD, stable disease; CAP, cisplatin arterial perfusion; CDF, continuously disease free; NED, no evidence of disease; DOD, died of disease.
Description of the Study Treatments and Outcome Measures
The adopted CAI + MSC + S treatment protocol is depicted in Figure 1. In general, MSCs usually consist of high-dose methotrexate (MTX), vincristine (VCR), adriamycin (ADM), CDDP and ifosfamide (IFO). Specifically, the routine CAI + MSC regimen was initiated with 24-hour continuous IV dripping of high-dose MTX at 10 g/m2 followed by 2 mg IV VCR the next day for the first group at Week 0; in Week 2, 120 mg/m2 CDDP AI over 3 to 6 hours and following 30 mg/m2/d IV ADM for 2 days were given to the second group; these 2 groups were repeated in Weeks 3 and 4; then, the resection surgery was performed 2 weeks after the neoadjuvant chemotherapy was finished. Notably, 160 mg/m2 was determined as the enhanced dosage of CDDP for tumors with the longest diameter over 8 cm in CE-MRI slices. In addition, IV IFO at 2 g/m2/d for 5 days was given in Week 5 for tumors over 8 cm after the 4-week routine regimen was completed. Central venous catheterization for MSC administration was performed under inhalation anesthesia if necessary. Before each CAI regimen, percutaneous punctuation of the femoral artery was performed using the Seldinger technique, and the catheter was inserted from the femoral artery of the contralateral side to the beginning of the artery trunk supplying the tumor with the assistance of CT-guided positioning.21 Then, CT arterial angiography was conducted. Each course of MSC and CAI was accompanied by IV hydration, diuretics, rescue and protecting drugs. The CDDP was perfused via the catheter with chemotherapy pumps (LimLess Infusion Pump; PFM Medical Inc, Cologne, Germany) in a pulsed manner (Bolus dose administrator; PFM Medical Inc, Cologne, Germany). The patients were asked to have strict bed rest under multiparameter monitoring. Routine blood tests for electrolytes and hepatic and renal function were performed on the first day after drug administration and every 3 days thereafter.Figure 1 The individualized pelvic osteosarcoma treatment protocol combined cisplatin arterial infusion, multidrug systematic chemotherapy and resection surgery (CAI + MSC + S).
To evaluate the therapeutic response, primary plain X-ray (Figure 2A) and physical examination parameters of the tumor, including pre- and postchemotherapy size, tenderness, pain and inflammation, were collected. More importantly, CE-MRI was performed to monitor the tumor chemotherapy response before and after routine neoadjuvant CAI + MSC administration. (Figure 2B–E) According to the RECIST 1.1 guidelines, tumor size was calculated in gadolinium-enhancing T1-weighted fat‐saturated coronal images using the following criteria: complete response (CR), complete elimination of target lesion; partial response (PR), ≥30% decrease in the diameter of target lesion compared to baseline); progressive disease (PD), ≥20% increase in the diameter of target lesion compared to baseline or new metastatic lesion); and stable disease (SD) or observed changes in the diameter of the target lesion between 30% decrease and 20% increase compared to baseline. Each tumor lesion was assessed by orthopedic oncologists and interventional radiologists who were blinded to the treatment allocation and clinical outcome data. For patients who achieved PD after the routine neoadjuvant regimen was finished, surgery was performed immediately. For patients who demonstrated CR or PR, surgery was performed 2 weeks after the neoadjuvant regimen as usual. For patients who presented SD, the same IFO course as that mentioned in the adjustment for large tumors was added to maximize the tumor response of the neoadjuvant regimen. Then, a multidisciplinary consultation was conducted to identify the achievement of maximal tumor response. If any uncertainty of maximal response achievement was left, one more course of IFO could be given, and patients received resection surgery no later than 9 weeks after the first diagnosis.Figure 2 (A) Pelvis X-ray of a 36-year-old female with an osteosarcoma in the pubis. (B) and (C) Fat-saturated T1- and T2-weighted coronal slices of contrast-enhanced MRI showing the maximum diameter of the tumor at the first diagnosis, which showed heterogeneous enhancement, thick septa and obscure boundaries of the tumor. (D) and (E) MRI reevaluation after completion of the neoadjuvant CAI + MSC regimen, showing thin septa, clear boundaries and stable disease according to RECIST 1.1 with a decrease in the tumor diameter. (F) Pelvis plain X-ray of this patient. (The identifiable captions in these images are occluded.).
A chest CT scan, a full-body bone scan and a pelvic CE-MRI scan (Figure 2D and E) were repeated before surgery. The tumor response per RECIST 1.1 measured in the last CE-MRI examination was compared with the baseline level. Surgical excision extension was determined by the involved scope of the tumor and the tumor response category according to the CE-MRI assessment per RECIST 1.1. The pelvic reconstruction project depended on the morbidity site, excision extension, bone mineral density and functional requirements.
In case of uncontrollable hemorrhage during the resection surgery, a temporary balloon blocking technique for the abdominal aorta was performed under the guidance of CTA 4 hours before resection surgery. A balloon compatible in size to the abdominal aortic diameter was placed intraarterially at the level of 2 to 3 cm above the bifurcation of the common iliac arteries. The injection of saline with 0.1% heparin inflated the balloon, consequently blocking blood perfusion of the surgical site. Angiography was performed to confirm the satisfactory blockage of the iliac arteries and unobstruction of the renal arteries. Then, the balloon was deflated until the surgery began. Each deflation was performed with an interval of 60 min during the resection surgery before satisfactory hemostasis was achieved.
Histopathologic examination was conducted using the method reported by Huvos et al to quantify the necrosis ratio of the tumor after removal.22 Patients with a ≥90% tumor necrosis rate (TNR) (Grade III and IV) were classified as good responders. The other (Grade Ⅰ and Ⅱ) were deemed poor responders.
The postoperative IV chemotherapy cycle was repeated every 3 weeks. The recovery of hematopoietic function in patients was required before each course, which was defined as a white blood cell count over 1×104/mm3 and a platelet count over 5×106/mm3 for 3 successive days without hematopoietic stimulants. For good responders, the duration of postoperative MSC was usually 3 courses, which could be extended to the maximum of 6 courses accompanied by the existence of high-risk factors, including SD or PD in the CE-MRI per RECIST 1.1 before surgery or histology-proven tumor involvement in the surgical margin (R1 resection). For poor responders, IFO at 2 g/m2/d for 5 days and etoposide (ETOP) at 100 mg/m2/d for 5 days were given sequentially as one cycle repeated every 3 weeks for 6 cycles.23
After the planned treatment was finished, the discontinuation of chemotherapy was allowed by the orthopedic oncologist if X-ray (Figure 2F) and CE-MRI of the primary morbidity site along with chest X-ray every 2 months, chest CT scanning every 6 months in the first year off the treatment prove no local recurrence or lung metastasis. Routine blood tests and hepatic and renal function tests were deployed every week until the recovery of hematopoietic function.
Statistical Analysis
We used the Kaplan-Meier method to analyze the overall survival (OS) and EFS, which were calculated from the day the preoperative MSC + CAI regimen began. The events were defined as local recurrence, distant metastasis or death from the disease. Additionally, the OS and EFS in groups with different histopathologic chemotherapy responses or tumor sizes were calculated. All statistical analyses were conducted with SPSS software packages (SPSS Inc., Chicago, IL, USA).
Results
Chemotherapy Response
Significant improvement in physical examination parameters was observed in 10 of 12 patients after the neoadjuvant regimen, including alleviation of pain. In terms of tumor response measurement per RECIST 1.1, 4 patients had PR and 5 had SD after routine neoadjuvant CAI + MSC administration. Three patients had to undergo resection surgery ahead of schedule because of PD, as shown by CE-MRI after neoadjuvant CAI + MSC administration. No patient demonstrated CR.
According to the histopathologic assessment, 66.7% (8 of 12) of patients demonstrated TNR over 90%. One of the 3 patients with PD according to the CE-MRI assessment turned out to be good responders with Grade III histopathologic results.
Surgery
Three patients underwent local radical excision and lower limb amputation because of neurovascular bundle involvement. The remaining 9 patients received limb salvage surgery followed by pelvic reconstruction using a modular prosthesis (Lidakang Inc., Beijing, China), tumor bone devitalization and replantation, or just bone fusion. As a result, 1 patient who underwent primary limb salvage surgery developed local recurrence and underwent secondary amputation and local reresection. Two patients had surgical site infections but were cured 2 months after surgery. One patient who developed a periprosthetic infection underwent a secondary amputation.
Survival
A total of 58.3% of patients (7 of 12) remained continuously disease free in an average follow-up period of 65.1 months (range, 34–93 months). One patient who developed local recurrence was proven alive with no evidence of disease for 31 months after receiving a secondary amputation and resection. Four patients (3 lung metastases and 1 local recurrence) died of refractory disease progression. Kaplan-Meier survival analysis suggested an OS rate of 57.8% and an EFS of 52.5% at 5 years (Figure 3). For patients with a good chemotherapy response, the 5-year OS and EFS rates were 68.6%, both of which showed significant differences (P = 0.04 for OS and 0.01 for EFS) compared with the corresponding measures for poor responders (Table 2). The comparison of patients with tumor sizes greater (n = 4) or less (n = 8) than 8 cm did not yield statistical significance (P = 0.32 and 0.13, respectively). As shown in the pathological report, 75% (9 of 12) patients received R0 resection and 25% (3 of 12) had R1 resection. There was no significant difference in the OS but in the EFS between patient group with R0 or R1 surgical resection (P = 0.15 and 0.05, respectively). The confidence interval of all OS and EFS are 95%.Table 2 Overall Survival (OS) and Event-Free Survival (EFS) Rate
Variables 1 y 5 y
All patients – OS 91.7% 57.8%
All patients – EFS 91.7% 52.5%
Good responders – OS 100.0% 68.6%
Good responders – EFS 100.0% 68.6%
Poor responders – OS 75.0% 50.0%
Poor responders – EFS 75.0% 25.0%
Patients with tumor size ≥8 cm – OS 75.0% 50.0%
Patients with tumor size ≥8 cm – EFS 75.0% 25.0%
Patients with tumor size<8 cm – OS 100.0% 62.5%
Patients with tumor size<8 cm – EFS 100.0% 64.3%
R0 resection – OS 85.7% 70.0%
R0 resection – EFS 88.9% 71.1%
R1 resection – OS 66.7% 33.3%
R1 resection – EFS 66.7% 33.3%
Note: Confidence Interval = 95%
Figure 3 The Kaplan-Meier survival curve for overall survival (OS) and event-free survival (EFS) rates of 12 pelvic osteosarcoma patients treated with the CAI + MSC + S protocol.
Chemotherapy Toxicity
We recorded the adverse effects referred to in the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.24 The statistics of CAI-related adverse events are summarized in Table 3. Three of 12 patients had local adverse events, including grade 1 to 2 skin pelvic soft tissue necrosis in muscle and hyperpigmentation, which exhibited no effect on the surgical method choice or wound healing. Nausea and vomiting were the most common systematic adverse events, with 41.7% of patients developing grade 3 events. A 36-year-old female received a reduced dosage of MTX (7 g/m2) due to intolerable vomiting after the first MTX course. Four of 12 patients developed grade 1 infusion-related reactions.Table 3 Statistics of CAI-Related Adverse Events
Adverse Events No. of Courses Percentage of Patients with Grade 3–4 Adverse Events
Skin hyperpigmentation 12.5% (3/24) 0% (0/12)
Pelvic soft tissue necrosis (muscle) 4.2% (1/24) 0% (0/12)
Pelvic pain 16.7% (4/24) 8.3% (1/12)
Nausea and vomiting 75.0% (18/24) 41.7% (5/12)
Anemia 8.3% (2/24) 8.3% (1/12)
Increase in creatinine level 8.3% (2/24) 0% (0/12)
Increase in aminotransferase level 4.2% (1/24) 0% (0/12)
Infusion related reaction 29.2% (7/24) 0% (0/12)
During the postoperative MSC period, one 12-year-old child complained of grade 1 palpitations and chest pain. Therefore, we replaced ADM with ETOP, and the complaint disappeared with no evidence reported in Doppler echocardiography. Three patients out of 12 developed grade 1 to 2 increases in alanine/aspartate aminotransferase levels.
Three children developed oral mucositis at grade 2 to 3, 2 of whom were under IV nutrition, and one used a mouth rinse with metronidazole to treat thrush. All patients eventually resumed normal oral food intake.
Blood system disorders were commonly noted in patients after the second cycle of postoperative MSC administration. Three patients developed febrile neutropenia and were treated by injection of recombinant human granulocyte stimulating factor.
Discussion
Conventional IV adjuvant chemotherapy and neoadjuvant chemotherapy have been applied extensively in multimodal osteosarcoma treatment for over 45 years.25 Though changes in drug combination, dosage, and administration duration were made to optimize the regimen, no significant improvement was achieved based on the approximately 50% to 70% 5-year OS and EFS rates in the past decade.26–28 As a modified approach to augment the potential of chemotherapy drugs, the AI technique combined with MSCs has been studied for years.13,29,30 In the present study, we attempted to investigate the therapeutic effect of the CAI + MSC + S protocol in osteosarcoma treatment. The 5-year OS and EFS rates were 57.8% and 52.5%, respectively.
The CAI regimen and its outcome measurements were first documented by Jaffe et al in 1983.31 Then, a series of studies concerning CAI-facilitated multidrug chemotherapy followed.13,30,32–37 Information on all 9 studies, including the present study, is listed in Table 4.Table 4 Synopsis of IA CDDP Information Reported in the Literature
Authors Type of Study No. of Patients Ages (y) Sites Metastases Preoperative CDDP Courses No. >90% TN OS EFS
Winkler et al and Fuchs et al30,34 Nonrandomized, 2 arms 50 <40 All Included 2 68% 67% at 10 y 63% at 10 y
Ferrari et al33 Single arm 164 <40 Extremity Excluded 2 NA 72% at 8 y 63% at 8 y
Ferrari et al33 Randomized, 2 arms 59 <40 Extremity Excluded 2 64% 61% at 8 y 54% at 8 y
Rha et al35 Single arm 37 8~41 Extremity ? 3 75% 78% at 3 y 55% at 3 y
Bacci et al32 Randomized, 2 arms 40 <40 Extremity Included 2 77% NA 26% at 5 y
Bacci et al32 Randomized, 2 arms 72 <40 Extremity Included 2 80% NA 61% at 5 y
Wilkins et al37 Single arm 47 <21 Extremity Excluded 3–5 (response dependent) 87% 92% at 10 y 84% at 10 y
Wilkins et al36 Single arm 62 <22 Extremity Excluded 3–5 (response dependent) 87% 93% at 10 y 86% at 10 y
Xie et al13 Nonrandomized, 2 arms 48 NA Extremity Included 3 63% 64% at 5 y 60% at 5 y
Hu et al (Current study) Single arm 12 11~69 Pelvis Excluded 2 66.7% 57.8% at 5 y 52.5% at 5 y
Abbreviations: IA, intraarterial; CDDP, cisplatin; TN, tumor necrosis; OS, overall survival; EFS, event-free survival.
Among these 9 studies, 8 used CAI and systematic chemotherapy sequentially before surgery, and 5 studies scheduled a 2-course preoperative regimen. Six of 9 studies suggested a higher chemotherapy response rate and/or survival rate in the CAI group compared with the IV CDDP group; 2 of these investigations were 2-arm randomized cohort studies and reported a statistically significant improvement in the good-response ratio (21% and 31%, respectively). In the third randomized cohort study reported by Rha et al, the improvement was not statistically significant, probably because the limited sample size was insufficient to test the 9% difference between the two groups.35 In the multicenter study reported by Winkler et al and Fuchs et al in the 1990s, no difference in chemotherapy response was observed between the intraarterial and IV CDDP groups.30,34 Similarly, Xie et al also proved a superior histological response rate but equivalent survival in the CAI group versus the IV group in 2019.13 However, the reliability of the conclusions in the 2 studies may be impaired by the nonrandomized grouping design conducted at the researchers’ discretion, which could be affected by the severity of disease. Although CAI may bring benefits to chemotherapy response augmentation and survival rates in limb osteosarcoma patients, how pelvic osteosarcoma reacts to CAI-facilitated multidrug chemotherapy remains elusive.
Pelvic tumor resection surgeries such as hemipelvectomy are notoriously known as one of the most destructive operations in modern orthopedic surgery.38 Due to the adjacency of the vascular network, nerves and viscera in the pelvis, surgeons have to weigh tumor eradication against functional preservation in the determination of the extent of surgical excision. This dilemma makes the treatment more challenging. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate compared with the extremity-morbidity population, which could be explained by the higher rate of not only failure of surgical remission but also advanced age, large tumor size, primary metastasis, prolonged latency periods and poor chemotherapy responses.11,39 Thus, it is critical to maximize the chemotherapy response and achieve better survival outcomes in pelvic osteosarcoma patients.
The combination of agents in our MSC protocol was determined by reference to NCCN guidelines for bone cancer and the study reported by Xie et al.13 Although the agent numbers and categories differed, all of the above-reviewed studies and the present study deployed a multidrug protocol to treat tumor cells in different phases of the cell cycle. Unfortunately, insufficient data are available to appropriately compare the therapeutic effect of CAI alone or in various combinations with MTX, VCR, ADM and IFO because of great heterogeneity. In the present study, we used high-dose MTX at 10 g/m2 and CAI at 120 mg/m2 in 2 doses as routine preoperative treatment. For patients with tumors over 8 cm, we employed an enhanced dose of CAI at 160 mg/m2. Additionally, additional IFO courses were given to slow responders. This individualized regimen directly yielded a 66.7% prevalence of good histopathologic responders and contributed to the 5-year survival rate of 57.8% in pelvic osteosarcoma. Both of the two figures were seemingly improved when compared to those from conventional systematic chemotherapy.11
The cumulative dosage of CDDP was 780 mg/m2 for a good responder with a tumor size ≤ 8 cm in the present study. Wilkins et al reported the highest accumulated dose of CDDP at 960 mg/m2 and a single dose at 160 mg/m2 over 24 h as an enhanced regimen for patients with tumors over 10 cm versus 120 mg/m2 over 6 h as routine, which consequently yielded the highest 10-year OS and EFS rates (93% and 86%, respectively) among all reviewed studies. Notably, Ferrari et al and Xie et al investigated CDDP administration at equivalent doses to those in the present study but yielded poorer survival outcomes seemingly.13,33 This may be because 120 mg/m2 CDDP was given intraarterially in 72 h in the first study, which is too long to achieve a high enough blood concentration; patients with tumor metastases at the initial diagnosis were included in the second study so that the survival rate would be reduced. We used relatively high-dose CDDP administered over 3 to 6 h combined with 4 other drugs, including ETOP, and made individualized adjustments to the protocol for patients with high-risk factors. This may have contributed to the 57.8% OS and 52.5% EFS rate at 5 years, which is favorable for pelvic osteosarcoma. Moreover, we discovered that the OS and EFS rates in the population with tumors ≤ or >8 cm showed insignificant differences. Patients who received R0 resection also shared equivalent OS but higher EFS with R1 patients. These finding suggest that this protocol with risk-dependent adjustment in the drug dosage and combination could be beneficial to bridge the gap in survival rate between patients with large or small tumors, and those who received R0 or R1 resection.
We noticed that 3 of 5 cases developing SD turned out to demonstrate TNR >90%, which probably means that good response of osteosarcoma is not necessarily accompanied with tumor size decrease. This may be attributed to the formation of tumor bone generated by subtypes like osteoblastic osteosarcoma, which could prevent tumors from shrinkage.40
Only 4 poor responders were observed, 3 of whom developed tumor relapses. Two of the 3 patients died of metastasis during postoperative MSC; another showed no evidence of disease after receiving secondary amputation and resection for local recurrence. This protocol seemed to provide limited benefit to the poor responders. However, the present data are so limited that few tenable conclusions can be drawn from it to guide salvage treatment for poor responders.
Although the AI technique and additional courses were given in this protocol, no patients received an overdose of chemotherapy drugs compared with previous studies using similar drug combinations. No AI-relative grade 4 or 5 adverse events were observed. Although systematic adverse events, including nausea, vomiting, anemia and an increase in creatinine/aminotransferase levels, shared equivalent incidence rates and severities with the study reported by Xie et al, local skin hyperpigmentation and pelvic soft tissue necrosis in muscle occurred after only 3 and 1 of 24 CAI events (12.5% and 4.2%, respectively), which is more favorable than the situation reported in the most reviewed studies concerning extremity osteosarcoma.13,30,33 This finding could be explained by the shorter local drug-retention time since the pelvis has a more sufficient blood supply and drainage.
In terms of the postoperative MSC regimen for poor responders, we determined the IFO + ETOP regimen by reference to the second-line chemotherapy recommended in NCCN guidelines for bone cancer, which is supported by the study reported by Goorin et al and Miser et al.23,41 These two studies were conducted in patients with initial metastasis or recurrence of osteosarcoma, and the former one used IFO + ETOP as an induction regimen accompanied by surgical resection and continuation MSC of MTX + ADM + ETOP + IFO. Therefore, we adopted the regimen similar as the one reported by Miser et al However, the study of EURAMOS reported by Marina et al suggested that treatment with MTX + ADM + CDDP + IFO + ETOP resulted in similar EFS to MTX + ADM + CDDP and increased toxicity. In the present study, we found it hard for patients to accept 12 cycles of second-line therapy in 3 years in view of the high expenditure and physical discomfort. Therefore, the number of cycles was reduced to 6 for poor responders, which is equivalent to a half of the regimen of Miser et al in accumulative dosage and duration time. During the postoperative MSC period, there was no early death. The reported cardiac irritation, increase in creatinine/aminotransferase, oral mucosa inflammation and hematologic system abnormality were acceptable. In summary, our chemotherapy regimen seems to be well tolerated.
To monitor the chemotherapy response, several methods have been reported in previous studies. In the studies reported by Winkler et al and Fuch et al, plain X-ray, local CT and emission CT of bone were used to monitor the TNR before the surgery.30,34 Bacci et al, Wilkins et al and Xie et al deployed CT arterial angiography, which yielded sensitivity and specificity over 90% and 50%, respectively.13,32,36,37 Nevertheless, a repeated CT arterial angiography assessment is difficult to be accepted by patients because it requires multiple invasive operations and high expenditure. RECIST-1.1-based MRI remains one of the most commonly used approaches in tumor response evaluation.42,43 In the present study, we used CE-MRI to detect the tumor response and guide the adjustment of treatment for each patient. Although the results did not seem to suggest that this method is highly predictive of the histopathologic chemotherapy response, the equivalent survival rate between patients with large and small tumors may reflect the effectiveness of the individualized treatment.
There were several limitations in our investigation. First, the design was restricted to a small-sample-size single-arm clinical study due to the rarity of pelvis osteosarcoma morbidity, therefore reducing the reliability of the conclusions. Second, several previous studies reported that pathological subtypes of osteosarcoma, such as chondroblastic and telangiectatic osteosarcoma, respond differently to chemotherapy.39,44 However, the pathological subtype of each patient was not analyzed as an independent prognostic factor in our study. Heterogeneity of the osteosarcoma subtype constitution could distort chemotherapy response and survival outcomes. Third, we used CE-MRI per RECIST 1.1 to monitor the tumor response before surgery and guide the individualized adjustment of the treatment protocol. However, CE-MRI evaluation was not the gold standard for TNR prediction. Multiple innovative approaches for TNR prediction in osteosarcoma have been researched in the past 30 years, such as dynamic CE-MRI with sensitivity and specificity over 70% and 80%, respectively, according to previous studies.45–47 We would attempt to deploy approaches with higher accuracy to evaluate viable tumors in hope of providing more precise guidance for individualized pelvic osteosarcoma treatment in further studies.
Conclusions
In the present study, we employed CAI in the multimodal treatment of pelvic osteosarcoma patients. Our findings suggest that the CAI-facilitated chemotherapy regimen demonstrated great potential for improving the survival of patients with pelvic osteosarcoma. This treatment protocol yielded high tolerance with acceptable adverse effects. However, further randomized controlled trials with large sample sizes are required to elucidate the findings of this preliminary study.
Acknowledgments
We would like to thank all patients for their devotion to taking unidentified risks in this clinical trial. We are also grateful to the participating orthopedic oncologists and interventional radiologists for their prudence and patience in the therapeutic effect evaluation and the multidisciplinary consultation.
Abbreviations
ADM, adriamycin; CAI, effect of cisplatin arterial infusion; CDDP, cis-diamine-dichloro platinum; CE-MRI, contrast-enhanced MRI; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; EFS, event-free survival; ETOP, etoposide; IFO, ifosfamide; IV, intravenous; MSC, multidrug systematic chemotherapy; MTX, methotrexate; OS, overall survival; PD, progressive disease; PR, partial response; RECIST, response evaluation criteria in solid tumors version; S, surgery; SD, stable disease; TNR, tumor necrosis rate; VCR, vincristine.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics Approval and Informed Consent
This study was approved by the ethics committees and the institutional review board of the Second Xiangya Hospital. All patients provided written informed consent for receiving this treatment protocol. The requirement of obtaining specific informed consent for this retrospective study was waived for the reason mentioned before.
Consent for Publication
This study conforms to Declaration of Helsinki. The requirement of obtaining specific informed consent from the patients for the publication of the case presentation and any accompanying images.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
No commercial sponsorship was involved in any part of this study. The authors report no conflicts of interest related to this work. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33623429 | 19,834,554 | 2021 |
What was the administration route of drug 'METHOTREXATE SODIUM'? | Effect of Cisplatin Arterial Infusion (CAI) on Primary Nonmetastatic Pelvic Osteosarcoma: A Preliminary Study.
The critical role of arterial infusion chemotherapy in the multimodal treatment of extremity bone cancer has been investigated extensively, but few studies have focused on pelvic osteosarcoma. Therefore, we attempted to evaluate the clinical significance of arterial infusion chemotherapy in the treatment of pelvic osteosarcoma.
We combined a cisplatin arterial infusion regimen with multidrug systematic chemotherapy as a neoadjuvant protocol for the treatment of pelvic osteosarcoma. The course number and dosage of cisplatin arterial infusion were adjusted to achieve a maximal tumor response evaluated by contrast-enhanced MRI per RECIST 1.1. Good responders received the same systematic combination for postoperative chemotherapy, and poor responders received second-line therapy. Twelve patients with nonmetastatic high-grade pelvic osteosarcoma were included. Survival, chemotherapy response and adverse events data were analyzed.
The mean follow-up period was 56.1 months. Four patients died of refractory tumor progression, and 1 patient with local recurrence had no evidence of disease for 27 months after receiving secondary amputation and resection. Kaplan-Meier survival analysis demonstrated a 57.8% overall survival and 52.5% event-free survival rate at 5 years. Eight of 12 patients had a >90% tumor necrosis rate according to histopathologic examinations. The rates of local adverse events were lower than those reported for extremity osteosarcoma.
Our study initially indicated that the cisplatin arterial infusion regimen was a potential therapy with good tolerance in the treatment of pelvic osteosarcoma.
Introduction
Osteosarcoma is the most common solid malignant tumor of bone with a highly aggressive behavior.1 The most susceptible age of osteosarcoma is bimodal, which is characterized by one peak at 10-to-20 years and another at over 60 years.2,3 Although this disease endangers the health of both adolescent and aged populations, limited progress has been made to improve survival and functional prognosis, especially in patients with pelvic osteosarcoma.4–6 Osteosarcoma patients treated with mere immediate surgical resection register a recurrence rate up to 60–90%.7 (Since 1980s, traditional adjuvant intravenous (IV) systematic chemotherapy produces an improved five-year event-free survival (EFS) rate of 61%.8 In the early 2000s, the propagation of a multidrug neoadjuvant chemotherapy regimen elevated this rate to 60% and above.9,10) Henceforth, numerous explorations have been conducted to optimize the category, dosage, combination and duration of chemotherapy drug administration. The most recent studies of EURAMOS revealed a 5-year EFS of 65–70% for localized osteosarcoma treated by multidrug neoadjuvant chemotherapy. However, there are few studies focusing on arterial infusion as an improved method and its clinical outcome in the treatment of pelvic osteosarcoma.
Osteosarcoma in pelvic bone is more notorious than that in extremities. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate than those with extremity lesions, which may be associated with a poor chemotherapy response and an inability to achieve adequate surgical resection.11 Therefore, more challenges are faced in the management of pelvic osteosarcoma.
Platinum complexes, such as cis-diamine-dichloro platinum (cisplatin, CDDP), have been proven to be cell cycle-nonspecific agents and to have multiple broad-spectrum antitumor effects.12 Several clinical trials reported that employing an arterial infusion technique to deliver CDDP, in combination with an IV systematic chemotherapy regimen or not, can elevate the local drug concentration to fivefold that of IV administration and can produce better survival in the treatment of extremity osteosarcoma.13–15 Therefore, the arterial infusion of CDDP might have potential in the treatment of pelvic osteosarcoma.
The histopathologic response of surgically removed tumors has been shown to be one of most critical indicators of chemotherapeutic effectiveness and survival prognosis.16,17 However, preoperative examination is more valuable to predict tumor response and allow individualized neoadjuvant chemotherapy. Response evaluation criteria in solid tumors version 1.1 (RECIST 1.1), which was commonly adopted for the tumor-response evaluation of a variety of cancers, affirmed the value of sectional radiological imaging measurement.18–20 Therefore, preoperative contrast-enhanced MRI (CE-MRI) evaluation based on RECIST 1.1 is expected to guide the adjustment of treatment for optimal surgical timing in pelvic osteosarcoma.
Given all these findings, we combined CDDP arterial infusion (CAI) with individualized multidrug systematic chemotherapy (MSC) and surgery (S) to treat nonmetastatic pelvic osteosarcoma and attempted to investigate (1) the chemotherapy response and survival yielded from this protocol, (2) the individualized adjustment of the neoadjuvant MSC regimen necessary to achieve the maximal tumor response according to RECIST-1.1-based CE-MRI reassessment, and (3) the potential adverse effects caused by the arterial infusion technique and the multidrug systematic chemotherapy regimen.
Patients and Methods
Study Design and Consent
This is a retrospective cohort study (Level III evidence) in which subjects received a protocol comprising multidrug systematic chemotherapy, cisplatin arterial infusion and resection surgery (CAI + MSC + S). The study design conformed with the Declaration of Helsinki, and the treatment protocol was approved by the hospital institutional review board. All patients provided written informed consent for receiving this treatment protocol. All data used in the present study were obtained from the electronic medical records of our hospital and treated with strict confidentiality; therefore, the requirement of obtaining specific informed consent for this retrospective study was waived.
Patients
Inclusion criteria for subjects included (1) histopathologically defined primary osteosarcoma of pelvic bone; (2) no metastatic foci; (3) no past history of cancer treatment; and (4) normal cardiac, hepatic and renal function. All patients were confirmed to have high-grade osteosarcoma morbidity via biopsy. Pretreatment baseline safety indexes were determined with routine blood tests, hepatic and renal function tests, and Doppler echocardiography. A peripherally inserted central catheter was placed in each patient for the IV administration of neoadjuvant chemotherapy agents.
From January 2010 to June 2015, 21 patients were consecutively diagnosed with osteosarcoma of the pelvic bones in our work unit. A total of 4 patients were excluded for the following reasons: 2 patients had evidence of distant metastasis, and 2 tumors involved the femur or lumbar vertebra. Among the eligible people, 2 refused to take CAI + MSC + S treatment: 1 had hemophilia with severely impaired coagulation function; 1 intended to transfer to another hospital after being definitively diagnosed via biopsy. Subsequently, 15 patients took the CAI + MSC + S treatment, but 1 of them stopped midway (because of intolerance to vomiting as the adverse effect in the first two rounds of IV multidrug therapy) and turned to other treatment. Two patients were lost to follow-up after surgical resection. Eventually, 12 patients finished the treatment protocol and yielded analyzable data for survival, chemotherapy response and toxicity assessment.
The data of these 12 patients are listed in Table 1. The study population consisted of 7 (58.3%) males and 5 (41.7%) females with an average age of 28.8 years (11 to 69 years). The morbid sites included the pubis (n = 2), ilium (n = 4), ischium (n = 1), sacrum (n = 1) and unclear sites (n = 4).Table 1 Patient Data
Case No. Age (y) Sex Tumor Size (cm) Morbid Site MRI Tumor Response Before Surgery Surgical Margins Histopathologic Response Diagnosis Date Surgery Type Follow-Up (Month) First Relapse Status
1 62 F <8 Unclear +27.4%, PD R0 <90% 5/19/2010 1 42 CDF
2 19 M <8 Ilium −35.1%, PR R0 >90% 10/4/2010 2 46 Jan. 2014 DOD
3 14 M <8 Unclear +14.6%, SD R0 95% 7/23/2011 2 52 CDF
4 53 F >8 Sacrum −7.3%, SD R1 <90% 6/30/2012 4 57 Feb. 2015 NED
5 15 M <8 Ilium −32.7%, PR R0 >90% 10/28/2012 2 93 CDF
6 21 F 7 Ilium +25.9%, PD R0 >90% 4/24/2013 2 87 CDF
7 16 M >8 Unclear +8.6%, SD R1 <90% 9/22/2013 2 37 Aug. 2015 DOD
8 36 F 9 Pubis −24.1%, SD R0 >90% 4/14/2014 2 76 CDF
9 69 M 12 Ischium +43.7% PD R1 <90% 5/17/2014 3 15 Jan. 2015 DOD
10 12 F <8 Unclear −37.4%, PR R0 99% 8/21/2014 2 72 CDF
11 41 M <8 Pubis +33.5%, PR R0 >90% 3/6/2015 2 34 CDF
12 47 M <8 Ilium +16.6%, SD R0 95% 6/30/2015 2 62 Dec. 2019 DOD
Notes: Surgical type = 1) primary lower limb amputation; 2) lower limb salvage surgery; 3) secondary amputation and reresection due to local recurrence; 4) revision surgery due to periprosthetic infection.
Abbreviations: CAI, cisplatin arterial infusion; PR, partial response; PD, progressive disease; SD, stable disease; CAP, cisplatin arterial perfusion; CDF, continuously disease free; NED, no evidence of disease; DOD, died of disease.
Description of the Study Treatments and Outcome Measures
The adopted CAI + MSC + S treatment protocol is depicted in Figure 1. In general, MSCs usually consist of high-dose methotrexate (MTX), vincristine (VCR), adriamycin (ADM), CDDP and ifosfamide (IFO). Specifically, the routine CAI + MSC regimen was initiated with 24-hour continuous IV dripping of high-dose MTX at 10 g/m2 followed by 2 mg IV VCR the next day for the first group at Week 0; in Week 2, 120 mg/m2 CDDP AI over 3 to 6 hours and following 30 mg/m2/d IV ADM for 2 days were given to the second group; these 2 groups were repeated in Weeks 3 and 4; then, the resection surgery was performed 2 weeks after the neoadjuvant chemotherapy was finished. Notably, 160 mg/m2 was determined as the enhanced dosage of CDDP for tumors with the longest diameter over 8 cm in CE-MRI slices. In addition, IV IFO at 2 g/m2/d for 5 days was given in Week 5 for tumors over 8 cm after the 4-week routine regimen was completed. Central venous catheterization for MSC administration was performed under inhalation anesthesia if necessary. Before each CAI regimen, percutaneous punctuation of the femoral artery was performed using the Seldinger technique, and the catheter was inserted from the femoral artery of the contralateral side to the beginning of the artery trunk supplying the tumor with the assistance of CT-guided positioning.21 Then, CT arterial angiography was conducted. Each course of MSC and CAI was accompanied by IV hydration, diuretics, rescue and protecting drugs. The CDDP was perfused via the catheter with chemotherapy pumps (LimLess Infusion Pump; PFM Medical Inc, Cologne, Germany) in a pulsed manner (Bolus dose administrator; PFM Medical Inc, Cologne, Germany). The patients were asked to have strict bed rest under multiparameter monitoring. Routine blood tests for electrolytes and hepatic and renal function were performed on the first day after drug administration and every 3 days thereafter.Figure 1 The individualized pelvic osteosarcoma treatment protocol combined cisplatin arterial infusion, multidrug systematic chemotherapy and resection surgery (CAI + MSC + S).
To evaluate the therapeutic response, primary plain X-ray (Figure 2A) and physical examination parameters of the tumor, including pre- and postchemotherapy size, tenderness, pain and inflammation, were collected. More importantly, CE-MRI was performed to monitor the tumor chemotherapy response before and after routine neoadjuvant CAI + MSC administration. (Figure 2B–E) According to the RECIST 1.1 guidelines, tumor size was calculated in gadolinium-enhancing T1-weighted fat‐saturated coronal images using the following criteria: complete response (CR), complete elimination of target lesion; partial response (PR), ≥30% decrease in the diameter of target lesion compared to baseline); progressive disease (PD), ≥20% increase in the diameter of target lesion compared to baseline or new metastatic lesion); and stable disease (SD) or observed changes in the diameter of the target lesion between 30% decrease and 20% increase compared to baseline. Each tumor lesion was assessed by orthopedic oncologists and interventional radiologists who were blinded to the treatment allocation and clinical outcome data. For patients who achieved PD after the routine neoadjuvant regimen was finished, surgery was performed immediately. For patients who demonstrated CR or PR, surgery was performed 2 weeks after the neoadjuvant regimen as usual. For patients who presented SD, the same IFO course as that mentioned in the adjustment for large tumors was added to maximize the tumor response of the neoadjuvant regimen. Then, a multidisciplinary consultation was conducted to identify the achievement of maximal tumor response. If any uncertainty of maximal response achievement was left, one more course of IFO could be given, and patients received resection surgery no later than 9 weeks after the first diagnosis.Figure 2 (A) Pelvis X-ray of a 36-year-old female with an osteosarcoma in the pubis. (B) and (C) Fat-saturated T1- and T2-weighted coronal slices of contrast-enhanced MRI showing the maximum diameter of the tumor at the first diagnosis, which showed heterogeneous enhancement, thick septa and obscure boundaries of the tumor. (D) and (E) MRI reevaluation after completion of the neoadjuvant CAI + MSC regimen, showing thin septa, clear boundaries and stable disease according to RECIST 1.1 with a decrease in the tumor diameter. (F) Pelvis plain X-ray of this patient. (The identifiable captions in these images are occluded.).
A chest CT scan, a full-body bone scan and a pelvic CE-MRI scan (Figure 2D and E) were repeated before surgery. The tumor response per RECIST 1.1 measured in the last CE-MRI examination was compared with the baseline level. Surgical excision extension was determined by the involved scope of the tumor and the tumor response category according to the CE-MRI assessment per RECIST 1.1. The pelvic reconstruction project depended on the morbidity site, excision extension, bone mineral density and functional requirements.
In case of uncontrollable hemorrhage during the resection surgery, a temporary balloon blocking technique for the abdominal aorta was performed under the guidance of CTA 4 hours before resection surgery. A balloon compatible in size to the abdominal aortic diameter was placed intraarterially at the level of 2 to 3 cm above the bifurcation of the common iliac arteries. The injection of saline with 0.1% heparin inflated the balloon, consequently blocking blood perfusion of the surgical site. Angiography was performed to confirm the satisfactory blockage of the iliac arteries and unobstruction of the renal arteries. Then, the balloon was deflated until the surgery began. Each deflation was performed with an interval of 60 min during the resection surgery before satisfactory hemostasis was achieved.
Histopathologic examination was conducted using the method reported by Huvos et al to quantify the necrosis ratio of the tumor after removal.22 Patients with a ≥90% tumor necrosis rate (TNR) (Grade III and IV) were classified as good responders. The other (Grade Ⅰ and Ⅱ) were deemed poor responders.
The postoperative IV chemotherapy cycle was repeated every 3 weeks. The recovery of hematopoietic function in patients was required before each course, which was defined as a white blood cell count over 1×104/mm3 and a platelet count over 5×106/mm3 for 3 successive days without hematopoietic stimulants. For good responders, the duration of postoperative MSC was usually 3 courses, which could be extended to the maximum of 6 courses accompanied by the existence of high-risk factors, including SD or PD in the CE-MRI per RECIST 1.1 before surgery or histology-proven tumor involvement in the surgical margin (R1 resection). For poor responders, IFO at 2 g/m2/d for 5 days and etoposide (ETOP) at 100 mg/m2/d for 5 days were given sequentially as one cycle repeated every 3 weeks for 6 cycles.23
After the planned treatment was finished, the discontinuation of chemotherapy was allowed by the orthopedic oncologist if X-ray (Figure 2F) and CE-MRI of the primary morbidity site along with chest X-ray every 2 months, chest CT scanning every 6 months in the first year off the treatment prove no local recurrence or lung metastasis. Routine blood tests and hepatic and renal function tests were deployed every week until the recovery of hematopoietic function.
Statistical Analysis
We used the Kaplan-Meier method to analyze the overall survival (OS) and EFS, which were calculated from the day the preoperative MSC + CAI regimen began. The events were defined as local recurrence, distant metastasis or death from the disease. Additionally, the OS and EFS in groups with different histopathologic chemotherapy responses or tumor sizes were calculated. All statistical analyses were conducted with SPSS software packages (SPSS Inc., Chicago, IL, USA).
Results
Chemotherapy Response
Significant improvement in physical examination parameters was observed in 10 of 12 patients after the neoadjuvant regimen, including alleviation of pain. In terms of tumor response measurement per RECIST 1.1, 4 patients had PR and 5 had SD after routine neoadjuvant CAI + MSC administration. Three patients had to undergo resection surgery ahead of schedule because of PD, as shown by CE-MRI after neoadjuvant CAI + MSC administration. No patient demonstrated CR.
According to the histopathologic assessment, 66.7% (8 of 12) of patients demonstrated TNR over 90%. One of the 3 patients with PD according to the CE-MRI assessment turned out to be good responders with Grade III histopathologic results.
Surgery
Three patients underwent local radical excision and lower limb amputation because of neurovascular bundle involvement. The remaining 9 patients received limb salvage surgery followed by pelvic reconstruction using a modular prosthesis (Lidakang Inc., Beijing, China), tumor bone devitalization and replantation, or just bone fusion. As a result, 1 patient who underwent primary limb salvage surgery developed local recurrence and underwent secondary amputation and local reresection. Two patients had surgical site infections but were cured 2 months after surgery. One patient who developed a periprosthetic infection underwent a secondary amputation.
Survival
A total of 58.3% of patients (7 of 12) remained continuously disease free in an average follow-up period of 65.1 months (range, 34–93 months). One patient who developed local recurrence was proven alive with no evidence of disease for 31 months after receiving a secondary amputation and resection. Four patients (3 lung metastases and 1 local recurrence) died of refractory disease progression. Kaplan-Meier survival analysis suggested an OS rate of 57.8% and an EFS of 52.5% at 5 years (Figure 3). For patients with a good chemotherapy response, the 5-year OS and EFS rates were 68.6%, both of which showed significant differences (P = 0.04 for OS and 0.01 for EFS) compared with the corresponding measures for poor responders (Table 2). The comparison of patients with tumor sizes greater (n = 4) or less (n = 8) than 8 cm did not yield statistical significance (P = 0.32 and 0.13, respectively). As shown in the pathological report, 75% (9 of 12) patients received R0 resection and 25% (3 of 12) had R1 resection. There was no significant difference in the OS but in the EFS between patient group with R0 or R1 surgical resection (P = 0.15 and 0.05, respectively). The confidence interval of all OS and EFS are 95%.Table 2 Overall Survival (OS) and Event-Free Survival (EFS) Rate
Variables 1 y 5 y
All patients – OS 91.7% 57.8%
All patients – EFS 91.7% 52.5%
Good responders – OS 100.0% 68.6%
Good responders – EFS 100.0% 68.6%
Poor responders – OS 75.0% 50.0%
Poor responders – EFS 75.0% 25.0%
Patients with tumor size ≥8 cm – OS 75.0% 50.0%
Patients with tumor size ≥8 cm – EFS 75.0% 25.0%
Patients with tumor size<8 cm – OS 100.0% 62.5%
Patients with tumor size<8 cm – EFS 100.0% 64.3%
R0 resection – OS 85.7% 70.0%
R0 resection – EFS 88.9% 71.1%
R1 resection – OS 66.7% 33.3%
R1 resection – EFS 66.7% 33.3%
Note: Confidence Interval = 95%
Figure 3 The Kaplan-Meier survival curve for overall survival (OS) and event-free survival (EFS) rates of 12 pelvic osteosarcoma patients treated with the CAI + MSC + S protocol.
Chemotherapy Toxicity
We recorded the adverse effects referred to in the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.24 The statistics of CAI-related adverse events are summarized in Table 3. Three of 12 patients had local adverse events, including grade 1 to 2 skin pelvic soft tissue necrosis in muscle and hyperpigmentation, which exhibited no effect on the surgical method choice or wound healing. Nausea and vomiting were the most common systematic adverse events, with 41.7% of patients developing grade 3 events. A 36-year-old female received a reduced dosage of MTX (7 g/m2) due to intolerable vomiting after the first MTX course. Four of 12 patients developed grade 1 infusion-related reactions.Table 3 Statistics of CAI-Related Adverse Events
Adverse Events No. of Courses Percentage of Patients with Grade 3–4 Adverse Events
Skin hyperpigmentation 12.5% (3/24) 0% (0/12)
Pelvic soft tissue necrosis (muscle) 4.2% (1/24) 0% (0/12)
Pelvic pain 16.7% (4/24) 8.3% (1/12)
Nausea and vomiting 75.0% (18/24) 41.7% (5/12)
Anemia 8.3% (2/24) 8.3% (1/12)
Increase in creatinine level 8.3% (2/24) 0% (0/12)
Increase in aminotransferase level 4.2% (1/24) 0% (0/12)
Infusion related reaction 29.2% (7/24) 0% (0/12)
During the postoperative MSC period, one 12-year-old child complained of grade 1 palpitations and chest pain. Therefore, we replaced ADM with ETOP, and the complaint disappeared with no evidence reported in Doppler echocardiography. Three patients out of 12 developed grade 1 to 2 increases in alanine/aspartate aminotransferase levels.
Three children developed oral mucositis at grade 2 to 3, 2 of whom were under IV nutrition, and one used a mouth rinse with metronidazole to treat thrush. All patients eventually resumed normal oral food intake.
Blood system disorders were commonly noted in patients after the second cycle of postoperative MSC administration. Three patients developed febrile neutropenia and were treated by injection of recombinant human granulocyte stimulating factor.
Discussion
Conventional IV adjuvant chemotherapy and neoadjuvant chemotherapy have been applied extensively in multimodal osteosarcoma treatment for over 45 years.25 Though changes in drug combination, dosage, and administration duration were made to optimize the regimen, no significant improvement was achieved based on the approximately 50% to 70% 5-year OS and EFS rates in the past decade.26–28 As a modified approach to augment the potential of chemotherapy drugs, the AI technique combined with MSCs has been studied for years.13,29,30 In the present study, we attempted to investigate the therapeutic effect of the CAI + MSC + S protocol in osteosarcoma treatment. The 5-year OS and EFS rates were 57.8% and 52.5%, respectively.
The CAI regimen and its outcome measurements were first documented by Jaffe et al in 1983.31 Then, a series of studies concerning CAI-facilitated multidrug chemotherapy followed.13,30,32–37 Information on all 9 studies, including the present study, is listed in Table 4.Table 4 Synopsis of IA CDDP Information Reported in the Literature
Authors Type of Study No. of Patients Ages (y) Sites Metastases Preoperative CDDP Courses No. >90% TN OS EFS
Winkler et al and Fuchs et al30,34 Nonrandomized, 2 arms 50 <40 All Included 2 68% 67% at 10 y 63% at 10 y
Ferrari et al33 Single arm 164 <40 Extremity Excluded 2 NA 72% at 8 y 63% at 8 y
Ferrari et al33 Randomized, 2 arms 59 <40 Extremity Excluded 2 64% 61% at 8 y 54% at 8 y
Rha et al35 Single arm 37 8~41 Extremity ? 3 75% 78% at 3 y 55% at 3 y
Bacci et al32 Randomized, 2 arms 40 <40 Extremity Included 2 77% NA 26% at 5 y
Bacci et al32 Randomized, 2 arms 72 <40 Extremity Included 2 80% NA 61% at 5 y
Wilkins et al37 Single arm 47 <21 Extremity Excluded 3–5 (response dependent) 87% 92% at 10 y 84% at 10 y
Wilkins et al36 Single arm 62 <22 Extremity Excluded 3–5 (response dependent) 87% 93% at 10 y 86% at 10 y
Xie et al13 Nonrandomized, 2 arms 48 NA Extremity Included 3 63% 64% at 5 y 60% at 5 y
Hu et al (Current study) Single arm 12 11~69 Pelvis Excluded 2 66.7% 57.8% at 5 y 52.5% at 5 y
Abbreviations: IA, intraarterial; CDDP, cisplatin; TN, tumor necrosis; OS, overall survival; EFS, event-free survival.
Among these 9 studies, 8 used CAI and systematic chemotherapy sequentially before surgery, and 5 studies scheduled a 2-course preoperative regimen. Six of 9 studies suggested a higher chemotherapy response rate and/or survival rate in the CAI group compared with the IV CDDP group; 2 of these investigations were 2-arm randomized cohort studies and reported a statistically significant improvement in the good-response ratio (21% and 31%, respectively). In the third randomized cohort study reported by Rha et al, the improvement was not statistically significant, probably because the limited sample size was insufficient to test the 9% difference between the two groups.35 In the multicenter study reported by Winkler et al and Fuchs et al in the 1990s, no difference in chemotherapy response was observed between the intraarterial and IV CDDP groups.30,34 Similarly, Xie et al also proved a superior histological response rate but equivalent survival in the CAI group versus the IV group in 2019.13 However, the reliability of the conclusions in the 2 studies may be impaired by the nonrandomized grouping design conducted at the researchers’ discretion, which could be affected by the severity of disease. Although CAI may bring benefits to chemotherapy response augmentation and survival rates in limb osteosarcoma patients, how pelvic osteosarcoma reacts to CAI-facilitated multidrug chemotherapy remains elusive.
Pelvic tumor resection surgeries such as hemipelvectomy are notoriously known as one of the most destructive operations in modern orthopedic surgery.38 Due to the adjacency of the vascular network, nerves and viscera in the pelvis, surgeons have to weigh tumor eradication against functional preservation in the determination of the extent of surgical excision. This dilemma makes the treatment more challenging. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate compared with the extremity-morbidity population, which could be explained by the higher rate of not only failure of surgical remission but also advanced age, large tumor size, primary metastasis, prolonged latency periods and poor chemotherapy responses.11,39 Thus, it is critical to maximize the chemotherapy response and achieve better survival outcomes in pelvic osteosarcoma patients.
The combination of agents in our MSC protocol was determined by reference to NCCN guidelines for bone cancer and the study reported by Xie et al.13 Although the agent numbers and categories differed, all of the above-reviewed studies and the present study deployed a multidrug protocol to treat tumor cells in different phases of the cell cycle. Unfortunately, insufficient data are available to appropriately compare the therapeutic effect of CAI alone or in various combinations with MTX, VCR, ADM and IFO because of great heterogeneity. In the present study, we used high-dose MTX at 10 g/m2 and CAI at 120 mg/m2 in 2 doses as routine preoperative treatment. For patients with tumors over 8 cm, we employed an enhanced dose of CAI at 160 mg/m2. Additionally, additional IFO courses were given to slow responders. This individualized regimen directly yielded a 66.7% prevalence of good histopathologic responders and contributed to the 5-year survival rate of 57.8% in pelvic osteosarcoma. Both of the two figures were seemingly improved when compared to those from conventional systematic chemotherapy.11
The cumulative dosage of CDDP was 780 mg/m2 for a good responder with a tumor size ≤ 8 cm in the present study. Wilkins et al reported the highest accumulated dose of CDDP at 960 mg/m2 and a single dose at 160 mg/m2 over 24 h as an enhanced regimen for patients with tumors over 10 cm versus 120 mg/m2 over 6 h as routine, which consequently yielded the highest 10-year OS and EFS rates (93% and 86%, respectively) among all reviewed studies. Notably, Ferrari et al and Xie et al investigated CDDP administration at equivalent doses to those in the present study but yielded poorer survival outcomes seemingly.13,33 This may be because 120 mg/m2 CDDP was given intraarterially in 72 h in the first study, which is too long to achieve a high enough blood concentration; patients with tumor metastases at the initial diagnosis were included in the second study so that the survival rate would be reduced. We used relatively high-dose CDDP administered over 3 to 6 h combined with 4 other drugs, including ETOP, and made individualized adjustments to the protocol for patients with high-risk factors. This may have contributed to the 57.8% OS and 52.5% EFS rate at 5 years, which is favorable for pelvic osteosarcoma. Moreover, we discovered that the OS and EFS rates in the population with tumors ≤ or >8 cm showed insignificant differences. Patients who received R0 resection also shared equivalent OS but higher EFS with R1 patients. These finding suggest that this protocol with risk-dependent adjustment in the drug dosage and combination could be beneficial to bridge the gap in survival rate between patients with large or small tumors, and those who received R0 or R1 resection.
We noticed that 3 of 5 cases developing SD turned out to demonstrate TNR >90%, which probably means that good response of osteosarcoma is not necessarily accompanied with tumor size decrease. This may be attributed to the formation of tumor bone generated by subtypes like osteoblastic osteosarcoma, which could prevent tumors from shrinkage.40
Only 4 poor responders were observed, 3 of whom developed tumor relapses. Two of the 3 patients died of metastasis during postoperative MSC; another showed no evidence of disease after receiving secondary amputation and resection for local recurrence. This protocol seemed to provide limited benefit to the poor responders. However, the present data are so limited that few tenable conclusions can be drawn from it to guide salvage treatment for poor responders.
Although the AI technique and additional courses were given in this protocol, no patients received an overdose of chemotherapy drugs compared with previous studies using similar drug combinations. No AI-relative grade 4 or 5 adverse events were observed. Although systematic adverse events, including nausea, vomiting, anemia and an increase in creatinine/aminotransferase levels, shared equivalent incidence rates and severities with the study reported by Xie et al, local skin hyperpigmentation and pelvic soft tissue necrosis in muscle occurred after only 3 and 1 of 24 CAI events (12.5% and 4.2%, respectively), which is more favorable than the situation reported in the most reviewed studies concerning extremity osteosarcoma.13,30,33 This finding could be explained by the shorter local drug-retention time since the pelvis has a more sufficient blood supply and drainage.
In terms of the postoperative MSC regimen for poor responders, we determined the IFO + ETOP regimen by reference to the second-line chemotherapy recommended in NCCN guidelines for bone cancer, which is supported by the study reported by Goorin et al and Miser et al.23,41 These two studies were conducted in patients with initial metastasis or recurrence of osteosarcoma, and the former one used IFO + ETOP as an induction regimen accompanied by surgical resection and continuation MSC of MTX + ADM + ETOP + IFO. Therefore, we adopted the regimen similar as the one reported by Miser et al However, the study of EURAMOS reported by Marina et al suggested that treatment with MTX + ADM + CDDP + IFO + ETOP resulted in similar EFS to MTX + ADM + CDDP and increased toxicity. In the present study, we found it hard for patients to accept 12 cycles of second-line therapy in 3 years in view of the high expenditure and physical discomfort. Therefore, the number of cycles was reduced to 6 for poor responders, which is equivalent to a half of the regimen of Miser et al in accumulative dosage and duration time. During the postoperative MSC period, there was no early death. The reported cardiac irritation, increase in creatinine/aminotransferase, oral mucosa inflammation and hematologic system abnormality were acceptable. In summary, our chemotherapy regimen seems to be well tolerated.
To monitor the chemotherapy response, several methods have been reported in previous studies. In the studies reported by Winkler et al and Fuch et al, plain X-ray, local CT and emission CT of bone were used to monitor the TNR before the surgery.30,34 Bacci et al, Wilkins et al and Xie et al deployed CT arterial angiography, which yielded sensitivity and specificity over 90% and 50%, respectively.13,32,36,37 Nevertheless, a repeated CT arterial angiography assessment is difficult to be accepted by patients because it requires multiple invasive operations and high expenditure. RECIST-1.1-based MRI remains one of the most commonly used approaches in tumor response evaluation.42,43 In the present study, we used CE-MRI to detect the tumor response and guide the adjustment of treatment for each patient. Although the results did not seem to suggest that this method is highly predictive of the histopathologic chemotherapy response, the equivalent survival rate between patients with large and small tumors may reflect the effectiveness of the individualized treatment.
There were several limitations in our investigation. First, the design was restricted to a small-sample-size single-arm clinical study due to the rarity of pelvis osteosarcoma morbidity, therefore reducing the reliability of the conclusions. Second, several previous studies reported that pathological subtypes of osteosarcoma, such as chondroblastic and telangiectatic osteosarcoma, respond differently to chemotherapy.39,44 However, the pathological subtype of each patient was not analyzed as an independent prognostic factor in our study. Heterogeneity of the osteosarcoma subtype constitution could distort chemotherapy response and survival outcomes. Third, we used CE-MRI per RECIST 1.1 to monitor the tumor response before surgery and guide the individualized adjustment of the treatment protocol. However, CE-MRI evaluation was not the gold standard for TNR prediction. Multiple innovative approaches for TNR prediction in osteosarcoma have been researched in the past 30 years, such as dynamic CE-MRI with sensitivity and specificity over 70% and 80%, respectively, according to previous studies.45–47 We would attempt to deploy approaches with higher accuracy to evaluate viable tumors in hope of providing more precise guidance for individualized pelvic osteosarcoma treatment in further studies.
Conclusions
In the present study, we employed CAI in the multimodal treatment of pelvic osteosarcoma patients. Our findings suggest that the CAI-facilitated chemotherapy regimen demonstrated great potential for improving the survival of patients with pelvic osteosarcoma. This treatment protocol yielded high tolerance with acceptable adverse effects. However, further randomized controlled trials with large sample sizes are required to elucidate the findings of this preliminary study.
Acknowledgments
We would like to thank all patients for their devotion to taking unidentified risks in this clinical trial. We are also grateful to the participating orthopedic oncologists and interventional radiologists for their prudence and patience in the therapeutic effect evaluation and the multidisciplinary consultation.
Abbreviations
ADM, adriamycin; CAI, effect of cisplatin arterial infusion; CDDP, cis-diamine-dichloro platinum; CE-MRI, contrast-enhanced MRI; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; EFS, event-free survival; ETOP, etoposide; IFO, ifosfamide; IV, intravenous; MSC, multidrug systematic chemotherapy; MTX, methotrexate; OS, overall survival; PD, progressive disease; PR, partial response; RECIST, response evaluation criteria in solid tumors version; S, surgery; SD, stable disease; TNR, tumor necrosis rate; VCR, vincristine.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics Approval and Informed Consent
This study was approved by the ethics committees and the institutional review board of the Second Xiangya Hospital. All patients provided written informed consent for receiving this treatment protocol. The requirement of obtaining specific informed consent for this retrospective study was waived for the reason mentioned before.
Consent for Publication
This study conforms to Declaration of Helsinki. The requirement of obtaining specific informed consent from the patients for the publication of the case presentation and any accompanying images.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
No commercial sponsorship was involved in any part of this study. The authors report no conflicts of interest related to this work. | Intravenous drip | DrugAdministrationRoute | CC BY-NC | 33623429 | 19,834,554 | 2021 |
What was the administration route of drug 'VINCRISTINE'? | Effect of Cisplatin Arterial Infusion (CAI) on Primary Nonmetastatic Pelvic Osteosarcoma: A Preliminary Study.
The critical role of arterial infusion chemotherapy in the multimodal treatment of extremity bone cancer has been investigated extensively, but few studies have focused on pelvic osteosarcoma. Therefore, we attempted to evaluate the clinical significance of arterial infusion chemotherapy in the treatment of pelvic osteosarcoma.
We combined a cisplatin arterial infusion regimen with multidrug systematic chemotherapy as a neoadjuvant protocol for the treatment of pelvic osteosarcoma. The course number and dosage of cisplatin arterial infusion were adjusted to achieve a maximal tumor response evaluated by contrast-enhanced MRI per RECIST 1.1. Good responders received the same systematic combination for postoperative chemotherapy, and poor responders received second-line therapy. Twelve patients with nonmetastatic high-grade pelvic osteosarcoma were included. Survival, chemotherapy response and adverse events data were analyzed.
The mean follow-up period was 56.1 months. Four patients died of refractory tumor progression, and 1 patient with local recurrence had no evidence of disease for 27 months after receiving secondary amputation and resection. Kaplan-Meier survival analysis demonstrated a 57.8% overall survival and 52.5% event-free survival rate at 5 years. Eight of 12 patients had a >90% tumor necrosis rate according to histopathologic examinations. The rates of local adverse events were lower than those reported for extremity osteosarcoma.
Our study initially indicated that the cisplatin arterial infusion regimen was a potential therapy with good tolerance in the treatment of pelvic osteosarcoma.
Introduction
Osteosarcoma is the most common solid malignant tumor of bone with a highly aggressive behavior.1 The most susceptible age of osteosarcoma is bimodal, which is characterized by one peak at 10-to-20 years and another at over 60 years.2,3 Although this disease endangers the health of both adolescent and aged populations, limited progress has been made to improve survival and functional prognosis, especially in patients with pelvic osteosarcoma.4–6 Osteosarcoma patients treated with mere immediate surgical resection register a recurrence rate up to 60–90%.7 (Since 1980s, traditional adjuvant intravenous (IV) systematic chemotherapy produces an improved five-year event-free survival (EFS) rate of 61%.8 In the early 2000s, the propagation of a multidrug neoadjuvant chemotherapy regimen elevated this rate to 60% and above.9,10) Henceforth, numerous explorations have been conducted to optimize the category, dosage, combination and duration of chemotherapy drug administration. The most recent studies of EURAMOS revealed a 5-year EFS of 65–70% for localized osteosarcoma treated by multidrug neoadjuvant chemotherapy. However, there are few studies focusing on arterial infusion as an improved method and its clinical outcome in the treatment of pelvic osteosarcoma.
Osteosarcoma in pelvic bone is more notorious than that in extremities. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate than those with extremity lesions, which may be associated with a poor chemotherapy response and an inability to achieve adequate surgical resection.11 Therefore, more challenges are faced in the management of pelvic osteosarcoma.
Platinum complexes, such as cis-diamine-dichloro platinum (cisplatin, CDDP), have been proven to be cell cycle-nonspecific agents and to have multiple broad-spectrum antitumor effects.12 Several clinical trials reported that employing an arterial infusion technique to deliver CDDP, in combination with an IV systematic chemotherapy regimen or not, can elevate the local drug concentration to fivefold that of IV administration and can produce better survival in the treatment of extremity osteosarcoma.13–15 Therefore, the arterial infusion of CDDP might have potential in the treatment of pelvic osteosarcoma.
The histopathologic response of surgically removed tumors has been shown to be one of most critical indicators of chemotherapeutic effectiveness and survival prognosis.16,17 However, preoperative examination is more valuable to predict tumor response and allow individualized neoadjuvant chemotherapy. Response evaluation criteria in solid tumors version 1.1 (RECIST 1.1), which was commonly adopted for the tumor-response evaluation of a variety of cancers, affirmed the value of sectional radiological imaging measurement.18–20 Therefore, preoperative contrast-enhanced MRI (CE-MRI) evaluation based on RECIST 1.1 is expected to guide the adjustment of treatment for optimal surgical timing in pelvic osteosarcoma.
Given all these findings, we combined CDDP arterial infusion (CAI) with individualized multidrug systematic chemotherapy (MSC) and surgery (S) to treat nonmetastatic pelvic osteosarcoma and attempted to investigate (1) the chemotherapy response and survival yielded from this protocol, (2) the individualized adjustment of the neoadjuvant MSC regimen necessary to achieve the maximal tumor response according to RECIST-1.1-based CE-MRI reassessment, and (3) the potential adverse effects caused by the arterial infusion technique and the multidrug systematic chemotherapy regimen.
Patients and Methods
Study Design and Consent
This is a retrospective cohort study (Level III evidence) in which subjects received a protocol comprising multidrug systematic chemotherapy, cisplatin arterial infusion and resection surgery (CAI + MSC + S). The study design conformed with the Declaration of Helsinki, and the treatment protocol was approved by the hospital institutional review board. All patients provided written informed consent for receiving this treatment protocol. All data used in the present study were obtained from the electronic medical records of our hospital and treated with strict confidentiality; therefore, the requirement of obtaining specific informed consent for this retrospective study was waived.
Patients
Inclusion criteria for subjects included (1) histopathologically defined primary osteosarcoma of pelvic bone; (2) no metastatic foci; (3) no past history of cancer treatment; and (4) normal cardiac, hepatic and renal function. All patients were confirmed to have high-grade osteosarcoma morbidity via biopsy. Pretreatment baseline safety indexes were determined with routine blood tests, hepatic and renal function tests, and Doppler echocardiography. A peripherally inserted central catheter was placed in each patient for the IV administration of neoadjuvant chemotherapy agents.
From January 2010 to June 2015, 21 patients were consecutively diagnosed with osteosarcoma of the pelvic bones in our work unit. A total of 4 patients were excluded for the following reasons: 2 patients had evidence of distant metastasis, and 2 tumors involved the femur or lumbar vertebra. Among the eligible people, 2 refused to take CAI + MSC + S treatment: 1 had hemophilia with severely impaired coagulation function; 1 intended to transfer to another hospital after being definitively diagnosed via biopsy. Subsequently, 15 patients took the CAI + MSC + S treatment, but 1 of them stopped midway (because of intolerance to vomiting as the adverse effect in the first two rounds of IV multidrug therapy) and turned to other treatment. Two patients were lost to follow-up after surgical resection. Eventually, 12 patients finished the treatment protocol and yielded analyzable data for survival, chemotherapy response and toxicity assessment.
The data of these 12 patients are listed in Table 1. The study population consisted of 7 (58.3%) males and 5 (41.7%) females with an average age of 28.8 years (11 to 69 years). The morbid sites included the pubis (n = 2), ilium (n = 4), ischium (n = 1), sacrum (n = 1) and unclear sites (n = 4).Table 1 Patient Data
Case No. Age (y) Sex Tumor Size (cm) Morbid Site MRI Tumor Response Before Surgery Surgical Margins Histopathologic Response Diagnosis Date Surgery Type Follow-Up (Month) First Relapse Status
1 62 F <8 Unclear +27.4%, PD R0 <90% 5/19/2010 1 42 CDF
2 19 M <8 Ilium −35.1%, PR R0 >90% 10/4/2010 2 46 Jan. 2014 DOD
3 14 M <8 Unclear +14.6%, SD R0 95% 7/23/2011 2 52 CDF
4 53 F >8 Sacrum −7.3%, SD R1 <90% 6/30/2012 4 57 Feb. 2015 NED
5 15 M <8 Ilium −32.7%, PR R0 >90% 10/28/2012 2 93 CDF
6 21 F 7 Ilium +25.9%, PD R0 >90% 4/24/2013 2 87 CDF
7 16 M >8 Unclear +8.6%, SD R1 <90% 9/22/2013 2 37 Aug. 2015 DOD
8 36 F 9 Pubis −24.1%, SD R0 >90% 4/14/2014 2 76 CDF
9 69 M 12 Ischium +43.7% PD R1 <90% 5/17/2014 3 15 Jan. 2015 DOD
10 12 F <8 Unclear −37.4%, PR R0 99% 8/21/2014 2 72 CDF
11 41 M <8 Pubis +33.5%, PR R0 >90% 3/6/2015 2 34 CDF
12 47 M <8 Ilium +16.6%, SD R0 95% 6/30/2015 2 62 Dec. 2019 DOD
Notes: Surgical type = 1) primary lower limb amputation; 2) lower limb salvage surgery; 3) secondary amputation and reresection due to local recurrence; 4) revision surgery due to periprosthetic infection.
Abbreviations: CAI, cisplatin arterial infusion; PR, partial response; PD, progressive disease; SD, stable disease; CAP, cisplatin arterial perfusion; CDF, continuously disease free; NED, no evidence of disease; DOD, died of disease.
Description of the Study Treatments and Outcome Measures
The adopted CAI + MSC + S treatment protocol is depicted in Figure 1. In general, MSCs usually consist of high-dose methotrexate (MTX), vincristine (VCR), adriamycin (ADM), CDDP and ifosfamide (IFO). Specifically, the routine CAI + MSC regimen was initiated with 24-hour continuous IV dripping of high-dose MTX at 10 g/m2 followed by 2 mg IV VCR the next day for the first group at Week 0; in Week 2, 120 mg/m2 CDDP AI over 3 to 6 hours and following 30 mg/m2/d IV ADM for 2 days were given to the second group; these 2 groups were repeated in Weeks 3 and 4; then, the resection surgery was performed 2 weeks after the neoadjuvant chemotherapy was finished. Notably, 160 mg/m2 was determined as the enhanced dosage of CDDP for tumors with the longest diameter over 8 cm in CE-MRI slices. In addition, IV IFO at 2 g/m2/d for 5 days was given in Week 5 for tumors over 8 cm after the 4-week routine regimen was completed. Central venous catheterization for MSC administration was performed under inhalation anesthesia if necessary. Before each CAI regimen, percutaneous punctuation of the femoral artery was performed using the Seldinger technique, and the catheter was inserted from the femoral artery of the contralateral side to the beginning of the artery trunk supplying the tumor with the assistance of CT-guided positioning.21 Then, CT arterial angiography was conducted. Each course of MSC and CAI was accompanied by IV hydration, diuretics, rescue and protecting drugs. The CDDP was perfused via the catheter with chemotherapy pumps (LimLess Infusion Pump; PFM Medical Inc, Cologne, Germany) in a pulsed manner (Bolus dose administrator; PFM Medical Inc, Cologne, Germany). The patients were asked to have strict bed rest under multiparameter monitoring. Routine blood tests for electrolytes and hepatic and renal function were performed on the first day after drug administration and every 3 days thereafter.Figure 1 The individualized pelvic osteosarcoma treatment protocol combined cisplatin arterial infusion, multidrug systematic chemotherapy and resection surgery (CAI + MSC + S).
To evaluate the therapeutic response, primary plain X-ray (Figure 2A) and physical examination parameters of the tumor, including pre- and postchemotherapy size, tenderness, pain and inflammation, were collected. More importantly, CE-MRI was performed to monitor the tumor chemotherapy response before and after routine neoadjuvant CAI + MSC administration. (Figure 2B–E) According to the RECIST 1.1 guidelines, tumor size was calculated in gadolinium-enhancing T1-weighted fat‐saturated coronal images using the following criteria: complete response (CR), complete elimination of target lesion; partial response (PR), ≥30% decrease in the diameter of target lesion compared to baseline); progressive disease (PD), ≥20% increase in the diameter of target lesion compared to baseline or new metastatic lesion); and stable disease (SD) or observed changes in the diameter of the target lesion between 30% decrease and 20% increase compared to baseline. Each tumor lesion was assessed by orthopedic oncologists and interventional radiologists who were blinded to the treatment allocation and clinical outcome data. For patients who achieved PD after the routine neoadjuvant regimen was finished, surgery was performed immediately. For patients who demonstrated CR or PR, surgery was performed 2 weeks after the neoadjuvant regimen as usual. For patients who presented SD, the same IFO course as that mentioned in the adjustment for large tumors was added to maximize the tumor response of the neoadjuvant regimen. Then, a multidisciplinary consultation was conducted to identify the achievement of maximal tumor response. If any uncertainty of maximal response achievement was left, one more course of IFO could be given, and patients received resection surgery no later than 9 weeks after the first diagnosis.Figure 2 (A) Pelvis X-ray of a 36-year-old female with an osteosarcoma in the pubis. (B) and (C) Fat-saturated T1- and T2-weighted coronal slices of contrast-enhanced MRI showing the maximum diameter of the tumor at the first diagnosis, which showed heterogeneous enhancement, thick septa and obscure boundaries of the tumor. (D) and (E) MRI reevaluation after completion of the neoadjuvant CAI + MSC regimen, showing thin septa, clear boundaries and stable disease according to RECIST 1.1 with a decrease in the tumor diameter. (F) Pelvis plain X-ray of this patient. (The identifiable captions in these images are occluded.).
A chest CT scan, a full-body bone scan and a pelvic CE-MRI scan (Figure 2D and E) were repeated before surgery. The tumor response per RECIST 1.1 measured in the last CE-MRI examination was compared with the baseline level. Surgical excision extension was determined by the involved scope of the tumor and the tumor response category according to the CE-MRI assessment per RECIST 1.1. The pelvic reconstruction project depended on the morbidity site, excision extension, bone mineral density and functional requirements.
In case of uncontrollable hemorrhage during the resection surgery, a temporary balloon blocking technique for the abdominal aorta was performed under the guidance of CTA 4 hours before resection surgery. A balloon compatible in size to the abdominal aortic diameter was placed intraarterially at the level of 2 to 3 cm above the bifurcation of the common iliac arteries. The injection of saline with 0.1% heparin inflated the balloon, consequently blocking blood perfusion of the surgical site. Angiography was performed to confirm the satisfactory blockage of the iliac arteries and unobstruction of the renal arteries. Then, the balloon was deflated until the surgery began. Each deflation was performed with an interval of 60 min during the resection surgery before satisfactory hemostasis was achieved.
Histopathologic examination was conducted using the method reported by Huvos et al to quantify the necrosis ratio of the tumor after removal.22 Patients with a ≥90% tumor necrosis rate (TNR) (Grade III and IV) were classified as good responders. The other (Grade Ⅰ and Ⅱ) were deemed poor responders.
The postoperative IV chemotherapy cycle was repeated every 3 weeks. The recovery of hematopoietic function in patients was required before each course, which was defined as a white blood cell count over 1×104/mm3 and a platelet count over 5×106/mm3 for 3 successive days without hematopoietic stimulants. For good responders, the duration of postoperative MSC was usually 3 courses, which could be extended to the maximum of 6 courses accompanied by the existence of high-risk factors, including SD or PD in the CE-MRI per RECIST 1.1 before surgery or histology-proven tumor involvement in the surgical margin (R1 resection). For poor responders, IFO at 2 g/m2/d for 5 days and etoposide (ETOP) at 100 mg/m2/d for 5 days were given sequentially as one cycle repeated every 3 weeks for 6 cycles.23
After the planned treatment was finished, the discontinuation of chemotherapy was allowed by the orthopedic oncologist if X-ray (Figure 2F) and CE-MRI of the primary morbidity site along with chest X-ray every 2 months, chest CT scanning every 6 months in the first year off the treatment prove no local recurrence or lung metastasis. Routine blood tests and hepatic and renal function tests were deployed every week until the recovery of hematopoietic function.
Statistical Analysis
We used the Kaplan-Meier method to analyze the overall survival (OS) and EFS, which were calculated from the day the preoperative MSC + CAI regimen began. The events were defined as local recurrence, distant metastasis or death from the disease. Additionally, the OS and EFS in groups with different histopathologic chemotherapy responses or tumor sizes were calculated. All statistical analyses were conducted with SPSS software packages (SPSS Inc., Chicago, IL, USA).
Results
Chemotherapy Response
Significant improvement in physical examination parameters was observed in 10 of 12 patients after the neoadjuvant regimen, including alleviation of pain. In terms of tumor response measurement per RECIST 1.1, 4 patients had PR and 5 had SD after routine neoadjuvant CAI + MSC administration. Three patients had to undergo resection surgery ahead of schedule because of PD, as shown by CE-MRI after neoadjuvant CAI + MSC administration. No patient demonstrated CR.
According to the histopathologic assessment, 66.7% (8 of 12) of patients demonstrated TNR over 90%. One of the 3 patients with PD according to the CE-MRI assessment turned out to be good responders with Grade III histopathologic results.
Surgery
Three patients underwent local radical excision and lower limb amputation because of neurovascular bundle involvement. The remaining 9 patients received limb salvage surgery followed by pelvic reconstruction using a modular prosthesis (Lidakang Inc., Beijing, China), tumor bone devitalization and replantation, or just bone fusion. As a result, 1 patient who underwent primary limb salvage surgery developed local recurrence and underwent secondary amputation and local reresection. Two patients had surgical site infections but were cured 2 months after surgery. One patient who developed a periprosthetic infection underwent a secondary amputation.
Survival
A total of 58.3% of patients (7 of 12) remained continuously disease free in an average follow-up period of 65.1 months (range, 34–93 months). One patient who developed local recurrence was proven alive with no evidence of disease for 31 months after receiving a secondary amputation and resection. Four patients (3 lung metastases and 1 local recurrence) died of refractory disease progression. Kaplan-Meier survival analysis suggested an OS rate of 57.8% and an EFS of 52.5% at 5 years (Figure 3). For patients with a good chemotherapy response, the 5-year OS and EFS rates were 68.6%, both of which showed significant differences (P = 0.04 for OS and 0.01 for EFS) compared with the corresponding measures for poor responders (Table 2). The comparison of patients with tumor sizes greater (n = 4) or less (n = 8) than 8 cm did not yield statistical significance (P = 0.32 and 0.13, respectively). As shown in the pathological report, 75% (9 of 12) patients received R0 resection and 25% (3 of 12) had R1 resection. There was no significant difference in the OS but in the EFS between patient group with R0 or R1 surgical resection (P = 0.15 and 0.05, respectively). The confidence interval of all OS and EFS are 95%.Table 2 Overall Survival (OS) and Event-Free Survival (EFS) Rate
Variables 1 y 5 y
All patients – OS 91.7% 57.8%
All patients – EFS 91.7% 52.5%
Good responders – OS 100.0% 68.6%
Good responders – EFS 100.0% 68.6%
Poor responders – OS 75.0% 50.0%
Poor responders – EFS 75.0% 25.0%
Patients with tumor size ≥8 cm – OS 75.0% 50.0%
Patients with tumor size ≥8 cm – EFS 75.0% 25.0%
Patients with tumor size<8 cm – OS 100.0% 62.5%
Patients with tumor size<8 cm – EFS 100.0% 64.3%
R0 resection – OS 85.7% 70.0%
R0 resection – EFS 88.9% 71.1%
R1 resection – OS 66.7% 33.3%
R1 resection – EFS 66.7% 33.3%
Note: Confidence Interval = 95%
Figure 3 The Kaplan-Meier survival curve for overall survival (OS) and event-free survival (EFS) rates of 12 pelvic osteosarcoma patients treated with the CAI + MSC + S protocol.
Chemotherapy Toxicity
We recorded the adverse effects referred to in the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.24 The statistics of CAI-related adverse events are summarized in Table 3. Three of 12 patients had local adverse events, including grade 1 to 2 skin pelvic soft tissue necrosis in muscle and hyperpigmentation, which exhibited no effect on the surgical method choice or wound healing. Nausea and vomiting were the most common systematic adverse events, with 41.7% of patients developing grade 3 events. A 36-year-old female received a reduced dosage of MTX (7 g/m2) due to intolerable vomiting after the first MTX course. Four of 12 patients developed grade 1 infusion-related reactions.Table 3 Statistics of CAI-Related Adverse Events
Adverse Events No. of Courses Percentage of Patients with Grade 3–4 Adverse Events
Skin hyperpigmentation 12.5% (3/24) 0% (0/12)
Pelvic soft tissue necrosis (muscle) 4.2% (1/24) 0% (0/12)
Pelvic pain 16.7% (4/24) 8.3% (1/12)
Nausea and vomiting 75.0% (18/24) 41.7% (5/12)
Anemia 8.3% (2/24) 8.3% (1/12)
Increase in creatinine level 8.3% (2/24) 0% (0/12)
Increase in aminotransferase level 4.2% (1/24) 0% (0/12)
Infusion related reaction 29.2% (7/24) 0% (0/12)
During the postoperative MSC period, one 12-year-old child complained of grade 1 palpitations and chest pain. Therefore, we replaced ADM with ETOP, and the complaint disappeared with no evidence reported in Doppler echocardiography. Three patients out of 12 developed grade 1 to 2 increases in alanine/aspartate aminotransferase levels.
Three children developed oral mucositis at grade 2 to 3, 2 of whom were under IV nutrition, and one used a mouth rinse with metronidazole to treat thrush. All patients eventually resumed normal oral food intake.
Blood system disorders were commonly noted in patients after the second cycle of postoperative MSC administration. Three patients developed febrile neutropenia and were treated by injection of recombinant human granulocyte stimulating factor.
Discussion
Conventional IV adjuvant chemotherapy and neoadjuvant chemotherapy have been applied extensively in multimodal osteosarcoma treatment for over 45 years.25 Though changes in drug combination, dosage, and administration duration were made to optimize the regimen, no significant improvement was achieved based on the approximately 50% to 70% 5-year OS and EFS rates in the past decade.26–28 As a modified approach to augment the potential of chemotherapy drugs, the AI technique combined with MSCs has been studied for years.13,29,30 In the present study, we attempted to investigate the therapeutic effect of the CAI + MSC + S protocol in osteosarcoma treatment. The 5-year OS and EFS rates were 57.8% and 52.5%, respectively.
The CAI regimen and its outcome measurements were first documented by Jaffe et al in 1983.31 Then, a series of studies concerning CAI-facilitated multidrug chemotherapy followed.13,30,32–37 Information on all 9 studies, including the present study, is listed in Table 4.Table 4 Synopsis of IA CDDP Information Reported in the Literature
Authors Type of Study No. of Patients Ages (y) Sites Metastases Preoperative CDDP Courses No. >90% TN OS EFS
Winkler et al and Fuchs et al30,34 Nonrandomized, 2 arms 50 <40 All Included 2 68% 67% at 10 y 63% at 10 y
Ferrari et al33 Single arm 164 <40 Extremity Excluded 2 NA 72% at 8 y 63% at 8 y
Ferrari et al33 Randomized, 2 arms 59 <40 Extremity Excluded 2 64% 61% at 8 y 54% at 8 y
Rha et al35 Single arm 37 8~41 Extremity ? 3 75% 78% at 3 y 55% at 3 y
Bacci et al32 Randomized, 2 arms 40 <40 Extremity Included 2 77% NA 26% at 5 y
Bacci et al32 Randomized, 2 arms 72 <40 Extremity Included 2 80% NA 61% at 5 y
Wilkins et al37 Single arm 47 <21 Extremity Excluded 3–5 (response dependent) 87% 92% at 10 y 84% at 10 y
Wilkins et al36 Single arm 62 <22 Extremity Excluded 3–5 (response dependent) 87% 93% at 10 y 86% at 10 y
Xie et al13 Nonrandomized, 2 arms 48 NA Extremity Included 3 63% 64% at 5 y 60% at 5 y
Hu et al (Current study) Single arm 12 11~69 Pelvis Excluded 2 66.7% 57.8% at 5 y 52.5% at 5 y
Abbreviations: IA, intraarterial; CDDP, cisplatin; TN, tumor necrosis; OS, overall survival; EFS, event-free survival.
Among these 9 studies, 8 used CAI and systematic chemotherapy sequentially before surgery, and 5 studies scheduled a 2-course preoperative regimen. Six of 9 studies suggested a higher chemotherapy response rate and/or survival rate in the CAI group compared with the IV CDDP group; 2 of these investigations were 2-arm randomized cohort studies and reported a statistically significant improvement in the good-response ratio (21% and 31%, respectively). In the third randomized cohort study reported by Rha et al, the improvement was not statistically significant, probably because the limited sample size was insufficient to test the 9% difference between the two groups.35 In the multicenter study reported by Winkler et al and Fuchs et al in the 1990s, no difference in chemotherapy response was observed between the intraarterial and IV CDDP groups.30,34 Similarly, Xie et al also proved a superior histological response rate but equivalent survival in the CAI group versus the IV group in 2019.13 However, the reliability of the conclusions in the 2 studies may be impaired by the nonrandomized grouping design conducted at the researchers’ discretion, which could be affected by the severity of disease. Although CAI may bring benefits to chemotherapy response augmentation and survival rates in limb osteosarcoma patients, how pelvic osteosarcoma reacts to CAI-facilitated multidrug chemotherapy remains elusive.
Pelvic tumor resection surgeries such as hemipelvectomy are notoriously known as one of the most destructive operations in modern orthopedic surgery.38 Due to the adjacency of the vascular network, nerves and viscera in the pelvis, surgeons have to weigh tumor eradication against functional preservation in the determination of the extent of surgical excision. This dilemma makes the treatment more challenging. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate compared with the extremity-morbidity population, which could be explained by the higher rate of not only failure of surgical remission but also advanced age, large tumor size, primary metastasis, prolonged latency periods and poor chemotherapy responses.11,39 Thus, it is critical to maximize the chemotherapy response and achieve better survival outcomes in pelvic osteosarcoma patients.
The combination of agents in our MSC protocol was determined by reference to NCCN guidelines for bone cancer and the study reported by Xie et al.13 Although the agent numbers and categories differed, all of the above-reviewed studies and the present study deployed a multidrug protocol to treat tumor cells in different phases of the cell cycle. Unfortunately, insufficient data are available to appropriately compare the therapeutic effect of CAI alone or in various combinations with MTX, VCR, ADM and IFO because of great heterogeneity. In the present study, we used high-dose MTX at 10 g/m2 and CAI at 120 mg/m2 in 2 doses as routine preoperative treatment. For patients with tumors over 8 cm, we employed an enhanced dose of CAI at 160 mg/m2. Additionally, additional IFO courses were given to slow responders. This individualized regimen directly yielded a 66.7% prevalence of good histopathologic responders and contributed to the 5-year survival rate of 57.8% in pelvic osteosarcoma. Both of the two figures were seemingly improved when compared to those from conventional systematic chemotherapy.11
The cumulative dosage of CDDP was 780 mg/m2 for a good responder with a tumor size ≤ 8 cm in the present study. Wilkins et al reported the highest accumulated dose of CDDP at 960 mg/m2 and a single dose at 160 mg/m2 over 24 h as an enhanced regimen for patients with tumors over 10 cm versus 120 mg/m2 over 6 h as routine, which consequently yielded the highest 10-year OS and EFS rates (93% and 86%, respectively) among all reviewed studies. Notably, Ferrari et al and Xie et al investigated CDDP administration at equivalent doses to those in the present study but yielded poorer survival outcomes seemingly.13,33 This may be because 120 mg/m2 CDDP was given intraarterially in 72 h in the first study, which is too long to achieve a high enough blood concentration; patients with tumor metastases at the initial diagnosis were included in the second study so that the survival rate would be reduced. We used relatively high-dose CDDP administered over 3 to 6 h combined with 4 other drugs, including ETOP, and made individualized adjustments to the protocol for patients with high-risk factors. This may have contributed to the 57.8% OS and 52.5% EFS rate at 5 years, which is favorable for pelvic osteosarcoma. Moreover, we discovered that the OS and EFS rates in the population with tumors ≤ or >8 cm showed insignificant differences. Patients who received R0 resection also shared equivalent OS but higher EFS with R1 patients. These finding suggest that this protocol with risk-dependent adjustment in the drug dosage and combination could be beneficial to bridge the gap in survival rate between patients with large or small tumors, and those who received R0 or R1 resection.
We noticed that 3 of 5 cases developing SD turned out to demonstrate TNR >90%, which probably means that good response of osteosarcoma is not necessarily accompanied with tumor size decrease. This may be attributed to the formation of tumor bone generated by subtypes like osteoblastic osteosarcoma, which could prevent tumors from shrinkage.40
Only 4 poor responders were observed, 3 of whom developed tumor relapses. Two of the 3 patients died of metastasis during postoperative MSC; another showed no evidence of disease after receiving secondary amputation and resection for local recurrence. This protocol seemed to provide limited benefit to the poor responders. However, the present data are so limited that few tenable conclusions can be drawn from it to guide salvage treatment for poor responders.
Although the AI technique and additional courses were given in this protocol, no patients received an overdose of chemotherapy drugs compared with previous studies using similar drug combinations. No AI-relative grade 4 or 5 adverse events were observed. Although systematic adverse events, including nausea, vomiting, anemia and an increase in creatinine/aminotransferase levels, shared equivalent incidence rates and severities with the study reported by Xie et al, local skin hyperpigmentation and pelvic soft tissue necrosis in muscle occurred after only 3 and 1 of 24 CAI events (12.5% and 4.2%, respectively), which is more favorable than the situation reported in the most reviewed studies concerning extremity osteosarcoma.13,30,33 This finding could be explained by the shorter local drug-retention time since the pelvis has a more sufficient blood supply and drainage.
In terms of the postoperative MSC regimen for poor responders, we determined the IFO + ETOP regimen by reference to the second-line chemotherapy recommended in NCCN guidelines for bone cancer, which is supported by the study reported by Goorin et al and Miser et al.23,41 These two studies were conducted in patients with initial metastasis or recurrence of osteosarcoma, and the former one used IFO + ETOP as an induction regimen accompanied by surgical resection and continuation MSC of MTX + ADM + ETOP + IFO. Therefore, we adopted the regimen similar as the one reported by Miser et al However, the study of EURAMOS reported by Marina et al suggested that treatment with MTX + ADM + CDDP + IFO + ETOP resulted in similar EFS to MTX + ADM + CDDP and increased toxicity. In the present study, we found it hard for patients to accept 12 cycles of second-line therapy in 3 years in view of the high expenditure and physical discomfort. Therefore, the number of cycles was reduced to 6 for poor responders, which is equivalent to a half of the regimen of Miser et al in accumulative dosage and duration time. During the postoperative MSC period, there was no early death. The reported cardiac irritation, increase in creatinine/aminotransferase, oral mucosa inflammation and hematologic system abnormality were acceptable. In summary, our chemotherapy regimen seems to be well tolerated.
To monitor the chemotherapy response, several methods have been reported in previous studies. In the studies reported by Winkler et al and Fuch et al, plain X-ray, local CT and emission CT of bone were used to monitor the TNR before the surgery.30,34 Bacci et al, Wilkins et al and Xie et al deployed CT arterial angiography, which yielded sensitivity and specificity over 90% and 50%, respectively.13,32,36,37 Nevertheless, a repeated CT arterial angiography assessment is difficult to be accepted by patients because it requires multiple invasive operations and high expenditure. RECIST-1.1-based MRI remains one of the most commonly used approaches in tumor response evaluation.42,43 In the present study, we used CE-MRI to detect the tumor response and guide the adjustment of treatment for each patient. Although the results did not seem to suggest that this method is highly predictive of the histopathologic chemotherapy response, the equivalent survival rate between patients with large and small tumors may reflect the effectiveness of the individualized treatment.
There were several limitations in our investigation. First, the design was restricted to a small-sample-size single-arm clinical study due to the rarity of pelvis osteosarcoma morbidity, therefore reducing the reliability of the conclusions. Second, several previous studies reported that pathological subtypes of osteosarcoma, such as chondroblastic and telangiectatic osteosarcoma, respond differently to chemotherapy.39,44 However, the pathological subtype of each patient was not analyzed as an independent prognostic factor in our study. Heterogeneity of the osteosarcoma subtype constitution could distort chemotherapy response and survival outcomes. Third, we used CE-MRI per RECIST 1.1 to monitor the tumor response before surgery and guide the individualized adjustment of the treatment protocol. However, CE-MRI evaluation was not the gold standard for TNR prediction. Multiple innovative approaches for TNR prediction in osteosarcoma have been researched in the past 30 years, such as dynamic CE-MRI with sensitivity and specificity over 70% and 80%, respectively, according to previous studies.45–47 We would attempt to deploy approaches with higher accuracy to evaluate viable tumors in hope of providing more precise guidance for individualized pelvic osteosarcoma treatment in further studies.
Conclusions
In the present study, we employed CAI in the multimodal treatment of pelvic osteosarcoma patients. Our findings suggest that the CAI-facilitated chemotherapy regimen demonstrated great potential for improving the survival of patients with pelvic osteosarcoma. This treatment protocol yielded high tolerance with acceptable adverse effects. However, further randomized controlled trials with large sample sizes are required to elucidate the findings of this preliminary study.
Acknowledgments
We would like to thank all patients for their devotion to taking unidentified risks in this clinical trial. We are also grateful to the participating orthopedic oncologists and interventional radiologists for their prudence and patience in the therapeutic effect evaluation and the multidisciplinary consultation.
Abbreviations
ADM, adriamycin; CAI, effect of cisplatin arterial infusion; CDDP, cis-diamine-dichloro platinum; CE-MRI, contrast-enhanced MRI; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; EFS, event-free survival; ETOP, etoposide; IFO, ifosfamide; IV, intravenous; MSC, multidrug systematic chemotherapy; MTX, methotrexate; OS, overall survival; PD, progressive disease; PR, partial response; RECIST, response evaluation criteria in solid tumors version; S, surgery; SD, stable disease; TNR, tumor necrosis rate; VCR, vincristine.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics Approval and Informed Consent
This study was approved by the ethics committees and the institutional review board of the Second Xiangya Hospital. All patients provided written informed consent for receiving this treatment protocol. The requirement of obtaining specific informed consent for this retrospective study was waived for the reason mentioned before.
Consent for Publication
This study conforms to Declaration of Helsinki. The requirement of obtaining specific informed consent from the patients for the publication of the case presentation and any accompanying images.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
No commercial sponsorship was involved in any part of this study. The authors report no conflicts of interest related to this work. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33623429 | 19,834,554 | 2021 |
What was the dosage of drug 'CISPLATIN'? | Effect of Cisplatin Arterial Infusion (CAI) on Primary Nonmetastatic Pelvic Osteosarcoma: A Preliminary Study.
The critical role of arterial infusion chemotherapy in the multimodal treatment of extremity bone cancer has been investigated extensively, but few studies have focused on pelvic osteosarcoma. Therefore, we attempted to evaluate the clinical significance of arterial infusion chemotherapy in the treatment of pelvic osteosarcoma.
We combined a cisplatin arterial infusion regimen with multidrug systematic chemotherapy as a neoadjuvant protocol for the treatment of pelvic osteosarcoma. The course number and dosage of cisplatin arterial infusion were adjusted to achieve a maximal tumor response evaluated by contrast-enhanced MRI per RECIST 1.1. Good responders received the same systematic combination for postoperative chemotherapy, and poor responders received second-line therapy. Twelve patients with nonmetastatic high-grade pelvic osteosarcoma were included. Survival, chemotherapy response and adverse events data were analyzed.
The mean follow-up period was 56.1 months. Four patients died of refractory tumor progression, and 1 patient with local recurrence had no evidence of disease for 27 months after receiving secondary amputation and resection. Kaplan-Meier survival analysis demonstrated a 57.8% overall survival and 52.5% event-free survival rate at 5 years. Eight of 12 patients had a >90% tumor necrosis rate according to histopathologic examinations. The rates of local adverse events were lower than those reported for extremity osteosarcoma.
Our study initially indicated that the cisplatin arterial infusion regimen was a potential therapy with good tolerance in the treatment of pelvic osteosarcoma.
Introduction
Osteosarcoma is the most common solid malignant tumor of bone with a highly aggressive behavior.1 The most susceptible age of osteosarcoma is bimodal, which is characterized by one peak at 10-to-20 years and another at over 60 years.2,3 Although this disease endangers the health of both adolescent and aged populations, limited progress has been made to improve survival and functional prognosis, especially in patients with pelvic osteosarcoma.4–6 Osteosarcoma patients treated with mere immediate surgical resection register a recurrence rate up to 60–90%.7 (Since 1980s, traditional adjuvant intravenous (IV) systematic chemotherapy produces an improved five-year event-free survival (EFS) rate of 61%.8 In the early 2000s, the propagation of a multidrug neoadjuvant chemotherapy regimen elevated this rate to 60% and above.9,10) Henceforth, numerous explorations have been conducted to optimize the category, dosage, combination and duration of chemotherapy drug administration. The most recent studies of EURAMOS revealed a 5-year EFS of 65–70% for localized osteosarcoma treated by multidrug neoadjuvant chemotherapy. However, there are few studies focusing on arterial infusion as an improved method and its clinical outcome in the treatment of pelvic osteosarcoma.
Osteosarcoma in pelvic bone is more notorious than that in extremities. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate than those with extremity lesions, which may be associated with a poor chemotherapy response and an inability to achieve adequate surgical resection.11 Therefore, more challenges are faced in the management of pelvic osteosarcoma.
Platinum complexes, such as cis-diamine-dichloro platinum (cisplatin, CDDP), have been proven to be cell cycle-nonspecific agents and to have multiple broad-spectrum antitumor effects.12 Several clinical trials reported that employing an arterial infusion technique to deliver CDDP, in combination with an IV systematic chemotherapy regimen or not, can elevate the local drug concentration to fivefold that of IV administration and can produce better survival in the treatment of extremity osteosarcoma.13–15 Therefore, the arterial infusion of CDDP might have potential in the treatment of pelvic osteosarcoma.
The histopathologic response of surgically removed tumors has been shown to be one of most critical indicators of chemotherapeutic effectiveness and survival prognosis.16,17 However, preoperative examination is more valuable to predict tumor response and allow individualized neoadjuvant chemotherapy. Response evaluation criteria in solid tumors version 1.1 (RECIST 1.1), which was commonly adopted for the tumor-response evaluation of a variety of cancers, affirmed the value of sectional radiological imaging measurement.18–20 Therefore, preoperative contrast-enhanced MRI (CE-MRI) evaluation based on RECIST 1.1 is expected to guide the adjustment of treatment for optimal surgical timing in pelvic osteosarcoma.
Given all these findings, we combined CDDP arterial infusion (CAI) with individualized multidrug systematic chemotherapy (MSC) and surgery (S) to treat nonmetastatic pelvic osteosarcoma and attempted to investigate (1) the chemotherapy response and survival yielded from this protocol, (2) the individualized adjustment of the neoadjuvant MSC regimen necessary to achieve the maximal tumor response according to RECIST-1.1-based CE-MRI reassessment, and (3) the potential adverse effects caused by the arterial infusion technique and the multidrug systematic chemotherapy regimen.
Patients and Methods
Study Design and Consent
This is a retrospective cohort study (Level III evidence) in which subjects received a protocol comprising multidrug systematic chemotherapy, cisplatin arterial infusion and resection surgery (CAI + MSC + S). The study design conformed with the Declaration of Helsinki, and the treatment protocol was approved by the hospital institutional review board. All patients provided written informed consent for receiving this treatment protocol. All data used in the present study were obtained from the electronic medical records of our hospital and treated with strict confidentiality; therefore, the requirement of obtaining specific informed consent for this retrospective study was waived.
Patients
Inclusion criteria for subjects included (1) histopathologically defined primary osteosarcoma of pelvic bone; (2) no metastatic foci; (3) no past history of cancer treatment; and (4) normal cardiac, hepatic and renal function. All patients were confirmed to have high-grade osteosarcoma morbidity via biopsy. Pretreatment baseline safety indexes were determined with routine blood tests, hepatic and renal function tests, and Doppler echocardiography. A peripherally inserted central catheter was placed in each patient for the IV administration of neoadjuvant chemotherapy agents.
From January 2010 to June 2015, 21 patients were consecutively diagnosed with osteosarcoma of the pelvic bones in our work unit. A total of 4 patients were excluded for the following reasons: 2 patients had evidence of distant metastasis, and 2 tumors involved the femur or lumbar vertebra. Among the eligible people, 2 refused to take CAI + MSC + S treatment: 1 had hemophilia with severely impaired coagulation function; 1 intended to transfer to another hospital after being definitively diagnosed via biopsy. Subsequently, 15 patients took the CAI + MSC + S treatment, but 1 of them stopped midway (because of intolerance to vomiting as the adverse effect in the first two rounds of IV multidrug therapy) and turned to other treatment. Two patients were lost to follow-up after surgical resection. Eventually, 12 patients finished the treatment protocol and yielded analyzable data for survival, chemotherapy response and toxicity assessment.
The data of these 12 patients are listed in Table 1. The study population consisted of 7 (58.3%) males and 5 (41.7%) females with an average age of 28.8 years (11 to 69 years). The morbid sites included the pubis (n = 2), ilium (n = 4), ischium (n = 1), sacrum (n = 1) and unclear sites (n = 4).Table 1 Patient Data
Case No. Age (y) Sex Tumor Size (cm) Morbid Site MRI Tumor Response Before Surgery Surgical Margins Histopathologic Response Diagnosis Date Surgery Type Follow-Up (Month) First Relapse Status
1 62 F <8 Unclear +27.4%, PD R0 <90% 5/19/2010 1 42 CDF
2 19 M <8 Ilium −35.1%, PR R0 >90% 10/4/2010 2 46 Jan. 2014 DOD
3 14 M <8 Unclear +14.6%, SD R0 95% 7/23/2011 2 52 CDF
4 53 F >8 Sacrum −7.3%, SD R1 <90% 6/30/2012 4 57 Feb. 2015 NED
5 15 M <8 Ilium −32.7%, PR R0 >90% 10/28/2012 2 93 CDF
6 21 F 7 Ilium +25.9%, PD R0 >90% 4/24/2013 2 87 CDF
7 16 M >8 Unclear +8.6%, SD R1 <90% 9/22/2013 2 37 Aug. 2015 DOD
8 36 F 9 Pubis −24.1%, SD R0 >90% 4/14/2014 2 76 CDF
9 69 M 12 Ischium +43.7% PD R1 <90% 5/17/2014 3 15 Jan. 2015 DOD
10 12 F <8 Unclear −37.4%, PR R0 99% 8/21/2014 2 72 CDF
11 41 M <8 Pubis +33.5%, PR R0 >90% 3/6/2015 2 34 CDF
12 47 M <8 Ilium +16.6%, SD R0 95% 6/30/2015 2 62 Dec. 2019 DOD
Notes: Surgical type = 1) primary lower limb amputation; 2) lower limb salvage surgery; 3) secondary amputation and reresection due to local recurrence; 4) revision surgery due to periprosthetic infection.
Abbreviations: CAI, cisplatin arterial infusion; PR, partial response; PD, progressive disease; SD, stable disease; CAP, cisplatin arterial perfusion; CDF, continuously disease free; NED, no evidence of disease; DOD, died of disease.
Description of the Study Treatments and Outcome Measures
The adopted CAI + MSC + S treatment protocol is depicted in Figure 1. In general, MSCs usually consist of high-dose methotrexate (MTX), vincristine (VCR), adriamycin (ADM), CDDP and ifosfamide (IFO). Specifically, the routine CAI + MSC regimen was initiated with 24-hour continuous IV dripping of high-dose MTX at 10 g/m2 followed by 2 mg IV VCR the next day for the first group at Week 0; in Week 2, 120 mg/m2 CDDP AI over 3 to 6 hours and following 30 mg/m2/d IV ADM for 2 days were given to the second group; these 2 groups were repeated in Weeks 3 and 4; then, the resection surgery was performed 2 weeks after the neoadjuvant chemotherapy was finished. Notably, 160 mg/m2 was determined as the enhanced dosage of CDDP for tumors with the longest diameter over 8 cm in CE-MRI slices. In addition, IV IFO at 2 g/m2/d for 5 days was given in Week 5 for tumors over 8 cm after the 4-week routine regimen was completed. Central venous catheterization for MSC administration was performed under inhalation anesthesia if necessary. Before each CAI regimen, percutaneous punctuation of the femoral artery was performed using the Seldinger technique, and the catheter was inserted from the femoral artery of the contralateral side to the beginning of the artery trunk supplying the tumor with the assistance of CT-guided positioning.21 Then, CT arterial angiography was conducted. Each course of MSC and CAI was accompanied by IV hydration, diuretics, rescue and protecting drugs. The CDDP was perfused via the catheter with chemotherapy pumps (LimLess Infusion Pump; PFM Medical Inc, Cologne, Germany) in a pulsed manner (Bolus dose administrator; PFM Medical Inc, Cologne, Germany). The patients were asked to have strict bed rest under multiparameter monitoring. Routine blood tests for electrolytes and hepatic and renal function were performed on the first day after drug administration and every 3 days thereafter.Figure 1 The individualized pelvic osteosarcoma treatment protocol combined cisplatin arterial infusion, multidrug systematic chemotherapy and resection surgery (CAI + MSC + S).
To evaluate the therapeutic response, primary plain X-ray (Figure 2A) and physical examination parameters of the tumor, including pre- and postchemotherapy size, tenderness, pain and inflammation, were collected. More importantly, CE-MRI was performed to monitor the tumor chemotherapy response before and after routine neoadjuvant CAI + MSC administration. (Figure 2B–E) According to the RECIST 1.1 guidelines, tumor size was calculated in gadolinium-enhancing T1-weighted fat‐saturated coronal images using the following criteria: complete response (CR), complete elimination of target lesion; partial response (PR), ≥30% decrease in the diameter of target lesion compared to baseline); progressive disease (PD), ≥20% increase in the diameter of target lesion compared to baseline or new metastatic lesion); and stable disease (SD) or observed changes in the diameter of the target lesion between 30% decrease and 20% increase compared to baseline. Each tumor lesion was assessed by orthopedic oncologists and interventional radiologists who were blinded to the treatment allocation and clinical outcome data. For patients who achieved PD after the routine neoadjuvant regimen was finished, surgery was performed immediately. For patients who demonstrated CR or PR, surgery was performed 2 weeks after the neoadjuvant regimen as usual. For patients who presented SD, the same IFO course as that mentioned in the adjustment for large tumors was added to maximize the tumor response of the neoadjuvant regimen. Then, a multidisciplinary consultation was conducted to identify the achievement of maximal tumor response. If any uncertainty of maximal response achievement was left, one more course of IFO could be given, and patients received resection surgery no later than 9 weeks after the first diagnosis.Figure 2 (A) Pelvis X-ray of a 36-year-old female with an osteosarcoma in the pubis. (B) and (C) Fat-saturated T1- and T2-weighted coronal slices of contrast-enhanced MRI showing the maximum diameter of the tumor at the first diagnosis, which showed heterogeneous enhancement, thick septa and obscure boundaries of the tumor. (D) and (E) MRI reevaluation after completion of the neoadjuvant CAI + MSC regimen, showing thin septa, clear boundaries and stable disease according to RECIST 1.1 with a decrease in the tumor diameter. (F) Pelvis plain X-ray of this patient. (The identifiable captions in these images are occluded.).
A chest CT scan, a full-body bone scan and a pelvic CE-MRI scan (Figure 2D and E) were repeated before surgery. The tumor response per RECIST 1.1 measured in the last CE-MRI examination was compared with the baseline level. Surgical excision extension was determined by the involved scope of the tumor and the tumor response category according to the CE-MRI assessment per RECIST 1.1. The pelvic reconstruction project depended on the morbidity site, excision extension, bone mineral density and functional requirements.
In case of uncontrollable hemorrhage during the resection surgery, a temporary balloon blocking technique for the abdominal aorta was performed under the guidance of CTA 4 hours before resection surgery. A balloon compatible in size to the abdominal aortic diameter was placed intraarterially at the level of 2 to 3 cm above the bifurcation of the common iliac arteries. The injection of saline with 0.1% heparin inflated the balloon, consequently blocking blood perfusion of the surgical site. Angiography was performed to confirm the satisfactory blockage of the iliac arteries and unobstruction of the renal arteries. Then, the balloon was deflated until the surgery began. Each deflation was performed with an interval of 60 min during the resection surgery before satisfactory hemostasis was achieved.
Histopathologic examination was conducted using the method reported by Huvos et al to quantify the necrosis ratio of the tumor after removal.22 Patients with a ≥90% tumor necrosis rate (TNR) (Grade III and IV) were classified as good responders. The other (Grade Ⅰ and Ⅱ) were deemed poor responders.
The postoperative IV chemotherapy cycle was repeated every 3 weeks. The recovery of hematopoietic function in patients was required before each course, which was defined as a white blood cell count over 1×104/mm3 and a platelet count over 5×106/mm3 for 3 successive days without hematopoietic stimulants. For good responders, the duration of postoperative MSC was usually 3 courses, which could be extended to the maximum of 6 courses accompanied by the existence of high-risk factors, including SD or PD in the CE-MRI per RECIST 1.1 before surgery or histology-proven tumor involvement in the surgical margin (R1 resection). For poor responders, IFO at 2 g/m2/d for 5 days and etoposide (ETOP) at 100 mg/m2/d for 5 days were given sequentially as one cycle repeated every 3 weeks for 6 cycles.23
After the planned treatment was finished, the discontinuation of chemotherapy was allowed by the orthopedic oncologist if X-ray (Figure 2F) and CE-MRI of the primary morbidity site along with chest X-ray every 2 months, chest CT scanning every 6 months in the first year off the treatment prove no local recurrence or lung metastasis. Routine blood tests and hepatic and renal function tests were deployed every week until the recovery of hematopoietic function.
Statistical Analysis
We used the Kaplan-Meier method to analyze the overall survival (OS) and EFS, which were calculated from the day the preoperative MSC + CAI regimen began. The events were defined as local recurrence, distant metastasis or death from the disease. Additionally, the OS and EFS in groups with different histopathologic chemotherapy responses or tumor sizes were calculated. All statistical analyses were conducted with SPSS software packages (SPSS Inc., Chicago, IL, USA).
Results
Chemotherapy Response
Significant improvement in physical examination parameters was observed in 10 of 12 patients after the neoadjuvant regimen, including alleviation of pain. In terms of tumor response measurement per RECIST 1.1, 4 patients had PR and 5 had SD after routine neoadjuvant CAI + MSC administration. Three patients had to undergo resection surgery ahead of schedule because of PD, as shown by CE-MRI after neoadjuvant CAI + MSC administration. No patient demonstrated CR.
According to the histopathologic assessment, 66.7% (8 of 12) of patients demonstrated TNR over 90%. One of the 3 patients with PD according to the CE-MRI assessment turned out to be good responders with Grade III histopathologic results.
Surgery
Three patients underwent local radical excision and lower limb amputation because of neurovascular bundle involvement. The remaining 9 patients received limb salvage surgery followed by pelvic reconstruction using a modular prosthesis (Lidakang Inc., Beijing, China), tumor bone devitalization and replantation, or just bone fusion. As a result, 1 patient who underwent primary limb salvage surgery developed local recurrence and underwent secondary amputation and local reresection. Two patients had surgical site infections but were cured 2 months after surgery. One patient who developed a periprosthetic infection underwent a secondary amputation.
Survival
A total of 58.3% of patients (7 of 12) remained continuously disease free in an average follow-up period of 65.1 months (range, 34–93 months). One patient who developed local recurrence was proven alive with no evidence of disease for 31 months after receiving a secondary amputation and resection. Four patients (3 lung metastases and 1 local recurrence) died of refractory disease progression. Kaplan-Meier survival analysis suggested an OS rate of 57.8% and an EFS of 52.5% at 5 years (Figure 3). For patients with a good chemotherapy response, the 5-year OS and EFS rates were 68.6%, both of which showed significant differences (P = 0.04 for OS and 0.01 for EFS) compared with the corresponding measures for poor responders (Table 2). The comparison of patients with tumor sizes greater (n = 4) or less (n = 8) than 8 cm did not yield statistical significance (P = 0.32 and 0.13, respectively). As shown in the pathological report, 75% (9 of 12) patients received R0 resection and 25% (3 of 12) had R1 resection. There was no significant difference in the OS but in the EFS between patient group with R0 or R1 surgical resection (P = 0.15 and 0.05, respectively). The confidence interval of all OS and EFS are 95%.Table 2 Overall Survival (OS) and Event-Free Survival (EFS) Rate
Variables 1 y 5 y
All patients – OS 91.7% 57.8%
All patients – EFS 91.7% 52.5%
Good responders – OS 100.0% 68.6%
Good responders – EFS 100.0% 68.6%
Poor responders – OS 75.0% 50.0%
Poor responders – EFS 75.0% 25.0%
Patients with tumor size ≥8 cm – OS 75.0% 50.0%
Patients with tumor size ≥8 cm – EFS 75.0% 25.0%
Patients with tumor size<8 cm – OS 100.0% 62.5%
Patients with tumor size<8 cm – EFS 100.0% 64.3%
R0 resection – OS 85.7% 70.0%
R0 resection – EFS 88.9% 71.1%
R1 resection – OS 66.7% 33.3%
R1 resection – EFS 66.7% 33.3%
Note: Confidence Interval = 95%
Figure 3 The Kaplan-Meier survival curve for overall survival (OS) and event-free survival (EFS) rates of 12 pelvic osteosarcoma patients treated with the CAI + MSC + S protocol.
Chemotherapy Toxicity
We recorded the adverse effects referred to in the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.24 The statistics of CAI-related adverse events are summarized in Table 3. Three of 12 patients had local adverse events, including grade 1 to 2 skin pelvic soft tissue necrosis in muscle and hyperpigmentation, which exhibited no effect on the surgical method choice or wound healing. Nausea and vomiting were the most common systematic adverse events, with 41.7% of patients developing grade 3 events. A 36-year-old female received a reduced dosage of MTX (7 g/m2) due to intolerable vomiting after the first MTX course. Four of 12 patients developed grade 1 infusion-related reactions.Table 3 Statistics of CAI-Related Adverse Events
Adverse Events No. of Courses Percentage of Patients with Grade 3–4 Adverse Events
Skin hyperpigmentation 12.5% (3/24) 0% (0/12)
Pelvic soft tissue necrosis (muscle) 4.2% (1/24) 0% (0/12)
Pelvic pain 16.7% (4/24) 8.3% (1/12)
Nausea and vomiting 75.0% (18/24) 41.7% (5/12)
Anemia 8.3% (2/24) 8.3% (1/12)
Increase in creatinine level 8.3% (2/24) 0% (0/12)
Increase in aminotransferase level 4.2% (1/24) 0% (0/12)
Infusion related reaction 29.2% (7/24) 0% (0/12)
During the postoperative MSC period, one 12-year-old child complained of grade 1 palpitations and chest pain. Therefore, we replaced ADM with ETOP, and the complaint disappeared with no evidence reported in Doppler echocardiography. Three patients out of 12 developed grade 1 to 2 increases in alanine/aspartate aminotransferase levels.
Three children developed oral mucositis at grade 2 to 3, 2 of whom were under IV nutrition, and one used a mouth rinse with metronidazole to treat thrush. All patients eventually resumed normal oral food intake.
Blood system disorders were commonly noted in patients after the second cycle of postoperative MSC administration. Three patients developed febrile neutropenia and were treated by injection of recombinant human granulocyte stimulating factor.
Discussion
Conventional IV adjuvant chemotherapy and neoadjuvant chemotherapy have been applied extensively in multimodal osteosarcoma treatment for over 45 years.25 Though changes in drug combination, dosage, and administration duration were made to optimize the regimen, no significant improvement was achieved based on the approximately 50% to 70% 5-year OS and EFS rates in the past decade.26–28 As a modified approach to augment the potential of chemotherapy drugs, the AI technique combined with MSCs has been studied for years.13,29,30 In the present study, we attempted to investigate the therapeutic effect of the CAI + MSC + S protocol in osteosarcoma treatment. The 5-year OS and EFS rates were 57.8% and 52.5%, respectively.
The CAI regimen and its outcome measurements were first documented by Jaffe et al in 1983.31 Then, a series of studies concerning CAI-facilitated multidrug chemotherapy followed.13,30,32–37 Information on all 9 studies, including the present study, is listed in Table 4.Table 4 Synopsis of IA CDDP Information Reported in the Literature
Authors Type of Study No. of Patients Ages (y) Sites Metastases Preoperative CDDP Courses No. >90% TN OS EFS
Winkler et al and Fuchs et al30,34 Nonrandomized, 2 arms 50 <40 All Included 2 68% 67% at 10 y 63% at 10 y
Ferrari et al33 Single arm 164 <40 Extremity Excluded 2 NA 72% at 8 y 63% at 8 y
Ferrari et al33 Randomized, 2 arms 59 <40 Extremity Excluded 2 64% 61% at 8 y 54% at 8 y
Rha et al35 Single arm 37 8~41 Extremity ? 3 75% 78% at 3 y 55% at 3 y
Bacci et al32 Randomized, 2 arms 40 <40 Extremity Included 2 77% NA 26% at 5 y
Bacci et al32 Randomized, 2 arms 72 <40 Extremity Included 2 80% NA 61% at 5 y
Wilkins et al37 Single arm 47 <21 Extremity Excluded 3–5 (response dependent) 87% 92% at 10 y 84% at 10 y
Wilkins et al36 Single arm 62 <22 Extremity Excluded 3–5 (response dependent) 87% 93% at 10 y 86% at 10 y
Xie et al13 Nonrandomized, 2 arms 48 NA Extremity Included 3 63% 64% at 5 y 60% at 5 y
Hu et al (Current study) Single arm 12 11~69 Pelvis Excluded 2 66.7% 57.8% at 5 y 52.5% at 5 y
Abbreviations: IA, intraarterial; CDDP, cisplatin; TN, tumor necrosis; OS, overall survival; EFS, event-free survival.
Among these 9 studies, 8 used CAI and systematic chemotherapy sequentially before surgery, and 5 studies scheduled a 2-course preoperative regimen. Six of 9 studies suggested a higher chemotherapy response rate and/or survival rate in the CAI group compared with the IV CDDP group; 2 of these investigations were 2-arm randomized cohort studies and reported a statistically significant improvement in the good-response ratio (21% and 31%, respectively). In the third randomized cohort study reported by Rha et al, the improvement was not statistically significant, probably because the limited sample size was insufficient to test the 9% difference between the two groups.35 In the multicenter study reported by Winkler et al and Fuchs et al in the 1990s, no difference in chemotherapy response was observed between the intraarterial and IV CDDP groups.30,34 Similarly, Xie et al also proved a superior histological response rate but equivalent survival in the CAI group versus the IV group in 2019.13 However, the reliability of the conclusions in the 2 studies may be impaired by the nonrandomized grouping design conducted at the researchers’ discretion, which could be affected by the severity of disease. Although CAI may bring benefits to chemotherapy response augmentation and survival rates in limb osteosarcoma patients, how pelvic osteosarcoma reacts to CAI-facilitated multidrug chemotherapy remains elusive.
Pelvic tumor resection surgeries such as hemipelvectomy are notoriously known as one of the most destructive operations in modern orthopedic surgery.38 Due to the adjacency of the vascular network, nerves and viscera in the pelvis, surgeons have to weigh tumor eradication against functional preservation in the determination of the extent of surgical excision. This dilemma makes the treatment more challenging. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate compared with the extremity-morbidity population, which could be explained by the higher rate of not only failure of surgical remission but also advanced age, large tumor size, primary metastasis, prolonged latency periods and poor chemotherapy responses.11,39 Thus, it is critical to maximize the chemotherapy response and achieve better survival outcomes in pelvic osteosarcoma patients.
The combination of agents in our MSC protocol was determined by reference to NCCN guidelines for bone cancer and the study reported by Xie et al.13 Although the agent numbers and categories differed, all of the above-reviewed studies and the present study deployed a multidrug protocol to treat tumor cells in different phases of the cell cycle. Unfortunately, insufficient data are available to appropriately compare the therapeutic effect of CAI alone or in various combinations with MTX, VCR, ADM and IFO because of great heterogeneity. In the present study, we used high-dose MTX at 10 g/m2 and CAI at 120 mg/m2 in 2 doses as routine preoperative treatment. For patients with tumors over 8 cm, we employed an enhanced dose of CAI at 160 mg/m2. Additionally, additional IFO courses were given to slow responders. This individualized regimen directly yielded a 66.7% prevalence of good histopathologic responders and contributed to the 5-year survival rate of 57.8% in pelvic osteosarcoma. Both of the two figures were seemingly improved when compared to those from conventional systematic chemotherapy.11
The cumulative dosage of CDDP was 780 mg/m2 for a good responder with a tumor size ≤ 8 cm in the present study. Wilkins et al reported the highest accumulated dose of CDDP at 960 mg/m2 and a single dose at 160 mg/m2 over 24 h as an enhanced regimen for patients with tumors over 10 cm versus 120 mg/m2 over 6 h as routine, which consequently yielded the highest 10-year OS and EFS rates (93% and 86%, respectively) among all reviewed studies. Notably, Ferrari et al and Xie et al investigated CDDP administration at equivalent doses to those in the present study but yielded poorer survival outcomes seemingly.13,33 This may be because 120 mg/m2 CDDP was given intraarterially in 72 h in the first study, which is too long to achieve a high enough blood concentration; patients with tumor metastases at the initial diagnosis were included in the second study so that the survival rate would be reduced. We used relatively high-dose CDDP administered over 3 to 6 h combined with 4 other drugs, including ETOP, and made individualized adjustments to the protocol for patients with high-risk factors. This may have contributed to the 57.8% OS and 52.5% EFS rate at 5 years, which is favorable for pelvic osteosarcoma. Moreover, we discovered that the OS and EFS rates in the population with tumors ≤ or >8 cm showed insignificant differences. Patients who received R0 resection also shared equivalent OS but higher EFS with R1 patients. These finding suggest that this protocol with risk-dependent adjustment in the drug dosage and combination could be beneficial to bridge the gap in survival rate between patients with large or small tumors, and those who received R0 or R1 resection.
We noticed that 3 of 5 cases developing SD turned out to demonstrate TNR >90%, which probably means that good response of osteosarcoma is not necessarily accompanied with tumor size decrease. This may be attributed to the formation of tumor bone generated by subtypes like osteoblastic osteosarcoma, which could prevent tumors from shrinkage.40
Only 4 poor responders were observed, 3 of whom developed tumor relapses. Two of the 3 patients died of metastasis during postoperative MSC; another showed no evidence of disease after receiving secondary amputation and resection for local recurrence. This protocol seemed to provide limited benefit to the poor responders. However, the present data are so limited that few tenable conclusions can be drawn from it to guide salvage treatment for poor responders.
Although the AI technique and additional courses were given in this protocol, no patients received an overdose of chemotherapy drugs compared with previous studies using similar drug combinations. No AI-relative grade 4 or 5 adverse events were observed. Although systematic adverse events, including nausea, vomiting, anemia and an increase in creatinine/aminotransferase levels, shared equivalent incidence rates and severities with the study reported by Xie et al, local skin hyperpigmentation and pelvic soft tissue necrosis in muscle occurred after only 3 and 1 of 24 CAI events (12.5% and 4.2%, respectively), which is more favorable than the situation reported in the most reviewed studies concerning extremity osteosarcoma.13,30,33 This finding could be explained by the shorter local drug-retention time since the pelvis has a more sufficient blood supply and drainage.
In terms of the postoperative MSC regimen for poor responders, we determined the IFO + ETOP regimen by reference to the second-line chemotherapy recommended in NCCN guidelines for bone cancer, which is supported by the study reported by Goorin et al and Miser et al.23,41 These two studies were conducted in patients with initial metastasis or recurrence of osteosarcoma, and the former one used IFO + ETOP as an induction regimen accompanied by surgical resection and continuation MSC of MTX + ADM + ETOP + IFO. Therefore, we adopted the regimen similar as the one reported by Miser et al However, the study of EURAMOS reported by Marina et al suggested that treatment with MTX + ADM + CDDP + IFO + ETOP resulted in similar EFS to MTX + ADM + CDDP and increased toxicity. In the present study, we found it hard for patients to accept 12 cycles of second-line therapy in 3 years in view of the high expenditure and physical discomfort. Therefore, the number of cycles was reduced to 6 for poor responders, which is equivalent to a half of the regimen of Miser et al in accumulative dosage and duration time. During the postoperative MSC period, there was no early death. The reported cardiac irritation, increase in creatinine/aminotransferase, oral mucosa inflammation and hematologic system abnormality were acceptable. In summary, our chemotherapy regimen seems to be well tolerated.
To monitor the chemotherapy response, several methods have been reported in previous studies. In the studies reported by Winkler et al and Fuch et al, plain X-ray, local CT and emission CT of bone were used to monitor the TNR before the surgery.30,34 Bacci et al, Wilkins et al and Xie et al deployed CT arterial angiography, which yielded sensitivity and specificity over 90% and 50%, respectively.13,32,36,37 Nevertheless, a repeated CT arterial angiography assessment is difficult to be accepted by patients because it requires multiple invasive operations and high expenditure. RECIST-1.1-based MRI remains one of the most commonly used approaches in tumor response evaluation.42,43 In the present study, we used CE-MRI to detect the tumor response and guide the adjustment of treatment for each patient. Although the results did not seem to suggest that this method is highly predictive of the histopathologic chemotherapy response, the equivalent survival rate between patients with large and small tumors may reflect the effectiveness of the individualized treatment.
There were several limitations in our investigation. First, the design was restricted to a small-sample-size single-arm clinical study due to the rarity of pelvis osteosarcoma morbidity, therefore reducing the reliability of the conclusions. Second, several previous studies reported that pathological subtypes of osteosarcoma, such as chondroblastic and telangiectatic osteosarcoma, respond differently to chemotherapy.39,44 However, the pathological subtype of each patient was not analyzed as an independent prognostic factor in our study. Heterogeneity of the osteosarcoma subtype constitution could distort chemotherapy response and survival outcomes. Third, we used CE-MRI per RECIST 1.1 to monitor the tumor response before surgery and guide the individualized adjustment of the treatment protocol. However, CE-MRI evaluation was not the gold standard for TNR prediction. Multiple innovative approaches for TNR prediction in osteosarcoma have been researched in the past 30 years, such as dynamic CE-MRI with sensitivity and specificity over 70% and 80%, respectively, according to previous studies.45–47 We would attempt to deploy approaches with higher accuracy to evaluate viable tumors in hope of providing more precise guidance for individualized pelvic osteosarcoma treatment in further studies.
Conclusions
In the present study, we employed CAI in the multimodal treatment of pelvic osteosarcoma patients. Our findings suggest that the CAI-facilitated chemotherapy regimen demonstrated great potential for improving the survival of patients with pelvic osteosarcoma. This treatment protocol yielded high tolerance with acceptable adverse effects. However, further randomized controlled trials with large sample sizes are required to elucidate the findings of this preliminary study.
Acknowledgments
We would like to thank all patients for their devotion to taking unidentified risks in this clinical trial. We are also grateful to the participating orthopedic oncologists and interventional radiologists for their prudence and patience in the therapeutic effect evaluation and the multidisciplinary consultation.
Abbreviations
ADM, adriamycin; CAI, effect of cisplatin arterial infusion; CDDP, cis-diamine-dichloro platinum; CE-MRI, contrast-enhanced MRI; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; EFS, event-free survival; ETOP, etoposide; IFO, ifosfamide; IV, intravenous; MSC, multidrug systematic chemotherapy; MTX, methotrexate; OS, overall survival; PD, progressive disease; PR, partial response; RECIST, response evaluation criteria in solid tumors version; S, surgery; SD, stable disease; TNR, tumor necrosis rate; VCR, vincristine.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics Approval and Informed Consent
This study was approved by the ethics committees and the institutional review board of the Second Xiangya Hospital. All patients provided written informed consent for receiving this treatment protocol. The requirement of obtaining specific informed consent for this retrospective study was waived for the reason mentioned before.
Consent for Publication
This study conforms to Declaration of Helsinki. The requirement of obtaining specific informed consent from the patients for the publication of the case presentation and any accompanying images.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
No commercial sponsorship was involved in any part of this study. The authors report no conflicts of interest related to this work. | 120 MG/M2, DAILY, OVER 3?6H | DrugDosageText | CC BY-NC | 33623429 | 19,834,554 | 2021 |
What was the dosage of drug 'DOXORUBICIN HYDROCHLORIDE'? | Effect of Cisplatin Arterial Infusion (CAI) on Primary Nonmetastatic Pelvic Osteosarcoma: A Preliminary Study.
The critical role of arterial infusion chemotherapy in the multimodal treatment of extremity bone cancer has been investigated extensively, but few studies have focused on pelvic osteosarcoma. Therefore, we attempted to evaluate the clinical significance of arterial infusion chemotherapy in the treatment of pelvic osteosarcoma.
We combined a cisplatin arterial infusion regimen with multidrug systematic chemotherapy as a neoadjuvant protocol for the treatment of pelvic osteosarcoma. The course number and dosage of cisplatin arterial infusion were adjusted to achieve a maximal tumor response evaluated by contrast-enhanced MRI per RECIST 1.1. Good responders received the same systematic combination for postoperative chemotherapy, and poor responders received second-line therapy. Twelve patients with nonmetastatic high-grade pelvic osteosarcoma were included. Survival, chemotherapy response and adverse events data were analyzed.
The mean follow-up period was 56.1 months. Four patients died of refractory tumor progression, and 1 patient with local recurrence had no evidence of disease for 27 months after receiving secondary amputation and resection. Kaplan-Meier survival analysis demonstrated a 57.8% overall survival and 52.5% event-free survival rate at 5 years. Eight of 12 patients had a >90% tumor necrosis rate according to histopathologic examinations. The rates of local adverse events were lower than those reported for extremity osteosarcoma.
Our study initially indicated that the cisplatin arterial infusion regimen was a potential therapy with good tolerance in the treatment of pelvic osteosarcoma.
Introduction
Osteosarcoma is the most common solid malignant tumor of bone with a highly aggressive behavior.1 The most susceptible age of osteosarcoma is bimodal, which is characterized by one peak at 10-to-20 years and another at over 60 years.2,3 Although this disease endangers the health of both adolescent and aged populations, limited progress has been made to improve survival and functional prognosis, especially in patients with pelvic osteosarcoma.4–6 Osteosarcoma patients treated with mere immediate surgical resection register a recurrence rate up to 60–90%.7 (Since 1980s, traditional adjuvant intravenous (IV) systematic chemotherapy produces an improved five-year event-free survival (EFS) rate of 61%.8 In the early 2000s, the propagation of a multidrug neoadjuvant chemotherapy regimen elevated this rate to 60% and above.9,10) Henceforth, numerous explorations have been conducted to optimize the category, dosage, combination and duration of chemotherapy drug administration. The most recent studies of EURAMOS revealed a 5-year EFS of 65–70% for localized osteosarcoma treated by multidrug neoadjuvant chemotherapy. However, there are few studies focusing on arterial infusion as an improved method and its clinical outcome in the treatment of pelvic osteosarcoma.
Osteosarcoma in pelvic bone is more notorious than that in extremities. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate than those with extremity lesions, which may be associated with a poor chemotherapy response and an inability to achieve adequate surgical resection.11 Therefore, more challenges are faced in the management of pelvic osteosarcoma.
Platinum complexes, such as cis-diamine-dichloro platinum (cisplatin, CDDP), have been proven to be cell cycle-nonspecific agents and to have multiple broad-spectrum antitumor effects.12 Several clinical trials reported that employing an arterial infusion technique to deliver CDDP, in combination with an IV systematic chemotherapy regimen or not, can elevate the local drug concentration to fivefold that of IV administration and can produce better survival in the treatment of extremity osteosarcoma.13–15 Therefore, the arterial infusion of CDDP might have potential in the treatment of pelvic osteosarcoma.
The histopathologic response of surgically removed tumors has been shown to be one of most critical indicators of chemotherapeutic effectiveness and survival prognosis.16,17 However, preoperative examination is more valuable to predict tumor response and allow individualized neoadjuvant chemotherapy. Response evaluation criteria in solid tumors version 1.1 (RECIST 1.1), which was commonly adopted for the tumor-response evaluation of a variety of cancers, affirmed the value of sectional radiological imaging measurement.18–20 Therefore, preoperative contrast-enhanced MRI (CE-MRI) evaluation based on RECIST 1.1 is expected to guide the adjustment of treatment for optimal surgical timing in pelvic osteosarcoma.
Given all these findings, we combined CDDP arterial infusion (CAI) with individualized multidrug systematic chemotherapy (MSC) and surgery (S) to treat nonmetastatic pelvic osteosarcoma and attempted to investigate (1) the chemotherapy response and survival yielded from this protocol, (2) the individualized adjustment of the neoadjuvant MSC regimen necessary to achieve the maximal tumor response according to RECIST-1.1-based CE-MRI reassessment, and (3) the potential adverse effects caused by the arterial infusion technique and the multidrug systematic chemotherapy regimen.
Patients and Methods
Study Design and Consent
This is a retrospective cohort study (Level III evidence) in which subjects received a protocol comprising multidrug systematic chemotherapy, cisplatin arterial infusion and resection surgery (CAI + MSC + S). The study design conformed with the Declaration of Helsinki, and the treatment protocol was approved by the hospital institutional review board. All patients provided written informed consent for receiving this treatment protocol. All data used in the present study were obtained from the electronic medical records of our hospital and treated with strict confidentiality; therefore, the requirement of obtaining specific informed consent for this retrospective study was waived.
Patients
Inclusion criteria for subjects included (1) histopathologically defined primary osteosarcoma of pelvic bone; (2) no metastatic foci; (3) no past history of cancer treatment; and (4) normal cardiac, hepatic and renal function. All patients were confirmed to have high-grade osteosarcoma morbidity via biopsy. Pretreatment baseline safety indexes were determined with routine blood tests, hepatic and renal function tests, and Doppler echocardiography. A peripherally inserted central catheter was placed in each patient for the IV administration of neoadjuvant chemotherapy agents.
From January 2010 to June 2015, 21 patients were consecutively diagnosed with osteosarcoma of the pelvic bones in our work unit. A total of 4 patients were excluded for the following reasons: 2 patients had evidence of distant metastasis, and 2 tumors involved the femur or lumbar vertebra. Among the eligible people, 2 refused to take CAI + MSC + S treatment: 1 had hemophilia with severely impaired coagulation function; 1 intended to transfer to another hospital after being definitively diagnosed via biopsy. Subsequently, 15 patients took the CAI + MSC + S treatment, but 1 of them stopped midway (because of intolerance to vomiting as the adverse effect in the first two rounds of IV multidrug therapy) and turned to other treatment. Two patients were lost to follow-up after surgical resection. Eventually, 12 patients finished the treatment protocol and yielded analyzable data for survival, chemotherapy response and toxicity assessment.
The data of these 12 patients are listed in Table 1. The study population consisted of 7 (58.3%) males and 5 (41.7%) females with an average age of 28.8 years (11 to 69 years). The morbid sites included the pubis (n = 2), ilium (n = 4), ischium (n = 1), sacrum (n = 1) and unclear sites (n = 4).Table 1 Patient Data
Case No. Age (y) Sex Tumor Size (cm) Morbid Site MRI Tumor Response Before Surgery Surgical Margins Histopathologic Response Diagnosis Date Surgery Type Follow-Up (Month) First Relapse Status
1 62 F <8 Unclear +27.4%, PD R0 <90% 5/19/2010 1 42 CDF
2 19 M <8 Ilium −35.1%, PR R0 >90% 10/4/2010 2 46 Jan. 2014 DOD
3 14 M <8 Unclear +14.6%, SD R0 95% 7/23/2011 2 52 CDF
4 53 F >8 Sacrum −7.3%, SD R1 <90% 6/30/2012 4 57 Feb. 2015 NED
5 15 M <8 Ilium −32.7%, PR R0 >90% 10/28/2012 2 93 CDF
6 21 F 7 Ilium +25.9%, PD R0 >90% 4/24/2013 2 87 CDF
7 16 M >8 Unclear +8.6%, SD R1 <90% 9/22/2013 2 37 Aug. 2015 DOD
8 36 F 9 Pubis −24.1%, SD R0 >90% 4/14/2014 2 76 CDF
9 69 M 12 Ischium +43.7% PD R1 <90% 5/17/2014 3 15 Jan. 2015 DOD
10 12 F <8 Unclear −37.4%, PR R0 99% 8/21/2014 2 72 CDF
11 41 M <8 Pubis +33.5%, PR R0 >90% 3/6/2015 2 34 CDF
12 47 M <8 Ilium +16.6%, SD R0 95% 6/30/2015 2 62 Dec. 2019 DOD
Notes: Surgical type = 1) primary lower limb amputation; 2) lower limb salvage surgery; 3) secondary amputation and reresection due to local recurrence; 4) revision surgery due to periprosthetic infection.
Abbreviations: CAI, cisplatin arterial infusion; PR, partial response; PD, progressive disease; SD, stable disease; CAP, cisplatin arterial perfusion; CDF, continuously disease free; NED, no evidence of disease; DOD, died of disease.
Description of the Study Treatments and Outcome Measures
The adopted CAI + MSC + S treatment protocol is depicted in Figure 1. In general, MSCs usually consist of high-dose methotrexate (MTX), vincristine (VCR), adriamycin (ADM), CDDP and ifosfamide (IFO). Specifically, the routine CAI + MSC regimen was initiated with 24-hour continuous IV dripping of high-dose MTX at 10 g/m2 followed by 2 mg IV VCR the next day for the first group at Week 0; in Week 2, 120 mg/m2 CDDP AI over 3 to 6 hours and following 30 mg/m2/d IV ADM for 2 days were given to the second group; these 2 groups were repeated in Weeks 3 and 4; then, the resection surgery was performed 2 weeks after the neoadjuvant chemotherapy was finished. Notably, 160 mg/m2 was determined as the enhanced dosage of CDDP for tumors with the longest diameter over 8 cm in CE-MRI slices. In addition, IV IFO at 2 g/m2/d for 5 days was given in Week 5 for tumors over 8 cm after the 4-week routine regimen was completed. Central venous catheterization for MSC administration was performed under inhalation anesthesia if necessary. Before each CAI regimen, percutaneous punctuation of the femoral artery was performed using the Seldinger technique, and the catheter was inserted from the femoral artery of the contralateral side to the beginning of the artery trunk supplying the tumor with the assistance of CT-guided positioning.21 Then, CT arterial angiography was conducted. Each course of MSC and CAI was accompanied by IV hydration, diuretics, rescue and protecting drugs. The CDDP was perfused via the catheter with chemotherapy pumps (LimLess Infusion Pump; PFM Medical Inc, Cologne, Germany) in a pulsed manner (Bolus dose administrator; PFM Medical Inc, Cologne, Germany). The patients were asked to have strict bed rest under multiparameter monitoring. Routine blood tests for electrolytes and hepatic and renal function were performed on the first day after drug administration and every 3 days thereafter.Figure 1 The individualized pelvic osteosarcoma treatment protocol combined cisplatin arterial infusion, multidrug systematic chemotherapy and resection surgery (CAI + MSC + S).
To evaluate the therapeutic response, primary plain X-ray (Figure 2A) and physical examination parameters of the tumor, including pre- and postchemotherapy size, tenderness, pain and inflammation, were collected. More importantly, CE-MRI was performed to monitor the tumor chemotherapy response before and after routine neoadjuvant CAI + MSC administration. (Figure 2B–E) According to the RECIST 1.1 guidelines, tumor size was calculated in gadolinium-enhancing T1-weighted fat‐saturated coronal images using the following criteria: complete response (CR), complete elimination of target lesion; partial response (PR), ≥30% decrease in the diameter of target lesion compared to baseline); progressive disease (PD), ≥20% increase in the diameter of target lesion compared to baseline or new metastatic lesion); and stable disease (SD) or observed changes in the diameter of the target lesion between 30% decrease and 20% increase compared to baseline. Each tumor lesion was assessed by orthopedic oncologists and interventional radiologists who were blinded to the treatment allocation and clinical outcome data. For patients who achieved PD after the routine neoadjuvant regimen was finished, surgery was performed immediately. For patients who demonstrated CR or PR, surgery was performed 2 weeks after the neoadjuvant regimen as usual. For patients who presented SD, the same IFO course as that mentioned in the adjustment for large tumors was added to maximize the tumor response of the neoadjuvant regimen. Then, a multidisciplinary consultation was conducted to identify the achievement of maximal tumor response. If any uncertainty of maximal response achievement was left, one more course of IFO could be given, and patients received resection surgery no later than 9 weeks after the first diagnosis.Figure 2 (A) Pelvis X-ray of a 36-year-old female with an osteosarcoma in the pubis. (B) and (C) Fat-saturated T1- and T2-weighted coronal slices of contrast-enhanced MRI showing the maximum diameter of the tumor at the first diagnosis, which showed heterogeneous enhancement, thick septa and obscure boundaries of the tumor. (D) and (E) MRI reevaluation after completion of the neoadjuvant CAI + MSC regimen, showing thin septa, clear boundaries and stable disease according to RECIST 1.1 with a decrease in the tumor diameter. (F) Pelvis plain X-ray of this patient. (The identifiable captions in these images are occluded.).
A chest CT scan, a full-body bone scan and a pelvic CE-MRI scan (Figure 2D and E) were repeated before surgery. The tumor response per RECIST 1.1 measured in the last CE-MRI examination was compared with the baseline level. Surgical excision extension was determined by the involved scope of the tumor and the tumor response category according to the CE-MRI assessment per RECIST 1.1. The pelvic reconstruction project depended on the morbidity site, excision extension, bone mineral density and functional requirements.
In case of uncontrollable hemorrhage during the resection surgery, a temporary balloon blocking technique for the abdominal aorta was performed under the guidance of CTA 4 hours before resection surgery. A balloon compatible in size to the abdominal aortic diameter was placed intraarterially at the level of 2 to 3 cm above the bifurcation of the common iliac arteries. The injection of saline with 0.1% heparin inflated the balloon, consequently blocking blood perfusion of the surgical site. Angiography was performed to confirm the satisfactory blockage of the iliac arteries and unobstruction of the renal arteries. Then, the balloon was deflated until the surgery began. Each deflation was performed with an interval of 60 min during the resection surgery before satisfactory hemostasis was achieved.
Histopathologic examination was conducted using the method reported by Huvos et al to quantify the necrosis ratio of the tumor after removal.22 Patients with a ≥90% tumor necrosis rate (TNR) (Grade III and IV) were classified as good responders. The other (Grade Ⅰ and Ⅱ) were deemed poor responders.
The postoperative IV chemotherapy cycle was repeated every 3 weeks. The recovery of hematopoietic function in patients was required before each course, which was defined as a white blood cell count over 1×104/mm3 and a platelet count over 5×106/mm3 for 3 successive days without hematopoietic stimulants. For good responders, the duration of postoperative MSC was usually 3 courses, which could be extended to the maximum of 6 courses accompanied by the existence of high-risk factors, including SD or PD in the CE-MRI per RECIST 1.1 before surgery or histology-proven tumor involvement in the surgical margin (R1 resection). For poor responders, IFO at 2 g/m2/d for 5 days and etoposide (ETOP) at 100 mg/m2/d for 5 days were given sequentially as one cycle repeated every 3 weeks for 6 cycles.23
After the planned treatment was finished, the discontinuation of chemotherapy was allowed by the orthopedic oncologist if X-ray (Figure 2F) and CE-MRI of the primary morbidity site along with chest X-ray every 2 months, chest CT scanning every 6 months in the first year off the treatment prove no local recurrence or lung metastasis. Routine blood tests and hepatic and renal function tests were deployed every week until the recovery of hematopoietic function.
Statistical Analysis
We used the Kaplan-Meier method to analyze the overall survival (OS) and EFS, which were calculated from the day the preoperative MSC + CAI regimen began. The events were defined as local recurrence, distant metastasis or death from the disease. Additionally, the OS and EFS in groups with different histopathologic chemotherapy responses or tumor sizes were calculated. All statistical analyses were conducted with SPSS software packages (SPSS Inc., Chicago, IL, USA).
Results
Chemotherapy Response
Significant improvement in physical examination parameters was observed in 10 of 12 patients after the neoadjuvant regimen, including alleviation of pain. In terms of tumor response measurement per RECIST 1.1, 4 patients had PR and 5 had SD after routine neoadjuvant CAI + MSC administration. Three patients had to undergo resection surgery ahead of schedule because of PD, as shown by CE-MRI after neoadjuvant CAI + MSC administration. No patient demonstrated CR.
According to the histopathologic assessment, 66.7% (8 of 12) of patients demonstrated TNR over 90%. One of the 3 patients with PD according to the CE-MRI assessment turned out to be good responders with Grade III histopathologic results.
Surgery
Three patients underwent local radical excision and lower limb amputation because of neurovascular bundle involvement. The remaining 9 patients received limb salvage surgery followed by pelvic reconstruction using a modular prosthesis (Lidakang Inc., Beijing, China), tumor bone devitalization and replantation, or just bone fusion. As a result, 1 patient who underwent primary limb salvage surgery developed local recurrence and underwent secondary amputation and local reresection. Two patients had surgical site infections but were cured 2 months after surgery. One patient who developed a periprosthetic infection underwent a secondary amputation.
Survival
A total of 58.3% of patients (7 of 12) remained continuously disease free in an average follow-up period of 65.1 months (range, 34–93 months). One patient who developed local recurrence was proven alive with no evidence of disease for 31 months after receiving a secondary amputation and resection. Four patients (3 lung metastases and 1 local recurrence) died of refractory disease progression. Kaplan-Meier survival analysis suggested an OS rate of 57.8% and an EFS of 52.5% at 5 years (Figure 3). For patients with a good chemotherapy response, the 5-year OS and EFS rates were 68.6%, both of which showed significant differences (P = 0.04 for OS and 0.01 for EFS) compared with the corresponding measures for poor responders (Table 2). The comparison of patients with tumor sizes greater (n = 4) or less (n = 8) than 8 cm did not yield statistical significance (P = 0.32 and 0.13, respectively). As shown in the pathological report, 75% (9 of 12) patients received R0 resection and 25% (3 of 12) had R1 resection. There was no significant difference in the OS but in the EFS between patient group with R0 or R1 surgical resection (P = 0.15 and 0.05, respectively). The confidence interval of all OS and EFS are 95%.Table 2 Overall Survival (OS) and Event-Free Survival (EFS) Rate
Variables 1 y 5 y
All patients – OS 91.7% 57.8%
All patients – EFS 91.7% 52.5%
Good responders – OS 100.0% 68.6%
Good responders – EFS 100.0% 68.6%
Poor responders – OS 75.0% 50.0%
Poor responders – EFS 75.0% 25.0%
Patients with tumor size ≥8 cm – OS 75.0% 50.0%
Patients with tumor size ≥8 cm – EFS 75.0% 25.0%
Patients with tumor size<8 cm – OS 100.0% 62.5%
Patients with tumor size<8 cm – EFS 100.0% 64.3%
R0 resection – OS 85.7% 70.0%
R0 resection – EFS 88.9% 71.1%
R1 resection – OS 66.7% 33.3%
R1 resection – EFS 66.7% 33.3%
Note: Confidence Interval = 95%
Figure 3 The Kaplan-Meier survival curve for overall survival (OS) and event-free survival (EFS) rates of 12 pelvic osteosarcoma patients treated with the CAI + MSC + S protocol.
Chemotherapy Toxicity
We recorded the adverse effects referred to in the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.24 The statistics of CAI-related adverse events are summarized in Table 3. Three of 12 patients had local adverse events, including grade 1 to 2 skin pelvic soft tissue necrosis in muscle and hyperpigmentation, which exhibited no effect on the surgical method choice or wound healing. Nausea and vomiting were the most common systematic adverse events, with 41.7% of patients developing grade 3 events. A 36-year-old female received a reduced dosage of MTX (7 g/m2) due to intolerable vomiting after the first MTX course. Four of 12 patients developed grade 1 infusion-related reactions.Table 3 Statistics of CAI-Related Adverse Events
Adverse Events No. of Courses Percentage of Patients with Grade 3–4 Adverse Events
Skin hyperpigmentation 12.5% (3/24) 0% (0/12)
Pelvic soft tissue necrosis (muscle) 4.2% (1/24) 0% (0/12)
Pelvic pain 16.7% (4/24) 8.3% (1/12)
Nausea and vomiting 75.0% (18/24) 41.7% (5/12)
Anemia 8.3% (2/24) 8.3% (1/12)
Increase in creatinine level 8.3% (2/24) 0% (0/12)
Increase in aminotransferase level 4.2% (1/24) 0% (0/12)
Infusion related reaction 29.2% (7/24) 0% (0/12)
During the postoperative MSC period, one 12-year-old child complained of grade 1 palpitations and chest pain. Therefore, we replaced ADM with ETOP, and the complaint disappeared with no evidence reported in Doppler echocardiography. Three patients out of 12 developed grade 1 to 2 increases in alanine/aspartate aminotransferase levels.
Three children developed oral mucositis at grade 2 to 3, 2 of whom were under IV nutrition, and one used a mouth rinse with metronidazole to treat thrush. All patients eventually resumed normal oral food intake.
Blood system disorders were commonly noted in patients after the second cycle of postoperative MSC administration. Three patients developed febrile neutropenia and were treated by injection of recombinant human granulocyte stimulating factor.
Discussion
Conventional IV adjuvant chemotherapy and neoadjuvant chemotherapy have been applied extensively in multimodal osteosarcoma treatment for over 45 years.25 Though changes in drug combination, dosage, and administration duration were made to optimize the regimen, no significant improvement was achieved based on the approximately 50% to 70% 5-year OS and EFS rates in the past decade.26–28 As a modified approach to augment the potential of chemotherapy drugs, the AI technique combined with MSCs has been studied for years.13,29,30 In the present study, we attempted to investigate the therapeutic effect of the CAI + MSC + S protocol in osteosarcoma treatment. The 5-year OS and EFS rates were 57.8% and 52.5%, respectively.
The CAI regimen and its outcome measurements were first documented by Jaffe et al in 1983.31 Then, a series of studies concerning CAI-facilitated multidrug chemotherapy followed.13,30,32–37 Information on all 9 studies, including the present study, is listed in Table 4.Table 4 Synopsis of IA CDDP Information Reported in the Literature
Authors Type of Study No. of Patients Ages (y) Sites Metastases Preoperative CDDP Courses No. >90% TN OS EFS
Winkler et al and Fuchs et al30,34 Nonrandomized, 2 arms 50 <40 All Included 2 68% 67% at 10 y 63% at 10 y
Ferrari et al33 Single arm 164 <40 Extremity Excluded 2 NA 72% at 8 y 63% at 8 y
Ferrari et al33 Randomized, 2 arms 59 <40 Extremity Excluded 2 64% 61% at 8 y 54% at 8 y
Rha et al35 Single arm 37 8~41 Extremity ? 3 75% 78% at 3 y 55% at 3 y
Bacci et al32 Randomized, 2 arms 40 <40 Extremity Included 2 77% NA 26% at 5 y
Bacci et al32 Randomized, 2 arms 72 <40 Extremity Included 2 80% NA 61% at 5 y
Wilkins et al37 Single arm 47 <21 Extremity Excluded 3–5 (response dependent) 87% 92% at 10 y 84% at 10 y
Wilkins et al36 Single arm 62 <22 Extremity Excluded 3–5 (response dependent) 87% 93% at 10 y 86% at 10 y
Xie et al13 Nonrandomized, 2 arms 48 NA Extremity Included 3 63% 64% at 5 y 60% at 5 y
Hu et al (Current study) Single arm 12 11~69 Pelvis Excluded 2 66.7% 57.8% at 5 y 52.5% at 5 y
Abbreviations: IA, intraarterial; CDDP, cisplatin; TN, tumor necrosis; OS, overall survival; EFS, event-free survival.
Among these 9 studies, 8 used CAI and systematic chemotherapy sequentially before surgery, and 5 studies scheduled a 2-course preoperative regimen. Six of 9 studies suggested a higher chemotherapy response rate and/or survival rate in the CAI group compared with the IV CDDP group; 2 of these investigations were 2-arm randomized cohort studies and reported a statistically significant improvement in the good-response ratio (21% and 31%, respectively). In the third randomized cohort study reported by Rha et al, the improvement was not statistically significant, probably because the limited sample size was insufficient to test the 9% difference between the two groups.35 In the multicenter study reported by Winkler et al and Fuchs et al in the 1990s, no difference in chemotherapy response was observed between the intraarterial and IV CDDP groups.30,34 Similarly, Xie et al also proved a superior histological response rate but equivalent survival in the CAI group versus the IV group in 2019.13 However, the reliability of the conclusions in the 2 studies may be impaired by the nonrandomized grouping design conducted at the researchers’ discretion, which could be affected by the severity of disease. Although CAI may bring benefits to chemotherapy response augmentation and survival rates in limb osteosarcoma patients, how pelvic osteosarcoma reacts to CAI-facilitated multidrug chemotherapy remains elusive.
Pelvic tumor resection surgeries such as hemipelvectomy are notoriously known as one of the most destructive operations in modern orthopedic surgery.38 Due to the adjacency of the vascular network, nerves and viscera in the pelvis, surgeons have to weigh tumor eradication against functional preservation in the determination of the extent of surgical excision. This dilemma makes the treatment more challenging. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate compared with the extremity-morbidity population, which could be explained by the higher rate of not only failure of surgical remission but also advanced age, large tumor size, primary metastasis, prolonged latency periods and poor chemotherapy responses.11,39 Thus, it is critical to maximize the chemotherapy response and achieve better survival outcomes in pelvic osteosarcoma patients.
The combination of agents in our MSC protocol was determined by reference to NCCN guidelines for bone cancer and the study reported by Xie et al.13 Although the agent numbers and categories differed, all of the above-reviewed studies and the present study deployed a multidrug protocol to treat tumor cells in different phases of the cell cycle. Unfortunately, insufficient data are available to appropriately compare the therapeutic effect of CAI alone or in various combinations with MTX, VCR, ADM and IFO because of great heterogeneity. In the present study, we used high-dose MTX at 10 g/m2 and CAI at 120 mg/m2 in 2 doses as routine preoperative treatment. For patients with tumors over 8 cm, we employed an enhanced dose of CAI at 160 mg/m2. Additionally, additional IFO courses were given to slow responders. This individualized regimen directly yielded a 66.7% prevalence of good histopathologic responders and contributed to the 5-year survival rate of 57.8% in pelvic osteosarcoma. Both of the two figures were seemingly improved when compared to those from conventional systematic chemotherapy.11
The cumulative dosage of CDDP was 780 mg/m2 for a good responder with a tumor size ≤ 8 cm in the present study. Wilkins et al reported the highest accumulated dose of CDDP at 960 mg/m2 and a single dose at 160 mg/m2 over 24 h as an enhanced regimen for patients with tumors over 10 cm versus 120 mg/m2 over 6 h as routine, which consequently yielded the highest 10-year OS and EFS rates (93% and 86%, respectively) among all reviewed studies. Notably, Ferrari et al and Xie et al investigated CDDP administration at equivalent doses to those in the present study but yielded poorer survival outcomes seemingly.13,33 This may be because 120 mg/m2 CDDP was given intraarterially in 72 h in the first study, which is too long to achieve a high enough blood concentration; patients with tumor metastases at the initial diagnosis were included in the second study so that the survival rate would be reduced. We used relatively high-dose CDDP administered over 3 to 6 h combined with 4 other drugs, including ETOP, and made individualized adjustments to the protocol for patients with high-risk factors. This may have contributed to the 57.8% OS and 52.5% EFS rate at 5 years, which is favorable for pelvic osteosarcoma. Moreover, we discovered that the OS and EFS rates in the population with tumors ≤ or >8 cm showed insignificant differences. Patients who received R0 resection also shared equivalent OS but higher EFS with R1 patients. These finding suggest that this protocol with risk-dependent adjustment in the drug dosage and combination could be beneficial to bridge the gap in survival rate between patients with large or small tumors, and those who received R0 or R1 resection.
We noticed that 3 of 5 cases developing SD turned out to demonstrate TNR >90%, which probably means that good response of osteosarcoma is not necessarily accompanied with tumor size decrease. This may be attributed to the formation of tumor bone generated by subtypes like osteoblastic osteosarcoma, which could prevent tumors from shrinkage.40
Only 4 poor responders were observed, 3 of whom developed tumor relapses. Two of the 3 patients died of metastasis during postoperative MSC; another showed no evidence of disease after receiving secondary amputation and resection for local recurrence. This protocol seemed to provide limited benefit to the poor responders. However, the present data are so limited that few tenable conclusions can be drawn from it to guide salvage treatment for poor responders.
Although the AI technique and additional courses were given in this protocol, no patients received an overdose of chemotherapy drugs compared with previous studies using similar drug combinations. No AI-relative grade 4 or 5 adverse events were observed. Although systematic adverse events, including nausea, vomiting, anemia and an increase in creatinine/aminotransferase levels, shared equivalent incidence rates and severities with the study reported by Xie et al, local skin hyperpigmentation and pelvic soft tissue necrosis in muscle occurred after only 3 and 1 of 24 CAI events (12.5% and 4.2%, respectively), which is more favorable than the situation reported in the most reviewed studies concerning extremity osteosarcoma.13,30,33 This finding could be explained by the shorter local drug-retention time since the pelvis has a more sufficient blood supply and drainage.
In terms of the postoperative MSC regimen for poor responders, we determined the IFO + ETOP regimen by reference to the second-line chemotherapy recommended in NCCN guidelines for bone cancer, which is supported by the study reported by Goorin et al and Miser et al.23,41 These two studies were conducted in patients with initial metastasis or recurrence of osteosarcoma, and the former one used IFO + ETOP as an induction regimen accompanied by surgical resection and continuation MSC of MTX + ADM + ETOP + IFO. Therefore, we adopted the regimen similar as the one reported by Miser et al However, the study of EURAMOS reported by Marina et al suggested that treatment with MTX + ADM + CDDP + IFO + ETOP resulted in similar EFS to MTX + ADM + CDDP and increased toxicity. In the present study, we found it hard for patients to accept 12 cycles of second-line therapy in 3 years in view of the high expenditure and physical discomfort. Therefore, the number of cycles was reduced to 6 for poor responders, which is equivalent to a half of the regimen of Miser et al in accumulative dosage and duration time. During the postoperative MSC period, there was no early death. The reported cardiac irritation, increase in creatinine/aminotransferase, oral mucosa inflammation and hematologic system abnormality were acceptable. In summary, our chemotherapy regimen seems to be well tolerated.
To monitor the chemotherapy response, several methods have been reported in previous studies. In the studies reported by Winkler et al and Fuch et al, plain X-ray, local CT and emission CT of bone were used to monitor the TNR before the surgery.30,34 Bacci et al, Wilkins et al and Xie et al deployed CT arterial angiography, which yielded sensitivity and specificity over 90% and 50%, respectively.13,32,36,37 Nevertheless, a repeated CT arterial angiography assessment is difficult to be accepted by patients because it requires multiple invasive operations and high expenditure. RECIST-1.1-based MRI remains one of the most commonly used approaches in tumor response evaluation.42,43 In the present study, we used CE-MRI to detect the tumor response and guide the adjustment of treatment for each patient. Although the results did not seem to suggest that this method is highly predictive of the histopathologic chemotherapy response, the equivalent survival rate between patients with large and small tumors may reflect the effectiveness of the individualized treatment.
There were several limitations in our investigation. First, the design was restricted to a small-sample-size single-arm clinical study due to the rarity of pelvis osteosarcoma morbidity, therefore reducing the reliability of the conclusions. Second, several previous studies reported that pathological subtypes of osteosarcoma, such as chondroblastic and telangiectatic osteosarcoma, respond differently to chemotherapy.39,44 However, the pathological subtype of each patient was not analyzed as an independent prognostic factor in our study. Heterogeneity of the osteosarcoma subtype constitution could distort chemotherapy response and survival outcomes. Third, we used CE-MRI per RECIST 1.1 to monitor the tumor response before surgery and guide the individualized adjustment of the treatment protocol. However, CE-MRI evaluation was not the gold standard for TNR prediction. Multiple innovative approaches for TNR prediction in osteosarcoma have been researched in the past 30 years, such as dynamic CE-MRI with sensitivity and specificity over 70% and 80%, respectively, according to previous studies.45–47 We would attempt to deploy approaches with higher accuracy to evaluate viable tumors in hope of providing more precise guidance for individualized pelvic osteosarcoma treatment in further studies.
Conclusions
In the present study, we employed CAI in the multimodal treatment of pelvic osteosarcoma patients. Our findings suggest that the CAI-facilitated chemotherapy regimen demonstrated great potential for improving the survival of patients with pelvic osteosarcoma. This treatment protocol yielded high tolerance with acceptable adverse effects. However, further randomized controlled trials with large sample sizes are required to elucidate the findings of this preliminary study.
Acknowledgments
We would like to thank all patients for their devotion to taking unidentified risks in this clinical trial. We are also grateful to the participating orthopedic oncologists and interventional radiologists for their prudence and patience in the therapeutic effect evaluation and the multidisciplinary consultation.
Abbreviations
ADM, adriamycin; CAI, effect of cisplatin arterial infusion; CDDP, cis-diamine-dichloro platinum; CE-MRI, contrast-enhanced MRI; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; EFS, event-free survival; ETOP, etoposide; IFO, ifosfamide; IV, intravenous; MSC, multidrug systematic chemotherapy; MTX, methotrexate; OS, overall survival; PD, progressive disease; PR, partial response; RECIST, response evaluation criteria in solid tumors version; S, surgery; SD, stable disease; TNR, tumor necrosis rate; VCR, vincristine.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics Approval and Informed Consent
This study was approved by the ethics committees and the institutional review board of the Second Xiangya Hospital. All patients provided written informed consent for receiving this treatment protocol. The requirement of obtaining specific informed consent for this retrospective study was waived for the reason mentioned before.
Consent for Publication
This study conforms to Declaration of Helsinki. The requirement of obtaining specific informed consent from the patients for the publication of the case presentation and any accompanying images.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
No commercial sponsorship was involved in any part of this study. The authors report no conflicts of interest related to this work. | 30 MG/M2, DAILY, FOR 2 DAYS | DrugDosageText | CC BY-NC | 33623429 | 19,834,554 | 2021 |
What was the dosage of drug 'METHOTREXATE SODIUM'? | Effect of Cisplatin Arterial Infusion (CAI) on Primary Nonmetastatic Pelvic Osteosarcoma: A Preliminary Study.
The critical role of arterial infusion chemotherapy in the multimodal treatment of extremity bone cancer has been investigated extensively, but few studies have focused on pelvic osteosarcoma. Therefore, we attempted to evaluate the clinical significance of arterial infusion chemotherapy in the treatment of pelvic osteosarcoma.
We combined a cisplatin arterial infusion regimen with multidrug systematic chemotherapy as a neoadjuvant protocol for the treatment of pelvic osteosarcoma. The course number and dosage of cisplatin arterial infusion were adjusted to achieve a maximal tumor response evaluated by contrast-enhanced MRI per RECIST 1.1. Good responders received the same systematic combination for postoperative chemotherapy, and poor responders received second-line therapy. Twelve patients with nonmetastatic high-grade pelvic osteosarcoma were included. Survival, chemotherapy response and adverse events data were analyzed.
The mean follow-up period was 56.1 months. Four patients died of refractory tumor progression, and 1 patient with local recurrence had no evidence of disease for 27 months after receiving secondary amputation and resection. Kaplan-Meier survival analysis demonstrated a 57.8% overall survival and 52.5% event-free survival rate at 5 years. Eight of 12 patients had a >90% tumor necrosis rate according to histopathologic examinations. The rates of local adverse events were lower than those reported for extremity osteosarcoma.
Our study initially indicated that the cisplatin arterial infusion regimen was a potential therapy with good tolerance in the treatment of pelvic osteosarcoma.
Introduction
Osteosarcoma is the most common solid malignant tumor of bone with a highly aggressive behavior.1 The most susceptible age of osteosarcoma is bimodal, which is characterized by one peak at 10-to-20 years and another at over 60 years.2,3 Although this disease endangers the health of both adolescent and aged populations, limited progress has been made to improve survival and functional prognosis, especially in patients with pelvic osteosarcoma.4–6 Osteosarcoma patients treated with mere immediate surgical resection register a recurrence rate up to 60–90%.7 (Since 1980s, traditional adjuvant intravenous (IV) systematic chemotherapy produces an improved five-year event-free survival (EFS) rate of 61%.8 In the early 2000s, the propagation of a multidrug neoadjuvant chemotherapy regimen elevated this rate to 60% and above.9,10) Henceforth, numerous explorations have been conducted to optimize the category, dosage, combination and duration of chemotherapy drug administration. The most recent studies of EURAMOS revealed a 5-year EFS of 65–70% for localized osteosarcoma treated by multidrug neoadjuvant chemotherapy. However, there are few studies focusing on arterial infusion as an improved method and its clinical outcome in the treatment of pelvic osteosarcoma.
Osteosarcoma in pelvic bone is more notorious than that in extremities. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate than those with extremity lesions, which may be associated with a poor chemotherapy response and an inability to achieve adequate surgical resection.11 Therefore, more challenges are faced in the management of pelvic osteosarcoma.
Platinum complexes, such as cis-diamine-dichloro platinum (cisplatin, CDDP), have been proven to be cell cycle-nonspecific agents and to have multiple broad-spectrum antitumor effects.12 Several clinical trials reported that employing an arterial infusion technique to deliver CDDP, in combination with an IV systematic chemotherapy regimen or not, can elevate the local drug concentration to fivefold that of IV administration and can produce better survival in the treatment of extremity osteosarcoma.13–15 Therefore, the arterial infusion of CDDP might have potential in the treatment of pelvic osteosarcoma.
The histopathologic response of surgically removed tumors has been shown to be one of most critical indicators of chemotherapeutic effectiveness and survival prognosis.16,17 However, preoperative examination is more valuable to predict tumor response and allow individualized neoadjuvant chemotherapy. Response evaluation criteria in solid tumors version 1.1 (RECIST 1.1), which was commonly adopted for the tumor-response evaluation of a variety of cancers, affirmed the value of sectional radiological imaging measurement.18–20 Therefore, preoperative contrast-enhanced MRI (CE-MRI) evaluation based on RECIST 1.1 is expected to guide the adjustment of treatment for optimal surgical timing in pelvic osteosarcoma.
Given all these findings, we combined CDDP arterial infusion (CAI) with individualized multidrug systematic chemotherapy (MSC) and surgery (S) to treat nonmetastatic pelvic osteosarcoma and attempted to investigate (1) the chemotherapy response and survival yielded from this protocol, (2) the individualized adjustment of the neoadjuvant MSC regimen necessary to achieve the maximal tumor response according to RECIST-1.1-based CE-MRI reassessment, and (3) the potential adverse effects caused by the arterial infusion technique and the multidrug systematic chemotherapy regimen.
Patients and Methods
Study Design and Consent
This is a retrospective cohort study (Level III evidence) in which subjects received a protocol comprising multidrug systematic chemotherapy, cisplatin arterial infusion and resection surgery (CAI + MSC + S). The study design conformed with the Declaration of Helsinki, and the treatment protocol was approved by the hospital institutional review board. All patients provided written informed consent for receiving this treatment protocol. All data used in the present study were obtained from the electronic medical records of our hospital and treated with strict confidentiality; therefore, the requirement of obtaining specific informed consent for this retrospective study was waived.
Patients
Inclusion criteria for subjects included (1) histopathologically defined primary osteosarcoma of pelvic bone; (2) no metastatic foci; (3) no past history of cancer treatment; and (4) normal cardiac, hepatic and renal function. All patients were confirmed to have high-grade osteosarcoma morbidity via biopsy. Pretreatment baseline safety indexes were determined with routine blood tests, hepatic and renal function tests, and Doppler echocardiography. A peripherally inserted central catheter was placed in each patient for the IV administration of neoadjuvant chemotherapy agents.
From January 2010 to June 2015, 21 patients were consecutively diagnosed with osteosarcoma of the pelvic bones in our work unit. A total of 4 patients were excluded for the following reasons: 2 patients had evidence of distant metastasis, and 2 tumors involved the femur or lumbar vertebra. Among the eligible people, 2 refused to take CAI + MSC + S treatment: 1 had hemophilia with severely impaired coagulation function; 1 intended to transfer to another hospital after being definitively diagnosed via biopsy. Subsequently, 15 patients took the CAI + MSC + S treatment, but 1 of them stopped midway (because of intolerance to vomiting as the adverse effect in the first two rounds of IV multidrug therapy) and turned to other treatment. Two patients were lost to follow-up after surgical resection. Eventually, 12 patients finished the treatment protocol and yielded analyzable data for survival, chemotherapy response and toxicity assessment.
The data of these 12 patients are listed in Table 1. The study population consisted of 7 (58.3%) males and 5 (41.7%) females with an average age of 28.8 years (11 to 69 years). The morbid sites included the pubis (n = 2), ilium (n = 4), ischium (n = 1), sacrum (n = 1) and unclear sites (n = 4).Table 1 Patient Data
Case No. Age (y) Sex Tumor Size (cm) Morbid Site MRI Tumor Response Before Surgery Surgical Margins Histopathologic Response Diagnosis Date Surgery Type Follow-Up (Month) First Relapse Status
1 62 F <8 Unclear +27.4%, PD R0 <90% 5/19/2010 1 42 CDF
2 19 M <8 Ilium −35.1%, PR R0 >90% 10/4/2010 2 46 Jan. 2014 DOD
3 14 M <8 Unclear +14.6%, SD R0 95% 7/23/2011 2 52 CDF
4 53 F >8 Sacrum −7.3%, SD R1 <90% 6/30/2012 4 57 Feb. 2015 NED
5 15 M <8 Ilium −32.7%, PR R0 >90% 10/28/2012 2 93 CDF
6 21 F 7 Ilium +25.9%, PD R0 >90% 4/24/2013 2 87 CDF
7 16 M >8 Unclear +8.6%, SD R1 <90% 9/22/2013 2 37 Aug. 2015 DOD
8 36 F 9 Pubis −24.1%, SD R0 >90% 4/14/2014 2 76 CDF
9 69 M 12 Ischium +43.7% PD R1 <90% 5/17/2014 3 15 Jan. 2015 DOD
10 12 F <8 Unclear −37.4%, PR R0 99% 8/21/2014 2 72 CDF
11 41 M <8 Pubis +33.5%, PR R0 >90% 3/6/2015 2 34 CDF
12 47 M <8 Ilium +16.6%, SD R0 95% 6/30/2015 2 62 Dec. 2019 DOD
Notes: Surgical type = 1) primary lower limb amputation; 2) lower limb salvage surgery; 3) secondary amputation and reresection due to local recurrence; 4) revision surgery due to periprosthetic infection.
Abbreviations: CAI, cisplatin arterial infusion; PR, partial response; PD, progressive disease; SD, stable disease; CAP, cisplatin arterial perfusion; CDF, continuously disease free; NED, no evidence of disease; DOD, died of disease.
Description of the Study Treatments and Outcome Measures
The adopted CAI + MSC + S treatment protocol is depicted in Figure 1. In general, MSCs usually consist of high-dose methotrexate (MTX), vincristine (VCR), adriamycin (ADM), CDDP and ifosfamide (IFO). Specifically, the routine CAI + MSC regimen was initiated with 24-hour continuous IV dripping of high-dose MTX at 10 g/m2 followed by 2 mg IV VCR the next day for the first group at Week 0; in Week 2, 120 mg/m2 CDDP AI over 3 to 6 hours and following 30 mg/m2/d IV ADM for 2 days were given to the second group; these 2 groups were repeated in Weeks 3 and 4; then, the resection surgery was performed 2 weeks after the neoadjuvant chemotherapy was finished. Notably, 160 mg/m2 was determined as the enhanced dosage of CDDP for tumors with the longest diameter over 8 cm in CE-MRI slices. In addition, IV IFO at 2 g/m2/d for 5 days was given in Week 5 for tumors over 8 cm after the 4-week routine regimen was completed. Central venous catheterization for MSC administration was performed under inhalation anesthesia if necessary. Before each CAI regimen, percutaneous punctuation of the femoral artery was performed using the Seldinger technique, and the catheter was inserted from the femoral artery of the contralateral side to the beginning of the artery trunk supplying the tumor with the assistance of CT-guided positioning.21 Then, CT arterial angiography was conducted. Each course of MSC and CAI was accompanied by IV hydration, diuretics, rescue and protecting drugs. The CDDP was perfused via the catheter with chemotherapy pumps (LimLess Infusion Pump; PFM Medical Inc, Cologne, Germany) in a pulsed manner (Bolus dose administrator; PFM Medical Inc, Cologne, Germany). The patients were asked to have strict bed rest under multiparameter monitoring. Routine blood tests for electrolytes and hepatic and renal function were performed on the first day after drug administration and every 3 days thereafter.Figure 1 The individualized pelvic osteosarcoma treatment protocol combined cisplatin arterial infusion, multidrug systematic chemotherapy and resection surgery (CAI + MSC + S).
To evaluate the therapeutic response, primary plain X-ray (Figure 2A) and physical examination parameters of the tumor, including pre- and postchemotherapy size, tenderness, pain and inflammation, were collected. More importantly, CE-MRI was performed to monitor the tumor chemotherapy response before and after routine neoadjuvant CAI + MSC administration. (Figure 2B–E) According to the RECIST 1.1 guidelines, tumor size was calculated in gadolinium-enhancing T1-weighted fat‐saturated coronal images using the following criteria: complete response (CR), complete elimination of target lesion; partial response (PR), ≥30% decrease in the diameter of target lesion compared to baseline); progressive disease (PD), ≥20% increase in the diameter of target lesion compared to baseline or new metastatic lesion); and stable disease (SD) or observed changes in the diameter of the target lesion between 30% decrease and 20% increase compared to baseline. Each tumor lesion was assessed by orthopedic oncologists and interventional radiologists who were blinded to the treatment allocation and clinical outcome data. For patients who achieved PD after the routine neoadjuvant regimen was finished, surgery was performed immediately. For patients who demonstrated CR or PR, surgery was performed 2 weeks after the neoadjuvant regimen as usual. For patients who presented SD, the same IFO course as that mentioned in the adjustment for large tumors was added to maximize the tumor response of the neoadjuvant regimen. Then, a multidisciplinary consultation was conducted to identify the achievement of maximal tumor response. If any uncertainty of maximal response achievement was left, one more course of IFO could be given, and patients received resection surgery no later than 9 weeks after the first diagnosis.Figure 2 (A) Pelvis X-ray of a 36-year-old female with an osteosarcoma in the pubis. (B) and (C) Fat-saturated T1- and T2-weighted coronal slices of contrast-enhanced MRI showing the maximum diameter of the tumor at the first diagnosis, which showed heterogeneous enhancement, thick septa and obscure boundaries of the tumor. (D) and (E) MRI reevaluation after completion of the neoadjuvant CAI + MSC regimen, showing thin septa, clear boundaries and stable disease according to RECIST 1.1 with a decrease in the tumor diameter. (F) Pelvis plain X-ray of this patient. (The identifiable captions in these images are occluded.).
A chest CT scan, a full-body bone scan and a pelvic CE-MRI scan (Figure 2D and E) were repeated before surgery. The tumor response per RECIST 1.1 measured in the last CE-MRI examination was compared with the baseline level. Surgical excision extension was determined by the involved scope of the tumor and the tumor response category according to the CE-MRI assessment per RECIST 1.1. The pelvic reconstruction project depended on the morbidity site, excision extension, bone mineral density and functional requirements.
In case of uncontrollable hemorrhage during the resection surgery, a temporary balloon blocking technique for the abdominal aorta was performed under the guidance of CTA 4 hours before resection surgery. A balloon compatible in size to the abdominal aortic diameter was placed intraarterially at the level of 2 to 3 cm above the bifurcation of the common iliac arteries. The injection of saline with 0.1% heparin inflated the balloon, consequently blocking blood perfusion of the surgical site. Angiography was performed to confirm the satisfactory blockage of the iliac arteries and unobstruction of the renal arteries. Then, the balloon was deflated until the surgery began. Each deflation was performed with an interval of 60 min during the resection surgery before satisfactory hemostasis was achieved.
Histopathologic examination was conducted using the method reported by Huvos et al to quantify the necrosis ratio of the tumor after removal.22 Patients with a ≥90% tumor necrosis rate (TNR) (Grade III and IV) were classified as good responders. The other (Grade Ⅰ and Ⅱ) were deemed poor responders.
The postoperative IV chemotherapy cycle was repeated every 3 weeks. The recovery of hematopoietic function in patients was required before each course, which was defined as a white blood cell count over 1×104/mm3 and a platelet count over 5×106/mm3 for 3 successive days without hematopoietic stimulants. For good responders, the duration of postoperative MSC was usually 3 courses, which could be extended to the maximum of 6 courses accompanied by the existence of high-risk factors, including SD or PD in the CE-MRI per RECIST 1.1 before surgery or histology-proven tumor involvement in the surgical margin (R1 resection). For poor responders, IFO at 2 g/m2/d for 5 days and etoposide (ETOP) at 100 mg/m2/d for 5 days were given sequentially as one cycle repeated every 3 weeks for 6 cycles.23
After the planned treatment was finished, the discontinuation of chemotherapy was allowed by the orthopedic oncologist if X-ray (Figure 2F) and CE-MRI of the primary morbidity site along with chest X-ray every 2 months, chest CT scanning every 6 months in the first year off the treatment prove no local recurrence or lung metastasis. Routine blood tests and hepatic and renal function tests were deployed every week until the recovery of hematopoietic function.
Statistical Analysis
We used the Kaplan-Meier method to analyze the overall survival (OS) and EFS, which were calculated from the day the preoperative MSC + CAI regimen began. The events were defined as local recurrence, distant metastasis or death from the disease. Additionally, the OS and EFS in groups with different histopathologic chemotherapy responses or tumor sizes were calculated. All statistical analyses were conducted with SPSS software packages (SPSS Inc., Chicago, IL, USA).
Results
Chemotherapy Response
Significant improvement in physical examination parameters was observed in 10 of 12 patients after the neoadjuvant regimen, including alleviation of pain. In terms of tumor response measurement per RECIST 1.1, 4 patients had PR and 5 had SD after routine neoadjuvant CAI + MSC administration. Three patients had to undergo resection surgery ahead of schedule because of PD, as shown by CE-MRI after neoadjuvant CAI + MSC administration. No patient demonstrated CR.
According to the histopathologic assessment, 66.7% (8 of 12) of patients demonstrated TNR over 90%. One of the 3 patients with PD according to the CE-MRI assessment turned out to be good responders with Grade III histopathologic results.
Surgery
Three patients underwent local radical excision and lower limb amputation because of neurovascular bundle involvement. The remaining 9 patients received limb salvage surgery followed by pelvic reconstruction using a modular prosthesis (Lidakang Inc., Beijing, China), tumor bone devitalization and replantation, or just bone fusion. As a result, 1 patient who underwent primary limb salvage surgery developed local recurrence and underwent secondary amputation and local reresection. Two patients had surgical site infections but were cured 2 months after surgery. One patient who developed a periprosthetic infection underwent a secondary amputation.
Survival
A total of 58.3% of patients (7 of 12) remained continuously disease free in an average follow-up period of 65.1 months (range, 34–93 months). One patient who developed local recurrence was proven alive with no evidence of disease for 31 months after receiving a secondary amputation and resection. Four patients (3 lung metastases and 1 local recurrence) died of refractory disease progression. Kaplan-Meier survival analysis suggested an OS rate of 57.8% and an EFS of 52.5% at 5 years (Figure 3). For patients with a good chemotherapy response, the 5-year OS and EFS rates were 68.6%, both of which showed significant differences (P = 0.04 for OS and 0.01 for EFS) compared with the corresponding measures for poor responders (Table 2). The comparison of patients with tumor sizes greater (n = 4) or less (n = 8) than 8 cm did not yield statistical significance (P = 0.32 and 0.13, respectively). As shown in the pathological report, 75% (9 of 12) patients received R0 resection and 25% (3 of 12) had R1 resection. There was no significant difference in the OS but in the EFS between patient group with R0 or R1 surgical resection (P = 0.15 and 0.05, respectively). The confidence interval of all OS and EFS are 95%.Table 2 Overall Survival (OS) and Event-Free Survival (EFS) Rate
Variables 1 y 5 y
All patients – OS 91.7% 57.8%
All patients – EFS 91.7% 52.5%
Good responders – OS 100.0% 68.6%
Good responders – EFS 100.0% 68.6%
Poor responders – OS 75.0% 50.0%
Poor responders – EFS 75.0% 25.0%
Patients with tumor size ≥8 cm – OS 75.0% 50.0%
Patients with tumor size ≥8 cm – EFS 75.0% 25.0%
Patients with tumor size<8 cm – OS 100.0% 62.5%
Patients with tumor size<8 cm – EFS 100.0% 64.3%
R0 resection – OS 85.7% 70.0%
R0 resection – EFS 88.9% 71.1%
R1 resection – OS 66.7% 33.3%
R1 resection – EFS 66.7% 33.3%
Note: Confidence Interval = 95%
Figure 3 The Kaplan-Meier survival curve for overall survival (OS) and event-free survival (EFS) rates of 12 pelvic osteosarcoma patients treated with the CAI + MSC + S protocol.
Chemotherapy Toxicity
We recorded the adverse effects referred to in the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.24 The statistics of CAI-related adverse events are summarized in Table 3. Three of 12 patients had local adverse events, including grade 1 to 2 skin pelvic soft tissue necrosis in muscle and hyperpigmentation, which exhibited no effect on the surgical method choice or wound healing. Nausea and vomiting were the most common systematic adverse events, with 41.7% of patients developing grade 3 events. A 36-year-old female received a reduced dosage of MTX (7 g/m2) due to intolerable vomiting after the first MTX course. Four of 12 patients developed grade 1 infusion-related reactions.Table 3 Statistics of CAI-Related Adverse Events
Adverse Events No. of Courses Percentage of Patients with Grade 3–4 Adverse Events
Skin hyperpigmentation 12.5% (3/24) 0% (0/12)
Pelvic soft tissue necrosis (muscle) 4.2% (1/24) 0% (0/12)
Pelvic pain 16.7% (4/24) 8.3% (1/12)
Nausea and vomiting 75.0% (18/24) 41.7% (5/12)
Anemia 8.3% (2/24) 8.3% (1/12)
Increase in creatinine level 8.3% (2/24) 0% (0/12)
Increase in aminotransferase level 4.2% (1/24) 0% (0/12)
Infusion related reaction 29.2% (7/24) 0% (0/12)
During the postoperative MSC period, one 12-year-old child complained of grade 1 palpitations and chest pain. Therefore, we replaced ADM with ETOP, and the complaint disappeared with no evidence reported in Doppler echocardiography. Three patients out of 12 developed grade 1 to 2 increases in alanine/aspartate aminotransferase levels.
Three children developed oral mucositis at grade 2 to 3, 2 of whom were under IV nutrition, and one used a mouth rinse with metronidazole to treat thrush. All patients eventually resumed normal oral food intake.
Blood system disorders were commonly noted in patients after the second cycle of postoperative MSC administration. Three patients developed febrile neutropenia and were treated by injection of recombinant human granulocyte stimulating factor.
Discussion
Conventional IV adjuvant chemotherapy and neoadjuvant chemotherapy have been applied extensively in multimodal osteosarcoma treatment for over 45 years.25 Though changes in drug combination, dosage, and administration duration were made to optimize the regimen, no significant improvement was achieved based on the approximately 50% to 70% 5-year OS and EFS rates in the past decade.26–28 As a modified approach to augment the potential of chemotherapy drugs, the AI technique combined with MSCs has been studied for years.13,29,30 In the present study, we attempted to investigate the therapeutic effect of the CAI + MSC + S protocol in osteosarcoma treatment. The 5-year OS and EFS rates were 57.8% and 52.5%, respectively.
The CAI regimen and its outcome measurements were first documented by Jaffe et al in 1983.31 Then, a series of studies concerning CAI-facilitated multidrug chemotherapy followed.13,30,32–37 Information on all 9 studies, including the present study, is listed in Table 4.Table 4 Synopsis of IA CDDP Information Reported in the Literature
Authors Type of Study No. of Patients Ages (y) Sites Metastases Preoperative CDDP Courses No. >90% TN OS EFS
Winkler et al and Fuchs et al30,34 Nonrandomized, 2 arms 50 <40 All Included 2 68% 67% at 10 y 63% at 10 y
Ferrari et al33 Single arm 164 <40 Extremity Excluded 2 NA 72% at 8 y 63% at 8 y
Ferrari et al33 Randomized, 2 arms 59 <40 Extremity Excluded 2 64% 61% at 8 y 54% at 8 y
Rha et al35 Single arm 37 8~41 Extremity ? 3 75% 78% at 3 y 55% at 3 y
Bacci et al32 Randomized, 2 arms 40 <40 Extremity Included 2 77% NA 26% at 5 y
Bacci et al32 Randomized, 2 arms 72 <40 Extremity Included 2 80% NA 61% at 5 y
Wilkins et al37 Single arm 47 <21 Extremity Excluded 3–5 (response dependent) 87% 92% at 10 y 84% at 10 y
Wilkins et al36 Single arm 62 <22 Extremity Excluded 3–5 (response dependent) 87% 93% at 10 y 86% at 10 y
Xie et al13 Nonrandomized, 2 arms 48 NA Extremity Included 3 63% 64% at 5 y 60% at 5 y
Hu et al (Current study) Single arm 12 11~69 Pelvis Excluded 2 66.7% 57.8% at 5 y 52.5% at 5 y
Abbreviations: IA, intraarterial; CDDP, cisplatin; TN, tumor necrosis; OS, overall survival; EFS, event-free survival.
Among these 9 studies, 8 used CAI and systematic chemotherapy sequentially before surgery, and 5 studies scheduled a 2-course preoperative regimen. Six of 9 studies suggested a higher chemotherapy response rate and/or survival rate in the CAI group compared with the IV CDDP group; 2 of these investigations were 2-arm randomized cohort studies and reported a statistically significant improvement in the good-response ratio (21% and 31%, respectively). In the third randomized cohort study reported by Rha et al, the improvement was not statistically significant, probably because the limited sample size was insufficient to test the 9% difference between the two groups.35 In the multicenter study reported by Winkler et al and Fuchs et al in the 1990s, no difference in chemotherapy response was observed between the intraarterial and IV CDDP groups.30,34 Similarly, Xie et al also proved a superior histological response rate but equivalent survival in the CAI group versus the IV group in 2019.13 However, the reliability of the conclusions in the 2 studies may be impaired by the nonrandomized grouping design conducted at the researchers’ discretion, which could be affected by the severity of disease. Although CAI may bring benefits to chemotherapy response augmentation and survival rates in limb osteosarcoma patients, how pelvic osteosarcoma reacts to CAI-facilitated multidrug chemotherapy remains elusive.
Pelvic tumor resection surgeries such as hemipelvectomy are notoriously known as one of the most destructive operations in modern orthopedic surgery.38 Due to the adjacency of the vascular network, nerves and viscera in the pelvis, surgeons have to weigh tumor eradication against functional preservation in the determination of the extent of surgical excision. This dilemma makes the treatment more challenging. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate compared with the extremity-morbidity population, which could be explained by the higher rate of not only failure of surgical remission but also advanced age, large tumor size, primary metastasis, prolonged latency periods and poor chemotherapy responses.11,39 Thus, it is critical to maximize the chemotherapy response and achieve better survival outcomes in pelvic osteosarcoma patients.
The combination of agents in our MSC protocol was determined by reference to NCCN guidelines for bone cancer and the study reported by Xie et al.13 Although the agent numbers and categories differed, all of the above-reviewed studies and the present study deployed a multidrug protocol to treat tumor cells in different phases of the cell cycle. Unfortunately, insufficient data are available to appropriately compare the therapeutic effect of CAI alone or in various combinations with MTX, VCR, ADM and IFO because of great heterogeneity. In the present study, we used high-dose MTX at 10 g/m2 and CAI at 120 mg/m2 in 2 doses as routine preoperative treatment. For patients with tumors over 8 cm, we employed an enhanced dose of CAI at 160 mg/m2. Additionally, additional IFO courses were given to slow responders. This individualized regimen directly yielded a 66.7% prevalence of good histopathologic responders and contributed to the 5-year survival rate of 57.8% in pelvic osteosarcoma. Both of the two figures were seemingly improved when compared to those from conventional systematic chemotherapy.11
The cumulative dosage of CDDP was 780 mg/m2 for a good responder with a tumor size ≤ 8 cm in the present study. Wilkins et al reported the highest accumulated dose of CDDP at 960 mg/m2 and a single dose at 160 mg/m2 over 24 h as an enhanced regimen for patients with tumors over 10 cm versus 120 mg/m2 over 6 h as routine, which consequently yielded the highest 10-year OS and EFS rates (93% and 86%, respectively) among all reviewed studies. Notably, Ferrari et al and Xie et al investigated CDDP administration at equivalent doses to those in the present study but yielded poorer survival outcomes seemingly.13,33 This may be because 120 mg/m2 CDDP was given intraarterially in 72 h in the first study, which is too long to achieve a high enough blood concentration; patients with tumor metastases at the initial diagnosis were included in the second study so that the survival rate would be reduced. We used relatively high-dose CDDP administered over 3 to 6 h combined with 4 other drugs, including ETOP, and made individualized adjustments to the protocol for patients with high-risk factors. This may have contributed to the 57.8% OS and 52.5% EFS rate at 5 years, which is favorable for pelvic osteosarcoma. Moreover, we discovered that the OS and EFS rates in the population with tumors ≤ or >8 cm showed insignificant differences. Patients who received R0 resection also shared equivalent OS but higher EFS with R1 patients. These finding suggest that this protocol with risk-dependent adjustment in the drug dosage and combination could be beneficial to bridge the gap in survival rate between patients with large or small tumors, and those who received R0 or R1 resection.
We noticed that 3 of 5 cases developing SD turned out to demonstrate TNR >90%, which probably means that good response of osteosarcoma is not necessarily accompanied with tumor size decrease. This may be attributed to the formation of tumor bone generated by subtypes like osteoblastic osteosarcoma, which could prevent tumors from shrinkage.40
Only 4 poor responders were observed, 3 of whom developed tumor relapses. Two of the 3 patients died of metastasis during postoperative MSC; another showed no evidence of disease after receiving secondary amputation and resection for local recurrence. This protocol seemed to provide limited benefit to the poor responders. However, the present data are so limited that few tenable conclusions can be drawn from it to guide salvage treatment for poor responders.
Although the AI technique and additional courses were given in this protocol, no patients received an overdose of chemotherapy drugs compared with previous studies using similar drug combinations. No AI-relative grade 4 or 5 adverse events were observed. Although systematic adverse events, including nausea, vomiting, anemia and an increase in creatinine/aminotransferase levels, shared equivalent incidence rates and severities with the study reported by Xie et al, local skin hyperpigmentation and pelvic soft tissue necrosis in muscle occurred after only 3 and 1 of 24 CAI events (12.5% and 4.2%, respectively), which is more favorable than the situation reported in the most reviewed studies concerning extremity osteosarcoma.13,30,33 This finding could be explained by the shorter local drug-retention time since the pelvis has a more sufficient blood supply and drainage.
In terms of the postoperative MSC regimen for poor responders, we determined the IFO + ETOP regimen by reference to the second-line chemotherapy recommended in NCCN guidelines for bone cancer, which is supported by the study reported by Goorin et al and Miser et al.23,41 These two studies were conducted in patients with initial metastasis or recurrence of osteosarcoma, and the former one used IFO + ETOP as an induction regimen accompanied by surgical resection and continuation MSC of MTX + ADM + ETOP + IFO. Therefore, we adopted the regimen similar as the one reported by Miser et al However, the study of EURAMOS reported by Marina et al suggested that treatment with MTX + ADM + CDDP + IFO + ETOP resulted in similar EFS to MTX + ADM + CDDP and increased toxicity. In the present study, we found it hard for patients to accept 12 cycles of second-line therapy in 3 years in view of the high expenditure and physical discomfort. Therefore, the number of cycles was reduced to 6 for poor responders, which is equivalent to a half of the regimen of Miser et al in accumulative dosage and duration time. During the postoperative MSC period, there was no early death. The reported cardiac irritation, increase in creatinine/aminotransferase, oral mucosa inflammation and hematologic system abnormality were acceptable. In summary, our chemotherapy regimen seems to be well tolerated.
To monitor the chemotherapy response, several methods have been reported in previous studies. In the studies reported by Winkler et al and Fuch et al, plain X-ray, local CT and emission CT of bone were used to monitor the TNR before the surgery.30,34 Bacci et al, Wilkins et al and Xie et al deployed CT arterial angiography, which yielded sensitivity and specificity over 90% and 50%, respectively.13,32,36,37 Nevertheless, a repeated CT arterial angiography assessment is difficult to be accepted by patients because it requires multiple invasive operations and high expenditure. RECIST-1.1-based MRI remains one of the most commonly used approaches in tumor response evaluation.42,43 In the present study, we used CE-MRI to detect the tumor response and guide the adjustment of treatment for each patient. Although the results did not seem to suggest that this method is highly predictive of the histopathologic chemotherapy response, the equivalent survival rate between patients with large and small tumors may reflect the effectiveness of the individualized treatment.
There were several limitations in our investigation. First, the design was restricted to a small-sample-size single-arm clinical study due to the rarity of pelvis osteosarcoma morbidity, therefore reducing the reliability of the conclusions. Second, several previous studies reported that pathological subtypes of osteosarcoma, such as chondroblastic and telangiectatic osteosarcoma, respond differently to chemotherapy.39,44 However, the pathological subtype of each patient was not analyzed as an independent prognostic factor in our study. Heterogeneity of the osteosarcoma subtype constitution could distort chemotherapy response and survival outcomes. Third, we used CE-MRI per RECIST 1.1 to monitor the tumor response before surgery and guide the individualized adjustment of the treatment protocol. However, CE-MRI evaluation was not the gold standard for TNR prediction. Multiple innovative approaches for TNR prediction in osteosarcoma have been researched in the past 30 years, such as dynamic CE-MRI with sensitivity and specificity over 70% and 80%, respectively, according to previous studies.45–47 We would attempt to deploy approaches with higher accuracy to evaluate viable tumors in hope of providing more precise guidance for individualized pelvic osteosarcoma treatment in further studies.
Conclusions
In the present study, we employed CAI in the multimodal treatment of pelvic osteosarcoma patients. Our findings suggest that the CAI-facilitated chemotherapy regimen demonstrated great potential for improving the survival of patients with pelvic osteosarcoma. This treatment protocol yielded high tolerance with acceptable adverse effects. However, further randomized controlled trials with large sample sizes are required to elucidate the findings of this preliminary study.
Acknowledgments
We would like to thank all patients for their devotion to taking unidentified risks in this clinical trial. We are also grateful to the participating orthopedic oncologists and interventional radiologists for their prudence and patience in the therapeutic effect evaluation and the multidisciplinary consultation.
Abbreviations
ADM, adriamycin; CAI, effect of cisplatin arterial infusion; CDDP, cis-diamine-dichloro platinum; CE-MRI, contrast-enhanced MRI; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; EFS, event-free survival; ETOP, etoposide; IFO, ifosfamide; IV, intravenous; MSC, multidrug systematic chemotherapy; MTX, methotrexate; OS, overall survival; PD, progressive disease; PR, partial response; RECIST, response evaluation criteria in solid tumors version; S, surgery; SD, stable disease; TNR, tumor necrosis rate; VCR, vincristine.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics Approval and Informed Consent
This study was approved by the ethics committees and the institutional review board of the Second Xiangya Hospital. All patients provided written informed consent for receiving this treatment protocol. The requirement of obtaining specific informed consent for this retrospective study was waived for the reason mentioned before.
Consent for Publication
This study conforms to Declaration of Helsinki. The requirement of obtaining specific informed consent from the patients for the publication of the case presentation and any accompanying images.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
No commercial sponsorship was involved in any part of this study. The authors report no conflicts of interest related to this work. | 10 G/M2 DAILY FOR ONE DAY | DrugDosageText | CC BY-NC | 33623429 | 19,834,554 | 2021 |
What was the dosage of drug 'VINCRISTINE'? | Effect of Cisplatin Arterial Infusion (CAI) on Primary Nonmetastatic Pelvic Osteosarcoma: A Preliminary Study.
The critical role of arterial infusion chemotherapy in the multimodal treatment of extremity bone cancer has been investigated extensively, but few studies have focused on pelvic osteosarcoma. Therefore, we attempted to evaluate the clinical significance of arterial infusion chemotherapy in the treatment of pelvic osteosarcoma.
We combined a cisplatin arterial infusion regimen with multidrug systematic chemotherapy as a neoadjuvant protocol for the treatment of pelvic osteosarcoma. The course number and dosage of cisplatin arterial infusion were adjusted to achieve a maximal tumor response evaluated by contrast-enhanced MRI per RECIST 1.1. Good responders received the same systematic combination for postoperative chemotherapy, and poor responders received second-line therapy. Twelve patients with nonmetastatic high-grade pelvic osteosarcoma were included. Survival, chemotherapy response and adverse events data were analyzed.
The mean follow-up period was 56.1 months. Four patients died of refractory tumor progression, and 1 patient with local recurrence had no evidence of disease for 27 months after receiving secondary amputation and resection. Kaplan-Meier survival analysis demonstrated a 57.8% overall survival and 52.5% event-free survival rate at 5 years. Eight of 12 patients had a >90% tumor necrosis rate according to histopathologic examinations. The rates of local adverse events were lower than those reported for extremity osteosarcoma.
Our study initially indicated that the cisplatin arterial infusion regimen was a potential therapy with good tolerance in the treatment of pelvic osteosarcoma.
Introduction
Osteosarcoma is the most common solid malignant tumor of bone with a highly aggressive behavior.1 The most susceptible age of osteosarcoma is bimodal, which is characterized by one peak at 10-to-20 years and another at over 60 years.2,3 Although this disease endangers the health of both adolescent and aged populations, limited progress has been made to improve survival and functional prognosis, especially in patients with pelvic osteosarcoma.4–6 Osteosarcoma patients treated with mere immediate surgical resection register a recurrence rate up to 60–90%.7 (Since 1980s, traditional adjuvant intravenous (IV) systematic chemotherapy produces an improved five-year event-free survival (EFS) rate of 61%.8 In the early 2000s, the propagation of a multidrug neoadjuvant chemotherapy regimen elevated this rate to 60% and above.9,10) Henceforth, numerous explorations have been conducted to optimize the category, dosage, combination and duration of chemotherapy drug administration. The most recent studies of EURAMOS revealed a 5-year EFS of 65–70% for localized osteosarcoma treated by multidrug neoadjuvant chemotherapy. However, there are few studies focusing on arterial infusion as an improved method and its clinical outcome in the treatment of pelvic osteosarcoma.
Osteosarcoma in pelvic bone is more notorious than that in extremities. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate than those with extremity lesions, which may be associated with a poor chemotherapy response and an inability to achieve adequate surgical resection.11 Therefore, more challenges are faced in the management of pelvic osteosarcoma.
Platinum complexes, such as cis-diamine-dichloro platinum (cisplatin, CDDP), have been proven to be cell cycle-nonspecific agents and to have multiple broad-spectrum antitumor effects.12 Several clinical trials reported that employing an arterial infusion technique to deliver CDDP, in combination with an IV systematic chemotherapy regimen or not, can elevate the local drug concentration to fivefold that of IV administration and can produce better survival in the treatment of extremity osteosarcoma.13–15 Therefore, the arterial infusion of CDDP might have potential in the treatment of pelvic osteosarcoma.
The histopathologic response of surgically removed tumors has been shown to be one of most critical indicators of chemotherapeutic effectiveness and survival prognosis.16,17 However, preoperative examination is more valuable to predict tumor response and allow individualized neoadjuvant chemotherapy. Response evaluation criteria in solid tumors version 1.1 (RECIST 1.1), which was commonly adopted for the tumor-response evaluation of a variety of cancers, affirmed the value of sectional radiological imaging measurement.18–20 Therefore, preoperative contrast-enhanced MRI (CE-MRI) evaluation based on RECIST 1.1 is expected to guide the adjustment of treatment for optimal surgical timing in pelvic osteosarcoma.
Given all these findings, we combined CDDP arterial infusion (CAI) with individualized multidrug systematic chemotherapy (MSC) and surgery (S) to treat nonmetastatic pelvic osteosarcoma and attempted to investigate (1) the chemotherapy response and survival yielded from this protocol, (2) the individualized adjustment of the neoadjuvant MSC regimen necessary to achieve the maximal tumor response according to RECIST-1.1-based CE-MRI reassessment, and (3) the potential adverse effects caused by the arterial infusion technique and the multidrug systematic chemotherapy regimen.
Patients and Methods
Study Design and Consent
This is a retrospective cohort study (Level III evidence) in which subjects received a protocol comprising multidrug systematic chemotherapy, cisplatin arterial infusion and resection surgery (CAI + MSC + S). The study design conformed with the Declaration of Helsinki, and the treatment protocol was approved by the hospital institutional review board. All patients provided written informed consent for receiving this treatment protocol. All data used in the present study were obtained from the electronic medical records of our hospital and treated with strict confidentiality; therefore, the requirement of obtaining specific informed consent for this retrospective study was waived.
Patients
Inclusion criteria for subjects included (1) histopathologically defined primary osteosarcoma of pelvic bone; (2) no metastatic foci; (3) no past history of cancer treatment; and (4) normal cardiac, hepatic and renal function. All patients were confirmed to have high-grade osteosarcoma morbidity via biopsy. Pretreatment baseline safety indexes were determined with routine blood tests, hepatic and renal function tests, and Doppler echocardiography. A peripherally inserted central catheter was placed in each patient for the IV administration of neoadjuvant chemotherapy agents.
From January 2010 to June 2015, 21 patients were consecutively diagnosed with osteosarcoma of the pelvic bones in our work unit. A total of 4 patients were excluded for the following reasons: 2 patients had evidence of distant metastasis, and 2 tumors involved the femur or lumbar vertebra. Among the eligible people, 2 refused to take CAI + MSC + S treatment: 1 had hemophilia with severely impaired coagulation function; 1 intended to transfer to another hospital after being definitively diagnosed via biopsy. Subsequently, 15 patients took the CAI + MSC + S treatment, but 1 of them stopped midway (because of intolerance to vomiting as the adverse effect in the first two rounds of IV multidrug therapy) and turned to other treatment. Two patients were lost to follow-up after surgical resection. Eventually, 12 patients finished the treatment protocol and yielded analyzable data for survival, chemotherapy response and toxicity assessment.
The data of these 12 patients are listed in Table 1. The study population consisted of 7 (58.3%) males and 5 (41.7%) females with an average age of 28.8 years (11 to 69 years). The morbid sites included the pubis (n = 2), ilium (n = 4), ischium (n = 1), sacrum (n = 1) and unclear sites (n = 4).Table 1 Patient Data
Case No. Age (y) Sex Tumor Size (cm) Morbid Site MRI Tumor Response Before Surgery Surgical Margins Histopathologic Response Diagnosis Date Surgery Type Follow-Up (Month) First Relapse Status
1 62 F <8 Unclear +27.4%, PD R0 <90% 5/19/2010 1 42 CDF
2 19 M <8 Ilium −35.1%, PR R0 >90% 10/4/2010 2 46 Jan. 2014 DOD
3 14 M <8 Unclear +14.6%, SD R0 95% 7/23/2011 2 52 CDF
4 53 F >8 Sacrum −7.3%, SD R1 <90% 6/30/2012 4 57 Feb. 2015 NED
5 15 M <8 Ilium −32.7%, PR R0 >90% 10/28/2012 2 93 CDF
6 21 F 7 Ilium +25.9%, PD R0 >90% 4/24/2013 2 87 CDF
7 16 M >8 Unclear +8.6%, SD R1 <90% 9/22/2013 2 37 Aug. 2015 DOD
8 36 F 9 Pubis −24.1%, SD R0 >90% 4/14/2014 2 76 CDF
9 69 M 12 Ischium +43.7% PD R1 <90% 5/17/2014 3 15 Jan. 2015 DOD
10 12 F <8 Unclear −37.4%, PR R0 99% 8/21/2014 2 72 CDF
11 41 M <8 Pubis +33.5%, PR R0 >90% 3/6/2015 2 34 CDF
12 47 M <8 Ilium +16.6%, SD R0 95% 6/30/2015 2 62 Dec. 2019 DOD
Notes: Surgical type = 1) primary lower limb amputation; 2) lower limb salvage surgery; 3) secondary amputation and reresection due to local recurrence; 4) revision surgery due to periprosthetic infection.
Abbreviations: CAI, cisplatin arterial infusion; PR, partial response; PD, progressive disease; SD, stable disease; CAP, cisplatin arterial perfusion; CDF, continuously disease free; NED, no evidence of disease; DOD, died of disease.
Description of the Study Treatments and Outcome Measures
The adopted CAI + MSC + S treatment protocol is depicted in Figure 1. In general, MSCs usually consist of high-dose methotrexate (MTX), vincristine (VCR), adriamycin (ADM), CDDP and ifosfamide (IFO). Specifically, the routine CAI + MSC regimen was initiated with 24-hour continuous IV dripping of high-dose MTX at 10 g/m2 followed by 2 mg IV VCR the next day for the first group at Week 0; in Week 2, 120 mg/m2 CDDP AI over 3 to 6 hours and following 30 mg/m2/d IV ADM for 2 days were given to the second group; these 2 groups were repeated in Weeks 3 and 4; then, the resection surgery was performed 2 weeks after the neoadjuvant chemotherapy was finished. Notably, 160 mg/m2 was determined as the enhanced dosage of CDDP for tumors with the longest diameter over 8 cm in CE-MRI slices. In addition, IV IFO at 2 g/m2/d for 5 days was given in Week 5 for tumors over 8 cm after the 4-week routine regimen was completed. Central venous catheterization for MSC administration was performed under inhalation anesthesia if necessary. Before each CAI regimen, percutaneous punctuation of the femoral artery was performed using the Seldinger technique, and the catheter was inserted from the femoral artery of the contralateral side to the beginning of the artery trunk supplying the tumor with the assistance of CT-guided positioning.21 Then, CT arterial angiography was conducted. Each course of MSC and CAI was accompanied by IV hydration, diuretics, rescue and protecting drugs. The CDDP was perfused via the catheter with chemotherapy pumps (LimLess Infusion Pump; PFM Medical Inc, Cologne, Germany) in a pulsed manner (Bolus dose administrator; PFM Medical Inc, Cologne, Germany). The patients were asked to have strict bed rest under multiparameter monitoring. Routine blood tests for electrolytes and hepatic and renal function were performed on the first day after drug administration and every 3 days thereafter.Figure 1 The individualized pelvic osteosarcoma treatment protocol combined cisplatin arterial infusion, multidrug systematic chemotherapy and resection surgery (CAI + MSC + S).
To evaluate the therapeutic response, primary plain X-ray (Figure 2A) and physical examination parameters of the tumor, including pre- and postchemotherapy size, tenderness, pain and inflammation, were collected. More importantly, CE-MRI was performed to monitor the tumor chemotherapy response before and after routine neoadjuvant CAI + MSC administration. (Figure 2B–E) According to the RECIST 1.1 guidelines, tumor size was calculated in gadolinium-enhancing T1-weighted fat‐saturated coronal images using the following criteria: complete response (CR), complete elimination of target lesion; partial response (PR), ≥30% decrease in the diameter of target lesion compared to baseline); progressive disease (PD), ≥20% increase in the diameter of target lesion compared to baseline or new metastatic lesion); and stable disease (SD) or observed changes in the diameter of the target lesion between 30% decrease and 20% increase compared to baseline. Each tumor lesion was assessed by orthopedic oncologists and interventional radiologists who were blinded to the treatment allocation and clinical outcome data. For patients who achieved PD after the routine neoadjuvant regimen was finished, surgery was performed immediately. For patients who demonstrated CR or PR, surgery was performed 2 weeks after the neoadjuvant regimen as usual. For patients who presented SD, the same IFO course as that mentioned in the adjustment for large tumors was added to maximize the tumor response of the neoadjuvant regimen. Then, a multidisciplinary consultation was conducted to identify the achievement of maximal tumor response. If any uncertainty of maximal response achievement was left, one more course of IFO could be given, and patients received resection surgery no later than 9 weeks after the first diagnosis.Figure 2 (A) Pelvis X-ray of a 36-year-old female with an osteosarcoma in the pubis. (B) and (C) Fat-saturated T1- and T2-weighted coronal slices of contrast-enhanced MRI showing the maximum diameter of the tumor at the first diagnosis, which showed heterogeneous enhancement, thick septa and obscure boundaries of the tumor. (D) and (E) MRI reevaluation after completion of the neoadjuvant CAI + MSC regimen, showing thin septa, clear boundaries and stable disease according to RECIST 1.1 with a decrease in the tumor diameter. (F) Pelvis plain X-ray of this patient. (The identifiable captions in these images are occluded.).
A chest CT scan, a full-body bone scan and a pelvic CE-MRI scan (Figure 2D and E) were repeated before surgery. The tumor response per RECIST 1.1 measured in the last CE-MRI examination was compared with the baseline level. Surgical excision extension was determined by the involved scope of the tumor and the tumor response category according to the CE-MRI assessment per RECIST 1.1. The pelvic reconstruction project depended on the morbidity site, excision extension, bone mineral density and functional requirements.
In case of uncontrollable hemorrhage during the resection surgery, a temporary balloon blocking technique for the abdominal aorta was performed under the guidance of CTA 4 hours before resection surgery. A balloon compatible in size to the abdominal aortic diameter was placed intraarterially at the level of 2 to 3 cm above the bifurcation of the common iliac arteries. The injection of saline with 0.1% heparin inflated the balloon, consequently blocking blood perfusion of the surgical site. Angiography was performed to confirm the satisfactory blockage of the iliac arteries and unobstruction of the renal arteries. Then, the balloon was deflated until the surgery began. Each deflation was performed with an interval of 60 min during the resection surgery before satisfactory hemostasis was achieved.
Histopathologic examination was conducted using the method reported by Huvos et al to quantify the necrosis ratio of the tumor after removal.22 Patients with a ≥90% tumor necrosis rate (TNR) (Grade III and IV) were classified as good responders. The other (Grade Ⅰ and Ⅱ) were deemed poor responders.
The postoperative IV chemotherapy cycle was repeated every 3 weeks. The recovery of hematopoietic function in patients was required before each course, which was defined as a white blood cell count over 1×104/mm3 and a platelet count over 5×106/mm3 for 3 successive days without hematopoietic stimulants. For good responders, the duration of postoperative MSC was usually 3 courses, which could be extended to the maximum of 6 courses accompanied by the existence of high-risk factors, including SD or PD in the CE-MRI per RECIST 1.1 before surgery or histology-proven tumor involvement in the surgical margin (R1 resection). For poor responders, IFO at 2 g/m2/d for 5 days and etoposide (ETOP) at 100 mg/m2/d for 5 days were given sequentially as one cycle repeated every 3 weeks for 6 cycles.23
After the planned treatment was finished, the discontinuation of chemotherapy was allowed by the orthopedic oncologist if X-ray (Figure 2F) and CE-MRI of the primary morbidity site along with chest X-ray every 2 months, chest CT scanning every 6 months in the first year off the treatment prove no local recurrence or lung metastasis. Routine blood tests and hepatic and renal function tests were deployed every week until the recovery of hematopoietic function.
Statistical Analysis
We used the Kaplan-Meier method to analyze the overall survival (OS) and EFS, which were calculated from the day the preoperative MSC + CAI regimen began. The events were defined as local recurrence, distant metastasis or death from the disease. Additionally, the OS and EFS in groups with different histopathologic chemotherapy responses or tumor sizes were calculated. All statistical analyses were conducted with SPSS software packages (SPSS Inc., Chicago, IL, USA).
Results
Chemotherapy Response
Significant improvement in physical examination parameters was observed in 10 of 12 patients after the neoadjuvant regimen, including alleviation of pain. In terms of tumor response measurement per RECIST 1.1, 4 patients had PR and 5 had SD after routine neoadjuvant CAI + MSC administration. Three patients had to undergo resection surgery ahead of schedule because of PD, as shown by CE-MRI after neoadjuvant CAI + MSC administration. No patient demonstrated CR.
According to the histopathologic assessment, 66.7% (8 of 12) of patients demonstrated TNR over 90%. One of the 3 patients with PD according to the CE-MRI assessment turned out to be good responders with Grade III histopathologic results.
Surgery
Three patients underwent local radical excision and lower limb amputation because of neurovascular bundle involvement. The remaining 9 patients received limb salvage surgery followed by pelvic reconstruction using a modular prosthesis (Lidakang Inc., Beijing, China), tumor bone devitalization and replantation, or just bone fusion. As a result, 1 patient who underwent primary limb salvage surgery developed local recurrence and underwent secondary amputation and local reresection. Two patients had surgical site infections but were cured 2 months after surgery. One patient who developed a periprosthetic infection underwent a secondary amputation.
Survival
A total of 58.3% of patients (7 of 12) remained continuously disease free in an average follow-up period of 65.1 months (range, 34–93 months). One patient who developed local recurrence was proven alive with no evidence of disease for 31 months after receiving a secondary amputation and resection. Four patients (3 lung metastases and 1 local recurrence) died of refractory disease progression. Kaplan-Meier survival analysis suggested an OS rate of 57.8% and an EFS of 52.5% at 5 years (Figure 3). For patients with a good chemotherapy response, the 5-year OS and EFS rates were 68.6%, both of which showed significant differences (P = 0.04 for OS and 0.01 for EFS) compared with the corresponding measures for poor responders (Table 2). The comparison of patients with tumor sizes greater (n = 4) or less (n = 8) than 8 cm did not yield statistical significance (P = 0.32 and 0.13, respectively). As shown in the pathological report, 75% (9 of 12) patients received R0 resection and 25% (3 of 12) had R1 resection. There was no significant difference in the OS but in the EFS between patient group with R0 or R1 surgical resection (P = 0.15 and 0.05, respectively). The confidence interval of all OS and EFS are 95%.Table 2 Overall Survival (OS) and Event-Free Survival (EFS) Rate
Variables 1 y 5 y
All patients – OS 91.7% 57.8%
All patients – EFS 91.7% 52.5%
Good responders – OS 100.0% 68.6%
Good responders – EFS 100.0% 68.6%
Poor responders – OS 75.0% 50.0%
Poor responders – EFS 75.0% 25.0%
Patients with tumor size ≥8 cm – OS 75.0% 50.0%
Patients with tumor size ≥8 cm – EFS 75.0% 25.0%
Patients with tumor size<8 cm – OS 100.0% 62.5%
Patients with tumor size<8 cm – EFS 100.0% 64.3%
R0 resection – OS 85.7% 70.0%
R0 resection – EFS 88.9% 71.1%
R1 resection – OS 66.7% 33.3%
R1 resection – EFS 66.7% 33.3%
Note: Confidence Interval = 95%
Figure 3 The Kaplan-Meier survival curve for overall survival (OS) and event-free survival (EFS) rates of 12 pelvic osteosarcoma patients treated with the CAI + MSC + S protocol.
Chemotherapy Toxicity
We recorded the adverse effects referred to in the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.24 The statistics of CAI-related adverse events are summarized in Table 3. Three of 12 patients had local adverse events, including grade 1 to 2 skin pelvic soft tissue necrosis in muscle and hyperpigmentation, which exhibited no effect on the surgical method choice or wound healing. Nausea and vomiting were the most common systematic adverse events, with 41.7% of patients developing grade 3 events. A 36-year-old female received a reduced dosage of MTX (7 g/m2) due to intolerable vomiting after the first MTX course. Four of 12 patients developed grade 1 infusion-related reactions.Table 3 Statistics of CAI-Related Adverse Events
Adverse Events No. of Courses Percentage of Patients with Grade 3–4 Adverse Events
Skin hyperpigmentation 12.5% (3/24) 0% (0/12)
Pelvic soft tissue necrosis (muscle) 4.2% (1/24) 0% (0/12)
Pelvic pain 16.7% (4/24) 8.3% (1/12)
Nausea and vomiting 75.0% (18/24) 41.7% (5/12)
Anemia 8.3% (2/24) 8.3% (1/12)
Increase in creatinine level 8.3% (2/24) 0% (0/12)
Increase in aminotransferase level 4.2% (1/24) 0% (0/12)
Infusion related reaction 29.2% (7/24) 0% (0/12)
During the postoperative MSC period, one 12-year-old child complained of grade 1 palpitations and chest pain. Therefore, we replaced ADM with ETOP, and the complaint disappeared with no evidence reported in Doppler echocardiography. Three patients out of 12 developed grade 1 to 2 increases in alanine/aspartate aminotransferase levels.
Three children developed oral mucositis at grade 2 to 3, 2 of whom were under IV nutrition, and one used a mouth rinse with metronidazole to treat thrush. All patients eventually resumed normal oral food intake.
Blood system disorders were commonly noted in patients after the second cycle of postoperative MSC administration. Three patients developed febrile neutropenia and were treated by injection of recombinant human granulocyte stimulating factor.
Discussion
Conventional IV adjuvant chemotherapy and neoadjuvant chemotherapy have been applied extensively in multimodal osteosarcoma treatment for over 45 years.25 Though changes in drug combination, dosage, and administration duration were made to optimize the regimen, no significant improvement was achieved based on the approximately 50% to 70% 5-year OS and EFS rates in the past decade.26–28 As a modified approach to augment the potential of chemotherapy drugs, the AI technique combined with MSCs has been studied for years.13,29,30 In the present study, we attempted to investigate the therapeutic effect of the CAI + MSC + S protocol in osteosarcoma treatment. The 5-year OS and EFS rates were 57.8% and 52.5%, respectively.
The CAI regimen and its outcome measurements were first documented by Jaffe et al in 1983.31 Then, a series of studies concerning CAI-facilitated multidrug chemotherapy followed.13,30,32–37 Information on all 9 studies, including the present study, is listed in Table 4.Table 4 Synopsis of IA CDDP Information Reported in the Literature
Authors Type of Study No. of Patients Ages (y) Sites Metastases Preoperative CDDP Courses No. >90% TN OS EFS
Winkler et al and Fuchs et al30,34 Nonrandomized, 2 arms 50 <40 All Included 2 68% 67% at 10 y 63% at 10 y
Ferrari et al33 Single arm 164 <40 Extremity Excluded 2 NA 72% at 8 y 63% at 8 y
Ferrari et al33 Randomized, 2 arms 59 <40 Extremity Excluded 2 64% 61% at 8 y 54% at 8 y
Rha et al35 Single arm 37 8~41 Extremity ? 3 75% 78% at 3 y 55% at 3 y
Bacci et al32 Randomized, 2 arms 40 <40 Extremity Included 2 77% NA 26% at 5 y
Bacci et al32 Randomized, 2 arms 72 <40 Extremity Included 2 80% NA 61% at 5 y
Wilkins et al37 Single arm 47 <21 Extremity Excluded 3–5 (response dependent) 87% 92% at 10 y 84% at 10 y
Wilkins et al36 Single arm 62 <22 Extremity Excluded 3–5 (response dependent) 87% 93% at 10 y 86% at 10 y
Xie et al13 Nonrandomized, 2 arms 48 NA Extremity Included 3 63% 64% at 5 y 60% at 5 y
Hu et al (Current study) Single arm 12 11~69 Pelvis Excluded 2 66.7% 57.8% at 5 y 52.5% at 5 y
Abbreviations: IA, intraarterial; CDDP, cisplatin; TN, tumor necrosis; OS, overall survival; EFS, event-free survival.
Among these 9 studies, 8 used CAI and systematic chemotherapy sequentially before surgery, and 5 studies scheduled a 2-course preoperative regimen. Six of 9 studies suggested a higher chemotherapy response rate and/or survival rate in the CAI group compared with the IV CDDP group; 2 of these investigations were 2-arm randomized cohort studies and reported a statistically significant improvement in the good-response ratio (21% and 31%, respectively). In the third randomized cohort study reported by Rha et al, the improvement was not statistically significant, probably because the limited sample size was insufficient to test the 9% difference between the two groups.35 In the multicenter study reported by Winkler et al and Fuchs et al in the 1990s, no difference in chemotherapy response was observed between the intraarterial and IV CDDP groups.30,34 Similarly, Xie et al also proved a superior histological response rate but equivalent survival in the CAI group versus the IV group in 2019.13 However, the reliability of the conclusions in the 2 studies may be impaired by the nonrandomized grouping design conducted at the researchers’ discretion, which could be affected by the severity of disease. Although CAI may bring benefits to chemotherapy response augmentation and survival rates in limb osteosarcoma patients, how pelvic osteosarcoma reacts to CAI-facilitated multidrug chemotherapy remains elusive.
Pelvic tumor resection surgeries such as hemipelvectomy are notoriously known as one of the most destructive operations in modern orthopedic surgery.38 Due to the adjacency of the vascular network, nerves and viscera in the pelvis, surgeons have to weigh tumor eradication against functional preservation in the determination of the extent of surgical excision. This dilemma makes the treatment more challenging. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate compared with the extremity-morbidity population, which could be explained by the higher rate of not only failure of surgical remission but also advanced age, large tumor size, primary metastasis, prolonged latency periods and poor chemotherapy responses.11,39 Thus, it is critical to maximize the chemotherapy response and achieve better survival outcomes in pelvic osteosarcoma patients.
The combination of agents in our MSC protocol was determined by reference to NCCN guidelines for bone cancer and the study reported by Xie et al.13 Although the agent numbers and categories differed, all of the above-reviewed studies and the present study deployed a multidrug protocol to treat tumor cells in different phases of the cell cycle. Unfortunately, insufficient data are available to appropriately compare the therapeutic effect of CAI alone or in various combinations with MTX, VCR, ADM and IFO because of great heterogeneity. In the present study, we used high-dose MTX at 10 g/m2 and CAI at 120 mg/m2 in 2 doses as routine preoperative treatment. For patients with tumors over 8 cm, we employed an enhanced dose of CAI at 160 mg/m2. Additionally, additional IFO courses were given to slow responders. This individualized regimen directly yielded a 66.7% prevalence of good histopathologic responders and contributed to the 5-year survival rate of 57.8% in pelvic osteosarcoma. Both of the two figures were seemingly improved when compared to those from conventional systematic chemotherapy.11
The cumulative dosage of CDDP was 780 mg/m2 for a good responder with a tumor size ≤ 8 cm in the present study. Wilkins et al reported the highest accumulated dose of CDDP at 960 mg/m2 and a single dose at 160 mg/m2 over 24 h as an enhanced regimen for patients with tumors over 10 cm versus 120 mg/m2 over 6 h as routine, which consequently yielded the highest 10-year OS and EFS rates (93% and 86%, respectively) among all reviewed studies. Notably, Ferrari et al and Xie et al investigated CDDP administration at equivalent doses to those in the present study but yielded poorer survival outcomes seemingly.13,33 This may be because 120 mg/m2 CDDP was given intraarterially in 72 h in the first study, which is too long to achieve a high enough blood concentration; patients with tumor metastases at the initial diagnosis were included in the second study so that the survival rate would be reduced. We used relatively high-dose CDDP administered over 3 to 6 h combined with 4 other drugs, including ETOP, and made individualized adjustments to the protocol for patients with high-risk factors. This may have contributed to the 57.8% OS and 52.5% EFS rate at 5 years, which is favorable for pelvic osteosarcoma. Moreover, we discovered that the OS and EFS rates in the population with tumors ≤ or >8 cm showed insignificant differences. Patients who received R0 resection also shared equivalent OS but higher EFS with R1 patients. These finding suggest that this protocol with risk-dependent adjustment in the drug dosage and combination could be beneficial to bridge the gap in survival rate between patients with large or small tumors, and those who received R0 or R1 resection.
We noticed that 3 of 5 cases developing SD turned out to demonstrate TNR >90%, which probably means that good response of osteosarcoma is not necessarily accompanied with tumor size decrease. This may be attributed to the formation of tumor bone generated by subtypes like osteoblastic osteosarcoma, which could prevent tumors from shrinkage.40
Only 4 poor responders were observed, 3 of whom developed tumor relapses. Two of the 3 patients died of metastasis during postoperative MSC; another showed no evidence of disease after receiving secondary amputation and resection for local recurrence. This protocol seemed to provide limited benefit to the poor responders. However, the present data are so limited that few tenable conclusions can be drawn from it to guide salvage treatment for poor responders.
Although the AI technique and additional courses were given in this protocol, no patients received an overdose of chemotherapy drugs compared with previous studies using similar drug combinations. No AI-relative grade 4 or 5 adverse events were observed. Although systematic adverse events, including nausea, vomiting, anemia and an increase in creatinine/aminotransferase levels, shared equivalent incidence rates and severities with the study reported by Xie et al, local skin hyperpigmentation and pelvic soft tissue necrosis in muscle occurred after only 3 and 1 of 24 CAI events (12.5% and 4.2%, respectively), which is more favorable than the situation reported in the most reviewed studies concerning extremity osteosarcoma.13,30,33 This finding could be explained by the shorter local drug-retention time since the pelvis has a more sufficient blood supply and drainage.
In terms of the postoperative MSC regimen for poor responders, we determined the IFO + ETOP regimen by reference to the second-line chemotherapy recommended in NCCN guidelines for bone cancer, which is supported by the study reported by Goorin et al and Miser et al.23,41 These two studies were conducted in patients with initial metastasis or recurrence of osteosarcoma, and the former one used IFO + ETOP as an induction regimen accompanied by surgical resection and continuation MSC of MTX + ADM + ETOP + IFO. Therefore, we adopted the regimen similar as the one reported by Miser et al However, the study of EURAMOS reported by Marina et al suggested that treatment with MTX + ADM + CDDP + IFO + ETOP resulted in similar EFS to MTX + ADM + CDDP and increased toxicity. In the present study, we found it hard for patients to accept 12 cycles of second-line therapy in 3 years in view of the high expenditure and physical discomfort. Therefore, the number of cycles was reduced to 6 for poor responders, which is equivalent to a half of the regimen of Miser et al in accumulative dosage and duration time. During the postoperative MSC period, there was no early death. The reported cardiac irritation, increase in creatinine/aminotransferase, oral mucosa inflammation and hematologic system abnormality were acceptable. In summary, our chemotherapy regimen seems to be well tolerated.
To monitor the chemotherapy response, several methods have been reported in previous studies. In the studies reported by Winkler et al and Fuch et al, plain X-ray, local CT and emission CT of bone were used to monitor the TNR before the surgery.30,34 Bacci et al, Wilkins et al and Xie et al deployed CT arterial angiography, which yielded sensitivity and specificity over 90% and 50%, respectively.13,32,36,37 Nevertheless, a repeated CT arterial angiography assessment is difficult to be accepted by patients because it requires multiple invasive operations and high expenditure. RECIST-1.1-based MRI remains one of the most commonly used approaches in tumor response evaluation.42,43 In the present study, we used CE-MRI to detect the tumor response and guide the adjustment of treatment for each patient. Although the results did not seem to suggest that this method is highly predictive of the histopathologic chemotherapy response, the equivalent survival rate between patients with large and small tumors may reflect the effectiveness of the individualized treatment.
There were several limitations in our investigation. First, the design was restricted to a small-sample-size single-arm clinical study due to the rarity of pelvis osteosarcoma morbidity, therefore reducing the reliability of the conclusions. Second, several previous studies reported that pathological subtypes of osteosarcoma, such as chondroblastic and telangiectatic osteosarcoma, respond differently to chemotherapy.39,44 However, the pathological subtype of each patient was not analyzed as an independent prognostic factor in our study. Heterogeneity of the osteosarcoma subtype constitution could distort chemotherapy response and survival outcomes. Third, we used CE-MRI per RECIST 1.1 to monitor the tumor response before surgery and guide the individualized adjustment of the treatment protocol. However, CE-MRI evaluation was not the gold standard for TNR prediction. Multiple innovative approaches for TNR prediction in osteosarcoma have been researched in the past 30 years, such as dynamic CE-MRI with sensitivity and specificity over 70% and 80%, respectively, according to previous studies.45–47 We would attempt to deploy approaches with higher accuracy to evaluate viable tumors in hope of providing more precise guidance for individualized pelvic osteosarcoma treatment in further studies.
Conclusions
In the present study, we employed CAI in the multimodal treatment of pelvic osteosarcoma patients. Our findings suggest that the CAI-facilitated chemotherapy regimen demonstrated great potential for improving the survival of patients with pelvic osteosarcoma. This treatment protocol yielded high tolerance with acceptable adverse effects. However, further randomized controlled trials with large sample sizes are required to elucidate the findings of this preliminary study.
Acknowledgments
We would like to thank all patients for their devotion to taking unidentified risks in this clinical trial. We are also grateful to the participating orthopedic oncologists and interventional radiologists for their prudence and patience in the therapeutic effect evaluation and the multidisciplinary consultation.
Abbreviations
ADM, adriamycin; CAI, effect of cisplatin arterial infusion; CDDP, cis-diamine-dichloro platinum; CE-MRI, contrast-enhanced MRI; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; EFS, event-free survival; ETOP, etoposide; IFO, ifosfamide; IV, intravenous; MSC, multidrug systematic chemotherapy; MTX, methotrexate; OS, overall survival; PD, progressive disease; PR, partial response; RECIST, response evaluation criteria in solid tumors version; S, surgery; SD, stable disease; TNR, tumor necrosis rate; VCR, vincristine.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics Approval and Informed Consent
This study was approved by the ethics committees and the institutional review board of the Second Xiangya Hospital. All patients provided written informed consent for receiving this treatment protocol. The requirement of obtaining specific informed consent for this retrospective study was waived for the reason mentioned before.
Consent for Publication
This study conforms to Declaration of Helsinki. The requirement of obtaining specific informed consent from the patients for the publication of the case presentation and any accompanying images.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
No commercial sponsorship was involved in any part of this study. The authors report no conflicts of interest related to this work. | 2 MG, DAILY, FOR ONE DAY | DrugDosageText | CC BY-NC | 33623429 | 19,834,554 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Acute superior mesenteric artery thrombosis seven days after discharge for novel coronavirus pneumonia.
Since the emergence of novel coronavirus pneumonia (NCP), a number of reports have pointed out an increased coagulation activity in these patients mostly during acute phase of the disease. We are reporting a case of acute superior mesenteric thrombosis in a 55-year-old man with NCP 1 week after hospital discharge. He returned to the emergency department 7 days later with severe acute abdominal pain and found to have superior mesenteric artery thrombosis. He subsequently underwent emergent exploratory laparotomy, superior mesenteric artery thrombectomy, and bowel resection. Acute arterial thrombosis may occur in the posthospitalization period in patients with NCP.
pmcSince the emergence of novel coronavirus pneumonia (NCP) in December 2019, a number of reports have suggested that a large percentage of patients with novel coronavirus disease (COVID-19), particularly those who become critically ill, develop a prothrombotic state that places them at a significantly increased risk of thrombosis, especially during the acute phase that often requires intensive care unit stay with severe acute respiratory distress syndrome.1, 2, 3 Interestingly, a wide range of increases in d-dimer levels has also been documented in patients hospitalized with COVID-19 and there are early reports linking higher d-dimer levels to worse outcomes.4 Based on these reports, most centers used thrombosis prevention strategies ranging from prophylactic regimens to full anticoagulation during hospitalization for NCP with improved outcomes.5 The optimal potency and duration of antithrombotic management is not clear. In addition, there is little evidence on when the increased coagulation activity returns to normal levels after the onset of symptoms. We report a case of acute mesenteric ischemia due to superior mesenteric artery (SMA) thrombosis in a 55-year-old male patient with NCP 1 week after hospital discharge. Patient consent to publish the case report was obtained according to our institutional guidelines.
Case report
A 55-year-old African American man presented to the emergency department (ED) with complaints of a nonproductive cough, fatigue, myalgia, nausea, diarrhea, and abdominal pain for 4 days. His past medical history was significant for hypertension and Grave's disease. Medication history included atenolol 100 mg/d and methimazole 10 mg/d. The patient did not have a history of smoking or illicit drug abuse. He is a construction worker in the New York City area. On physical examination he had mild hypoxia and fever (87% on room air and 101°F). Laboratory tests revealed hyponatremia, hypokalemia, and elevated aspartate aminotransferase. A chest radiograph showed right basilar infiltrates. Influenza A/B was negative and a severe acute respiratory syndrome coronavirus-2 RNA test was positive. He was admitted and started on our hospital COVID-19 therapy regimen, including oral azithromycin 500 mg/d and hydroxychloroquine 400 mg/d for 5 days. During this time, he received prophylactic anticoagulation with heparin 5000 unit subcutaneously daily twice per day in the hospital.
A computed tomography scan with intravenous and oral contrast showed bilateral lower lobe, right middle lobe, and lingula ground glass opacification with distribution suggestive of COVID-19 pneumonitis. The abdomen and pelvis were unremarkable with no evidence of mesenteric vessel disease (Fig 1). After treatment initiation, the patient's oxygenation and nausea improved, and he was discharged home after 5 days of hospitalization with a 5-day course of levofloxacin 500 mg orally.Fig 1 Comparison of superior mesenteric artery (SMA) in computed tomography (CT) imaging with intravenous contrast between two admissions. A, initial CT scan, normal SMA. B, CT scan 7 days after discharge showing the SMA thrombus.
The patient returned to the ED 7 days after discharge complaining of acute onset of severe abdominal pain. On physical examination, he was tachycardic but did not have hypoxia or fever. The abdomen was tender with guarding. Laboratory results are summarized in the Table . Lactic acid was 6.2 and d-dimer was 2400. A computed tomography scan of chest, abdomen, and pelvis with intravenous contrast showed interval development of a 1.6 cm long low-density thrombus in the proximal SMA causing a high-grade luminal stenosis (Fig 1). His electrocardiogram showed sinus rhythm with no evidence of myocardial ischemia. A transthoracic echocardiogram was performed and was within normal limits. He was immediately heparinized in the ED and was taken to the operating room emergently for exploratory laparotomy and SMA thrombectomy.
Institutional COVID-19 precautions and guidelines were implemented during intubation and operation with appropriate personal protective equipment and gear. A midline incision was made from the xiphoid to the pubic symphysis. The abdomen was entered and explored. Upon exploration, a short segment of distal ileum seemed to be necrotic and not viable. The rest of small bowel seemed to be viable. The SMA did not have a palpable pulse. The SMA was dissected at the root of mesentery. After proximal and distal control was obtained, a small transverse arteriotomy was made and thrombectomy was performed with multiple passes of a #3 Fogarty catheter. The proximal thrombus was removed, and pulsatile flow was established. The specimen was sent to pathology. Distal thrombectomy was performed with a #2 Fogarty catheter and good back bleeding verified. The arteriotomy was then closed with interrupted 7-0 Prolene sutures. After release of the clamps, there were palpable pulses on the SMA proximal and distal to the arteriotomy. Doppler signals were present on both the mesenteric and the antimesenteric border of duodenum, jejunum, and proximal ileum.
The distal ileum seemed to be necrotic and not viable (Fig 2); therefore, a small bowel resection was performed with primary end-to-end anastomosis. The abdomen was then closed. The patient tolerated the procedure well and was extubated at the end of the procedure. Postoperatively, the patient was continued on a heparin drip and then transitioned to therapeutic enoxaparin on postoperative day 3. The pathology report showed evidence of acute arterial thrombus. His respiratory status remained stable during the hospital course. Oral intake was initiated slowly after bowel function was restored on postoperative day 3. He continued to improve and was discharged home on anticoagulation with therapeutic enoxaparin for 3 months. After the patient was discharged, he was evaluated for hypercoagulability. The preliminary results have been negative to the time of this writing. The patient 3-month follow-up visit showed no major complications.Fig 2 A and B, Distal ilium necrosis requiring bowel resection.
Discussion
The NCP pandemic continues to spread worldwide with significant morbidity and mortality in patients with comorbodities.6,7 There have been several reports indicating increased coagulation in these patients.1, 2, 3 Thrombotic events include autopsy-proven microvascular thrombosis in a variety of vascular beds (pulmonary, hepatic, and renal),8,9 likely contributing to end-organ function deterioration, as well as large vessel thrombosis such as extensive deep vein thromboses (DVT) or even arterial thromboses resulting in stroke, myocardial infarction, or lower extremity ischemia in otherwise low-risk patients. In a recently published study from China, it was reported that 25% of all patients with COVID-19 infection admitted in the ICU developed an acute DVT and that was associated with poor prognosis.2 It has also been reported that patients with active COVID-19 infection can manifest antiphospholipid antibodies, which may also contribute to hypercoagulopathy and thrombotic microangiopathy.1 Elevated d-dimer levels has been documented in hospitalized patients with COVID-19 and there are early reports that have linked higher d-dimer levels to worse outcomes.4,10,11
Tang et al5 reported 449 patients with severe COVID-19; 99 were treated with low-molecular-weight heparin. They reported that anticoagulant therapy seems to be associated with better outcomes in severe COVID-19 with markedly elevated d-dimer. Whether the increase in d-dimer level reflects a more severe prothrombotic state or is the result of a more intense inflammatory response (likely both) is not clear at this point. Although this prothrombotic state in COVID-19 patients is documented and widely accepted, a consensus on if and when patients should receive anticoagulation, what type, and for how long has not been reached. It is not surprising, therefore, that across geographical areas and institutions a wide spectrum of approaches to this issue are reported, ranging from prophylactic DVT regimens for all hospital admitted COVID-19 patients to therapeutic anticoagulation for all. Moreover, we were not able to find any reports related to posthospitalization thrombotic events. After this patient, we identified at least four previously hospitalized COVID-19 patients who returned to the ED within 7 days of discharge with symptomatic acute lower extremity DVT. Although the patient we report was treated with prophylactic anticoagulation during his initial hospital stay, he developed acute SMA thrombus 1 week after discharge. This result suggests that the prothrombotic state in some patients with COVID-19 may continue well past the acute symptomatic phase.
In our institution, we have an anticoagulation protocol for the patient with COVID-19 infection based on d-dimer levels. Patients with high d-dimer levels or proven thrombotic complications are placed on therapeutic anticoagulation with heparin unless otherwise contraindicated. Therapeutic anticoagulation continues until the patient is discharged and is extended in the posthospitalization period. Patients, however, who are only placed on prophylactic doses of low-molecular-weight heparin during their hospitalization are discharged with no thromboprophylaxis. It is conceivable that some of these patients may benefit from an outpatient course of thromboprophylaxis, but there are no data to support that supposition.
Future research is needed to better understand the role of coagulopathy and anticoagulation treatment in the management of patient with COVID-19 infection.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. | ATENOLOL, AZITHROMYCIN, HEPARIN SODIUM, HYDROXYCHLOROQUINE, METHIMAZOLE | DrugsGivenReaction | CC BY-NC-ND | 33623835 | 20,507,357 | 2021-09 |
What was the administration route of drug 'AZITHROMYCIN'? | Acute superior mesenteric artery thrombosis seven days after discharge for novel coronavirus pneumonia.
Since the emergence of novel coronavirus pneumonia (NCP), a number of reports have pointed out an increased coagulation activity in these patients mostly during acute phase of the disease. We are reporting a case of acute superior mesenteric thrombosis in a 55-year-old man with NCP 1 week after hospital discharge. He returned to the emergency department 7 days later with severe acute abdominal pain and found to have superior mesenteric artery thrombosis. He subsequently underwent emergent exploratory laparotomy, superior mesenteric artery thrombectomy, and bowel resection. Acute arterial thrombosis may occur in the posthospitalization period in patients with NCP.
pmcSince the emergence of novel coronavirus pneumonia (NCP) in December 2019, a number of reports have suggested that a large percentage of patients with novel coronavirus disease (COVID-19), particularly those who become critically ill, develop a prothrombotic state that places them at a significantly increased risk of thrombosis, especially during the acute phase that often requires intensive care unit stay with severe acute respiratory distress syndrome.1, 2, 3 Interestingly, a wide range of increases in d-dimer levels has also been documented in patients hospitalized with COVID-19 and there are early reports linking higher d-dimer levels to worse outcomes.4 Based on these reports, most centers used thrombosis prevention strategies ranging from prophylactic regimens to full anticoagulation during hospitalization for NCP with improved outcomes.5 The optimal potency and duration of antithrombotic management is not clear. In addition, there is little evidence on when the increased coagulation activity returns to normal levels after the onset of symptoms. We report a case of acute mesenteric ischemia due to superior mesenteric artery (SMA) thrombosis in a 55-year-old male patient with NCP 1 week after hospital discharge. Patient consent to publish the case report was obtained according to our institutional guidelines.
Case report
A 55-year-old African American man presented to the emergency department (ED) with complaints of a nonproductive cough, fatigue, myalgia, nausea, diarrhea, and abdominal pain for 4 days. His past medical history was significant for hypertension and Grave's disease. Medication history included atenolol 100 mg/d and methimazole 10 mg/d. The patient did not have a history of smoking or illicit drug abuse. He is a construction worker in the New York City area. On physical examination he had mild hypoxia and fever (87% on room air and 101°F). Laboratory tests revealed hyponatremia, hypokalemia, and elevated aspartate aminotransferase. A chest radiograph showed right basilar infiltrates. Influenza A/B was negative and a severe acute respiratory syndrome coronavirus-2 RNA test was positive. He was admitted and started on our hospital COVID-19 therapy regimen, including oral azithromycin 500 mg/d and hydroxychloroquine 400 mg/d for 5 days. During this time, he received prophylactic anticoagulation with heparin 5000 unit subcutaneously daily twice per day in the hospital.
A computed tomography scan with intravenous and oral contrast showed bilateral lower lobe, right middle lobe, and lingula ground glass opacification with distribution suggestive of COVID-19 pneumonitis. The abdomen and pelvis were unremarkable with no evidence of mesenteric vessel disease (Fig 1). After treatment initiation, the patient's oxygenation and nausea improved, and he was discharged home after 5 days of hospitalization with a 5-day course of levofloxacin 500 mg orally.Fig 1 Comparison of superior mesenteric artery (SMA) in computed tomography (CT) imaging with intravenous contrast between two admissions. A, initial CT scan, normal SMA. B, CT scan 7 days after discharge showing the SMA thrombus.
The patient returned to the ED 7 days after discharge complaining of acute onset of severe abdominal pain. On physical examination, he was tachycardic but did not have hypoxia or fever. The abdomen was tender with guarding. Laboratory results are summarized in the Table . Lactic acid was 6.2 and d-dimer was 2400. A computed tomography scan of chest, abdomen, and pelvis with intravenous contrast showed interval development of a 1.6 cm long low-density thrombus in the proximal SMA causing a high-grade luminal stenosis (Fig 1). His electrocardiogram showed sinus rhythm with no evidence of myocardial ischemia. A transthoracic echocardiogram was performed and was within normal limits. He was immediately heparinized in the ED and was taken to the operating room emergently for exploratory laparotomy and SMA thrombectomy.
Institutional COVID-19 precautions and guidelines were implemented during intubation and operation with appropriate personal protective equipment and gear. A midline incision was made from the xiphoid to the pubic symphysis. The abdomen was entered and explored. Upon exploration, a short segment of distal ileum seemed to be necrotic and not viable. The rest of small bowel seemed to be viable. The SMA did not have a palpable pulse. The SMA was dissected at the root of mesentery. After proximal and distal control was obtained, a small transverse arteriotomy was made and thrombectomy was performed with multiple passes of a #3 Fogarty catheter. The proximal thrombus was removed, and pulsatile flow was established. The specimen was sent to pathology. Distal thrombectomy was performed with a #2 Fogarty catheter and good back bleeding verified. The arteriotomy was then closed with interrupted 7-0 Prolene sutures. After release of the clamps, there were palpable pulses on the SMA proximal and distal to the arteriotomy. Doppler signals were present on both the mesenteric and the antimesenteric border of duodenum, jejunum, and proximal ileum.
The distal ileum seemed to be necrotic and not viable (Fig 2); therefore, a small bowel resection was performed with primary end-to-end anastomosis. The abdomen was then closed. The patient tolerated the procedure well and was extubated at the end of the procedure. Postoperatively, the patient was continued on a heparin drip and then transitioned to therapeutic enoxaparin on postoperative day 3. The pathology report showed evidence of acute arterial thrombus. His respiratory status remained stable during the hospital course. Oral intake was initiated slowly after bowel function was restored on postoperative day 3. He continued to improve and was discharged home on anticoagulation with therapeutic enoxaparin for 3 months. After the patient was discharged, he was evaluated for hypercoagulability. The preliminary results have been negative to the time of this writing. The patient 3-month follow-up visit showed no major complications.Fig 2 A and B, Distal ilium necrosis requiring bowel resection.
Discussion
The NCP pandemic continues to spread worldwide with significant morbidity and mortality in patients with comorbodities.6,7 There have been several reports indicating increased coagulation in these patients.1, 2, 3 Thrombotic events include autopsy-proven microvascular thrombosis in a variety of vascular beds (pulmonary, hepatic, and renal),8,9 likely contributing to end-organ function deterioration, as well as large vessel thrombosis such as extensive deep vein thromboses (DVT) or even arterial thromboses resulting in stroke, myocardial infarction, or lower extremity ischemia in otherwise low-risk patients. In a recently published study from China, it was reported that 25% of all patients with COVID-19 infection admitted in the ICU developed an acute DVT and that was associated with poor prognosis.2 It has also been reported that patients with active COVID-19 infection can manifest antiphospholipid antibodies, which may also contribute to hypercoagulopathy and thrombotic microangiopathy.1 Elevated d-dimer levels has been documented in hospitalized patients with COVID-19 and there are early reports that have linked higher d-dimer levels to worse outcomes.4,10,11
Tang et al5 reported 449 patients with severe COVID-19; 99 were treated with low-molecular-weight heparin. They reported that anticoagulant therapy seems to be associated with better outcomes in severe COVID-19 with markedly elevated d-dimer. Whether the increase in d-dimer level reflects a more severe prothrombotic state or is the result of a more intense inflammatory response (likely both) is not clear at this point. Although this prothrombotic state in COVID-19 patients is documented and widely accepted, a consensus on if and when patients should receive anticoagulation, what type, and for how long has not been reached. It is not surprising, therefore, that across geographical areas and institutions a wide spectrum of approaches to this issue are reported, ranging from prophylactic DVT regimens for all hospital admitted COVID-19 patients to therapeutic anticoagulation for all. Moreover, we were not able to find any reports related to posthospitalization thrombotic events. After this patient, we identified at least four previously hospitalized COVID-19 patients who returned to the ED within 7 days of discharge with symptomatic acute lower extremity DVT. Although the patient we report was treated with prophylactic anticoagulation during his initial hospital stay, he developed acute SMA thrombus 1 week after discharge. This result suggests that the prothrombotic state in some patients with COVID-19 may continue well past the acute symptomatic phase.
In our institution, we have an anticoagulation protocol for the patient with COVID-19 infection based on d-dimer levels. Patients with high d-dimer levels or proven thrombotic complications are placed on therapeutic anticoagulation with heparin unless otherwise contraindicated. Therapeutic anticoagulation continues until the patient is discharged and is extended in the posthospitalization period. Patients, however, who are only placed on prophylactic doses of low-molecular-weight heparin during their hospitalization are discharged with no thromboprophylaxis. It is conceivable that some of these patients may benefit from an outpatient course of thromboprophylaxis, but there are no data to support that supposition.
Future research is needed to better understand the role of coagulopathy and anticoagulation treatment in the management of patient with COVID-19 infection.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33623835 | 20,507,357 | 2021-09 |
What was the administration route of drug 'HEPARIN SODIUM'? | Acute superior mesenteric artery thrombosis seven days after discharge for novel coronavirus pneumonia.
Since the emergence of novel coronavirus pneumonia (NCP), a number of reports have pointed out an increased coagulation activity in these patients mostly during acute phase of the disease. We are reporting a case of acute superior mesenteric thrombosis in a 55-year-old man with NCP 1 week after hospital discharge. He returned to the emergency department 7 days later with severe acute abdominal pain and found to have superior mesenteric artery thrombosis. He subsequently underwent emergent exploratory laparotomy, superior mesenteric artery thrombectomy, and bowel resection. Acute arterial thrombosis may occur in the posthospitalization period in patients with NCP.
pmcSince the emergence of novel coronavirus pneumonia (NCP) in December 2019, a number of reports have suggested that a large percentage of patients with novel coronavirus disease (COVID-19), particularly those who become critically ill, develop a prothrombotic state that places them at a significantly increased risk of thrombosis, especially during the acute phase that often requires intensive care unit stay with severe acute respiratory distress syndrome.1, 2, 3 Interestingly, a wide range of increases in d-dimer levels has also been documented in patients hospitalized with COVID-19 and there are early reports linking higher d-dimer levels to worse outcomes.4 Based on these reports, most centers used thrombosis prevention strategies ranging from prophylactic regimens to full anticoagulation during hospitalization for NCP with improved outcomes.5 The optimal potency and duration of antithrombotic management is not clear. In addition, there is little evidence on when the increased coagulation activity returns to normal levels after the onset of symptoms. We report a case of acute mesenteric ischemia due to superior mesenteric artery (SMA) thrombosis in a 55-year-old male patient with NCP 1 week after hospital discharge. Patient consent to publish the case report was obtained according to our institutional guidelines.
Case report
A 55-year-old African American man presented to the emergency department (ED) with complaints of a nonproductive cough, fatigue, myalgia, nausea, diarrhea, and abdominal pain for 4 days. His past medical history was significant for hypertension and Grave's disease. Medication history included atenolol 100 mg/d and methimazole 10 mg/d. The patient did not have a history of smoking or illicit drug abuse. He is a construction worker in the New York City area. On physical examination he had mild hypoxia and fever (87% on room air and 101°F). Laboratory tests revealed hyponatremia, hypokalemia, and elevated aspartate aminotransferase. A chest radiograph showed right basilar infiltrates. Influenza A/B was negative and a severe acute respiratory syndrome coronavirus-2 RNA test was positive. He was admitted and started on our hospital COVID-19 therapy regimen, including oral azithromycin 500 mg/d and hydroxychloroquine 400 mg/d for 5 days. During this time, he received prophylactic anticoagulation with heparin 5000 unit subcutaneously daily twice per day in the hospital.
A computed tomography scan with intravenous and oral contrast showed bilateral lower lobe, right middle lobe, and lingula ground glass opacification with distribution suggestive of COVID-19 pneumonitis. The abdomen and pelvis were unremarkable with no evidence of mesenteric vessel disease (Fig 1). After treatment initiation, the patient's oxygenation and nausea improved, and he was discharged home after 5 days of hospitalization with a 5-day course of levofloxacin 500 mg orally.Fig 1 Comparison of superior mesenteric artery (SMA) in computed tomography (CT) imaging with intravenous contrast between two admissions. A, initial CT scan, normal SMA. B, CT scan 7 days after discharge showing the SMA thrombus.
The patient returned to the ED 7 days after discharge complaining of acute onset of severe abdominal pain. On physical examination, he was tachycardic but did not have hypoxia or fever. The abdomen was tender with guarding. Laboratory results are summarized in the Table . Lactic acid was 6.2 and d-dimer was 2400. A computed tomography scan of chest, abdomen, and pelvis with intravenous contrast showed interval development of a 1.6 cm long low-density thrombus in the proximal SMA causing a high-grade luminal stenosis (Fig 1). His electrocardiogram showed sinus rhythm with no evidence of myocardial ischemia. A transthoracic echocardiogram was performed and was within normal limits. He was immediately heparinized in the ED and was taken to the operating room emergently for exploratory laparotomy and SMA thrombectomy.
Institutional COVID-19 precautions and guidelines were implemented during intubation and operation with appropriate personal protective equipment and gear. A midline incision was made from the xiphoid to the pubic symphysis. The abdomen was entered and explored. Upon exploration, a short segment of distal ileum seemed to be necrotic and not viable. The rest of small bowel seemed to be viable. The SMA did not have a palpable pulse. The SMA was dissected at the root of mesentery. After proximal and distal control was obtained, a small transverse arteriotomy was made and thrombectomy was performed with multiple passes of a #3 Fogarty catheter. The proximal thrombus was removed, and pulsatile flow was established. The specimen was sent to pathology. Distal thrombectomy was performed with a #2 Fogarty catheter and good back bleeding verified. The arteriotomy was then closed with interrupted 7-0 Prolene sutures. After release of the clamps, there were palpable pulses on the SMA proximal and distal to the arteriotomy. Doppler signals were present on both the mesenteric and the antimesenteric border of duodenum, jejunum, and proximal ileum.
The distal ileum seemed to be necrotic and not viable (Fig 2); therefore, a small bowel resection was performed with primary end-to-end anastomosis. The abdomen was then closed. The patient tolerated the procedure well and was extubated at the end of the procedure. Postoperatively, the patient was continued on a heparin drip and then transitioned to therapeutic enoxaparin on postoperative day 3. The pathology report showed evidence of acute arterial thrombus. His respiratory status remained stable during the hospital course. Oral intake was initiated slowly after bowel function was restored on postoperative day 3. He continued to improve and was discharged home on anticoagulation with therapeutic enoxaparin for 3 months. After the patient was discharged, he was evaluated for hypercoagulability. The preliminary results have been negative to the time of this writing. The patient 3-month follow-up visit showed no major complications.Fig 2 A and B, Distal ilium necrosis requiring bowel resection.
Discussion
The NCP pandemic continues to spread worldwide with significant morbidity and mortality in patients with comorbodities.6,7 There have been several reports indicating increased coagulation in these patients.1, 2, 3 Thrombotic events include autopsy-proven microvascular thrombosis in a variety of vascular beds (pulmonary, hepatic, and renal),8,9 likely contributing to end-organ function deterioration, as well as large vessel thrombosis such as extensive deep vein thromboses (DVT) or even arterial thromboses resulting in stroke, myocardial infarction, or lower extremity ischemia in otherwise low-risk patients. In a recently published study from China, it was reported that 25% of all patients with COVID-19 infection admitted in the ICU developed an acute DVT and that was associated with poor prognosis.2 It has also been reported that patients with active COVID-19 infection can manifest antiphospholipid antibodies, which may also contribute to hypercoagulopathy and thrombotic microangiopathy.1 Elevated d-dimer levels has been documented in hospitalized patients with COVID-19 and there are early reports that have linked higher d-dimer levels to worse outcomes.4,10,11
Tang et al5 reported 449 patients with severe COVID-19; 99 were treated with low-molecular-weight heparin. They reported that anticoagulant therapy seems to be associated with better outcomes in severe COVID-19 with markedly elevated d-dimer. Whether the increase in d-dimer level reflects a more severe prothrombotic state or is the result of a more intense inflammatory response (likely both) is not clear at this point. Although this prothrombotic state in COVID-19 patients is documented and widely accepted, a consensus on if and when patients should receive anticoagulation, what type, and for how long has not been reached. It is not surprising, therefore, that across geographical areas and institutions a wide spectrum of approaches to this issue are reported, ranging from prophylactic DVT regimens for all hospital admitted COVID-19 patients to therapeutic anticoagulation for all. Moreover, we were not able to find any reports related to posthospitalization thrombotic events. After this patient, we identified at least four previously hospitalized COVID-19 patients who returned to the ED within 7 days of discharge with symptomatic acute lower extremity DVT. Although the patient we report was treated with prophylactic anticoagulation during his initial hospital stay, he developed acute SMA thrombus 1 week after discharge. This result suggests that the prothrombotic state in some patients with COVID-19 may continue well past the acute symptomatic phase.
In our institution, we have an anticoagulation protocol for the patient with COVID-19 infection based on d-dimer levels. Patients with high d-dimer levels or proven thrombotic complications are placed on therapeutic anticoagulation with heparin unless otherwise contraindicated. Therapeutic anticoagulation continues until the patient is discharged and is extended in the posthospitalization period. Patients, however, who are only placed on prophylactic doses of low-molecular-weight heparin during their hospitalization are discharged with no thromboprophylaxis. It is conceivable that some of these patients may benefit from an outpatient course of thromboprophylaxis, but there are no data to support that supposition.
Future research is needed to better understand the role of coagulopathy and anticoagulation treatment in the management of patient with COVID-19 infection.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. | Subcutaneous | DrugAdministrationRoute | CC BY-NC-ND | 33623835 | 20,507,357 | 2021-09 |
What was the dosage of drug 'ATENOLOL'? | Acute superior mesenteric artery thrombosis seven days after discharge for novel coronavirus pneumonia.
Since the emergence of novel coronavirus pneumonia (NCP), a number of reports have pointed out an increased coagulation activity in these patients mostly during acute phase of the disease. We are reporting a case of acute superior mesenteric thrombosis in a 55-year-old man with NCP 1 week after hospital discharge. He returned to the emergency department 7 days later with severe acute abdominal pain and found to have superior mesenteric artery thrombosis. He subsequently underwent emergent exploratory laparotomy, superior mesenteric artery thrombectomy, and bowel resection. Acute arterial thrombosis may occur in the posthospitalization period in patients with NCP.
pmcSince the emergence of novel coronavirus pneumonia (NCP) in December 2019, a number of reports have suggested that a large percentage of patients with novel coronavirus disease (COVID-19), particularly those who become critically ill, develop a prothrombotic state that places them at a significantly increased risk of thrombosis, especially during the acute phase that often requires intensive care unit stay with severe acute respiratory distress syndrome.1, 2, 3 Interestingly, a wide range of increases in d-dimer levels has also been documented in patients hospitalized with COVID-19 and there are early reports linking higher d-dimer levels to worse outcomes.4 Based on these reports, most centers used thrombosis prevention strategies ranging from prophylactic regimens to full anticoagulation during hospitalization for NCP with improved outcomes.5 The optimal potency and duration of antithrombotic management is not clear. In addition, there is little evidence on when the increased coagulation activity returns to normal levels after the onset of symptoms. We report a case of acute mesenteric ischemia due to superior mesenteric artery (SMA) thrombosis in a 55-year-old male patient with NCP 1 week after hospital discharge. Patient consent to publish the case report was obtained according to our institutional guidelines.
Case report
A 55-year-old African American man presented to the emergency department (ED) with complaints of a nonproductive cough, fatigue, myalgia, nausea, diarrhea, and abdominal pain for 4 days. His past medical history was significant for hypertension and Grave's disease. Medication history included atenolol 100 mg/d and methimazole 10 mg/d. The patient did not have a history of smoking or illicit drug abuse. He is a construction worker in the New York City area. On physical examination he had mild hypoxia and fever (87% on room air and 101°F). Laboratory tests revealed hyponatremia, hypokalemia, and elevated aspartate aminotransferase. A chest radiograph showed right basilar infiltrates. Influenza A/B was negative and a severe acute respiratory syndrome coronavirus-2 RNA test was positive. He was admitted and started on our hospital COVID-19 therapy regimen, including oral azithromycin 500 mg/d and hydroxychloroquine 400 mg/d for 5 days. During this time, he received prophylactic anticoagulation with heparin 5000 unit subcutaneously daily twice per day in the hospital.
A computed tomography scan with intravenous and oral contrast showed bilateral lower lobe, right middle lobe, and lingula ground glass opacification with distribution suggestive of COVID-19 pneumonitis. The abdomen and pelvis were unremarkable with no evidence of mesenteric vessel disease (Fig 1). After treatment initiation, the patient's oxygenation and nausea improved, and he was discharged home after 5 days of hospitalization with a 5-day course of levofloxacin 500 mg orally.Fig 1 Comparison of superior mesenteric artery (SMA) in computed tomography (CT) imaging with intravenous contrast between two admissions. A, initial CT scan, normal SMA. B, CT scan 7 days after discharge showing the SMA thrombus.
The patient returned to the ED 7 days after discharge complaining of acute onset of severe abdominal pain. On physical examination, he was tachycardic but did not have hypoxia or fever. The abdomen was tender with guarding. Laboratory results are summarized in the Table . Lactic acid was 6.2 and d-dimer was 2400. A computed tomography scan of chest, abdomen, and pelvis with intravenous contrast showed interval development of a 1.6 cm long low-density thrombus in the proximal SMA causing a high-grade luminal stenosis (Fig 1). His electrocardiogram showed sinus rhythm with no evidence of myocardial ischemia. A transthoracic echocardiogram was performed and was within normal limits. He was immediately heparinized in the ED and was taken to the operating room emergently for exploratory laparotomy and SMA thrombectomy.
Institutional COVID-19 precautions and guidelines were implemented during intubation and operation with appropriate personal protective equipment and gear. A midline incision was made from the xiphoid to the pubic symphysis. The abdomen was entered and explored. Upon exploration, a short segment of distal ileum seemed to be necrotic and not viable. The rest of small bowel seemed to be viable. The SMA did not have a palpable pulse. The SMA was dissected at the root of mesentery. After proximal and distal control was obtained, a small transverse arteriotomy was made and thrombectomy was performed with multiple passes of a #3 Fogarty catheter. The proximal thrombus was removed, and pulsatile flow was established. The specimen was sent to pathology. Distal thrombectomy was performed with a #2 Fogarty catheter and good back bleeding verified. The arteriotomy was then closed with interrupted 7-0 Prolene sutures. After release of the clamps, there were palpable pulses on the SMA proximal and distal to the arteriotomy. Doppler signals were present on both the mesenteric and the antimesenteric border of duodenum, jejunum, and proximal ileum.
The distal ileum seemed to be necrotic and not viable (Fig 2); therefore, a small bowel resection was performed with primary end-to-end anastomosis. The abdomen was then closed. The patient tolerated the procedure well and was extubated at the end of the procedure. Postoperatively, the patient was continued on a heparin drip and then transitioned to therapeutic enoxaparin on postoperative day 3. The pathology report showed evidence of acute arterial thrombus. His respiratory status remained stable during the hospital course. Oral intake was initiated slowly after bowel function was restored on postoperative day 3. He continued to improve and was discharged home on anticoagulation with therapeutic enoxaparin for 3 months. After the patient was discharged, he was evaluated for hypercoagulability. The preliminary results have been negative to the time of this writing. The patient 3-month follow-up visit showed no major complications.Fig 2 A and B, Distal ilium necrosis requiring bowel resection.
Discussion
The NCP pandemic continues to spread worldwide with significant morbidity and mortality in patients with comorbodities.6,7 There have been several reports indicating increased coagulation in these patients.1, 2, 3 Thrombotic events include autopsy-proven microvascular thrombosis in a variety of vascular beds (pulmonary, hepatic, and renal),8,9 likely contributing to end-organ function deterioration, as well as large vessel thrombosis such as extensive deep vein thromboses (DVT) or even arterial thromboses resulting in stroke, myocardial infarction, or lower extremity ischemia in otherwise low-risk patients. In a recently published study from China, it was reported that 25% of all patients with COVID-19 infection admitted in the ICU developed an acute DVT and that was associated with poor prognosis.2 It has also been reported that patients with active COVID-19 infection can manifest antiphospholipid antibodies, which may also contribute to hypercoagulopathy and thrombotic microangiopathy.1 Elevated d-dimer levels has been documented in hospitalized patients with COVID-19 and there are early reports that have linked higher d-dimer levels to worse outcomes.4,10,11
Tang et al5 reported 449 patients with severe COVID-19; 99 were treated with low-molecular-weight heparin. They reported that anticoagulant therapy seems to be associated with better outcomes in severe COVID-19 with markedly elevated d-dimer. Whether the increase in d-dimer level reflects a more severe prothrombotic state or is the result of a more intense inflammatory response (likely both) is not clear at this point. Although this prothrombotic state in COVID-19 patients is documented and widely accepted, a consensus on if and when patients should receive anticoagulation, what type, and for how long has not been reached. It is not surprising, therefore, that across geographical areas and institutions a wide spectrum of approaches to this issue are reported, ranging from prophylactic DVT regimens for all hospital admitted COVID-19 patients to therapeutic anticoagulation for all. Moreover, we were not able to find any reports related to posthospitalization thrombotic events. After this patient, we identified at least four previously hospitalized COVID-19 patients who returned to the ED within 7 days of discharge with symptomatic acute lower extremity DVT. Although the patient we report was treated with prophylactic anticoagulation during his initial hospital stay, he developed acute SMA thrombus 1 week after discharge. This result suggests that the prothrombotic state in some patients with COVID-19 may continue well past the acute symptomatic phase.
In our institution, we have an anticoagulation protocol for the patient with COVID-19 infection based on d-dimer levels. Patients with high d-dimer levels or proven thrombotic complications are placed on therapeutic anticoagulation with heparin unless otherwise contraindicated. Therapeutic anticoagulation continues until the patient is discharged and is extended in the posthospitalization period. Patients, however, who are only placed on prophylactic doses of low-molecular-weight heparin during their hospitalization are discharged with no thromboprophylaxis. It is conceivable that some of these patients may benefit from an outpatient course of thromboprophylaxis, but there are no data to support that supposition.
Future research is needed to better understand the role of coagulopathy and anticoagulation treatment in the management of patient with COVID-19 infection.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. | 100 MG, QD | DrugDosageText | CC BY-NC-ND | 33623835 | 20,507,357 | 2021-09 |
What was the dosage of drug 'AZITHROMYCIN'? | Acute superior mesenteric artery thrombosis seven days after discharge for novel coronavirus pneumonia.
Since the emergence of novel coronavirus pneumonia (NCP), a number of reports have pointed out an increased coagulation activity in these patients mostly during acute phase of the disease. We are reporting a case of acute superior mesenteric thrombosis in a 55-year-old man with NCP 1 week after hospital discharge. He returned to the emergency department 7 days later with severe acute abdominal pain and found to have superior mesenteric artery thrombosis. He subsequently underwent emergent exploratory laparotomy, superior mesenteric artery thrombectomy, and bowel resection. Acute arterial thrombosis may occur in the posthospitalization period in patients with NCP.
pmcSince the emergence of novel coronavirus pneumonia (NCP) in December 2019, a number of reports have suggested that a large percentage of patients with novel coronavirus disease (COVID-19), particularly those who become critically ill, develop a prothrombotic state that places them at a significantly increased risk of thrombosis, especially during the acute phase that often requires intensive care unit stay with severe acute respiratory distress syndrome.1, 2, 3 Interestingly, a wide range of increases in d-dimer levels has also been documented in patients hospitalized with COVID-19 and there are early reports linking higher d-dimer levels to worse outcomes.4 Based on these reports, most centers used thrombosis prevention strategies ranging from prophylactic regimens to full anticoagulation during hospitalization for NCP with improved outcomes.5 The optimal potency and duration of antithrombotic management is not clear. In addition, there is little evidence on when the increased coagulation activity returns to normal levels after the onset of symptoms. We report a case of acute mesenteric ischemia due to superior mesenteric artery (SMA) thrombosis in a 55-year-old male patient with NCP 1 week after hospital discharge. Patient consent to publish the case report was obtained according to our institutional guidelines.
Case report
A 55-year-old African American man presented to the emergency department (ED) with complaints of a nonproductive cough, fatigue, myalgia, nausea, diarrhea, and abdominal pain for 4 days. His past medical history was significant for hypertension and Grave's disease. Medication history included atenolol 100 mg/d and methimazole 10 mg/d. The patient did not have a history of smoking or illicit drug abuse. He is a construction worker in the New York City area. On physical examination he had mild hypoxia and fever (87% on room air and 101°F). Laboratory tests revealed hyponatremia, hypokalemia, and elevated aspartate aminotransferase. A chest radiograph showed right basilar infiltrates. Influenza A/B was negative and a severe acute respiratory syndrome coronavirus-2 RNA test was positive. He was admitted and started on our hospital COVID-19 therapy regimen, including oral azithromycin 500 mg/d and hydroxychloroquine 400 mg/d for 5 days. During this time, he received prophylactic anticoagulation with heparin 5000 unit subcutaneously daily twice per day in the hospital.
A computed tomography scan with intravenous and oral contrast showed bilateral lower lobe, right middle lobe, and lingula ground glass opacification with distribution suggestive of COVID-19 pneumonitis. The abdomen and pelvis were unremarkable with no evidence of mesenteric vessel disease (Fig 1). After treatment initiation, the patient's oxygenation and nausea improved, and he was discharged home after 5 days of hospitalization with a 5-day course of levofloxacin 500 mg orally.Fig 1 Comparison of superior mesenteric artery (SMA) in computed tomography (CT) imaging with intravenous contrast between two admissions. A, initial CT scan, normal SMA. B, CT scan 7 days after discharge showing the SMA thrombus.
The patient returned to the ED 7 days after discharge complaining of acute onset of severe abdominal pain. On physical examination, he was tachycardic but did not have hypoxia or fever. The abdomen was tender with guarding. Laboratory results are summarized in the Table . Lactic acid was 6.2 and d-dimer was 2400. A computed tomography scan of chest, abdomen, and pelvis with intravenous contrast showed interval development of a 1.6 cm long low-density thrombus in the proximal SMA causing a high-grade luminal stenosis (Fig 1). His electrocardiogram showed sinus rhythm with no evidence of myocardial ischemia. A transthoracic echocardiogram was performed and was within normal limits. He was immediately heparinized in the ED and was taken to the operating room emergently for exploratory laparotomy and SMA thrombectomy.
Institutional COVID-19 precautions and guidelines were implemented during intubation and operation with appropriate personal protective equipment and gear. A midline incision was made from the xiphoid to the pubic symphysis. The abdomen was entered and explored. Upon exploration, a short segment of distal ileum seemed to be necrotic and not viable. The rest of small bowel seemed to be viable. The SMA did not have a palpable pulse. The SMA was dissected at the root of mesentery. After proximal and distal control was obtained, a small transverse arteriotomy was made and thrombectomy was performed with multiple passes of a #3 Fogarty catheter. The proximal thrombus was removed, and pulsatile flow was established. The specimen was sent to pathology. Distal thrombectomy was performed with a #2 Fogarty catheter and good back bleeding verified. The arteriotomy was then closed with interrupted 7-0 Prolene sutures. After release of the clamps, there were palpable pulses on the SMA proximal and distal to the arteriotomy. Doppler signals were present on both the mesenteric and the antimesenteric border of duodenum, jejunum, and proximal ileum.
The distal ileum seemed to be necrotic and not viable (Fig 2); therefore, a small bowel resection was performed with primary end-to-end anastomosis. The abdomen was then closed. The patient tolerated the procedure well and was extubated at the end of the procedure. Postoperatively, the patient was continued on a heparin drip and then transitioned to therapeutic enoxaparin on postoperative day 3. The pathology report showed evidence of acute arterial thrombus. His respiratory status remained stable during the hospital course. Oral intake was initiated slowly after bowel function was restored on postoperative day 3. He continued to improve and was discharged home on anticoagulation with therapeutic enoxaparin for 3 months. After the patient was discharged, he was evaluated for hypercoagulability. The preliminary results have been negative to the time of this writing. The patient 3-month follow-up visit showed no major complications.Fig 2 A and B, Distal ilium necrosis requiring bowel resection.
Discussion
The NCP pandemic continues to spread worldwide with significant morbidity and mortality in patients with comorbodities.6,7 There have been several reports indicating increased coagulation in these patients.1, 2, 3 Thrombotic events include autopsy-proven microvascular thrombosis in a variety of vascular beds (pulmonary, hepatic, and renal),8,9 likely contributing to end-organ function deterioration, as well as large vessel thrombosis such as extensive deep vein thromboses (DVT) or even arterial thromboses resulting in stroke, myocardial infarction, or lower extremity ischemia in otherwise low-risk patients. In a recently published study from China, it was reported that 25% of all patients with COVID-19 infection admitted in the ICU developed an acute DVT and that was associated with poor prognosis.2 It has also been reported that patients with active COVID-19 infection can manifest antiphospholipid antibodies, which may also contribute to hypercoagulopathy and thrombotic microangiopathy.1 Elevated d-dimer levels has been documented in hospitalized patients with COVID-19 and there are early reports that have linked higher d-dimer levels to worse outcomes.4,10,11
Tang et al5 reported 449 patients with severe COVID-19; 99 were treated with low-molecular-weight heparin. They reported that anticoagulant therapy seems to be associated with better outcomes in severe COVID-19 with markedly elevated d-dimer. Whether the increase in d-dimer level reflects a more severe prothrombotic state or is the result of a more intense inflammatory response (likely both) is not clear at this point. Although this prothrombotic state in COVID-19 patients is documented and widely accepted, a consensus on if and when patients should receive anticoagulation, what type, and for how long has not been reached. It is not surprising, therefore, that across geographical areas and institutions a wide spectrum of approaches to this issue are reported, ranging from prophylactic DVT regimens for all hospital admitted COVID-19 patients to therapeutic anticoagulation for all. Moreover, we were not able to find any reports related to posthospitalization thrombotic events. After this patient, we identified at least four previously hospitalized COVID-19 patients who returned to the ED within 7 days of discharge with symptomatic acute lower extremity DVT. Although the patient we report was treated with prophylactic anticoagulation during his initial hospital stay, he developed acute SMA thrombus 1 week after discharge. This result suggests that the prothrombotic state in some patients with COVID-19 may continue well past the acute symptomatic phase.
In our institution, we have an anticoagulation protocol for the patient with COVID-19 infection based on d-dimer levels. Patients with high d-dimer levels or proven thrombotic complications are placed on therapeutic anticoagulation with heparin unless otherwise contraindicated. Therapeutic anticoagulation continues until the patient is discharged and is extended in the posthospitalization period. Patients, however, who are only placed on prophylactic doses of low-molecular-weight heparin during their hospitalization are discharged with no thromboprophylaxis. It is conceivable that some of these patients may benefit from an outpatient course of thromboprophylaxis, but there are no data to support that supposition.
Future research is needed to better understand the role of coagulopathy and anticoagulation treatment in the management of patient with COVID-19 infection.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. | 500 MG, QD | DrugDosageText | CC BY-NC-ND | 33623835 | 20,507,357 | 2021-09 |
What was the dosage of drug 'HEPARIN SODIUM'? | Acute superior mesenteric artery thrombosis seven days after discharge for novel coronavirus pneumonia.
Since the emergence of novel coronavirus pneumonia (NCP), a number of reports have pointed out an increased coagulation activity in these patients mostly during acute phase of the disease. We are reporting a case of acute superior mesenteric thrombosis in a 55-year-old man with NCP 1 week after hospital discharge. He returned to the emergency department 7 days later with severe acute abdominal pain and found to have superior mesenteric artery thrombosis. He subsequently underwent emergent exploratory laparotomy, superior mesenteric artery thrombectomy, and bowel resection. Acute arterial thrombosis may occur in the posthospitalization period in patients with NCP.
pmcSince the emergence of novel coronavirus pneumonia (NCP) in December 2019, a number of reports have suggested that a large percentage of patients with novel coronavirus disease (COVID-19), particularly those who become critically ill, develop a prothrombotic state that places them at a significantly increased risk of thrombosis, especially during the acute phase that often requires intensive care unit stay with severe acute respiratory distress syndrome.1, 2, 3 Interestingly, a wide range of increases in d-dimer levels has also been documented in patients hospitalized with COVID-19 and there are early reports linking higher d-dimer levels to worse outcomes.4 Based on these reports, most centers used thrombosis prevention strategies ranging from prophylactic regimens to full anticoagulation during hospitalization for NCP with improved outcomes.5 The optimal potency and duration of antithrombotic management is not clear. In addition, there is little evidence on when the increased coagulation activity returns to normal levels after the onset of symptoms. We report a case of acute mesenteric ischemia due to superior mesenteric artery (SMA) thrombosis in a 55-year-old male patient with NCP 1 week after hospital discharge. Patient consent to publish the case report was obtained according to our institutional guidelines.
Case report
A 55-year-old African American man presented to the emergency department (ED) with complaints of a nonproductive cough, fatigue, myalgia, nausea, diarrhea, and abdominal pain for 4 days. His past medical history was significant for hypertension and Grave's disease. Medication history included atenolol 100 mg/d and methimazole 10 mg/d. The patient did not have a history of smoking or illicit drug abuse. He is a construction worker in the New York City area. On physical examination he had mild hypoxia and fever (87% on room air and 101°F). Laboratory tests revealed hyponatremia, hypokalemia, and elevated aspartate aminotransferase. A chest radiograph showed right basilar infiltrates. Influenza A/B was negative and a severe acute respiratory syndrome coronavirus-2 RNA test was positive. He was admitted and started on our hospital COVID-19 therapy regimen, including oral azithromycin 500 mg/d and hydroxychloroquine 400 mg/d for 5 days. During this time, he received prophylactic anticoagulation with heparin 5000 unit subcutaneously daily twice per day in the hospital.
A computed tomography scan with intravenous and oral contrast showed bilateral lower lobe, right middle lobe, and lingula ground glass opacification with distribution suggestive of COVID-19 pneumonitis. The abdomen and pelvis were unremarkable with no evidence of mesenteric vessel disease (Fig 1). After treatment initiation, the patient's oxygenation and nausea improved, and he was discharged home after 5 days of hospitalization with a 5-day course of levofloxacin 500 mg orally.Fig 1 Comparison of superior mesenteric artery (SMA) in computed tomography (CT) imaging with intravenous contrast between two admissions. A, initial CT scan, normal SMA. B, CT scan 7 days after discharge showing the SMA thrombus.
The patient returned to the ED 7 days after discharge complaining of acute onset of severe abdominal pain. On physical examination, he was tachycardic but did not have hypoxia or fever. The abdomen was tender with guarding. Laboratory results are summarized in the Table . Lactic acid was 6.2 and d-dimer was 2400. A computed tomography scan of chest, abdomen, and pelvis with intravenous contrast showed interval development of a 1.6 cm long low-density thrombus in the proximal SMA causing a high-grade luminal stenosis (Fig 1). His electrocardiogram showed sinus rhythm with no evidence of myocardial ischemia. A transthoracic echocardiogram was performed and was within normal limits. He was immediately heparinized in the ED and was taken to the operating room emergently for exploratory laparotomy and SMA thrombectomy.
Institutional COVID-19 precautions and guidelines were implemented during intubation and operation with appropriate personal protective equipment and gear. A midline incision was made from the xiphoid to the pubic symphysis. The abdomen was entered and explored. Upon exploration, a short segment of distal ileum seemed to be necrotic and not viable. The rest of small bowel seemed to be viable. The SMA did not have a palpable pulse. The SMA was dissected at the root of mesentery. After proximal and distal control was obtained, a small transverse arteriotomy was made and thrombectomy was performed with multiple passes of a #3 Fogarty catheter. The proximal thrombus was removed, and pulsatile flow was established. The specimen was sent to pathology. Distal thrombectomy was performed with a #2 Fogarty catheter and good back bleeding verified. The arteriotomy was then closed with interrupted 7-0 Prolene sutures. After release of the clamps, there were palpable pulses on the SMA proximal and distal to the arteriotomy. Doppler signals were present on both the mesenteric and the antimesenteric border of duodenum, jejunum, and proximal ileum.
The distal ileum seemed to be necrotic and not viable (Fig 2); therefore, a small bowel resection was performed with primary end-to-end anastomosis. The abdomen was then closed. The patient tolerated the procedure well and was extubated at the end of the procedure. Postoperatively, the patient was continued on a heparin drip and then transitioned to therapeutic enoxaparin on postoperative day 3. The pathology report showed evidence of acute arterial thrombus. His respiratory status remained stable during the hospital course. Oral intake was initiated slowly after bowel function was restored on postoperative day 3. He continued to improve and was discharged home on anticoagulation with therapeutic enoxaparin for 3 months. After the patient was discharged, he was evaluated for hypercoagulability. The preliminary results have been negative to the time of this writing. The patient 3-month follow-up visit showed no major complications.Fig 2 A and B, Distal ilium necrosis requiring bowel resection.
Discussion
The NCP pandemic continues to spread worldwide with significant morbidity and mortality in patients with comorbodities.6,7 There have been several reports indicating increased coagulation in these patients.1, 2, 3 Thrombotic events include autopsy-proven microvascular thrombosis in a variety of vascular beds (pulmonary, hepatic, and renal),8,9 likely contributing to end-organ function deterioration, as well as large vessel thrombosis such as extensive deep vein thromboses (DVT) or even arterial thromboses resulting in stroke, myocardial infarction, or lower extremity ischemia in otherwise low-risk patients. In a recently published study from China, it was reported that 25% of all patients with COVID-19 infection admitted in the ICU developed an acute DVT and that was associated with poor prognosis.2 It has also been reported that patients with active COVID-19 infection can manifest antiphospholipid antibodies, which may also contribute to hypercoagulopathy and thrombotic microangiopathy.1 Elevated d-dimer levels has been documented in hospitalized patients with COVID-19 and there are early reports that have linked higher d-dimer levels to worse outcomes.4,10,11
Tang et al5 reported 449 patients with severe COVID-19; 99 were treated with low-molecular-weight heparin. They reported that anticoagulant therapy seems to be associated with better outcomes in severe COVID-19 with markedly elevated d-dimer. Whether the increase in d-dimer level reflects a more severe prothrombotic state or is the result of a more intense inflammatory response (likely both) is not clear at this point. Although this prothrombotic state in COVID-19 patients is documented and widely accepted, a consensus on if and when patients should receive anticoagulation, what type, and for how long has not been reached. It is not surprising, therefore, that across geographical areas and institutions a wide spectrum of approaches to this issue are reported, ranging from prophylactic DVT regimens for all hospital admitted COVID-19 patients to therapeutic anticoagulation for all. Moreover, we were not able to find any reports related to posthospitalization thrombotic events. After this patient, we identified at least four previously hospitalized COVID-19 patients who returned to the ED within 7 days of discharge with symptomatic acute lower extremity DVT. Although the patient we report was treated with prophylactic anticoagulation during his initial hospital stay, he developed acute SMA thrombus 1 week after discharge. This result suggests that the prothrombotic state in some patients with COVID-19 may continue well past the acute symptomatic phase.
In our institution, we have an anticoagulation protocol for the patient with COVID-19 infection based on d-dimer levels. Patients with high d-dimer levels or proven thrombotic complications are placed on therapeutic anticoagulation with heparin unless otherwise contraindicated. Therapeutic anticoagulation continues until the patient is discharged and is extended in the posthospitalization period. Patients, however, who are only placed on prophylactic doses of low-molecular-weight heparin during their hospitalization are discharged with no thromboprophylaxis. It is conceivable that some of these patients may benefit from an outpatient course of thromboprophylaxis, but there are no data to support that supposition.
Future research is needed to better understand the role of coagulopathy and anticoagulation treatment in the management of patient with COVID-19 infection.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. | 5000 INTERNATIONAL UNIT, BID | DrugDosageText | CC BY-NC-ND | 33623835 | 20,507,357 | 2021-09 |
What was the dosage of drug 'HYDROXYCHLOROQUINE'? | Acute superior mesenteric artery thrombosis seven days after discharge for novel coronavirus pneumonia.
Since the emergence of novel coronavirus pneumonia (NCP), a number of reports have pointed out an increased coagulation activity in these patients mostly during acute phase of the disease. We are reporting a case of acute superior mesenteric thrombosis in a 55-year-old man with NCP 1 week after hospital discharge. He returned to the emergency department 7 days later with severe acute abdominal pain and found to have superior mesenteric artery thrombosis. He subsequently underwent emergent exploratory laparotomy, superior mesenteric artery thrombectomy, and bowel resection. Acute arterial thrombosis may occur in the posthospitalization period in patients with NCP.
pmcSince the emergence of novel coronavirus pneumonia (NCP) in December 2019, a number of reports have suggested that a large percentage of patients with novel coronavirus disease (COVID-19), particularly those who become critically ill, develop a prothrombotic state that places them at a significantly increased risk of thrombosis, especially during the acute phase that often requires intensive care unit stay with severe acute respiratory distress syndrome.1, 2, 3 Interestingly, a wide range of increases in d-dimer levels has also been documented in patients hospitalized with COVID-19 and there are early reports linking higher d-dimer levels to worse outcomes.4 Based on these reports, most centers used thrombosis prevention strategies ranging from prophylactic regimens to full anticoagulation during hospitalization for NCP with improved outcomes.5 The optimal potency and duration of antithrombotic management is not clear. In addition, there is little evidence on when the increased coagulation activity returns to normal levels after the onset of symptoms. We report a case of acute mesenteric ischemia due to superior mesenteric artery (SMA) thrombosis in a 55-year-old male patient with NCP 1 week after hospital discharge. Patient consent to publish the case report was obtained according to our institutional guidelines.
Case report
A 55-year-old African American man presented to the emergency department (ED) with complaints of a nonproductive cough, fatigue, myalgia, nausea, diarrhea, and abdominal pain for 4 days. His past medical history was significant for hypertension and Grave's disease. Medication history included atenolol 100 mg/d and methimazole 10 mg/d. The patient did not have a history of smoking or illicit drug abuse. He is a construction worker in the New York City area. On physical examination he had mild hypoxia and fever (87% on room air and 101°F). Laboratory tests revealed hyponatremia, hypokalemia, and elevated aspartate aminotransferase. A chest radiograph showed right basilar infiltrates. Influenza A/B was negative and a severe acute respiratory syndrome coronavirus-2 RNA test was positive. He was admitted and started on our hospital COVID-19 therapy regimen, including oral azithromycin 500 mg/d and hydroxychloroquine 400 mg/d for 5 days. During this time, he received prophylactic anticoagulation with heparin 5000 unit subcutaneously daily twice per day in the hospital.
A computed tomography scan with intravenous and oral contrast showed bilateral lower lobe, right middle lobe, and lingula ground glass opacification with distribution suggestive of COVID-19 pneumonitis. The abdomen and pelvis were unremarkable with no evidence of mesenteric vessel disease (Fig 1). After treatment initiation, the patient's oxygenation and nausea improved, and he was discharged home after 5 days of hospitalization with a 5-day course of levofloxacin 500 mg orally.Fig 1 Comparison of superior mesenteric artery (SMA) in computed tomography (CT) imaging with intravenous contrast between two admissions. A, initial CT scan, normal SMA. B, CT scan 7 days after discharge showing the SMA thrombus.
The patient returned to the ED 7 days after discharge complaining of acute onset of severe abdominal pain. On physical examination, he was tachycardic but did not have hypoxia or fever. The abdomen was tender with guarding. Laboratory results are summarized in the Table . Lactic acid was 6.2 and d-dimer was 2400. A computed tomography scan of chest, abdomen, and pelvis with intravenous contrast showed interval development of a 1.6 cm long low-density thrombus in the proximal SMA causing a high-grade luminal stenosis (Fig 1). His electrocardiogram showed sinus rhythm with no evidence of myocardial ischemia. A transthoracic echocardiogram was performed and was within normal limits. He was immediately heparinized in the ED and was taken to the operating room emergently for exploratory laparotomy and SMA thrombectomy.
Institutional COVID-19 precautions and guidelines were implemented during intubation and operation with appropriate personal protective equipment and gear. A midline incision was made from the xiphoid to the pubic symphysis. The abdomen was entered and explored. Upon exploration, a short segment of distal ileum seemed to be necrotic and not viable. The rest of small bowel seemed to be viable. The SMA did not have a palpable pulse. The SMA was dissected at the root of mesentery. After proximal and distal control was obtained, a small transverse arteriotomy was made and thrombectomy was performed with multiple passes of a #3 Fogarty catheter. The proximal thrombus was removed, and pulsatile flow was established. The specimen was sent to pathology. Distal thrombectomy was performed with a #2 Fogarty catheter and good back bleeding verified. The arteriotomy was then closed with interrupted 7-0 Prolene sutures. After release of the clamps, there were palpable pulses on the SMA proximal and distal to the arteriotomy. Doppler signals were present on both the mesenteric and the antimesenteric border of duodenum, jejunum, and proximal ileum.
The distal ileum seemed to be necrotic and not viable (Fig 2); therefore, a small bowel resection was performed with primary end-to-end anastomosis. The abdomen was then closed. The patient tolerated the procedure well and was extubated at the end of the procedure. Postoperatively, the patient was continued on a heparin drip and then transitioned to therapeutic enoxaparin on postoperative day 3. The pathology report showed evidence of acute arterial thrombus. His respiratory status remained stable during the hospital course. Oral intake was initiated slowly after bowel function was restored on postoperative day 3. He continued to improve and was discharged home on anticoagulation with therapeutic enoxaparin for 3 months. After the patient was discharged, he was evaluated for hypercoagulability. The preliminary results have been negative to the time of this writing. The patient 3-month follow-up visit showed no major complications.Fig 2 A and B, Distal ilium necrosis requiring bowel resection.
Discussion
The NCP pandemic continues to spread worldwide with significant morbidity and mortality in patients with comorbodities.6,7 There have been several reports indicating increased coagulation in these patients.1, 2, 3 Thrombotic events include autopsy-proven microvascular thrombosis in a variety of vascular beds (pulmonary, hepatic, and renal),8,9 likely contributing to end-organ function deterioration, as well as large vessel thrombosis such as extensive deep vein thromboses (DVT) or even arterial thromboses resulting in stroke, myocardial infarction, or lower extremity ischemia in otherwise low-risk patients. In a recently published study from China, it was reported that 25% of all patients with COVID-19 infection admitted in the ICU developed an acute DVT and that was associated with poor prognosis.2 It has also been reported that patients with active COVID-19 infection can manifest antiphospholipid antibodies, which may also contribute to hypercoagulopathy and thrombotic microangiopathy.1 Elevated d-dimer levels has been documented in hospitalized patients with COVID-19 and there are early reports that have linked higher d-dimer levels to worse outcomes.4,10,11
Tang et al5 reported 449 patients with severe COVID-19; 99 were treated with low-molecular-weight heparin. They reported that anticoagulant therapy seems to be associated with better outcomes in severe COVID-19 with markedly elevated d-dimer. Whether the increase in d-dimer level reflects a more severe prothrombotic state or is the result of a more intense inflammatory response (likely both) is not clear at this point. Although this prothrombotic state in COVID-19 patients is documented and widely accepted, a consensus on if and when patients should receive anticoagulation, what type, and for how long has not been reached. It is not surprising, therefore, that across geographical areas and institutions a wide spectrum of approaches to this issue are reported, ranging from prophylactic DVT regimens for all hospital admitted COVID-19 patients to therapeutic anticoagulation for all. Moreover, we were not able to find any reports related to posthospitalization thrombotic events. After this patient, we identified at least four previously hospitalized COVID-19 patients who returned to the ED within 7 days of discharge with symptomatic acute lower extremity DVT. Although the patient we report was treated with prophylactic anticoagulation during his initial hospital stay, he developed acute SMA thrombus 1 week after discharge. This result suggests that the prothrombotic state in some patients with COVID-19 may continue well past the acute symptomatic phase.
In our institution, we have an anticoagulation protocol for the patient with COVID-19 infection based on d-dimer levels. Patients with high d-dimer levels or proven thrombotic complications are placed on therapeutic anticoagulation with heparin unless otherwise contraindicated. Therapeutic anticoagulation continues until the patient is discharged and is extended in the posthospitalization period. Patients, however, who are only placed on prophylactic doses of low-molecular-weight heparin during their hospitalization are discharged with no thromboprophylaxis. It is conceivable that some of these patients may benefit from an outpatient course of thromboprophylaxis, but there are no data to support that supposition.
Future research is needed to better understand the role of coagulopathy and anticoagulation treatment in the management of patient with COVID-19 infection.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. | 400 MG, QD | DrugDosageText | CC BY-NC-ND | 33623835 | 20,507,357 | 2021-09 |
What was the dosage of drug 'METHIMAZOLE'? | Acute superior mesenteric artery thrombosis seven days after discharge for novel coronavirus pneumonia.
Since the emergence of novel coronavirus pneumonia (NCP), a number of reports have pointed out an increased coagulation activity in these patients mostly during acute phase of the disease. We are reporting a case of acute superior mesenteric thrombosis in a 55-year-old man with NCP 1 week after hospital discharge. He returned to the emergency department 7 days later with severe acute abdominal pain and found to have superior mesenteric artery thrombosis. He subsequently underwent emergent exploratory laparotomy, superior mesenteric artery thrombectomy, and bowel resection. Acute arterial thrombosis may occur in the posthospitalization period in patients with NCP.
pmcSince the emergence of novel coronavirus pneumonia (NCP) in December 2019, a number of reports have suggested that a large percentage of patients with novel coronavirus disease (COVID-19), particularly those who become critically ill, develop a prothrombotic state that places them at a significantly increased risk of thrombosis, especially during the acute phase that often requires intensive care unit stay with severe acute respiratory distress syndrome.1, 2, 3 Interestingly, a wide range of increases in d-dimer levels has also been documented in patients hospitalized with COVID-19 and there are early reports linking higher d-dimer levels to worse outcomes.4 Based on these reports, most centers used thrombosis prevention strategies ranging from prophylactic regimens to full anticoagulation during hospitalization for NCP with improved outcomes.5 The optimal potency and duration of antithrombotic management is not clear. In addition, there is little evidence on when the increased coagulation activity returns to normal levels after the onset of symptoms. We report a case of acute mesenteric ischemia due to superior mesenteric artery (SMA) thrombosis in a 55-year-old male patient with NCP 1 week after hospital discharge. Patient consent to publish the case report was obtained according to our institutional guidelines.
Case report
A 55-year-old African American man presented to the emergency department (ED) with complaints of a nonproductive cough, fatigue, myalgia, nausea, diarrhea, and abdominal pain for 4 days. His past medical history was significant for hypertension and Grave's disease. Medication history included atenolol 100 mg/d and methimazole 10 mg/d. The patient did not have a history of smoking or illicit drug abuse. He is a construction worker in the New York City area. On physical examination he had mild hypoxia and fever (87% on room air and 101°F). Laboratory tests revealed hyponatremia, hypokalemia, and elevated aspartate aminotransferase. A chest radiograph showed right basilar infiltrates. Influenza A/B was negative and a severe acute respiratory syndrome coronavirus-2 RNA test was positive. He was admitted and started on our hospital COVID-19 therapy regimen, including oral azithromycin 500 mg/d and hydroxychloroquine 400 mg/d for 5 days. During this time, he received prophylactic anticoagulation with heparin 5000 unit subcutaneously daily twice per day in the hospital.
A computed tomography scan with intravenous and oral contrast showed bilateral lower lobe, right middle lobe, and lingula ground glass opacification with distribution suggestive of COVID-19 pneumonitis. The abdomen and pelvis were unremarkable with no evidence of mesenteric vessel disease (Fig 1). After treatment initiation, the patient's oxygenation and nausea improved, and he was discharged home after 5 days of hospitalization with a 5-day course of levofloxacin 500 mg orally.Fig 1 Comparison of superior mesenteric artery (SMA) in computed tomography (CT) imaging with intravenous contrast between two admissions. A, initial CT scan, normal SMA. B, CT scan 7 days after discharge showing the SMA thrombus.
The patient returned to the ED 7 days after discharge complaining of acute onset of severe abdominal pain. On physical examination, he was tachycardic but did not have hypoxia or fever. The abdomen was tender with guarding. Laboratory results are summarized in the Table . Lactic acid was 6.2 and d-dimer was 2400. A computed tomography scan of chest, abdomen, and pelvis with intravenous contrast showed interval development of a 1.6 cm long low-density thrombus in the proximal SMA causing a high-grade luminal stenosis (Fig 1). His electrocardiogram showed sinus rhythm with no evidence of myocardial ischemia. A transthoracic echocardiogram was performed and was within normal limits. He was immediately heparinized in the ED and was taken to the operating room emergently for exploratory laparotomy and SMA thrombectomy.
Institutional COVID-19 precautions and guidelines were implemented during intubation and operation with appropriate personal protective equipment and gear. A midline incision was made from the xiphoid to the pubic symphysis. The abdomen was entered and explored. Upon exploration, a short segment of distal ileum seemed to be necrotic and not viable. The rest of small bowel seemed to be viable. The SMA did not have a palpable pulse. The SMA was dissected at the root of mesentery. After proximal and distal control was obtained, a small transverse arteriotomy was made and thrombectomy was performed with multiple passes of a #3 Fogarty catheter. The proximal thrombus was removed, and pulsatile flow was established. The specimen was sent to pathology. Distal thrombectomy was performed with a #2 Fogarty catheter and good back bleeding verified. The arteriotomy was then closed with interrupted 7-0 Prolene sutures. After release of the clamps, there were palpable pulses on the SMA proximal and distal to the arteriotomy. Doppler signals were present on both the mesenteric and the antimesenteric border of duodenum, jejunum, and proximal ileum.
The distal ileum seemed to be necrotic and not viable (Fig 2); therefore, a small bowel resection was performed with primary end-to-end anastomosis. The abdomen was then closed. The patient tolerated the procedure well and was extubated at the end of the procedure. Postoperatively, the patient was continued on a heparin drip and then transitioned to therapeutic enoxaparin on postoperative day 3. The pathology report showed evidence of acute arterial thrombus. His respiratory status remained stable during the hospital course. Oral intake was initiated slowly after bowel function was restored on postoperative day 3. He continued to improve and was discharged home on anticoagulation with therapeutic enoxaparin for 3 months. After the patient was discharged, he was evaluated for hypercoagulability. The preliminary results have been negative to the time of this writing. The patient 3-month follow-up visit showed no major complications.Fig 2 A and B, Distal ilium necrosis requiring bowel resection.
Discussion
The NCP pandemic continues to spread worldwide with significant morbidity and mortality in patients with comorbodities.6,7 There have been several reports indicating increased coagulation in these patients.1, 2, 3 Thrombotic events include autopsy-proven microvascular thrombosis in a variety of vascular beds (pulmonary, hepatic, and renal),8,9 likely contributing to end-organ function deterioration, as well as large vessel thrombosis such as extensive deep vein thromboses (DVT) or even arterial thromboses resulting in stroke, myocardial infarction, or lower extremity ischemia in otherwise low-risk patients. In a recently published study from China, it was reported that 25% of all patients with COVID-19 infection admitted in the ICU developed an acute DVT and that was associated with poor prognosis.2 It has also been reported that patients with active COVID-19 infection can manifest antiphospholipid antibodies, which may also contribute to hypercoagulopathy and thrombotic microangiopathy.1 Elevated d-dimer levels has been documented in hospitalized patients with COVID-19 and there are early reports that have linked higher d-dimer levels to worse outcomes.4,10,11
Tang et al5 reported 449 patients with severe COVID-19; 99 were treated with low-molecular-weight heparin. They reported that anticoagulant therapy seems to be associated with better outcomes in severe COVID-19 with markedly elevated d-dimer. Whether the increase in d-dimer level reflects a more severe prothrombotic state or is the result of a more intense inflammatory response (likely both) is not clear at this point. Although this prothrombotic state in COVID-19 patients is documented and widely accepted, a consensus on if and when patients should receive anticoagulation, what type, and for how long has not been reached. It is not surprising, therefore, that across geographical areas and institutions a wide spectrum of approaches to this issue are reported, ranging from prophylactic DVT regimens for all hospital admitted COVID-19 patients to therapeutic anticoagulation for all. Moreover, we were not able to find any reports related to posthospitalization thrombotic events. After this patient, we identified at least four previously hospitalized COVID-19 patients who returned to the ED within 7 days of discharge with symptomatic acute lower extremity DVT. Although the patient we report was treated with prophylactic anticoagulation during his initial hospital stay, he developed acute SMA thrombus 1 week after discharge. This result suggests that the prothrombotic state in some patients with COVID-19 may continue well past the acute symptomatic phase.
In our institution, we have an anticoagulation protocol for the patient with COVID-19 infection based on d-dimer levels. Patients with high d-dimer levels or proven thrombotic complications are placed on therapeutic anticoagulation with heparin unless otherwise contraindicated. Therapeutic anticoagulation continues until the patient is discharged and is extended in the posthospitalization period. Patients, however, who are only placed on prophylactic doses of low-molecular-weight heparin during their hospitalization are discharged with no thromboprophylaxis. It is conceivable that some of these patients may benefit from an outpatient course of thromboprophylaxis, but there are no data to support that supposition.
Future research is needed to better understand the role of coagulopathy and anticoagulation treatment in the management of patient with COVID-19 infection.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. | 10 MG, QD | DrugDosageText | CC BY-NC-ND | 33623835 | 20,507,357 | 2021-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Durvalumab-induced lesions of bronchiolitis and fully reversible bronchiectasis in a patient with non-small cell lung cancer: A case report.
Durvalumab is a humanized monoclonal antibody targeting programmed cell death ligand-1 (PD-L1), leading to an antitumor activity, used as consolidation therapy in patients with locally advanced unresectable non-small cell lung cancer (NSCLC). Several immune-related adverse events (irAEs) have previously been described in patients following treatment with immune checkpoint inhibitors (ICIs). To the best of our knowledge, we report the first case of immunotherapy-induced fully reversible bronchiolitis and bronchiectasis, despite the fact that its pathophysiological mechanism has been previously considered to be irreversible.
INTRODUCTION
Durvalumab is a humanized monoclonal antibody targeting PD‐L1, recently approved as consolidation therapy in locally advanced unresectable NSCLC patients, with nonprogressive disease after two or more cycles of concomitant chemoradiotherapy. 1
Several irAEs have been previously described. 2 Concerning respiratory disorders, the main toxicities reported are diffuse interstitial lung diseases, rated in grade according to their severity, as shown in Tables 1 and 2. 3 , 4
TABLE 1 Immune‐induced pulmonary toxicities by European Society for Medical Oncology (ESMO) grade 3
ESMO grade Symptoms
Grade 1 Radiographic changes only (ex. ground‐glass change, nonspecific interstitial pneumonia)
Grade 2 Mild/moderate new symptoms (ex. dyspnea, cough, chest pain)
Grade 3–4 Severe new symptoms (ex. new/worsening hypoxia, life threatening, difficulty in breathing, acute respiratory distress syndrome)
Grade 5 Death
TABLE 2 Immune‐induced pulmonary toxicities by common terminology criteria for adverse events (CTCAE) grade (v5.0), with suggested management by Delaunay et al. 4
CTCAE grade 5.0 Definition Suggested management
Grade 1 Asymptomatic Continuation of IT, monitoring
Grade 2 Symptomatic, limiting instrumental ADL and requiring medical intervention Stop IT, oral corticosteroids 0,5–1 mg/kg, monitoring, potential rechallenge
Grade 3 Severe symptoms, limiting self‐care ADL and indicated oxygen Stop IT, oral corticosteroids 2–4 mg/kg, no rechallenge, monitoring
Grade 4 Life‐threatening respiratory compromise and indicated urgent intervention Stop IT, intravenous corticosteroids 4 mg/kg, no rechallenge, monitoring
Abbreviations: ADL, activities of daily living; IT, immunotherapy.
Bronchial toxicities induced by anti‐programmed cell death protein‐1 (PD‐1)/PD‐L1 immunotherapy have rarely been reported and rather as an exacerbation of chronic obstructive pulmonary disease (COPD). 5 , 6 Here, we report a case of a patient who developed a pattern of bronchiectasis with bronchiolitis during anti‐PD‐L1 treatment with a favorable outcome after discontinuation of immune checkpoint inhibitors (ICIs).
CASE REPORT
A 77‐year‐old Caucasian man presented with a new episode of respiratory distress and hemoptysis. His relevant medical history was a smoking cessation at 80‐pack‐year, a post‐tobacco COPD and a laryngeal cancer treated with chemoradiotherapy (carboplatin) in 2012. A locally advanced (stage IIIA N2 unresectable) squamous cell carcinoma of the left lower lobe was discovered in May 2018. PD‐L1 immunostaining was <1% (evaluated by the tumor proportion score with DAKO 22C3 antibody). Between June and July 2018, concomitant chemoradiotherapy was implemented, combining seven weekly courses of carboplatin (AUC 2) ‐ paclitaxel (45 mg/m2) and thoracic conformational radiotherapy up to 66 Gy. At the end of this treatment, re‐evaluation with a chest computed tomography (CT) scan showed an objective tumour response. Consolidation therapy with durvalumab (early access program) was initiated from October 12, 2018 (10 mg/kg every 15 days).
In December 2018, after five injections of durvalumab, he presented with the first episode of bronchopneumonia affecting the left lower lobe, undocumented and treated with amoxicillin‐clavulanate for 10 days. Subsequently, chronic purulent bronchorrhea set in. In February 2019, he was hospitalized because of similar respiratory symptoms, treated with cefepime and metronidazole. Bronchoalveolar lavage (BAL) did not identify any organism. Consolidation treatment with durvalumab was maintained. Because of persistent bronchorrhea and the appearance of exertional dyspnea, new bacteriological tests (BAL and sputum culture test) were performed, but they did not isolate any pathogenic bacteria, despite the presence of purulent and very sticky secretions in endobronchial studies. Cytological examination revealed an 85% neutrophil granulocyte count, with 10% macrophages and 5% lymphocytes over 3 500 cells per mm3. Chest CT highlighted the appearance of bronchiolitis lesions (bronchial wall thickening and tree‐in‐bud pattern) and bronchiectasis from January 2019, particularly in the nonirradiated areas (right lower lobe, contralateral to the initial tumour). These images appeared less than two months after durvalumab initiation and were consistent with the appearance of chronic purulent bronchorrhea and exertional dyspnea. Oral corticosteroids were introduced associated with triple long‐acting bronchodilator (beclometasone, formoterol, glycopyrronium), as well as anti‐inflammatory bronchial treatment with azithromycin 250 mg, three times a week, and bronchial drainage respiratory physiotherapy. These therapeutic adaptations did not bring any improvement in respiratory symptomatology. In view of the disabling respiratory symptoms and lack of improvement despite optimal treatment implemented, durvalumab was discontinued after 10 courses of treatment on March 29, 2019.
Chest CT monitoring was performed every three months and during follow‐up, CT lesions seemed to be more extensive at the first re‐evaluation in June 2019, 10 weeks after durvalumab discontinuation, suggestive of prolonged toxicity from this treatment. Thereafter, chest CT monitoring showed spontaneous regression of various lesions observed, especially in September 2019 (Figure 1). Clinically, respiratory symptoms significantly improved three months after durvalumab discontinuation.
FIGURE 1 Evolution of bronchiectasis and bronchiolitis lesions before, during and after durvalumab therapy; (a) chest computed tomography (CT) images, and (b) with maximum intensity projection (MIP) 5.0 mm post‐treatment. Lesions appeared to be more extensive in June 2019, 10 weeks after durvalumab discontinuation, and had fully disappeared in September 2019, six months after durvalumab discontinuation
DISCUSSION
To our knowledge, this is the first case reported of ICPI‐induced panbronchiolitis associated with bronchiectasis. Main pulmonary toxicities hitherto described are organizing pneumonia, ground‐glass opacities, interstitial lesions, hypersensitivity pneumonitis, or nonspecific interstitial pneumonitis. 7 Some studies have reported that pulmonary toxicities can be fatal, as in the case of acute respiratory distress syndrome (ARDS), 8 or severe acute asthma. 5 Recently, during durvalumab therapy, Yamakasi et al. described the appearance of a diffuse micronodular pattern, with predominantly ground‐glass micronodules. 9
Lesions of bronchiolitis observed in this case may be similar to the hypersensitivity pneumonitis pattern described by Naidoo et al. 7 and to diffuse panbronchiolitis, which is a complex genetic disease strongly associated with specific human leukocyte antigen, and very rare in Western countries. 10 Diffuse panbronchiolitis is characterized by chronic inflammation in respiratory bronchioles, which can lead to bronchi and bronchiole dilatation, as seen in Figure 1.
Bronchiectasis is a chronic inflammatory lung disease whose pathophysiological mechanism is not clearly identified, but seems to be based on a vicious circle in which chronic bronchial infection is responsible for persistent inflammation, causing an impaired mucociliary clearance and a priori irreversible structural damages, which in turn favors infection (Figure 2). 11
FIGURE 2 Bronchiectasis pathophysiological mechanism as reported by Polverino et al. 11
They occur in immune deficiency cases, or systemic inflammatory disease. 12 Neutrophils appear to play a key role, but it has also been shown that T cells, particularly via T helper 17 (Th17) subtype and interleukin‐17 secretion, participate in neutrophil recruitment and in a proinflammatory airway environment maintenance. 13
However, blocking the PD‐1/PD‐L1 interaction could induce a reorientation of the lymphocyte response towards Th17 differentiation, as demonstrated in mouse models. 14 As in the case of other irAE, Th17 cells appear to play the main role, via their ability to activate different actors of the immune system, such as macrophages, dendritic cells, or CD8+ cytotoxic T cells. 15
Finally, it could be hypothesized that blocking the PD‐1/PD‐L1 cosignal with an ICI such as durvalumab could direct the T cell differentiation towards Th17 cell subtype, inducing proinflammatory cytokine secretion, neutrophils activation, and airways proinflammatory environment creation that could favor bronchitis, bronchiolitis and then bronchiectasis development. This mechanism may also explain the COPD exacerbation reported cases, or immunotherapy‐induced asthma. 6 Treatment discontinuation would allow a return to a physiological immune response and disappearance of lesions. However, a complete regression of bronchiectasis is rare during adulthood, especially with high‐resolution CT, because of a suspected irreversible pathophysiology mechanism. Only a few case reports have previously been published without clear explanation concerning the mechanisms, alerting us to the possibility of pseudobronchiectasis due to pneumonia, 16 , 17 but there was no evidence on chest CT scan of pneumonia lesions in our patient at any time.
CONFLICT OF INTEREST
The authors declare that there are no conflicts of interest. | AZITHROMYCIN ANHYDROUS, BECLOMETHASONE DIPROPIONATE, DURVALUMAB, FORMOTEROL, GLYCOPYRRONIUM | DrugsGivenReaction | CC BY-NC-ND | 33624409 | 19,950,244 | 2021-04 |
What was the dosage of drug 'AZITHROMYCIN ANHYDROUS'? | Durvalumab-induced lesions of bronchiolitis and fully reversible bronchiectasis in a patient with non-small cell lung cancer: A case report.
Durvalumab is a humanized monoclonal antibody targeting programmed cell death ligand-1 (PD-L1), leading to an antitumor activity, used as consolidation therapy in patients with locally advanced unresectable non-small cell lung cancer (NSCLC). Several immune-related adverse events (irAEs) have previously been described in patients following treatment with immune checkpoint inhibitors (ICIs). To the best of our knowledge, we report the first case of immunotherapy-induced fully reversible bronchiolitis and bronchiectasis, despite the fact that its pathophysiological mechanism has been previously considered to be irreversible.
INTRODUCTION
Durvalumab is a humanized monoclonal antibody targeting PD‐L1, recently approved as consolidation therapy in locally advanced unresectable NSCLC patients, with nonprogressive disease after two or more cycles of concomitant chemoradiotherapy. 1
Several irAEs have been previously described. 2 Concerning respiratory disorders, the main toxicities reported are diffuse interstitial lung diseases, rated in grade according to their severity, as shown in Tables 1 and 2. 3 , 4
TABLE 1 Immune‐induced pulmonary toxicities by European Society for Medical Oncology (ESMO) grade 3
ESMO grade Symptoms
Grade 1 Radiographic changes only (ex. ground‐glass change, nonspecific interstitial pneumonia)
Grade 2 Mild/moderate new symptoms (ex. dyspnea, cough, chest pain)
Grade 3–4 Severe new symptoms (ex. new/worsening hypoxia, life threatening, difficulty in breathing, acute respiratory distress syndrome)
Grade 5 Death
TABLE 2 Immune‐induced pulmonary toxicities by common terminology criteria for adverse events (CTCAE) grade (v5.0), with suggested management by Delaunay et al. 4
CTCAE grade 5.0 Definition Suggested management
Grade 1 Asymptomatic Continuation of IT, monitoring
Grade 2 Symptomatic, limiting instrumental ADL and requiring medical intervention Stop IT, oral corticosteroids 0,5–1 mg/kg, monitoring, potential rechallenge
Grade 3 Severe symptoms, limiting self‐care ADL and indicated oxygen Stop IT, oral corticosteroids 2–4 mg/kg, no rechallenge, monitoring
Grade 4 Life‐threatening respiratory compromise and indicated urgent intervention Stop IT, intravenous corticosteroids 4 mg/kg, no rechallenge, monitoring
Abbreviations: ADL, activities of daily living; IT, immunotherapy.
Bronchial toxicities induced by anti‐programmed cell death protein‐1 (PD‐1)/PD‐L1 immunotherapy have rarely been reported and rather as an exacerbation of chronic obstructive pulmonary disease (COPD). 5 , 6 Here, we report a case of a patient who developed a pattern of bronchiectasis with bronchiolitis during anti‐PD‐L1 treatment with a favorable outcome after discontinuation of immune checkpoint inhibitors (ICIs).
CASE REPORT
A 77‐year‐old Caucasian man presented with a new episode of respiratory distress and hemoptysis. His relevant medical history was a smoking cessation at 80‐pack‐year, a post‐tobacco COPD and a laryngeal cancer treated with chemoradiotherapy (carboplatin) in 2012. A locally advanced (stage IIIA N2 unresectable) squamous cell carcinoma of the left lower lobe was discovered in May 2018. PD‐L1 immunostaining was <1% (evaluated by the tumor proportion score with DAKO 22C3 antibody). Between June and July 2018, concomitant chemoradiotherapy was implemented, combining seven weekly courses of carboplatin (AUC 2) ‐ paclitaxel (45 mg/m2) and thoracic conformational radiotherapy up to 66 Gy. At the end of this treatment, re‐evaluation with a chest computed tomography (CT) scan showed an objective tumour response. Consolidation therapy with durvalumab (early access program) was initiated from October 12, 2018 (10 mg/kg every 15 days).
In December 2018, after five injections of durvalumab, he presented with the first episode of bronchopneumonia affecting the left lower lobe, undocumented and treated with amoxicillin‐clavulanate for 10 days. Subsequently, chronic purulent bronchorrhea set in. In February 2019, he was hospitalized because of similar respiratory symptoms, treated with cefepime and metronidazole. Bronchoalveolar lavage (BAL) did not identify any organism. Consolidation treatment with durvalumab was maintained. Because of persistent bronchorrhea and the appearance of exertional dyspnea, new bacteriological tests (BAL and sputum culture test) were performed, but they did not isolate any pathogenic bacteria, despite the presence of purulent and very sticky secretions in endobronchial studies. Cytological examination revealed an 85% neutrophil granulocyte count, with 10% macrophages and 5% lymphocytes over 3 500 cells per mm3. Chest CT highlighted the appearance of bronchiolitis lesions (bronchial wall thickening and tree‐in‐bud pattern) and bronchiectasis from January 2019, particularly in the nonirradiated areas (right lower lobe, contralateral to the initial tumour). These images appeared less than two months after durvalumab initiation and were consistent with the appearance of chronic purulent bronchorrhea and exertional dyspnea. Oral corticosteroids were introduced associated with triple long‐acting bronchodilator (beclometasone, formoterol, glycopyrronium), as well as anti‐inflammatory bronchial treatment with azithromycin 250 mg, three times a week, and bronchial drainage respiratory physiotherapy. These therapeutic adaptations did not bring any improvement in respiratory symptomatology. In view of the disabling respiratory symptoms and lack of improvement despite optimal treatment implemented, durvalumab was discontinued after 10 courses of treatment on March 29, 2019.
Chest CT monitoring was performed every three months and during follow‐up, CT lesions seemed to be more extensive at the first re‐evaluation in June 2019, 10 weeks after durvalumab discontinuation, suggestive of prolonged toxicity from this treatment. Thereafter, chest CT monitoring showed spontaneous regression of various lesions observed, especially in September 2019 (Figure 1). Clinically, respiratory symptoms significantly improved three months after durvalumab discontinuation.
FIGURE 1 Evolution of bronchiectasis and bronchiolitis lesions before, during and after durvalumab therapy; (a) chest computed tomography (CT) images, and (b) with maximum intensity projection (MIP) 5.0 mm post‐treatment. Lesions appeared to be more extensive in June 2019, 10 weeks after durvalumab discontinuation, and had fully disappeared in September 2019, six months after durvalumab discontinuation
DISCUSSION
To our knowledge, this is the first case reported of ICPI‐induced panbronchiolitis associated with bronchiectasis. Main pulmonary toxicities hitherto described are organizing pneumonia, ground‐glass opacities, interstitial lesions, hypersensitivity pneumonitis, or nonspecific interstitial pneumonitis. 7 Some studies have reported that pulmonary toxicities can be fatal, as in the case of acute respiratory distress syndrome (ARDS), 8 or severe acute asthma. 5 Recently, during durvalumab therapy, Yamakasi et al. described the appearance of a diffuse micronodular pattern, with predominantly ground‐glass micronodules. 9
Lesions of bronchiolitis observed in this case may be similar to the hypersensitivity pneumonitis pattern described by Naidoo et al. 7 and to diffuse panbronchiolitis, which is a complex genetic disease strongly associated with specific human leukocyte antigen, and very rare in Western countries. 10 Diffuse panbronchiolitis is characterized by chronic inflammation in respiratory bronchioles, which can lead to bronchi and bronchiole dilatation, as seen in Figure 1.
Bronchiectasis is a chronic inflammatory lung disease whose pathophysiological mechanism is not clearly identified, but seems to be based on a vicious circle in which chronic bronchial infection is responsible for persistent inflammation, causing an impaired mucociliary clearance and a priori irreversible structural damages, which in turn favors infection (Figure 2). 11
FIGURE 2 Bronchiectasis pathophysiological mechanism as reported by Polverino et al. 11
They occur in immune deficiency cases, or systemic inflammatory disease. 12 Neutrophils appear to play a key role, but it has also been shown that T cells, particularly via T helper 17 (Th17) subtype and interleukin‐17 secretion, participate in neutrophil recruitment and in a proinflammatory airway environment maintenance. 13
However, blocking the PD‐1/PD‐L1 interaction could induce a reorientation of the lymphocyte response towards Th17 differentiation, as demonstrated in mouse models. 14 As in the case of other irAE, Th17 cells appear to play the main role, via their ability to activate different actors of the immune system, such as macrophages, dendritic cells, or CD8+ cytotoxic T cells. 15
Finally, it could be hypothesized that blocking the PD‐1/PD‐L1 cosignal with an ICI such as durvalumab could direct the T cell differentiation towards Th17 cell subtype, inducing proinflammatory cytokine secretion, neutrophils activation, and airways proinflammatory environment creation that could favor bronchitis, bronchiolitis and then bronchiectasis development. This mechanism may also explain the COPD exacerbation reported cases, or immunotherapy‐induced asthma. 6 Treatment discontinuation would allow a return to a physiological immune response and disappearance of lesions. However, a complete regression of bronchiectasis is rare during adulthood, especially with high‐resolution CT, because of a suspected irreversible pathophysiology mechanism. Only a few case reports have previously been published without clear explanation concerning the mechanisms, alerting us to the possibility of pseudobronchiectasis due to pneumonia, 16 , 17 but there was no evidence on chest CT scan of pneumonia lesions in our patient at any time.
CONFLICT OF INTEREST
The authors declare that there are no conflicts of interest. | 250 MG, THREE TIMES A WEEK | DrugDosageText | CC BY-NC-ND | 33624409 | 19,950,244 | 2021-04 |
What was the dosage of drug 'DURVALUMAB'? | Durvalumab-induced lesions of bronchiolitis and fully reversible bronchiectasis in a patient with non-small cell lung cancer: A case report.
Durvalumab is a humanized monoclonal antibody targeting programmed cell death ligand-1 (PD-L1), leading to an antitumor activity, used as consolidation therapy in patients with locally advanced unresectable non-small cell lung cancer (NSCLC). Several immune-related adverse events (irAEs) have previously been described in patients following treatment with immune checkpoint inhibitors (ICIs). To the best of our knowledge, we report the first case of immunotherapy-induced fully reversible bronchiolitis and bronchiectasis, despite the fact that its pathophysiological mechanism has been previously considered to be irreversible.
INTRODUCTION
Durvalumab is a humanized monoclonal antibody targeting PD‐L1, recently approved as consolidation therapy in locally advanced unresectable NSCLC patients, with nonprogressive disease after two or more cycles of concomitant chemoradiotherapy. 1
Several irAEs have been previously described. 2 Concerning respiratory disorders, the main toxicities reported are diffuse interstitial lung diseases, rated in grade according to their severity, as shown in Tables 1 and 2. 3 , 4
TABLE 1 Immune‐induced pulmonary toxicities by European Society for Medical Oncology (ESMO) grade 3
ESMO grade Symptoms
Grade 1 Radiographic changes only (ex. ground‐glass change, nonspecific interstitial pneumonia)
Grade 2 Mild/moderate new symptoms (ex. dyspnea, cough, chest pain)
Grade 3–4 Severe new symptoms (ex. new/worsening hypoxia, life threatening, difficulty in breathing, acute respiratory distress syndrome)
Grade 5 Death
TABLE 2 Immune‐induced pulmonary toxicities by common terminology criteria for adverse events (CTCAE) grade (v5.0), with suggested management by Delaunay et al. 4
CTCAE grade 5.0 Definition Suggested management
Grade 1 Asymptomatic Continuation of IT, monitoring
Grade 2 Symptomatic, limiting instrumental ADL and requiring medical intervention Stop IT, oral corticosteroids 0,5–1 mg/kg, monitoring, potential rechallenge
Grade 3 Severe symptoms, limiting self‐care ADL and indicated oxygen Stop IT, oral corticosteroids 2–4 mg/kg, no rechallenge, monitoring
Grade 4 Life‐threatening respiratory compromise and indicated urgent intervention Stop IT, intravenous corticosteroids 4 mg/kg, no rechallenge, monitoring
Abbreviations: ADL, activities of daily living; IT, immunotherapy.
Bronchial toxicities induced by anti‐programmed cell death protein‐1 (PD‐1)/PD‐L1 immunotherapy have rarely been reported and rather as an exacerbation of chronic obstructive pulmonary disease (COPD). 5 , 6 Here, we report a case of a patient who developed a pattern of bronchiectasis with bronchiolitis during anti‐PD‐L1 treatment with a favorable outcome after discontinuation of immune checkpoint inhibitors (ICIs).
CASE REPORT
A 77‐year‐old Caucasian man presented with a new episode of respiratory distress and hemoptysis. His relevant medical history was a smoking cessation at 80‐pack‐year, a post‐tobacco COPD and a laryngeal cancer treated with chemoradiotherapy (carboplatin) in 2012. A locally advanced (stage IIIA N2 unresectable) squamous cell carcinoma of the left lower lobe was discovered in May 2018. PD‐L1 immunostaining was <1% (evaluated by the tumor proportion score with DAKO 22C3 antibody). Between June and July 2018, concomitant chemoradiotherapy was implemented, combining seven weekly courses of carboplatin (AUC 2) ‐ paclitaxel (45 mg/m2) and thoracic conformational radiotherapy up to 66 Gy. At the end of this treatment, re‐evaluation with a chest computed tomography (CT) scan showed an objective tumour response. Consolidation therapy with durvalumab (early access program) was initiated from October 12, 2018 (10 mg/kg every 15 days).
In December 2018, after five injections of durvalumab, he presented with the first episode of bronchopneumonia affecting the left lower lobe, undocumented and treated with amoxicillin‐clavulanate for 10 days. Subsequently, chronic purulent bronchorrhea set in. In February 2019, he was hospitalized because of similar respiratory symptoms, treated with cefepime and metronidazole. Bronchoalveolar lavage (BAL) did not identify any organism. Consolidation treatment with durvalumab was maintained. Because of persistent bronchorrhea and the appearance of exertional dyspnea, new bacteriological tests (BAL and sputum culture test) were performed, but they did not isolate any pathogenic bacteria, despite the presence of purulent and very sticky secretions in endobronchial studies. Cytological examination revealed an 85% neutrophil granulocyte count, with 10% macrophages and 5% lymphocytes over 3 500 cells per mm3. Chest CT highlighted the appearance of bronchiolitis lesions (bronchial wall thickening and tree‐in‐bud pattern) and bronchiectasis from January 2019, particularly in the nonirradiated areas (right lower lobe, contralateral to the initial tumour). These images appeared less than two months after durvalumab initiation and were consistent with the appearance of chronic purulent bronchorrhea and exertional dyspnea. Oral corticosteroids were introduced associated with triple long‐acting bronchodilator (beclometasone, formoterol, glycopyrronium), as well as anti‐inflammatory bronchial treatment with azithromycin 250 mg, three times a week, and bronchial drainage respiratory physiotherapy. These therapeutic adaptations did not bring any improvement in respiratory symptomatology. In view of the disabling respiratory symptoms and lack of improvement despite optimal treatment implemented, durvalumab was discontinued after 10 courses of treatment on March 29, 2019.
Chest CT monitoring was performed every three months and during follow‐up, CT lesions seemed to be more extensive at the first re‐evaluation in June 2019, 10 weeks after durvalumab discontinuation, suggestive of prolonged toxicity from this treatment. Thereafter, chest CT monitoring showed spontaneous regression of various lesions observed, especially in September 2019 (Figure 1). Clinically, respiratory symptoms significantly improved three months after durvalumab discontinuation.
FIGURE 1 Evolution of bronchiectasis and bronchiolitis lesions before, during and after durvalumab therapy; (a) chest computed tomography (CT) images, and (b) with maximum intensity projection (MIP) 5.0 mm post‐treatment. Lesions appeared to be more extensive in June 2019, 10 weeks after durvalumab discontinuation, and had fully disappeared in September 2019, six months after durvalumab discontinuation
DISCUSSION
To our knowledge, this is the first case reported of ICPI‐induced panbronchiolitis associated with bronchiectasis. Main pulmonary toxicities hitherto described are organizing pneumonia, ground‐glass opacities, interstitial lesions, hypersensitivity pneumonitis, or nonspecific interstitial pneumonitis. 7 Some studies have reported that pulmonary toxicities can be fatal, as in the case of acute respiratory distress syndrome (ARDS), 8 or severe acute asthma. 5 Recently, during durvalumab therapy, Yamakasi et al. described the appearance of a diffuse micronodular pattern, with predominantly ground‐glass micronodules. 9
Lesions of bronchiolitis observed in this case may be similar to the hypersensitivity pneumonitis pattern described by Naidoo et al. 7 and to diffuse panbronchiolitis, which is a complex genetic disease strongly associated with specific human leukocyte antigen, and very rare in Western countries. 10 Diffuse panbronchiolitis is characterized by chronic inflammation in respiratory bronchioles, which can lead to bronchi and bronchiole dilatation, as seen in Figure 1.
Bronchiectasis is a chronic inflammatory lung disease whose pathophysiological mechanism is not clearly identified, but seems to be based on a vicious circle in which chronic bronchial infection is responsible for persistent inflammation, causing an impaired mucociliary clearance and a priori irreversible structural damages, which in turn favors infection (Figure 2). 11
FIGURE 2 Bronchiectasis pathophysiological mechanism as reported by Polverino et al. 11
They occur in immune deficiency cases, or systemic inflammatory disease. 12 Neutrophils appear to play a key role, but it has also been shown that T cells, particularly via T helper 17 (Th17) subtype and interleukin‐17 secretion, participate in neutrophil recruitment and in a proinflammatory airway environment maintenance. 13
However, blocking the PD‐1/PD‐L1 interaction could induce a reorientation of the lymphocyte response towards Th17 differentiation, as demonstrated in mouse models. 14 As in the case of other irAE, Th17 cells appear to play the main role, via their ability to activate different actors of the immune system, such as macrophages, dendritic cells, or CD8+ cytotoxic T cells. 15
Finally, it could be hypothesized that blocking the PD‐1/PD‐L1 cosignal with an ICI such as durvalumab could direct the T cell differentiation towards Th17 cell subtype, inducing proinflammatory cytokine secretion, neutrophils activation, and airways proinflammatory environment creation that could favor bronchitis, bronchiolitis and then bronchiectasis development. This mechanism may also explain the COPD exacerbation reported cases, or immunotherapy‐induced asthma. 6 Treatment discontinuation would allow a return to a physiological immune response and disappearance of lesions. However, a complete regression of bronchiectasis is rare during adulthood, especially with high‐resolution CT, because of a suspected irreversible pathophysiology mechanism. Only a few case reports have previously been published without clear explanation concerning the mechanisms, alerting us to the possibility of pseudobronchiectasis due to pneumonia, 16 , 17 but there was no evidence on chest CT scan of pneumonia lesions in our patient at any time.
CONFLICT OF INTEREST
The authors declare that there are no conflicts of interest. | 10 MG/KG EVERY 15 DAYS | DrugDosageText | CC BY-NC-ND | 33624409 | 19,950,244 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenia'. | High efficacy of BGD (bendamustine, gemcitabine, and dexamethasone) in relapsed/refractory Hodgkin Lymphoma.
The optimal salvage therapy in relapsed/refractory Hodgkin lymphoma (R/R HL) has not been defined so far. The goal of this multicenter retrospective study was to evaluate efficacy and safety of BGD (bendamustine, gemcitabine, dexamethasone) as a second or subsequent line of therapy in classical R/R HL. We have evaluated 92 consecutive R/R HL patients treated with BGD. Median age was 34.5 (19-82) years. Fifty-eight patients (63%) had received 2 or more lines of chemotherapy, 32 patients (34.8%) radiotherapy, and 21 patients (22.8%) an autologous hematopoietic stem cell transplantation (autoHCT). Forty-four patients (47.8%) were resistant to first line of chemotherapy. BGD therapy consisted of bendamustine 90 mg/m2 on days 1 and 2, gemcitabine 800 mg/m2 on days 1 and 4, dexamethasone 40 mg on days 1-4. Median number of BGD cycles was 4 (2-7). The following adverse events ≥ 3 grade were noted: neutropenia (22.8%), thrombocytopenia (20.7%), anemia (15.2%), infections (10.9%), AST/ALT increase (2.2%), and skin rush (1.1%). After BGD therapy, 51 (55.4%) patients achieved complete remission, 23 (25%)-partial response, 7 (7.6%)-stable disease, and 11 (12%) patients experienced progression disease. AutoHCT was conducted in 42 (45.7%) patients after BGD therapy, and allogeneic HCT (alloHCT) in 16 (17.4%) patients. Median progression-free survival was 21 months. BGD is a highly effective, well-tolerated salvage regimen for patients with R/R HL, providing an excellent bridge to auto- or alloHCT.
Introduction
Hodgkin lymphoma (HL), accounting for approximately 10% of all lymphomas, is one of the most curable malignancies. However, up to 30% of patients do not respond to the first-line therapy or relapse after initial response [1]. For patients with relapsed or refractory disease, salvage chemotherapy followed by high-dose chemotherapy with autologous hematopoietic stem cell transplantation (autoHCT) is still the treatment of choice [2, 3]. The long-term cure can be obtained in up to 80% of patients provided a complete metabolic remission (CMR) is achieved before transplant [4]. Consequently, the optimal salvage regimen should be highly effective but also should have a high mobilization rate. However, the standard for salvage chemotherapy before autoHCT is still not established. The most commonly used are platinum-based ICE (ifosfamide, carboplatin, etoposide); DHAP (dexamethasone, cytarabine, cisplatin); ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin); and gemcitabine-based GDP (gemcitabine, dexamethasone, cisplatin), GVD (gemcitabine, vinorelbine, liposomal doxorubicin), IGEV (ifosfamide, gemcitabine, vinorelbine), and GCD (gemcitabine, carboplatin, dexamethasone) combination chemotherapy with response rates ranging between 54 and 88% and mobilization rate of 86–100% [5–10]. Due to rather low rate of complete responses (CRs) achieved with the most frequently used salvage regimens, there is the persisting need to develop new salvage regimens especially in the second-line treatment. Recently, bendamustine both in monotherapy and in combination with other drugs was shown to induce high response rates with an acceptable toxicity profile in third or more line in patients with relapsed/refractory (R/R) HL [11–13]. Experience with bendamustine in the second line is very limited. Santoro et al. modified their original IGEV protocol substituting ifosfamide with bendamustine achieving a very high efficacy as a second-line therapy in patients with R/R HL [9, 14]. The Polish Lymphoma Research Group (PLRG) proposed replacement of vinorelbine with dexamethasone (bendamustine, gemcitabine, dexamethasone; BGD regimen) and is carrying out a prospective, multicenter study in patients with progressive disease during or after ABVD treatment [15] based on the very good preliminary results obtained with BGD in heavily pretreated R/R HL patients [16]. Here we report long-term outcome of these patients enrolled to the multicenter retrospective PLRG study aiming at evaluating the efficacy and toxicity of BGD in a real-life setting.
Methods
Study design
We retrospectively reviewed the data of all patients aged ≥ 18 years with R/R HL who were treated with BGD regimen between April 2012 and December 2018 in 15 centers allied within the PLRG. Primary refractory HL was defined as no CMR achieved after the first line or if progression occurred within 3 months after completion of the first-line chemotherapy. In patients with relapsed HL, the disease reappeared later after achieving CMR. Patients’ records were reviewed to obtain patient characteristics at diagnosis and the start of BGD treatment, including clinical stage according to the Lugano system, presence of B symptoms, extranodal site involvement, and bulky disease.
Treatment and response criteria
The dosage and administration schedule of BGD is shown in Table 1. The interim imaging assessment was performed after second or third cycle of BGD in 86 patients (93.5%). Patients could continue BGD treatment up to 4 cycles or longer at the discretion of a treating physician. The metabolic response to BGD treatment at the end of the therapy was assessed according to the Lugano treatment response criteria using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) [17]. The 18F-FDG uptake less than in the liver was defined as CMR. The higher 18F-FDG uptake, but decreased from baseline, was defined as partial metabolic response (PMR). In case of no significant change in 18F-FDG uptake from baseline or new FDG-avid foci, stable or progressive disease (SD or PD) were diagnosed, respectively. The overall response rate (ORR) was defined as the sum of CMR and PMR. Table 1 BGD regimen repeated every 4 weeks
Drug Dose Route of administrationa Day of administration
Bendamustine 90 mg/m2 i.v. 60 min 1 and 2
Gemcitabine 800 mg/m2 i.v. 30 min 1 and 4
Dexamethasone 40 mg i.v. or p.o. 1, 2, 3, and 4
ai.v., intravenous; p.o., per os
Study end-points and statistical analysis
Primary end-point was the percentage of CMR and ORR whereas progression-free survival (PFS) and overall survival (OS) as well as adverse events (AEs) were secondary end-points. PFS was defined as the time from start of BGD treatment to the date of documented disease progression, death from any cause, or start of new anticancer therapy. The patients at the time of autoHCT or allogeneic hematopoietic stem cell transplantation (alloHCT) were censored for PFS since transplants were not considered a new anticancer therapy. OS was defined as the time from the first BGD administration to death for any reason. AEs were evaluated using Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 [18]. PFS and OS were estimated using the Kaplan-Meier method. Ninety-five percent confidence intervals (CIs) for the survival curves were calculated for chosen times. The log-rank test was performed to compare survival curves between groups. Two-sided P values ≤ 0.05 were considered statistically significant. The statistics were performed descriptively. Statistical analysis was performed using Statistica software (version 13.1, Tulsa, OK, USA) and R statistical software package version 4.0.1. (R Foundation for Statistical Computing, http://www.r-project.org).
Results
Patients’ characteristics
The median age of 92 analyzed patients was 34.5 (range from 19 to 82 years) years with 9 patients at the age or above 60 years. More than 60% of patients were in advanced stages of HL at the time of diagnosis (III and IV according to the Lugano classification). Median number of prior chemotherapy lines was 2 (range from 1 to 6 lines). Thirty-four patients (37%) had previously been treated with only one line of chemotherapy. ABVD was the first-line therapy in 80.4% cases. Forty-four patients (47.8%) were primary refractory to the first-line chemotherapy. Almost 35% of patients had received radiotherapy prior to BGD treatment. Twenty-one patients (22.8%) underwent autoHCT, and three patients (3.3%) underwent alloHCT prior to BGD treatment. The median number of BGD cycles was 4 (range from 2 to 7 cycles). Demographic and clinical data are shown in Table 2. Table 2 Demographics and clinical characteristics of 92 subjects
Characteristic No. %
Age, years
- Median (range) 34.5 (19–82)
- ≥ 60 years 9 9.7
Sex
- Male 44 47.8
- Female 48 52.2
Lugano classification at diagnosis/before BGDa
- I 0/3 0/3.3
- II 33/38 35.9/41.3
- III 25/9 27.2/9.8
- IV 34/42 37/45.7
B-symptoms at diagnosis/before BGDa 67/27 72.9/29.3
Extranodal site involvement at diagnosis/before BGDa 32/39 34.8/42.4
Bulky disease at diagnosis/before BGDa 32/10 34.8/10.9
First-line treatment
ABVDb 74 80.4
BEACOPPc 13 14.1
Otherd 5 5.4
No. of previous treatment lines
- 1. 34 37
- 2. 26 28.3
- 3. 16 17.4
- 4. 9 9.8
- 5. 3 3.3
- 6. 4 4.3
Primary refractory to 1st-line treatment 44 47.8
Patents with late (> 12 months) relapse 20 21.7
No. of BGDa courses
- Median (range) 4 (2–7)
Radiotherapy prior to BGDa 32 34.8
Prior autoHCTe 21 22.8
Prior alloHCTf 3 3.3
aBGD, bendamustine, gemcitabine, dexamethasone
bABVD, adriamycin, bleomycin, vinblastine, dacarbazine
cBEACOPP, bleomycin, cyclophosphamide, doxorubicin, etoposide, prednisone, procarbazine, vincristine
dOther: PVAG, prednisone, vincristine, adriamycin, gemcitabine; OEPA/COPDAC, vincristine, etoposide, prednisone, doxorubicin/ cyclophosphamide, vincristine, prednisone, dacarbazine
eautoHCT, autologous hematopoietic cell transplantation
falloHCT, allogeneic hematopoietic cell transplantation
Efficacy of BGD
Out of 86 patients who were assessed by interim PET/CT after 2 or 3 cycles of BGD, 67 (77.9%) patients achieved overall response, including 33 (38.4%) CMRs. At the end of BGD therapy, ORR and CMR rate increased to 80.4% and 55.4%, respectively. Eleven patients (12%) experienced disease progression, and seven patients (7.6%) had stable disease. Among 34 patients who achieved PMR in the interim imaging test, 14 (41.2%) patients achieved CMR at the end of BGD treatment. In the subgroup of patients treated with BGD only as a second line of chemotherapy (n = 34), ORR was 79.4% while CMR rate was 64.7%. Out of 44 patients being refractory to the first line of chemotherapy, 30 (68.2%) patients achieved overall response and 34.1% achieved CMR. Among the whole study population, five patients were refractory to BEACOPP given as the first line of chemotherapy. All these patients achieved response and two of them (40%) achieved CMR after BGD. The autoHCT was successfully performed after BGD therapy in 42 (45.7%) patients. Furthermore, 16 (17.4%) patients underwent alloHCT after BGD therapy (Table 3). Among 21 patients treated with autoHCT before BGD therapy, 18 (85.7%) achieved response, 11 (52.4%) CMR, and 9 (42.9%) patients proceeded to alloHCT. PFS and OS are shown as Kaplan-Meier curves in Figs. 1 and 2. With a median follow-up of 18 months (range from 3 to 51 months), the median PFS for the overall population was 21 months while the median OS was not reached. PFS and OS rates at 2 years were 44.5% (95%CI: 33.7–58.8) and 75% (95%CI: 64.8–86.7), respectively. There were no differences between patients with relapsed or primary refractory HL in terms of PFS and OS (Figs. 3 and 4, P > 0.05). Similarly, no statistical differences in PFS and OS were noted between patients in whom BGD was used after first line or subsequent line of chemotherapy (Figs. 5 and 6, P > 0.05). Of note, most of the patients (80%) who responded to BGD maintain their response for at least 6 months (Fig. 1). In a subgroup of 9 patients ≥ 60 years old, 5 (55.6%) patients achieved CMR, 2 (22.2%)—PMR (ORR 77.8%), and 2 patients progressed during BGD treatment. PFS at 18 months was 62.2% (95%CI: 35.5–100) and OS at 23 months was 87.5% (95%CI: 67.3–100) (Figs. 7 and 8). Table 3 Response to BGD therapy
No. % (95%CI)
Interim (after 2–3 courses) n = 86
- PMDa 6 7 (1.6–12.4)
- SMDb 13 15.1 (7.5–22.7)
- PMRc 34 39.5 (29.2–49.9)
- CMRd 33 38.4 (28.1–48.6)
- ORRe 67 77.9 (69.1–86.7)
End of BGDf therapy n = 92
- PMDa 11 12 (5.3–18.6)
- SMDb 7 7.6 (2.2–13.0)
- PMRc 23 25 (16.2–33.8)
- CMRd 51 55.4 (45.3–65.6)
- ORRe 74 80.4 (2.3–88.5)
AutoHCTg after BGD therapy
- Yes 42 45.7
- No 50 54.3
AlloHCTh after BGD therapy
- Yes 16 17.4
- No 76 82.6
aPMD, progressive metabolic disease
bSMD, stable metabolic disease
cPMR, partial metabolic response
dCMR, complete metabolic response
eORR, overall response rate
fBGD, bendamustine, gemcitabine, dexamethasone
gautoHCT, autologous hematopoietic cell transplantation
halloHCT, allogeneic hematopoietic cell transplantation
Fig. 1 Progression-free survival (PFS) for the entire population
Fig. 2 Overall survival (OS) for the entire population
Fig. 3 Progression-free survival (PFS) for the subjects with relapsed or primary refractory Hodgkin lymphoma (HL)
Fig. 4 Overall survival (OS) for the subjects with relapsed or primary refractory Hodgkin lymphoma (HL)
Fig. 5 Progression-free survival (PFS) for patients treated with BGD as second or subsequent line of chemotherapy
Fig. 6 Overall survival (OS) for patients treated with BGD as second or subsequent line of chemotherapy
Fig. 7 Progression-free survival (PFS) for the subgroup of elderly patients (≥ 60 years)
Fig. 8 Overall survival (OS) for the subgroup of elderly patients (≥ 60 years)
Toxicity of BGD
The treatment-related AEs, mainly grade 1 or 2, were observed in 64 (69.6%) patients. Among grade ≥ 3 hematological toxicities, anemia was reported in 15.2% cases, thrombocytopenia in 20.7%, and neutropenia in 22.8% individuals. Severe non-hematological toxicities included infections (10.9%), alanine and/or aspartate aminotransferase (ALT or AST) increase (2.2%), and skin rush (1.1%). We recorded one death from unknown reasons during BGD therapy. All AEs reported during BGD therapy are shown in Table 4. In the subgroup of elderly patients (≥ 60 years), anemia and thrombocytopenia of grade 3 or 4 occurred in 2 (22.2%) patients, while neutropenia was found in 1 (11.1%) patient. Moreover, 2 (22.2%) patients experienced grade ≥ 3 infection, and 1 (11.1%) grade 3 skin rash in this subgroup. Table 4 Toxicity of BGD therapy
Toxicity Grade 1–2
No. (%) Grade 3–4
No. (%)
Hematological:
- Anemia 37 (40.2) 14 (15.2)
- Thrombocytopenia 25 (27.2) 19 (20.7)
- Neutropenia 19 (20.7) 21 (22.8)
Non-hematological:
- Infection 20 (21.7) 10 (10.9)
- ALT/ASTa increase 0 2 (2.2)
- Skin rush 7 (7.6) 1 (1.1)
- Fatigue 4 (4.3) 0
- Diarrhea 1 (1.1) 0
- Thrombotic events 2 (2.2) 0
- Guillain-Barré syndrome 1 (1.1) 0
- Autoimmune thyroiditis 1 (1.1) 0
Death from unknown reasons 1 (1.1)
aAlanine/aspartate aminotransferase
Discussion
Despite the significant progress in the management of patients with HL, relapsed and refractory disease constitutes a big challenge. According to the current treatment standards, high-dose chemotherapy followed by autoHCT has to be regarded as treatment of choice in the first relapse or primary progressive disease. However, even in the era of new agents such as brentuximab vedotin (BV) or immune checkpoint inhibitors, there are no accepted standards for salvage treatment before autoHCT. In the PLRG allied centers BGD was used since 2012 when the first cases of successful outcome of heavily pretreated patients were reported [16]. We had started to use BGD since both bendamustine and gemcitabine were effective in monotherapy as well as in combination with other agents.
Gemcitabine, a cytidine analog, was assessed in several studies. Kuruvilla et al. showed satisfactory (62%) response rate to GDP (gemcitabine, dexamethasone, and cisplatin) as a second-line therapy in patients with R/R HL [19]. Gemcitabine and vinerolbine combination showed ORR of 72% and 35% of CR [20]. In similar population, four-agent combination of gemcitabine with ifosfamide, vinorelbine, and prednisolone (IGEV) or double-agent schema of vinorelbine and pegylated liposomal doxorubicin (GVD) resulted in ORR of 81.3% and 70%, respectively [8, 9]. Bendamustine, another component of BGD, is a molecule containing the purine analog and the alkylating group. It was assessed in a phase II trial in heavily pretreated patients with HL (including those with relapse after auto- or alloHCT) at the dose of 120 mg/m2 and resulted in the intent-to-treat ORR of 53%, with CRs of 33% [11].
The combination of bendamustine with gemcitabine and vinorelbine (BeGEV) was first assessed in a multicenter phase II study by Santoro et al. [14]. The authors have demonstrated high efficacy of BeGEV as a second-line treatment in autoHCT-eligible patients (ORR 83%, CR 75%). In our retrospective analysis, ORR of BGD was similar to BeGEV although patient characteristics with regard to age and number of prior treatment regimens differ [14]. Moreover, almost one-fourth of patients in our study had been treated using autoHCT. This also most likely explains slightly higher rate of hematological toxicities at grade 3 or 4 in comparison to BeGEV. In contrast, severe non-hematological AEs occurred at similar incidence rates. We did not observe increased pulmonary toxicity which was reported by Cohen et al. in his cohort of patients. This might be due to the use of high dose of steroids (dexamethasone) in our regimen [21]. However, in spite of high efficacy of BGD in relation to ORR and CMR rate, estimated PFS in our study seems to be rather short (21 months). Most likely, this is a consequence of the large group of heavily pretreated patients (up to 6 previous line of therapy) including those after auto- and alloHCT and the subgroup of elderly patients in this cohort.
DHAP and ICE are among of the most commonly used salvage chemotherapy regimens in HL. Similar efficacy of these regimens as the second-line treatment was shown resulting in ORR of 88% for both, while CRs of 21% for DHAP and of 26.2% for ICE [5, 6]. Despite more heavily pretreated patients in our study, we report comparable ORR (80.4%) and much higher CMR rate (55.4%). Moreover, the difference in relation to CR rate increases in sub-analysis restricted to patients treated with BGD as the second line of chemotherapy (64.7%). The optimal number of BGD cycles is four, since about 40% of patients improved their response at the end of treatment compared to the interim assessment.
Most patients (80.4%) in this study were treated with ABVD as the first line of chemotherapy. Out of 13 patients being initially treated with BEACOPP, 5 (38.5%) patients were refractory to this regimen and all these patients achieved ORR after BGD therapy with CMR rate of 40%. In view of the fact that there are not many effective treatment options to overcome the BEACOPP refractoriness, this finding seems very interesting and encouraging for further studies.
In recent years, there have been many new agents evaluated for patients with R/R HL such as BV and immune checkpoint inhibitors. Brentuximab vedotin—an anti-CD30 antibody conjugated to antimicrotubule agent, monomethyl auristatin E—showed ORR of 75% and CR rate of 34% in heavily pretreated patients with HL after autoHCT [22]. Furthermore, BV showed similar efficacy as a second-line therapy in R/R HL (ORR 68%, CR 35%), and 89% of the subjects were able to proceed to autoHCT [23]. Addition of bendamustine to BV seems to increase its efficacy [12, 13]. However, in comparison to BGD regimen, BV does not appear to be superior both in monotherapy and in combination with bendamustine. Immune checkpoint inhibitors, mainly antibodies against programmed cell death protein 1 (PD-1) such as nivolumab or pembrolizumab, showed high efficacy as a salvage therapy for patients with R/R HL [24–27]. Ansell et al. reported ORR 87% in the heavily pretreated HL patients although CR rate was relatively low (17%) compared to BGD [24]. The authors reported similar incidence of AEs of any grade (78% vs. 69.6%) but relatively fewer cases of grade ≥ 3 AEs (22% vs. 38%) during nivolumab therapy when compared to BGD therapy [24].
The high efficacy of BGD in patients after failure of autoHCT is worth noting. This is a very challenging group, in which effective chemotherapy followed by alloHCT is the only option to achieve long-lasting remission. In this population checkpoint inhibitors, nivolumab and pembrolizumab resulted in high ORR rate (69% and 73%, respectively). However, once again, CR rates (16% and 14%, respectively) appear lower compared to BGD in our study (55.4%) and there are still some concerns about the increased incidence of immune complications after alloHCT in patients treated with immune checkpoint inhibitors before transplant [25, 26, 28, 29].
Another interesting finding of this study refers to elderly HL patients. We showed that in the patients at or above the age of 60 years BGD regimen has a similar efficacy (ORR 77.8%, CMR 55.6%) than in younger patients. Moreover, BGD-related toxicity seems to be acceptable in this subgroup.
Relatively small number of subjects included in the analysis as well as its retrospective nature and the lack of metabolic assessment in all patients are the major limitations of this study. Another important limitation of our study is a long accrual time. However, during this period, most of our patients were treated uniformly since novel therapies were not available due to reimbursement hurdles. Addition limitation may pose a large number of accruing centers. However, most of PLRG allied centers are reference centers with good-quality data management which somehow mitigate this flaw. However, our data clearly indicate that BGD which has a high rate of obtaining ORR and a relatively good time in response maintaining (5–6 months in 80% of patients) and an acceptable toxicity profile seems to provide a very good option for R/R HL patients even after BEACOPP first-line chemotherapy. In several patients, it opened a window to perform either autologous or allogeneic transplantation. Despite the fact that in recent years new treatment options, including BV and checkpoint inhibitors, showed promising results in treatment of patients with R/R HL, neither of them as yet is formally approved in the second-line treatment for HL. In addition, although pharmaco-economy was not a subject of this study, we speculate that BGD treatment may be a relatively cheap option. Therefore, we conclude that the BGD should be considered a viable option for patients with R/R HL and may serve as a bridge for individuals being candidates for auto- or alloHCT.
Author contributions
WKP, JMZ, and SG designed the study; all authors except for JMZ, AK, and AW enrolled patients; SG, RS, AK, and AW performed the bioinformatics and statistical analysis; RS and JMZ wrote the paper. All authors read and revised the manuscript critically.
Data availability
Not applicable
Code availability
Not applicable
Declarations
Ethics approval
According to Polish regulations, this was a retrospective study and it does not require approval of the bioethical committee. The study was approved by the board of The Polish Lymphoma Research Group.
Consent to participate
Not applicable
Consent for publication
Not applicable
Conflict of interest
The authors declare no conflict of interest.
The original version of this article was revised: This article was originally published with an incorrect affiliation. It should be 9 ( Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wrocław Medical University, Wrocław, Poland).
Wojciech Spychałowicz passed away during the writing of this article.
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Change history
3/24/2021
A Correction to this paper has been published: 10.1007/s00277-021-04503-1 | BENDAMUSTINE HYDROCHLORIDE, DEXAMETHASONE, GEMCITABINE | DrugsGivenReaction | CC BY | 33625572 | 19,756,838 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | High efficacy of BGD (bendamustine, gemcitabine, and dexamethasone) in relapsed/refractory Hodgkin Lymphoma.
The optimal salvage therapy in relapsed/refractory Hodgkin lymphoma (R/R HL) has not been defined so far. The goal of this multicenter retrospective study was to evaluate efficacy and safety of BGD (bendamustine, gemcitabine, dexamethasone) as a second or subsequent line of therapy in classical R/R HL. We have evaluated 92 consecutive R/R HL patients treated with BGD. Median age was 34.5 (19-82) years. Fifty-eight patients (63%) had received 2 or more lines of chemotherapy, 32 patients (34.8%) radiotherapy, and 21 patients (22.8%) an autologous hematopoietic stem cell transplantation (autoHCT). Forty-four patients (47.8%) were resistant to first line of chemotherapy. BGD therapy consisted of bendamustine 90 mg/m2 on days 1 and 2, gemcitabine 800 mg/m2 on days 1 and 4, dexamethasone 40 mg on days 1-4. Median number of BGD cycles was 4 (2-7). The following adverse events ≥ 3 grade were noted: neutropenia (22.8%), thrombocytopenia (20.7%), anemia (15.2%), infections (10.9%), AST/ALT increase (2.2%), and skin rush (1.1%). After BGD therapy, 51 (55.4%) patients achieved complete remission, 23 (25%)-partial response, 7 (7.6%)-stable disease, and 11 (12%) patients experienced progression disease. AutoHCT was conducted in 42 (45.7%) patients after BGD therapy, and allogeneic HCT (alloHCT) in 16 (17.4%) patients. Median progression-free survival was 21 months. BGD is a highly effective, well-tolerated salvage regimen for patients with R/R HL, providing an excellent bridge to auto- or alloHCT.
Introduction
Hodgkin lymphoma (HL), accounting for approximately 10% of all lymphomas, is one of the most curable malignancies. However, up to 30% of patients do not respond to the first-line therapy or relapse after initial response [1]. For patients with relapsed or refractory disease, salvage chemotherapy followed by high-dose chemotherapy with autologous hematopoietic stem cell transplantation (autoHCT) is still the treatment of choice [2, 3]. The long-term cure can be obtained in up to 80% of patients provided a complete metabolic remission (CMR) is achieved before transplant [4]. Consequently, the optimal salvage regimen should be highly effective but also should have a high mobilization rate. However, the standard for salvage chemotherapy before autoHCT is still not established. The most commonly used are platinum-based ICE (ifosfamide, carboplatin, etoposide); DHAP (dexamethasone, cytarabine, cisplatin); ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin); and gemcitabine-based GDP (gemcitabine, dexamethasone, cisplatin), GVD (gemcitabine, vinorelbine, liposomal doxorubicin), IGEV (ifosfamide, gemcitabine, vinorelbine), and GCD (gemcitabine, carboplatin, dexamethasone) combination chemotherapy with response rates ranging between 54 and 88% and mobilization rate of 86–100% [5–10]. Due to rather low rate of complete responses (CRs) achieved with the most frequently used salvage regimens, there is the persisting need to develop new salvage regimens especially in the second-line treatment. Recently, bendamustine both in monotherapy and in combination with other drugs was shown to induce high response rates with an acceptable toxicity profile in third or more line in patients with relapsed/refractory (R/R) HL [11–13]. Experience with bendamustine in the second line is very limited. Santoro et al. modified their original IGEV protocol substituting ifosfamide with bendamustine achieving a very high efficacy as a second-line therapy in patients with R/R HL [9, 14]. The Polish Lymphoma Research Group (PLRG) proposed replacement of vinorelbine with dexamethasone (bendamustine, gemcitabine, dexamethasone; BGD regimen) and is carrying out a prospective, multicenter study in patients with progressive disease during or after ABVD treatment [15] based on the very good preliminary results obtained with BGD in heavily pretreated R/R HL patients [16]. Here we report long-term outcome of these patients enrolled to the multicenter retrospective PLRG study aiming at evaluating the efficacy and toxicity of BGD in a real-life setting.
Methods
Study design
We retrospectively reviewed the data of all patients aged ≥ 18 years with R/R HL who were treated with BGD regimen between April 2012 and December 2018 in 15 centers allied within the PLRG. Primary refractory HL was defined as no CMR achieved after the first line or if progression occurred within 3 months after completion of the first-line chemotherapy. In patients with relapsed HL, the disease reappeared later after achieving CMR. Patients’ records were reviewed to obtain patient characteristics at diagnosis and the start of BGD treatment, including clinical stage according to the Lugano system, presence of B symptoms, extranodal site involvement, and bulky disease.
Treatment and response criteria
The dosage and administration schedule of BGD is shown in Table 1. The interim imaging assessment was performed after second or third cycle of BGD in 86 patients (93.5%). Patients could continue BGD treatment up to 4 cycles or longer at the discretion of a treating physician. The metabolic response to BGD treatment at the end of the therapy was assessed according to the Lugano treatment response criteria using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) [17]. The 18F-FDG uptake less than in the liver was defined as CMR. The higher 18F-FDG uptake, but decreased from baseline, was defined as partial metabolic response (PMR). In case of no significant change in 18F-FDG uptake from baseline or new FDG-avid foci, stable or progressive disease (SD or PD) were diagnosed, respectively. The overall response rate (ORR) was defined as the sum of CMR and PMR. Table 1 BGD regimen repeated every 4 weeks
Drug Dose Route of administrationa Day of administration
Bendamustine 90 mg/m2 i.v. 60 min 1 and 2
Gemcitabine 800 mg/m2 i.v. 30 min 1 and 4
Dexamethasone 40 mg i.v. or p.o. 1, 2, 3, and 4
ai.v., intravenous; p.o., per os
Study end-points and statistical analysis
Primary end-point was the percentage of CMR and ORR whereas progression-free survival (PFS) and overall survival (OS) as well as adverse events (AEs) were secondary end-points. PFS was defined as the time from start of BGD treatment to the date of documented disease progression, death from any cause, or start of new anticancer therapy. The patients at the time of autoHCT or allogeneic hematopoietic stem cell transplantation (alloHCT) were censored for PFS since transplants were not considered a new anticancer therapy. OS was defined as the time from the first BGD administration to death for any reason. AEs were evaluated using Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 [18]. PFS and OS were estimated using the Kaplan-Meier method. Ninety-five percent confidence intervals (CIs) for the survival curves were calculated for chosen times. The log-rank test was performed to compare survival curves between groups. Two-sided P values ≤ 0.05 were considered statistically significant. The statistics were performed descriptively. Statistical analysis was performed using Statistica software (version 13.1, Tulsa, OK, USA) and R statistical software package version 4.0.1. (R Foundation for Statistical Computing, http://www.r-project.org).
Results
Patients’ characteristics
The median age of 92 analyzed patients was 34.5 (range from 19 to 82 years) years with 9 patients at the age or above 60 years. More than 60% of patients were in advanced stages of HL at the time of diagnosis (III and IV according to the Lugano classification). Median number of prior chemotherapy lines was 2 (range from 1 to 6 lines). Thirty-four patients (37%) had previously been treated with only one line of chemotherapy. ABVD was the first-line therapy in 80.4% cases. Forty-four patients (47.8%) were primary refractory to the first-line chemotherapy. Almost 35% of patients had received radiotherapy prior to BGD treatment. Twenty-one patients (22.8%) underwent autoHCT, and three patients (3.3%) underwent alloHCT prior to BGD treatment. The median number of BGD cycles was 4 (range from 2 to 7 cycles). Demographic and clinical data are shown in Table 2. Table 2 Demographics and clinical characteristics of 92 subjects
Characteristic No. %
Age, years
- Median (range) 34.5 (19–82)
- ≥ 60 years 9 9.7
Sex
- Male 44 47.8
- Female 48 52.2
Lugano classification at diagnosis/before BGDa
- I 0/3 0/3.3
- II 33/38 35.9/41.3
- III 25/9 27.2/9.8
- IV 34/42 37/45.7
B-symptoms at diagnosis/before BGDa 67/27 72.9/29.3
Extranodal site involvement at diagnosis/before BGDa 32/39 34.8/42.4
Bulky disease at diagnosis/before BGDa 32/10 34.8/10.9
First-line treatment
ABVDb 74 80.4
BEACOPPc 13 14.1
Otherd 5 5.4
No. of previous treatment lines
- 1. 34 37
- 2. 26 28.3
- 3. 16 17.4
- 4. 9 9.8
- 5. 3 3.3
- 6. 4 4.3
Primary refractory to 1st-line treatment 44 47.8
Patents with late (> 12 months) relapse 20 21.7
No. of BGDa courses
- Median (range) 4 (2–7)
Radiotherapy prior to BGDa 32 34.8
Prior autoHCTe 21 22.8
Prior alloHCTf 3 3.3
aBGD, bendamustine, gemcitabine, dexamethasone
bABVD, adriamycin, bleomycin, vinblastine, dacarbazine
cBEACOPP, bleomycin, cyclophosphamide, doxorubicin, etoposide, prednisone, procarbazine, vincristine
dOther: PVAG, prednisone, vincristine, adriamycin, gemcitabine; OEPA/COPDAC, vincristine, etoposide, prednisone, doxorubicin/ cyclophosphamide, vincristine, prednisone, dacarbazine
eautoHCT, autologous hematopoietic cell transplantation
falloHCT, allogeneic hematopoietic cell transplantation
Efficacy of BGD
Out of 86 patients who were assessed by interim PET/CT after 2 or 3 cycles of BGD, 67 (77.9%) patients achieved overall response, including 33 (38.4%) CMRs. At the end of BGD therapy, ORR and CMR rate increased to 80.4% and 55.4%, respectively. Eleven patients (12%) experienced disease progression, and seven patients (7.6%) had stable disease. Among 34 patients who achieved PMR in the interim imaging test, 14 (41.2%) patients achieved CMR at the end of BGD treatment. In the subgroup of patients treated with BGD only as a second line of chemotherapy (n = 34), ORR was 79.4% while CMR rate was 64.7%. Out of 44 patients being refractory to the first line of chemotherapy, 30 (68.2%) patients achieved overall response and 34.1% achieved CMR. Among the whole study population, five patients were refractory to BEACOPP given as the first line of chemotherapy. All these patients achieved response and two of them (40%) achieved CMR after BGD. The autoHCT was successfully performed after BGD therapy in 42 (45.7%) patients. Furthermore, 16 (17.4%) patients underwent alloHCT after BGD therapy (Table 3). Among 21 patients treated with autoHCT before BGD therapy, 18 (85.7%) achieved response, 11 (52.4%) CMR, and 9 (42.9%) patients proceeded to alloHCT. PFS and OS are shown as Kaplan-Meier curves in Figs. 1 and 2. With a median follow-up of 18 months (range from 3 to 51 months), the median PFS for the overall population was 21 months while the median OS was not reached. PFS and OS rates at 2 years were 44.5% (95%CI: 33.7–58.8) and 75% (95%CI: 64.8–86.7), respectively. There were no differences between patients with relapsed or primary refractory HL in terms of PFS and OS (Figs. 3 and 4, P > 0.05). Similarly, no statistical differences in PFS and OS were noted between patients in whom BGD was used after first line or subsequent line of chemotherapy (Figs. 5 and 6, P > 0.05). Of note, most of the patients (80%) who responded to BGD maintain their response for at least 6 months (Fig. 1). In a subgroup of 9 patients ≥ 60 years old, 5 (55.6%) patients achieved CMR, 2 (22.2%)—PMR (ORR 77.8%), and 2 patients progressed during BGD treatment. PFS at 18 months was 62.2% (95%CI: 35.5–100) and OS at 23 months was 87.5% (95%CI: 67.3–100) (Figs. 7 and 8). Table 3 Response to BGD therapy
No. % (95%CI)
Interim (after 2–3 courses) n = 86
- PMDa 6 7 (1.6–12.4)
- SMDb 13 15.1 (7.5–22.7)
- PMRc 34 39.5 (29.2–49.9)
- CMRd 33 38.4 (28.1–48.6)
- ORRe 67 77.9 (69.1–86.7)
End of BGDf therapy n = 92
- PMDa 11 12 (5.3–18.6)
- SMDb 7 7.6 (2.2–13.0)
- PMRc 23 25 (16.2–33.8)
- CMRd 51 55.4 (45.3–65.6)
- ORRe 74 80.4 (2.3–88.5)
AutoHCTg after BGD therapy
- Yes 42 45.7
- No 50 54.3
AlloHCTh after BGD therapy
- Yes 16 17.4
- No 76 82.6
aPMD, progressive metabolic disease
bSMD, stable metabolic disease
cPMR, partial metabolic response
dCMR, complete metabolic response
eORR, overall response rate
fBGD, bendamustine, gemcitabine, dexamethasone
gautoHCT, autologous hematopoietic cell transplantation
halloHCT, allogeneic hematopoietic cell transplantation
Fig. 1 Progression-free survival (PFS) for the entire population
Fig. 2 Overall survival (OS) for the entire population
Fig. 3 Progression-free survival (PFS) for the subjects with relapsed or primary refractory Hodgkin lymphoma (HL)
Fig. 4 Overall survival (OS) for the subjects with relapsed or primary refractory Hodgkin lymphoma (HL)
Fig. 5 Progression-free survival (PFS) for patients treated with BGD as second or subsequent line of chemotherapy
Fig. 6 Overall survival (OS) for patients treated with BGD as second or subsequent line of chemotherapy
Fig. 7 Progression-free survival (PFS) for the subgroup of elderly patients (≥ 60 years)
Fig. 8 Overall survival (OS) for the subgroup of elderly patients (≥ 60 years)
Toxicity of BGD
The treatment-related AEs, mainly grade 1 or 2, were observed in 64 (69.6%) patients. Among grade ≥ 3 hematological toxicities, anemia was reported in 15.2% cases, thrombocytopenia in 20.7%, and neutropenia in 22.8% individuals. Severe non-hematological toxicities included infections (10.9%), alanine and/or aspartate aminotransferase (ALT or AST) increase (2.2%), and skin rush (1.1%). We recorded one death from unknown reasons during BGD therapy. All AEs reported during BGD therapy are shown in Table 4. In the subgroup of elderly patients (≥ 60 years), anemia and thrombocytopenia of grade 3 or 4 occurred in 2 (22.2%) patients, while neutropenia was found in 1 (11.1%) patient. Moreover, 2 (22.2%) patients experienced grade ≥ 3 infection, and 1 (11.1%) grade 3 skin rash in this subgroup. Table 4 Toxicity of BGD therapy
Toxicity Grade 1–2
No. (%) Grade 3–4
No. (%)
Hematological:
- Anemia 37 (40.2) 14 (15.2)
- Thrombocytopenia 25 (27.2) 19 (20.7)
- Neutropenia 19 (20.7) 21 (22.8)
Non-hematological:
- Infection 20 (21.7) 10 (10.9)
- ALT/ASTa increase 0 2 (2.2)
- Skin rush 7 (7.6) 1 (1.1)
- Fatigue 4 (4.3) 0
- Diarrhea 1 (1.1) 0
- Thrombotic events 2 (2.2) 0
- Guillain-Barré syndrome 1 (1.1) 0
- Autoimmune thyroiditis 1 (1.1) 0
Death from unknown reasons 1 (1.1)
aAlanine/aspartate aminotransferase
Discussion
Despite the significant progress in the management of patients with HL, relapsed and refractory disease constitutes a big challenge. According to the current treatment standards, high-dose chemotherapy followed by autoHCT has to be regarded as treatment of choice in the first relapse or primary progressive disease. However, even in the era of new agents such as brentuximab vedotin (BV) or immune checkpoint inhibitors, there are no accepted standards for salvage treatment before autoHCT. In the PLRG allied centers BGD was used since 2012 when the first cases of successful outcome of heavily pretreated patients were reported [16]. We had started to use BGD since both bendamustine and gemcitabine were effective in monotherapy as well as in combination with other agents.
Gemcitabine, a cytidine analog, was assessed in several studies. Kuruvilla et al. showed satisfactory (62%) response rate to GDP (gemcitabine, dexamethasone, and cisplatin) as a second-line therapy in patients with R/R HL [19]. Gemcitabine and vinerolbine combination showed ORR of 72% and 35% of CR [20]. In similar population, four-agent combination of gemcitabine with ifosfamide, vinorelbine, and prednisolone (IGEV) or double-agent schema of vinorelbine and pegylated liposomal doxorubicin (GVD) resulted in ORR of 81.3% and 70%, respectively [8, 9]. Bendamustine, another component of BGD, is a molecule containing the purine analog and the alkylating group. It was assessed in a phase II trial in heavily pretreated patients with HL (including those with relapse after auto- or alloHCT) at the dose of 120 mg/m2 and resulted in the intent-to-treat ORR of 53%, with CRs of 33% [11].
The combination of bendamustine with gemcitabine and vinorelbine (BeGEV) was first assessed in a multicenter phase II study by Santoro et al. [14]. The authors have demonstrated high efficacy of BeGEV as a second-line treatment in autoHCT-eligible patients (ORR 83%, CR 75%). In our retrospective analysis, ORR of BGD was similar to BeGEV although patient characteristics with regard to age and number of prior treatment regimens differ [14]. Moreover, almost one-fourth of patients in our study had been treated using autoHCT. This also most likely explains slightly higher rate of hematological toxicities at grade 3 or 4 in comparison to BeGEV. In contrast, severe non-hematological AEs occurred at similar incidence rates. We did not observe increased pulmonary toxicity which was reported by Cohen et al. in his cohort of patients. This might be due to the use of high dose of steroids (dexamethasone) in our regimen [21]. However, in spite of high efficacy of BGD in relation to ORR and CMR rate, estimated PFS in our study seems to be rather short (21 months). Most likely, this is a consequence of the large group of heavily pretreated patients (up to 6 previous line of therapy) including those after auto- and alloHCT and the subgroup of elderly patients in this cohort.
DHAP and ICE are among of the most commonly used salvage chemotherapy regimens in HL. Similar efficacy of these regimens as the second-line treatment was shown resulting in ORR of 88% for both, while CRs of 21% for DHAP and of 26.2% for ICE [5, 6]. Despite more heavily pretreated patients in our study, we report comparable ORR (80.4%) and much higher CMR rate (55.4%). Moreover, the difference in relation to CR rate increases in sub-analysis restricted to patients treated with BGD as the second line of chemotherapy (64.7%). The optimal number of BGD cycles is four, since about 40% of patients improved their response at the end of treatment compared to the interim assessment.
Most patients (80.4%) in this study were treated with ABVD as the first line of chemotherapy. Out of 13 patients being initially treated with BEACOPP, 5 (38.5%) patients were refractory to this regimen and all these patients achieved ORR after BGD therapy with CMR rate of 40%. In view of the fact that there are not many effective treatment options to overcome the BEACOPP refractoriness, this finding seems very interesting and encouraging for further studies.
In recent years, there have been many new agents evaluated for patients with R/R HL such as BV and immune checkpoint inhibitors. Brentuximab vedotin—an anti-CD30 antibody conjugated to antimicrotubule agent, monomethyl auristatin E—showed ORR of 75% and CR rate of 34% in heavily pretreated patients with HL after autoHCT [22]. Furthermore, BV showed similar efficacy as a second-line therapy in R/R HL (ORR 68%, CR 35%), and 89% of the subjects were able to proceed to autoHCT [23]. Addition of bendamustine to BV seems to increase its efficacy [12, 13]. However, in comparison to BGD regimen, BV does not appear to be superior both in monotherapy and in combination with bendamustine. Immune checkpoint inhibitors, mainly antibodies against programmed cell death protein 1 (PD-1) such as nivolumab or pembrolizumab, showed high efficacy as a salvage therapy for patients with R/R HL [24–27]. Ansell et al. reported ORR 87% in the heavily pretreated HL patients although CR rate was relatively low (17%) compared to BGD [24]. The authors reported similar incidence of AEs of any grade (78% vs. 69.6%) but relatively fewer cases of grade ≥ 3 AEs (22% vs. 38%) during nivolumab therapy when compared to BGD therapy [24].
The high efficacy of BGD in patients after failure of autoHCT is worth noting. This is a very challenging group, in which effective chemotherapy followed by alloHCT is the only option to achieve long-lasting remission. In this population checkpoint inhibitors, nivolumab and pembrolizumab resulted in high ORR rate (69% and 73%, respectively). However, once again, CR rates (16% and 14%, respectively) appear lower compared to BGD in our study (55.4%) and there are still some concerns about the increased incidence of immune complications after alloHCT in patients treated with immune checkpoint inhibitors before transplant [25, 26, 28, 29].
Another interesting finding of this study refers to elderly HL patients. We showed that in the patients at or above the age of 60 years BGD regimen has a similar efficacy (ORR 77.8%, CMR 55.6%) than in younger patients. Moreover, BGD-related toxicity seems to be acceptable in this subgroup.
Relatively small number of subjects included in the analysis as well as its retrospective nature and the lack of metabolic assessment in all patients are the major limitations of this study. Another important limitation of our study is a long accrual time. However, during this period, most of our patients were treated uniformly since novel therapies were not available due to reimbursement hurdles. Addition limitation may pose a large number of accruing centers. However, most of PLRG allied centers are reference centers with good-quality data management which somehow mitigate this flaw. However, our data clearly indicate that BGD which has a high rate of obtaining ORR and a relatively good time in response maintaining (5–6 months in 80% of patients) and an acceptable toxicity profile seems to provide a very good option for R/R HL patients even after BEACOPP first-line chemotherapy. In several patients, it opened a window to perform either autologous or allogeneic transplantation. Despite the fact that in recent years new treatment options, including BV and checkpoint inhibitors, showed promising results in treatment of patients with R/R HL, neither of them as yet is formally approved in the second-line treatment for HL. In addition, although pharmaco-economy was not a subject of this study, we speculate that BGD treatment may be a relatively cheap option. Therefore, we conclude that the BGD should be considered a viable option for patients with R/R HL and may serve as a bridge for individuals being candidates for auto- or alloHCT.
Author contributions
WKP, JMZ, and SG designed the study; all authors except for JMZ, AK, and AW enrolled patients; SG, RS, AK, and AW performed the bioinformatics and statistical analysis; RS and JMZ wrote the paper. All authors read and revised the manuscript critically.
Data availability
Not applicable
Code availability
Not applicable
Declarations
Ethics approval
According to Polish regulations, this was a retrospective study and it does not require approval of the bioethical committee. The study was approved by the board of The Polish Lymphoma Research Group.
Consent to participate
Not applicable
Consent for publication
Not applicable
Conflict of interest
The authors declare no conflict of interest.
The original version of this article was revised: This article was originally published with an incorrect affiliation. It should be 9 ( Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wrocław Medical University, Wrocław, Poland).
Wojciech Spychałowicz passed away during the writing of this article.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Change history
3/24/2021
A Correction to this paper has been published: 10.1007/s00277-021-04503-1 | BENDAMUSTINE HYDROCHLORIDE, DEXAMETHASONE, GEMCITABINE | DrugsGivenReaction | CC BY | 33625572 | 19,756,838 | 2021-07 |
What was the administration route of drug 'BENDAMUSTINE HYDROCHLORIDE'? | High efficacy of BGD (bendamustine, gemcitabine, and dexamethasone) in relapsed/refractory Hodgkin Lymphoma.
The optimal salvage therapy in relapsed/refractory Hodgkin lymphoma (R/R HL) has not been defined so far. The goal of this multicenter retrospective study was to evaluate efficacy and safety of BGD (bendamustine, gemcitabine, dexamethasone) as a second or subsequent line of therapy in classical R/R HL. We have evaluated 92 consecutive R/R HL patients treated with BGD. Median age was 34.5 (19-82) years. Fifty-eight patients (63%) had received 2 or more lines of chemotherapy, 32 patients (34.8%) radiotherapy, and 21 patients (22.8%) an autologous hematopoietic stem cell transplantation (autoHCT). Forty-four patients (47.8%) were resistant to first line of chemotherapy. BGD therapy consisted of bendamustine 90 mg/m2 on days 1 and 2, gemcitabine 800 mg/m2 on days 1 and 4, dexamethasone 40 mg on days 1-4. Median number of BGD cycles was 4 (2-7). The following adverse events ≥ 3 grade were noted: neutropenia (22.8%), thrombocytopenia (20.7%), anemia (15.2%), infections (10.9%), AST/ALT increase (2.2%), and skin rush (1.1%). After BGD therapy, 51 (55.4%) patients achieved complete remission, 23 (25%)-partial response, 7 (7.6%)-stable disease, and 11 (12%) patients experienced progression disease. AutoHCT was conducted in 42 (45.7%) patients after BGD therapy, and allogeneic HCT (alloHCT) in 16 (17.4%) patients. Median progression-free survival was 21 months. BGD is a highly effective, well-tolerated salvage regimen for patients with R/R HL, providing an excellent bridge to auto- or alloHCT.
Introduction
Hodgkin lymphoma (HL), accounting for approximately 10% of all lymphomas, is one of the most curable malignancies. However, up to 30% of patients do not respond to the first-line therapy or relapse after initial response [1]. For patients with relapsed or refractory disease, salvage chemotherapy followed by high-dose chemotherapy with autologous hematopoietic stem cell transplantation (autoHCT) is still the treatment of choice [2, 3]. The long-term cure can be obtained in up to 80% of patients provided a complete metabolic remission (CMR) is achieved before transplant [4]. Consequently, the optimal salvage regimen should be highly effective but also should have a high mobilization rate. However, the standard for salvage chemotherapy before autoHCT is still not established. The most commonly used are platinum-based ICE (ifosfamide, carboplatin, etoposide); DHAP (dexamethasone, cytarabine, cisplatin); ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin); and gemcitabine-based GDP (gemcitabine, dexamethasone, cisplatin), GVD (gemcitabine, vinorelbine, liposomal doxorubicin), IGEV (ifosfamide, gemcitabine, vinorelbine), and GCD (gemcitabine, carboplatin, dexamethasone) combination chemotherapy with response rates ranging between 54 and 88% and mobilization rate of 86–100% [5–10]. Due to rather low rate of complete responses (CRs) achieved with the most frequently used salvage regimens, there is the persisting need to develop new salvage regimens especially in the second-line treatment. Recently, bendamustine both in monotherapy and in combination with other drugs was shown to induce high response rates with an acceptable toxicity profile in third or more line in patients with relapsed/refractory (R/R) HL [11–13]. Experience with bendamustine in the second line is very limited. Santoro et al. modified their original IGEV protocol substituting ifosfamide with bendamustine achieving a very high efficacy as a second-line therapy in patients with R/R HL [9, 14]. The Polish Lymphoma Research Group (PLRG) proposed replacement of vinorelbine with dexamethasone (bendamustine, gemcitabine, dexamethasone; BGD regimen) and is carrying out a prospective, multicenter study in patients with progressive disease during or after ABVD treatment [15] based on the very good preliminary results obtained with BGD in heavily pretreated R/R HL patients [16]. Here we report long-term outcome of these patients enrolled to the multicenter retrospective PLRG study aiming at evaluating the efficacy and toxicity of BGD in a real-life setting.
Methods
Study design
We retrospectively reviewed the data of all patients aged ≥ 18 years with R/R HL who were treated with BGD regimen between April 2012 and December 2018 in 15 centers allied within the PLRG. Primary refractory HL was defined as no CMR achieved after the first line or if progression occurred within 3 months after completion of the first-line chemotherapy. In patients with relapsed HL, the disease reappeared later after achieving CMR. Patients’ records were reviewed to obtain patient characteristics at diagnosis and the start of BGD treatment, including clinical stage according to the Lugano system, presence of B symptoms, extranodal site involvement, and bulky disease.
Treatment and response criteria
The dosage and administration schedule of BGD is shown in Table 1. The interim imaging assessment was performed after second or third cycle of BGD in 86 patients (93.5%). Patients could continue BGD treatment up to 4 cycles or longer at the discretion of a treating physician. The metabolic response to BGD treatment at the end of the therapy was assessed according to the Lugano treatment response criteria using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) [17]. The 18F-FDG uptake less than in the liver was defined as CMR. The higher 18F-FDG uptake, but decreased from baseline, was defined as partial metabolic response (PMR). In case of no significant change in 18F-FDG uptake from baseline or new FDG-avid foci, stable or progressive disease (SD or PD) were diagnosed, respectively. The overall response rate (ORR) was defined as the sum of CMR and PMR. Table 1 BGD regimen repeated every 4 weeks
Drug Dose Route of administrationa Day of administration
Bendamustine 90 mg/m2 i.v. 60 min 1 and 2
Gemcitabine 800 mg/m2 i.v. 30 min 1 and 4
Dexamethasone 40 mg i.v. or p.o. 1, 2, 3, and 4
ai.v., intravenous; p.o., per os
Study end-points and statistical analysis
Primary end-point was the percentage of CMR and ORR whereas progression-free survival (PFS) and overall survival (OS) as well as adverse events (AEs) were secondary end-points. PFS was defined as the time from start of BGD treatment to the date of documented disease progression, death from any cause, or start of new anticancer therapy. The patients at the time of autoHCT or allogeneic hematopoietic stem cell transplantation (alloHCT) were censored for PFS since transplants were not considered a new anticancer therapy. OS was defined as the time from the first BGD administration to death for any reason. AEs were evaluated using Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 [18]. PFS and OS were estimated using the Kaplan-Meier method. Ninety-five percent confidence intervals (CIs) for the survival curves were calculated for chosen times. The log-rank test was performed to compare survival curves between groups. Two-sided P values ≤ 0.05 were considered statistically significant. The statistics were performed descriptively. Statistical analysis was performed using Statistica software (version 13.1, Tulsa, OK, USA) and R statistical software package version 4.0.1. (R Foundation for Statistical Computing, http://www.r-project.org).
Results
Patients’ characteristics
The median age of 92 analyzed patients was 34.5 (range from 19 to 82 years) years with 9 patients at the age or above 60 years. More than 60% of patients were in advanced stages of HL at the time of diagnosis (III and IV according to the Lugano classification). Median number of prior chemotherapy lines was 2 (range from 1 to 6 lines). Thirty-four patients (37%) had previously been treated with only one line of chemotherapy. ABVD was the first-line therapy in 80.4% cases. Forty-four patients (47.8%) were primary refractory to the first-line chemotherapy. Almost 35% of patients had received radiotherapy prior to BGD treatment. Twenty-one patients (22.8%) underwent autoHCT, and three patients (3.3%) underwent alloHCT prior to BGD treatment. The median number of BGD cycles was 4 (range from 2 to 7 cycles). Demographic and clinical data are shown in Table 2. Table 2 Demographics and clinical characteristics of 92 subjects
Characteristic No. %
Age, years
- Median (range) 34.5 (19–82)
- ≥ 60 years 9 9.7
Sex
- Male 44 47.8
- Female 48 52.2
Lugano classification at diagnosis/before BGDa
- I 0/3 0/3.3
- II 33/38 35.9/41.3
- III 25/9 27.2/9.8
- IV 34/42 37/45.7
B-symptoms at diagnosis/before BGDa 67/27 72.9/29.3
Extranodal site involvement at diagnosis/before BGDa 32/39 34.8/42.4
Bulky disease at diagnosis/before BGDa 32/10 34.8/10.9
First-line treatment
ABVDb 74 80.4
BEACOPPc 13 14.1
Otherd 5 5.4
No. of previous treatment lines
- 1. 34 37
- 2. 26 28.3
- 3. 16 17.4
- 4. 9 9.8
- 5. 3 3.3
- 6. 4 4.3
Primary refractory to 1st-line treatment 44 47.8
Patents with late (> 12 months) relapse 20 21.7
No. of BGDa courses
- Median (range) 4 (2–7)
Radiotherapy prior to BGDa 32 34.8
Prior autoHCTe 21 22.8
Prior alloHCTf 3 3.3
aBGD, bendamustine, gemcitabine, dexamethasone
bABVD, adriamycin, bleomycin, vinblastine, dacarbazine
cBEACOPP, bleomycin, cyclophosphamide, doxorubicin, etoposide, prednisone, procarbazine, vincristine
dOther: PVAG, prednisone, vincristine, adriamycin, gemcitabine; OEPA/COPDAC, vincristine, etoposide, prednisone, doxorubicin/ cyclophosphamide, vincristine, prednisone, dacarbazine
eautoHCT, autologous hematopoietic cell transplantation
falloHCT, allogeneic hematopoietic cell transplantation
Efficacy of BGD
Out of 86 patients who were assessed by interim PET/CT after 2 or 3 cycles of BGD, 67 (77.9%) patients achieved overall response, including 33 (38.4%) CMRs. At the end of BGD therapy, ORR and CMR rate increased to 80.4% and 55.4%, respectively. Eleven patients (12%) experienced disease progression, and seven patients (7.6%) had stable disease. Among 34 patients who achieved PMR in the interim imaging test, 14 (41.2%) patients achieved CMR at the end of BGD treatment. In the subgroup of patients treated with BGD only as a second line of chemotherapy (n = 34), ORR was 79.4% while CMR rate was 64.7%. Out of 44 patients being refractory to the first line of chemotherapy, 30 (68.2%) patients achieved overall response and 34.1% achieved CMR. Among the whole study population, five patients were refractory to BEACOPP given as the first line of chemotherapy. All these patients achieved response and two of them (40%) achieved CMR after BGD. The autoHCT was successfully performed after BGD therapy in 42 (45.7%) patients. Furthermore, 16 (17.4%) patients underwent alloHCT after BGD therapy (Table 3). Among 21 patients treated with autoHCT before BGD therapy, 18 (85.7%) achieved response, 11 (52.4%) CMR, and 9 (42.9%) patients proceeded to alloHCT. PFS and OS are shown as Kaplan-Meier curves in Figs. 1 and 2. With a median follow-up of 18 months (range from 3 to 51 months), the median PFS for the overall population was 21 months while the median OS was not reached. PFS and OS rates at 2 years were 44.5% (95%CI: 33.7–58.8) and 75% (95%CI: 64.8–86.7), respectively. There were no differences between patients with relapsed or primary refractory HL in terms of PFS and OS (Figs. 3 and 4, P > 0.05). Similarly, no statistical differences in PFS and OS were noted between patients in whom BGD was used after first line or subsequent line of chemotherapy (Figs. 5 and 6, P > 0.05). Of note, most of the patients (80%) who responded to BGD maintain their response for at least 6 months (Fig. 1). In a subgroup of 9 patients ≥ 60 years old, 5 (55.6%) patients achieved CMR, 2 (22.2%)—PMR (ORR 77.8%), and 2 patients progressed during BGD treatment. PFS at 18 months was 62.2% (95%CI: 35.5–100) and OS at 23 months was 87.5% (95%CI: 67.3–100) (Figs. 7 and 8). Table 3 Response to BGD therapy
No. % (95%CI)
Interim (after 2–3 courses) n = 86
- PMDa 6 7 (1.6–12.4)
- SMDb 13 15.1 (7.5–22.7)
- PMRc 34 39.5 (29.2–49.9)
- CMRd 33 38.4 (28.1–48.6)
- ORRe 67 77.9 (69.1–86.7)
End of BGDf therapy n = 92
- PMDa 11 12 (5.3–18.6)
- SMDb 7 7.6 (2.2–13.0)
- PMRc 23 25 (16.2–33.8)
- CMRd 51 55.4 (45.3–65.6)
- ORRe 74 80.4 (2.3–88.5)
AutoHCTg after BGD therapy
- Yes 42 45.7
- No 50 54.3
AlloHCTh after BGD therapy
- Yes 16 17.4
- No 76 82.6
aPMD, progressive metabolic disease
bSMD, stable metabolic disease
cPMR, partial metabolic response
dCMR, complete metabolic response
eORR, overall response rate
fBGD, bendamustine, gemcitabine, dexamethasone
gautoHCT, autologous hematopoietic cell transplantation
halloHCT, allogeneic hematopoietic cell transplantation
Fig. 1 Progression-free survival (PFS) for the entire population
Fig. 2 Overall survival (OS) for the entire population
Fig. 3 Progression-free survival (PFS) for the subjects with relapsed or primary refractory Hodgkin lymphoma (HL)
Fig. 4 Overall survival (OS) for the subjects with relapsed or primary refractory Hodgkin lymphoma (HL)
Fig. 5 Progression-free survival (PFS) for patients treated with BGD as second or subsequent line of chemotherapy
Fig. 6 Overall survival (OS) for patients treated with BGD as second or subsequent line of chemotherapy
Fig. 7 Progression-free survival (PFS) for the subgroup of elderly patients (≥ 60 years)
Fig. 8 Overall survival (OS) for the subgroup of elderly patients (≥ 60 years)
Toxicity of BGD
The treatment-related AEs, mainly grade 1 or 2, were observed in 64 (69.6%) patients. Among grade ≥ 3 hematological toxicities, anemia was reported in 15.2% cases, thrombocytopenia in 20.7%, and neutropenia in 22.8% individuals. Severe non-hematological toxicities included infections (10.9%), alanine and/or aspartate aminotransferase (ALT or AST) increase (2.2%), and skin rush (1.1%). We recorded one death from unknown reasons during BGD therapy. All AEs reported during BGD therapy are shown in Table 4. In the subgroup of elderly patients (≥ 60 years), anemia and thrombocytopenia of grade 3 or 4 occurred in 2 (22.2%) patients, while neutropenia was found in 1 (11.1%) patient. Moreover, 2 (22.2%) patients experienced grade ≥ 3 infection, and 1 (11.1%) grade 3 skin rash in this subgroup. Table 4 Toxicity of BGD therapy
Toxicity Grade 1–2
No. (%) Grade 3–4
No. (%)
Hematological:
- Anemia 37 (40.2) 14 (15.2)
- Thrombocytopenia 25 (27.2) 19 (20.7)
- Neutropenia 19 (20.7) 21 (22.8)
Non-hematological:
- Infection 20 (21.7) 10 (10.9)
- ALT/ASTa increase 0 2 (2.2)
- Skin rush 7 (7.6) 1 (1.1)
- Fatigue 4 (4.3) 0
- Diarrhea 1 (1.1) 0
- Thrombotic events 2 (2.2) 0
- Guillain-Barré syndrome 1 (1.1) 0
- Autoimmune thyroiditis 1 (1.1) 0
Death from unknown reasons 1 (1.1)
aAlanine/aspartate aminotransferase
Discussion
Despite the significant progress in the management of patients with HL, relapsed and refractory disease constitutes a big challenge. According to the current treatment standards, high-dose chemotherapy followed by autoHCT has to be regarded as treatment of choice in the first relapse or primary progressive disease. However, even in the era of new agents such as brentuximab vedotin (BV) or immune checkpoint inhibitors, there are no accepted standards for salvage treatment before autoHCT. In the PLRG allied centers BGD was used since 2012 when the first cases of successful outcome of heavily pretreated patients were reported [16]. We had started to use BGD since both bendamustine and gemcitabine were effective in monotherapy as well as in combination with other agents.
Gemcitabine, a cytidine analog, was assessed in several studies. Kuruvilla et al. showed satisfactory (62%) response rate to GDP (gemcitabine, dexamethasone, and cisplatin) as a second-line therapy in patients with R/R HL [19]. Gemcitabine and vinerolbine combination showed ORR of 72% and 35% of CR [20]. In similar population, four-agent combination of gemcitabine with ifosfamide, vinorelbine, and prednisolone (IGEV) or double-agent schema of vinorelbine and pegylated liposomal doxorubicin (GVD) resulted in ORR of 81.3% and 70%, respectively [8, 9]. Bendamustine, another component of BGD, is a molecule containing the purine analog and the alkylating group. It was assessed in a phase II trial in heavily pretreated patients with HL (including those with relapse after auto- or alloHCT) at the dose of 120 mg/m2 and resulted in the intent-to-treat ORR of 53%, with CRs of 33% [11].
The combination of bendamustine with gemcitabine and vinorelbine (BeGEV) was first assessed in a multicenter phase II study by Santoro et al. [14]. The authors have demonstrated high efficacy of BeGEV as a second-line treatment in autoHCT-eligible patients (ORR 83%, CR 75%). In our retrospective analysis, ORR of BGD was similar to BeGEV although patient characteristics with regard to age and number of prior treatment regimens differ [14]. Moreover, almost one-fourth of patients in our study had been treated using autoHCT. This also most likely explains slightly higher rate of hematological toxicities at grade 3 or 4 in comparison to BeGEV. In contrast, severe non-hematological AEs occurred at similar incidence rates. We did not observe increased pulmonary toxicity which was reported by Cohen et al. in his cohort of patients. This might be due to the use of high dose of steroids (dexamethasone) in our regimen [21]. However, in spite of high efficacy of BGD in relation to ORR and CMR rate, estimated PFS in our study seems to be rather short (21 months). Most likely, this is a consequence of the large group of heavily pretreated patients (up to 6 previous line of therapy) including those after auto- and alloHCT and the subgroup of elderly patients in this cohort.
DHAP and ICE are among of the most commonly used salvage chemotherapy regimens in HL. Similar efficacy of these regimens as the second-line treatment was shown resulting in ORR of 88% for both, while CRs of 21% for DHAP and of 26.2% for ICE [5, 6]. Despite more heavily pretreated patients in our study, we report comparable ORR (80.4%) and much higher CMR rate (55.4%). Moreover, the difference in relation to CR rate increases in sub-analysis restricted to patients treated with BGD as the second line of chemotherapy (64.7%). The optimal number of BGD cycles is four, since about 40% of patients improved their response at the end of treatment compared to the interim assessment.
Most patients (80.4%) in this study were treated with ABVD as the first line of chemotherapy. Out of 13 patients being initially treated with BEACOPP, 5 (38.5%) patients were refractory to this regimen and all these patients achieved ORR after BGD therapy with CMR rate of 40%. In view of the fact that there are not many effective treatment options to overcome the BEACOPP refractoriness, this finding seems very interesting and encouraging for further studies.
In recent years, there have been many new agents evaluated for patients with R/R HL such as BV and immune checkpoint inhibitors. Brentuximab vedotin—an anti-CD30 antibody conjugated to antimicrotubule agent, monomethyl auristatin E—showed ORR of 75% and CR rate of 34% in heavily pretreated patients with HL after autoHCT [22]. Furthermore, BV showed similar efficacy as a second-line therapy in R/R HL (ORR 68%, CR 35%), and 89% of the subjects were able to proceed to autoHCT [23]. Addition of bendamustine to BV seems to increase its efficacy [12, 13]. However, in comparison to BGD regimen, BV does not appear to be superior both in monotherapy and in combination with bendamustine. Immune checkpoint inhibitors, mainly antibodies against programmed cell death protein 1 (PD-1) such as nivolumab or pembrolizumab, showed high efficacy as a salvage therapy for patients with R/R HL [24–27]. Ansell et al. reported ORR 87% in the heavily pretreated HL patients although CR rate was relatively low (17%) compared to BGD [24]. The authors reported similar incidence of AEs of any grade (78% vs. 69.6%) but relatively fewer cases of grade ≥ 3 AEs (22% vs. 38%) during nivolumab therapy when compared to BGD therapy [24].
The high efficacy of BGD in patients after failure of autoHCT is worth noting. This is a very challenging group, in which effective chemotherapy followed by alloHCT is the only option to achieve long-lasting remission. In this population checkpoint inhibitors, nivolumab and pembrolizumab resulted in high ORR rate (69% and 73%, respectively). However, once again, CR rates (16% and 14%, respectively) appear lower compared to BGD in our study (55.4%) and there are still some concerns about the increased incidence of immune complications after alloHCT in patients treated with immune checkpoint inhibitors before transplant [25, 26, 28, 29].
Another interesting finding of this study refers to elderly HL patients. We showed that in the patients at or above the age of 60 years BGD regimen has a similar efficacy (ORR 77.8%, CMR 55.6%) than in younger patients. Moreover, BGD-related toxicity seems to be acceptable in this subgroup.
Relatively small number of subjects included in the analysis as well as its retrospective nature and the lack of metabolic assessment in all patients are the major limitations of this study. Another important limitation of our study is a long accrual time. However, during this period, most of our patients were treated uniformly since novel therapies were not available due to reimbursement hurdles. Addition limitation may pose a large number of accruing centers. However, most of PLRG allied centers are reference centers with good-quality data management which somehow mitigate this flaw. However, our data clearly indicate that BGD which has a high rate of obtaining ORR and a relatively good time in response maintaining (5–6 months in 80% of patients) and an acceptable toxicity profile seems to provide a very good option for R/R HL patients even after BEACOPP first-line chemotherapy. In several patients, it opened a window to perform either autologous or allogeneic transplantation. Despite the fact that in recent years new treatment options, including BV and checkpoint inhibitors, showed promising results in treatment of patients with R/R HL, neither of them as yet is formally approved in the second-line treatment for HL. In addition, although pharmaco-economy was not a subject of this study, we speculate that BGD treatment may be a relatively cheap option. Therefore, we conclude that the BGD should be considered a viable option for patients with R/R HL and may serve as a bridge for individuals being candidates for auto- or alloHCT.
Author contributions
WKP, JMZ, and SG designed the study; all authors except for JMZ, AK, and AW enrolled patients; SG, RS, AK, and AW performed the bioinformatics and statistical analysis; RS and JMZ wrote the paper. All authors read and revised the manuscript critically.
Data availability
Not applicable
Code availability
Not applicable
Declarations
Ethics approval
According to Polish regulations, this was a retrospective study and it does not require approval of the bioethical committee. The study was approved by the board of The Polish Lymphoma Research Group.
Consent to participate
Not applicable
Consent for publication
Not applicable
Conflict of interest
The authors declare no conflict of interest.
The original version of this article was revised: This article was originally published with an incorrect affiliation. It should be 9 ( Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wrocław Medical University, Wrocław, Poland).
Wojciech Spychałowicz passed away during the writing of this article.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Change history
3/24/2021
A Correction to this paper has been published: 10.1007/s00277-021-04503-1 | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33625572 | 19,756,838 | 2021-07 |
What was the administration route of drug 'GEMCITABINE'? | High efficacy of BGD (bendamustine, gemcitabine, and dexamethasone) in relapsed/refractory Hodgkin Lymphoma.
The optimal salvage therapy in relapsed/refractory Hodgkin lymphoma (R/R HL) has not been defined so far. The goal of this multicenter retrospective study was to evaluate efficacy and safety of BGD (bendamustine, gemcitabine, dexamethasone) as a second or subsequent line of therapy in classical R/R HL. We have evaluated 92 consecutive R/R HL patients treated with BGD. Median age was 34.5 (19-82) years. Fifty-eight patients (63%) had received 2 or more lines of chemotherapy, 32 patients (34.8%) radiotherapy, and 21 patients (22.8%) an autologous hematopoietic stem cell transplantation (autoHCT). Forty-four patients (47.8%) were resistant to first line of chemotherapy. BGD therapy consisted of bendamustine 90 mg/m2 on days 1 and 2, gemcitabine 800 mg/m2 on days 1 and 4, dexamethasone 40 mg on days 1-4. Median number of BGD cycles was 4 (2-7). The following adverse events ≥ 3 grade were noted: neutropenia (22.8%), thrombocytopenia (20.7%), anemia (15.2%), infections (10.9%), AST/ALT increase (2.2%), and skin rush (1.1%). After BGD therapy, 51 (55.4%) patients achieved complete remission, 23 (25%)-partial response, 7 (7.6%)-stable disease, and 11 (12%) patients experienced progression disease. AutoHCT was conducted in 42 (45.7%) patients after BGD therapy, and allogeneic HCT (alloHCT) in 16 (17.4%) patients. Median progression-free survival was 21 months. BGD is a highly effective, well-tolerated salvage regimen for patients with R/R HL, providing an excellent bridge to auto- or alloHCT.
Introduction
Hodgkin lymphoma (HL), accounting for approximately 10% of all lymphomas, is one of the most curable malignancies. However, up to 30% of patients do not respond to the first-line therapy or relapse after initial response [1]. For patients with relapsed or refractory disease, salvage chemotherapy followed by high-dose chemotherapy with autologous hematopoietic stem cell transplantation (autoHCT) is still the treatment of choice [2, 3]. The long-term cure can be obtained in up to 80% of patients provided a complete metabolic remission (CMR) is achieved before transplant [4]. Consequently, the optimal salvage regimen should be highly effective but also should have a high mobilization rate. However, the standard for salvage chemotherapy before autoHCT is still not established. The most commonly used are platinum-based ICE (ifosfamide, carboplatin, etoposide); DHAP (dexamethasone, cytarabine, cisplatin); ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin); and gemcitabine-based GDP (gemcitabine, dexamethasone, cisplatin), GVD (gemcitabine, vinorelbine, liposomal doxorubicin), IGEV (ifosfamide, gemcitabine, vinorelbine), and GCD (gemcitabine, carboplatin, dexamethasone) combination chemotherapy with response rates ranging between 54 and 88% and mobilization rate of 86–100% [5–10]. Due to rather low rate of complete responses (CRs) achieved with the most frequently used salvage regimens, there is the persisting need to develop new salvage regimens especially in the second-line treatment. Recently, bendamustine both in monotherapy and in combination with other drugs was shown to induce high response rates with an acceptable toxicity profile in third or more line in patients with relapsed/refractory (R/R) HL [11–13]. Experience with bendamustine in the second line is very limited. Santoro et al. modified their original IGEV protocol substituting ifosfamide with bendamustine achieving a very high efficacy as a second-line therapy in patients with R/R HL [9, 14]. The Polish Lymphoma Research Group (PLRG) proposed replacement of vinorelbine with dexamethasone (bendamustine, gemcitabine, dexamethasone; BGD regimen) and is carrying out a prospective, multicenter study in patients with progressive disease during or after ABVD treatment [15] based on the very good preliminary results obtained with BGD in heavily pretreated R/R HL patients [16]. Here we report long-term outcome of these patients enrolled to the multicenter retrospective PLRG study aiming at evaluating the efficacy and toxicity of BGD in a real-life setting.
Methods
Study design
We retrospectively reviewed the data of all patients aged ≥ 18 years with R/R HL who were treated with BGD regimen between April 2012 and December 2018 in 15 centers allied within the PLRG. Primary refractory HL was defined as no CMR achieved after the first line or if progression occurred within 3 months after completion of the first-line chemotherapy. In patients with relapsed HL, the disease reappeared later after achieving CMR. Patients’ records were reviewed to obtain patient characteristics at diagnosis and the start of BGD treatment, including clinical stage according to the Lugano system, presence of B symptoms, extranodal site involvement, and bulky disease.
Treatment and response criteria
The dosage and administration schedule of BGD is shown in Table 1. The interim imaging assessment was performed after second or third cycle of BGD in 86 patients (93.5%). Patients could continue BGD treatment up to 4 cycles or longer at the discretion of a treating physician. The metabolic response to BGD treatment at the end of the therapy was assessed according to the Lugano treatment response criteria using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) [17]. The 18F-FDG uptake less than in the liver was defined as CMR. The higher 18F-FDG uptake, but decreased from baseline, was defined as partial metabolic response (PMR). In case of no significant change in 18F-FDG uptake from baseline or new FDG-avid foci, stable or progressive disease (SD or PD) were diagnosed, respectively. The overall response rate (ORR) was defined as the sum of CMR and PMR. Table 1 BGD regimen repeated every 4 weeks
Drug Dose Route of administrationa Day of administration
Bendamustine 90 mg/m2 i.v. 60 min 1 and 2
Gemcitabine 800 mg/m2 i.v. 30 min 1 and 4
Dexamethasone 40 mg i.v. or p.o. 1, 2, 3, and 4
ai.v., intravenous; p.o., per os
Study end-points and statistical analysis
Primary end-point was the percentage of CMR and ORR whereas progression-free survival (PFS) and overall survival (OS) as well as adverse events (AEs) were secondary end-points. PFS was defined as the time from start of BGD treatment to the date of documented disease progression, death from any cause, or start of new anticancer therapy. The patients at the time of autoHCT or allogeneic hematopoietic stem cell transplantation (alloHCT) were censored for PFS since transplants were not considered a new anticancer therapy. OS was defined as the time from the first BGD administration to death for any reason. AEs were evaluated using Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 [18]. PFS and OS were estimated using the Kaplan-Meier method. Ninety-five percent confidence intervals (CIs) for the survival curves were calculated for chosen times. The log-rank test was performed to compare survival curves between groups. Two-sided P values ≤ 0.05 were considered statistically significant. The statistics were performed descriptively. Statistical analysis was performed using Statistica software (version 13.1, Tulsa, OK, USA) and R statistical software package version 4.0.1. (R Foundation for Statistical Computing, http://www.r-project.org).
Results
Patients’ characteristics
The median age of 92 analyzed patients was 34.5 (range from 19 to 82 years) years with 9 patients at the age or above 60 years. More than 60% of patients were in advanced stages of HL at the time of diagnosis (III and IV according to the Lugano classification). Median number of prior chemotherapy lines was 2 (range from 1 to 6 lines). Thirty-four patients (37%) had previously been treated with only one line of chemotherapy. ABVD was the first-line therapy in 80.4% cases. Forty-four patients (47.8%) were primary refractory to the first-line chemotherapy. Almost 35% of patients had received radiotherapy prior to BGD treatment. Twenty-one patients (22.8%) underwent autoHCT, and three patients (3.3%) underwent alloHCT prior to BGD treatment. The median number of BGD cycles was 4 (range from 2 to 7 cycles). Demographic and clinical data are shown in Table 2. Table 2 Demographics and clinical characteristics of 92 subjects
Characteristic No. %
Age, years
- Median (range) 34.5 (19–82)
- ≥ 60 years 9 9.7
Sex
- Male 44 47.8
- Female 48 52.2
Lugano classification at diagnosis/before BGDa
- I 0/3 0/3.3
- II 33/38 35.9/41.3
- III 25/9 27.2/9.8
- IV 34/42 37/45.7
B-symptoms at diagnosis/before BGDa 67/27 72.9/29.3
Extranodal site involvement at diagnosis/before BGDa 32/39 34.8/42.4
Bulky disease at diagnosis/before BGDa 32/10 34.8/10.9
First-line treatment
ABVDb 74 80.4
BEACOPPc 13 14.1
Otherd 5 5.4
No. of previous treatment lines
- 1. 34 37
- 2. 26 28.3
- 3. 16 17.4
- 4. 9 9.8
- 5. 3 3.3
- 6. 4 4.3
Primary refractory to 1st-line treatment 44 47.8
Patents with late (> 12 months) relapse 20 21.7
No. of BGDa courses
- Median (range) 4 (2–7)
Radiotherapy prior to BGDa 32 34.8
Prior autoHCTe 21 22.8
Prior alloHCTf 3 3.3
aBGD, bendamustine, gemcitabine, dexamethasone
bABVD, adriamycin, bleomycin, vinblastine, dacarbazine
cBEACOPP, bleomycin, cyclophosphamide, doxorubicin, etoposide, prednisone, procarbazine, vincristine
dOther: PVAG, prednisone, vincristine, adriamycin, gemcitabine; OEPA/COPDAC, vincristine, etoposide, prednisone, doxorubicin/ cyclophosphamide, vincristine, prednisone, dacarbazine
eautoHCT, autologous hematopoietic cell transplantation
falloHCT, allogeneic hematopoietic cell transplantation
Efficacy of BGD
Out of 86 patients who were assessed by interim PET/CT after 2 or 3 cycles of BGD, 67 (77.9%) patients achieved overall response, including 33 (38.4%) CMRs. At the end of BGD therapy, ORR and CMR rate increased to 80.4% and 55.4%, respectively. Eleven patients (12%) experienced disease progression, and seven patients (7.6%) had stable disease. Among 34 patients who achieved PMR in the interim imaging test, 14 (41.2%) patients achieved CMR at the end of BGD treatment. In the subgroup of patients treated with BGD only as a second line of chemotherapy (n = 34), ORR was 79.4% while CMR rate was 64.7%. Out of 44 patients being refractory to the first line of chemotherapy, 30 (68.2%) patients achieved overall response and 34.1% achieved CMR. Among the whole study population, five patients were refractory to BEACOPP given as the first line of chemotherapy. All these patients achieved response and two of them (40%) achieved CMR after BGD. The autoHCT was successfully performed after BGD therapy in 42 (45.7%) patients. Furthermore, 16 (17.4%) patients underwent alloHCT after BGD therapy (Table 3). Among 21 patients treated with autoHCT before BGD therapy, 18 (85.7%) achieved response, 11 (52.4%) CMR, and 9 (42.9%) patients proceeded to alloHCT. PFS and OS are shown as Kaplan-Meier curves in Figs. 1 and 2. With a median follow-up of 18 months (range from 3 to 51 months), the median PFS for the overall population was 21 months while the median OS was not reached. PFS and OS rates at 2 years were 44.5% (95%CI: 33.7–58.8) and 75% (95%CI: 64.8–86.7), respectively. There were no differences between patients with relapsed or primary refractory HL in terms of PFS and OS (Figs. 3 and 4, P > 0.05). Similarly, no statistical differences in PFS and OS were noted between patients in whom BGD was used after first line or subsequent line of chemotherapy (Figs. 5 and 6, P > 0.05). Of note, most of the patients (80%) who responded to BGD maintain their response for at least 6 months (Fig. 1). In a subgroup of 9 patients ≥ 60 years old, 5 (55.6%) patients achieved CMR, 2 (22.2%)—PMR (ORR 77.8%), and 2 patients progressed during BGD treatment. PFS at 18 months was 62.2% (95%CI: 35.5–100) and OS at 23 months was 87.5% (95%CI: 67.3–100) (Figs. 7 and 8). Table 3 Response to BGD therapy
No. % (95%CI)
Interim (after 2–3 courses) n = 86
- PMDa 6 7 (1.6–12.4)
- SMDb 13 15.1 (7.5–22.7)
- PMRc 34 39.5 (29.2–49.9)
- CMRd 33 38.4 (28.1–48.6)
- ORRe 67 77.9 (69.1–86.7)
End of BGDf therapy n = 92
- PMDa 11 12 (5.3–18.6)
- SMDb 7 7.6 (2.2–13.0)
- PMRc 23 25 (16.2–33.8)
- CMRd 51 55.4 (45.3–65.6)
- ORRe 74 80.4 (2.3–88.5)
AutoHCTg after BGD therapy
- Yes 42 45.7
- No 50 54.3
AlloHCTh after BGD therapy
- Yes 16 17.4
- No 76 82.6
aPMD, progressive metabolic disease
bSMD, stable metabolic disease
cPMR, partial metabolic response
dCMR, complete metabolic response
eORR, overall response rate
fBGD, bendamustine, gemcitabine, dexamethasone
gautoHCT, autologous hematopoietic cell transplantation
halloHCT, allogeneic hematopoietic cell transplantation
Fig. 1 Progression-free survival (PFS) for the entire population
Fig. 2 Overall survival (OS) for the entire population
Fig. 3 Progression-free survival (PFS) for the subjects with relapsed or primary refractory Hodgkin lymphoma (HL)
Fig. 4 Overall survival (OS) for the subjects with relapsed or primary refractory Hodgkin lymphoma (HL)
Fig. 5 Progression-free survival (PFS) for patients treated with BGD as second or subsequent line of chemotherapy
Fig. 6 Overall survival (OS) for patients treated with BGD as second or subsequent line of chemotherapy
Fig. 7 Progression-free survival (PFS) for the subgroup of elderly patients (≥ 60 years)
Fig. 8 Overall survival (OS) for the subgroup of elderly patients (≥ 60 years)
Toxicity of BGD
The treatment-related AEs, mainly grade 1 or 2, were observed in 64 (69.6%) patients. Among grade ≥ 3 hematological toxicities, anemia was reported in 15.2% cases, thrombocytopenia in 20.7%, and neutropenia in 22.8% individuals. Severe non-hematological toxicities included infections (10.9%), alanine and/or aspartate aminotransferase (ALT or AST) increase (2.2%), and skin rush (1.1%). We recorded one death from unknown reasons during BGD therapy. All AEs reported during BGD therapy are shown in Table 4. In the subgroup of elderly patients (≥ 60 years), anemia and thrombocytopenia of grade 3 or 4 occurred in 2 (22.2%) patients, while neutropenia was found in 1 (11.1%) patient. Moreover, 2 (22.2%) patients experienced grade ≥ 3 infection, and 1 (11.1%) grade 3 skin rash in this subgroup. Table 4 Toxicity of BGD therapy
Toxicity Grade 1–2
No. (%) Grade 3–4
No. (%)
Hematological:
- Anemia 37 (40.2) 14 (15.2)
- Thrombocytopenia 25 (27.2) 19 (20.7)
- Neutropenia 19 (20.7) 21 (22.8)
Non-hematological:
- Infection 20 (21.7) 10 (10.9)
- ALT/ASTa increase 0 2 (2.2)
- Skin rush 7 (7.6) 1 (1.1)
- Fatigue 4 (4.3) 0
- Diarrhea 1 (1.1) 0
- Thrombotic events 2 (2.2) 0
- Guillain-Barré syndrome 1 (1.1) 0
- Autoimmune thyroiditis 1 (1.1) 0
Death from unknown reasons 1 (1.1)
aAlanine/aspartate aminotransferase
Discussion
Despite the significant progress in the management of patients with HL, relapsed and refractory disease constitutes a big challenge. According to the current treatment standards, high-dose chemotherapy followed by autoHCT has to be regarded as treatment of choice in the first relapse or primary progressive disease. However, even in the era of new agents such as brentuximab vedotin (BV) or immune checkpoint inhibitors, there are no accepted standards for salvage treatment before autoHCT. In the PLRG allied centers BGD was used since 2012 when the first cases of successful outcome of heavily pretreated patients were reported [16]. We had started to use BGD since both bendamustine and gemcitabine were effective in monotherapy as well as in combination with other agents.
Gemcitabine, a cytidine analog, was assessed in several studies. Kuruvilla et al. showed satisfactory (62%) response rate to GDP (gemcitabine, dexamethasone, and cisplatin) as a second-line therapy in patients with R/R HL [19]. Gemcitabine and vinerolbine combination showed ORR of 72% and 35% of CR [20]. In similar population, four-agent combination of gemcitabine with ifosfamide, vinorelbine, and prednisolone (IGEV) or double-agent schema of vinorelbine and pegylated liposomal doxorubicin (GVD) resulted in ORR of 81.3% and 70%, respectively [8, 9]. Bendamustine, another component of BGD, is a molecule containing the purine analog and the alkylating group. It was assessed in a phase II trial in heavily pretreated patients with HL (including those with relapse after auto- or alloHCT) at the dose of 120 mg/m2 and resulted in the intent-to-treat ORR of 53%, with CRs of 33% [11].
The combination of bendamustine with gemcitabine and vinorelbine (BeGEV) was first assessed in a multicenter phase II study by Santoro et al. [14]. The authors have demonstrated high efficacy of BeGEV as a second-line treatment in autoHCT-eligible patients (ORR 83%, CR 75%). In our retrospective analysis, ORR of BGD was similar to BeGEV although patient characteristics with regard to age and number of prior treatment regimens differ [14]. Moreover, almost one-fourth of patients in our study had been treated using autoHCT. This also most likely explains slightly higher rate of hematological toxicities at grade 3 or 4 in comparison to BeGEV. In contrast, severe non-hematological AEs occurred at similar incidence rates. We did not observe increased pulmonary toxicity which was reported by Cohen et al. in his cohort of patients. This might be due to the use of high dose of steroids (dexamethasone) in our regimen [21]. However, in spite of high efficacy of BGD in relation to ORR and CMR rate, estimated PFS in our study seems to be rather short (21 months). Most likely, this is a consequence of the large group of heavily pretreated patients (up to 6 previous line of therapy) including those after auto- and alloHCT and the subgroup of elderly patients in this cohort.
DHAP and ICE are among of the most commonly used salvage chemotherapy regimens in HL. Similar efficacy of these regimens as the second-line treatment was shown resulting in ORR of 88% for both, while CRs of 21% for DHAP and of 26.2% for ICE [5, 6]. Despite more heavily pretreated patients in our study, we report comparable ORR (80.4%) and much higher CMR rate (55.4%). Moreover, the difference in relation to CR rate increases in sub-analysis restricted to patients treated with BGD as the second line of chemotherapy (64.7%). The optimal number of BGD cycles is four, since about 40% of patients improved their response at the end of treatment compared to the interim assessment.
Most patients (80.4%) in this study were treated with ABVD as the first line of chemotherapy. Out of 13 patients being initially treated with BEACOPP, 5 (38.5%) patients were refractory to this regimen and all these patients achieved ORR after BGD therapy with CMR rate of 40%. In view of the fact that there are not many effective treatment options to overcome the BEACOPP refractoriness, this finding seems very interesting and encouraging for further studies.
In recent years, there have been many new agents evaluated for patients with R/R HL such as BV and immune checkpoint inhibitors. Brentuximab vedotin—an anti-CD30 antibody conjugated to antimicrotubule agent, monomethyl auristatin E—showed ORR of 75% and CR rate of 34% in heavily pretreated patients with HL after autoHCT [22]. Furthermore, BV showed similar efficacy as a second-line therapy in R/R HL (ORR 68%, CR 35%), and 89% of the subjects were able to proceed to autoHCT [23]. Addition of bendamustine to BV seems to increase its efficacy [12, 13]. However, in comparison to BGD regimen, BV does not appear to be superior both in monotherapy and in combination with bendamustine. Immune checkpoint inhibitors, mainly antibodies against programmed cell death protein 1 (PD-1) such as nivolumab or pembrolizumab, showed high efficacy as a salvage therapy for patients with R/R HL [24–27]. Ansell et al. reported ORR 87% in the heavily pretreated HL patients although CR rate was relatively low (17%) compared to BGD [24]. The authors reported similar incidence of AEs of any grade (78% vs. 69.6%) but relatively fewer cases of grade ≥ 3 AEs (22% vs. 38%) during nivolumab therapy when compared to BGD therapy [24].
The high efficacy of BGD in patients after failure of autoHCT is worth noting. This is a very challenging group, in which effective chemotherapy followed by alloHCT is the only option to achieve long-lasting remission. In this population checkpoint inhibitors, nivolumab and pembrolizumab resulted in high ORR rate (69% and 73%, respectively). However, once again, CR rates (16% and 14%, respectively) appear lower compared to BGD in our study (55.4%) and there are still some concerns about the increased incidence of immune complications after alloHCT in patients treated with immune checkpoint inhibitors before transplant [25, 26, 28, 29].
Another interesting finding of this study refers to elderly HL patients. We showed that in the patients at or above the age of 60 years BGD regimen has a similar efficacy (ORR 77.8%, CMR 55.6%) than in younger patients. Moreover, BGD-related toxicity seems to be acceptable in this subgroup.
Relatively small number of subjects included in the analysis as well as its retrospective nature and the lack of metabolic assessment in all patients are the major limitations of this study. Another important limitation of our study is a long accrual time. However, during this period, most of our patients were treated uniformly since novel therapies were not available due to reimbursement hurdles. Addition limitation may pose a large number of accruing centers. However, most of PLRG allied centers are reference centers with good-quality data management which somehow mitigate this flaw. However, our data clearly indicate that BGD which has a high rate of obtaining ORR and a relatively good time in response maintaining (5–6 months in 80% of patients) and an acceptable toxicity profile seems to provide a very good option for R/R HL patients even after BEACOPP first-line chemotherapy. In several patients, it opened a window to perform either autologous or allogeneic transplantation. Despite the fact that in recent years new treatment options, including BV and checkpoint inhibitors, showed promising results in treatment of patients with R/R HL, neither of them as yet is formally approved in the second-line treatment for HL. In addition, although pharmaco-economy was not a subject of this study, we speculate that BGD treatment may be a relatively cheap option. Therefore, we conclude that the BGD should be considered a viable option for patients with R/R HL and may serve as a bridge for individuals being candidates for auto- or alloHCT.
Author contributions
WKP, JMZ, and SG designed the study; all authors except for JMZ, AK, and AW enrolled patients; SG, RS, AK, and AW performed the bioinformatics and statistical analysis; RS and JMZ wrote the paper. All authors read and revised the manuscript critically.
Data availability
Not applicable
Code availability
Not applicable
Declarations
Ethics approval
According to Polish regulations, this was a retrospective study and it does not require approval of the bioethical committee. The study was approved by the board of The Polish Lymphoma Research Group.
Consent to participate
Not applicable
Consent for publication
Not applicable
Conflict of interest
The authors declare no conflict of interest.
The original version of this article was revised: This article was originally published with an incorrect affiliation. It should be 9 ( Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wrocław Medical University, Wrocław, Poland).
Wojciech Spychałowicz passed away during the writing of this article.
Publisher’s note
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Change history
3/24/2021
A Correction to this paper has been published: 10.1007/s00277-021-04503-1 | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33625572 | 19,756,838 | 2021-07 |
What was the dosage of drug 'BENDAMUSTINE HYDROCHLORIDE'? | High efficacy of BGD (bendamustine, gemcitabine, and dexamethasone) in relapsed/refractory Hodgkin Lymphoma.
The optimal salvage therapy in relapsed/refractory Hodgkin lymphoma (R/R HL) has not been defined so far. The goal of this multicenter retrospective study was to evaluate efficacy and safety of BGD (bendamustine, gemcitabine, dexamethasone) as a second or subsequent line of therapy in classical R/R HL. We have evaluated 92 consecutive R/R HL patients treated with BGD. Median age was 34.5 (19-82) years. Fifty-eight patients (63%) had received 2 or more lines of chemotherapy, 32 patients (34.8%) radiotherapy, and 21 patients (22.8%) an autologous hematopoietic stem cell transplantation (autoHCT). Forty-four patients (47.8%) were resistant to first line of chemotherapy. BGD therapy consisted of bendamustine 90 mg/m2 on days 1 and 2, gemcitabine 800 mg/m2 on days 1 and 4, dexamethasone 40 mg on days 1-4. Median number of BGD cycles was 4 (2-7). The following adverse events ≥ 3 grade were noted: neutropenia (22.8%), thrombocytopenia (20.7%), anemia (15.2%), infections (10.9%), AST/ALT increase (2.2%), and skin rush (1.1%). After BGD therapy, 51 (55.4%) patients achieved complete remission, 23 (25%)-partial response, 7 (7.6%)-stable disease, and 11 (12%) patients experienced progression disease. AutoHCT was conducted in 42 (45.7%) patients after BGD therapy, and allogeneic HCT (alloHCT) in 16 (17.4%) patients. Median progression-free survival was 21 months. BGD is a highly effective, well-tolerated salvage regimen for patients with R/R HL, providing an excellent bridge to auto- or alloHCT.
Introduction
Hodgkin lymphoma (HL), accounting for approximately 10% of all lymphomas, is one of the most curable malignancies. However, up to 30% of patients do not respond to the first-line therapy or relapse after initial response [1]. For patients with relapsed or refractory disease, salvage chemotherapy followed by high-dose chemotherapy with autologous hematopoietic stem cell transplantation (autoHCT) is still the treatment of choice [2, 3]. The long-term cure can be obtained in up to 80% of patients provided a complete metabolic remission (CMR) is achieved before transplant [4]. Consequently, the optimal salvage regimen should be highly effective but also should have a high mobilization rate. However, the standard for salvage chemotherapy before autoHCT is still not established. The most commonly used are platinum-based ICE (ifosfamide, carboplatin, etoposide); DHAP (dexamethasone, cytarabine, cisplatin); ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin); and gemcitabine-based GDP (gemcitabine, dexamethasone, cisplatin), GVD (gemcitabine, vinorelbine, liposomal doxorubicin), IGEV (ifosfamide, gemcitabine, vinorelbine), and GCD (gemcitabine, carboplatin, dexamethasone) combination chemotherapy with response rates ranging between 54 and 88% and mobilization rate of 86–100% [5–10]. Due to rather low rate of complete responses (CRs) achieved with the most frequently used salvage regimens, there is the persisting need to develop new salvage regimens especially in the second-line treatment. Recently, bendamustine both in monotherapy and in combination with other drugs was shown to induce high response rates with an acceptable toxicity profile in third or more line in patients with relapsed/refractory (R/R) HL [11–13]. Experience with bendamustine in the second line is very limited. Santoro et al. modified their original IGEV protocol substituting ifosfamide with bendamustine achieving a very high efficacy as a second-line therapy in patients with R/R HL [9, 14]. The Polish Lymphoma Research Group (PLRG) proposed replacement of vinorelbine with dexamethasone (bendamustine, gemcitabine, dexamethasone; BGD regimen) and is carrying out a prospective, multicenter study in patients with progressive disease during or after ABVD treatment [15] based on the very good preliminary results obtained with BGD in heavily pretreated R/R HL patients [16]. Here we report long-term outcome of these patients enrolled to the multicenter retrospective PLRG study aiming at evaluating the efficacy and toxicity of BGD in a real-life setting.
Methods
Study design
We retrospectively reviewed the data of all patients aged ≥ 18 years with R/R HL who were treated with BGD regimen between April 2012 and December 2018 in 15 centers allied within the PLRG. Primary refractory HL was defined as no CMR achieved after the first line or if progression occurred within 3 months after completion of the first-line chemotherapy. In patients with relapsed HL, the disease reappeared later after achieving CMR. Patients’ records were reviewed to obtain patient characteristics at diagnosis and the start of BGD treatment, including clinical stage according to the Lugano system, presence of B symptoms, extranodal site involvement, and bulky disease.
Treatment and response criteria
The dosage and administration schedule of BGD is shown in Table 1. The interim imaging assessment was performed after second or third cycle of BGD in 86 patients (93.5%). Patients could continue BGD treatment up to 4 cycles or longer at the discretion of a treating physician. The metabolic response to BGD treatment at the end of the therapy was assessed according to the Lugano treatment response criteria using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) [17]. The 18F-FDG uptake less than in the liver was defined as CMR. The higher 18F-FDG uptake, but decreased from baseline, was defined as partial metabolic response (PMR). In case of no significant change in 18F-FDG uptake from baseline or new FDG-avid foci, stable or progressive disease (SD or PD) were diagnosed, respectively. The overall response rate (ORR) was defined as the sum of CMR and PMR. Table 1 BGD regimen repeated every 4 weeks
Drug Dose Route of administrationa Day of administration
Bendamustine 90 mg/m2 i.v. 60 min 1 and 2
Gemcitabine 800 mg/m2 i.v. 30 min 1 and 4
Dexamethasone 40 mg i.v. or p.o. 1, 2, 3, and 4
ai.v., intravenous; p.o., per os
Study end-points and statistical analysis
Primary end-point was the percentage of CMR and ORR whereas progression-free survival (PFS) and overall survival (OS) as well as adverse events (AEs) were secondary end-points. PFS was defined as the time from start of BGD treatment to the date of documented disease progression, death from any cause, or start of new anticancer therapy. The patients at the time of autoHCT or allogeneic hematopoietic stem cell transplantation (alloHCT) were censored for PFS since transplants were not considered a new anticancer therapy. OS was defined as the time from the first BGD administration to death for any reason. AEs were evaluated using Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 [18]. PFS and OS were estimated using the Kaplan-Meier method. Ninety-five percent confidence intervals (CIs) for the survival curves were calculated for chosen times. The log-rank test was performed to compare survival curves between groups. Two-sided P values ≤ 0.05 were considered statistically significant. The statistics were performed descriptively. Statistical analysis was performed using Statistica software (version 13.1, Tulsa, OK, USA) and R statistical software package version 4.0.1. (R Foundation for Statistical Computing, http://www.r-project.org).
Results
Patients’ characteristics
The median age of 92 analyzed patients was 34.5 (range from 19 to 82 years) years with 9 patients at the age or above 60 years. More than 60% of patients were in advanced stages of HL at the time of diagnosis (III and IV according to the Lugano classification). Median number of prior chemotherapy lines was 2 (range from 1 to 6 lines). Thirty-four patients (37%) had previously been treated with only one line of chemotherapy. ABVD was the first-line therapy in 80.4% cases. Forty-four patients (47.8%) were primary refractory to the first-line chemotherapy. Almost 35% of patients had received radiotherapy prior to BGD treatment. Twenty-one patients (22.8%) underwent autoHCT, and three patients (3.3%) underwent alloHCT prior to BGD treatment. The median number of BGD cycles was 4 (range from 2 to 7 cycles). Demographic and clinical data are shown in Table 2. Table 2 Demographics and clinical characteristics of 92 subjects
Characteristic No. %
Age, years
- Median (range) 34.5 (19–82)
- ≥ 60 years 9 9.7
Sex
- Male 44 47.8
- Female 48 52.2
Lugano classification at diagnosis/before BGDa
- I 0/3 0/3.3
- II 33/38 35.9/41.3
- III 25/9 27.2/9.8
- IV 34/42 37/45.7
B-symptoms at diagnosis/before BGDa 67/27 72.9/29.3
Extranodal site involvement at diagnosis/before BGDa 32/39 34.8/42.4
Bulky disease at diagnosis/before BGDa 32/10 34.8/10.9
First-line treatment
ABVDb 74 80.4
BEACOPPc 13 14.1
Otherd 5 5.4
No. of previous treatment lines
- 1. 34 37
- 2. 26 28.3
- 3. 16 17.4
- 4. 9 9.8
- 5. 3 3.3
- 6. 4 4.3
Primary refractory to 1st-line treatment 44 47.8
Patents with late (> 12 months) relapse 20 21.7
No. of BGDa courses
- Median (range) 4 (2–7)
Radiotherapy prior to BGDa 32 34.8
Prior autoHCTe 21 22.8
Prior alloHCTf 3 3.3
aBGD, bendamustine, gemcitabine, dexamethasone
bABVD, adriamycin, bleomycin, vinblastine, dacarbazine
cBEACOPP, bleomycin, cyclophosphamide, doxorubicin, etoposide, prednisone, procarbazine, vincristine
dOther: PVAG, prednisone, vincristine, adriamycin, gemcitabine; OEPA/COPDAC, vincristine, etoposide, prednisone, doxorubicin/ cyclophosphamide, vincristine, prednisone, dacarbazine
eautoHCT, autologous hematopoietic cell transplantation
falloHCT, allogeneic hematopoietic cell transplantation
Efficacy of BGD
Out of 86 patients who were assessed by interim PET/CT after 2 or 3 cycles of BGD, 67 (77.9%) patients achieved overall response, including 33 (38.4%) CMRs. At the end of BGD therapy, ORR and CMR rate increased to 80.4% and 55.4%, respectively. Eleven patients (12%) experienced disease progression, and seven patients (7.6%) had stable disease. Among 34 patients who achieved PMR in the interim imaging test, 14 (41.2%) patients achieved CMR at the end of BGD treatment. In the subgroup of patients treated with BGD only as a second line of chemotherapy (n = 34), ORR was 79.4% while CMR rate was 64.7%. Out of 44 patients being refractory to the first line of chemotherapy, 30 (68.2%) patients achieved overall response and 34.1% achieved CMR. Among the whole study population, five patients were refractory to BEACOPP given as the first line of chemotherapy. All these patients achieved response and two of them (40%) achieved CMR after BGD. The autoHCT was successfully performed after BGD therapy in 42 (45.7%) patients. Furthermore, 16 (17.4%) patients underwent alloHCT after BGD therapy (Table 3). Among 21 patients treated with autoHCT before BGD therapy, 18 (85.7%) achieved response, 11 (52.4%) CMR, and 9 (42.9%) patients proceeded to alloHCT. PFS and OS are shown as Kaplan-Meier curves in Figs. 1 and 2. With a median follow-up of 18 months (range from 3 to 51 months), the median PFS for the overall population was 21 months while the median OS was not reached. PFS and OS rates at 2 years were 44.5% (95%CI: 33.7–58.8) and 75% (95%CI: 64.8–86.7), respectively. There were no differences between patients with relapsed or primary refractory HL in terms of PFS and OS (Figs. 3 and 4, P > 0.05). Similarly, no statistical differences in PFS and OS were noted between patients in whom BGD was used after first line or subsequent line of chemotherapy (Figs. 5 and 6, P > 0.05). Of note, most of the patients (80%) who responded to BGD maintain their response for at least 6 months (Fig. 1). In a subgroup of 9 patients ≥ 60 years old, 5 (55.6%) patients achieved CMR, 2 (22.2%)—PMR (ORR 77.8%), and 2 patients progressed during BGD treatment. PFS at 18 months was 62.2% (95%CI: 35.5–100) and OS at 23 months was 87.5% (95%CI: 67.3–100) (Figs. 7 and 8). Table 3 Response to BGD therapy
No. % (95%CI)
Interim (after 2–3 courses) n = 86
- PMDa 6 7 (1.6–12.4)
- SMDb 13 15.1 (7.5–22.7)
- PMRc 34 39.5 (29.2–49.9)
- CMRd 33 38.4 (28.1–48.6)
- ORRe 67 77.9 (69.1–86.7)
End of BGDf therapy n = 92
- PMDa 11 12 (5.3–18.6)
- SMDb 7 7.6 (2.2–13.0)
- PMRc 23 25 (16.2–33.8)
- CMRd 51 55.4 (45.3–65.6)
- ORRe 74 80.4 (2.3–88.5)
AutoHCTg after BGD therapy
- Yes 42 45.7
- No 50 54.3
AlloHCTh after BGD therapy
- Yes 16 17.4
- No 76 82.6
aPMD, progressive metabolic disease
bSMD, stable metabolic disease
cPMR, partial metabolic response
dCMR, complete metabolic response
eORR, overall response rate
fBGD, bendamustine, gemcitabine, dexamethasone
gautoHCT, autologous hematopoietic cell transplantation
halloHCT, allogeneic hematopoietic cell transplantation
Fig. 1 Progression-free survival (PFS) for the entire population
Fig. 2 Overall survival (OS) for the entire population
Fig. 3 Progression-free survival (PFS) for the subjects with relapsed or primary refractory Hodgkin lymphoma (HL)
Fig. 4 Overall survival (OS) for the subjects with relapsed or primary refractory Hodgkin lymphoma (HL)
Fig. 5 Progression-free survival (PFS) for patients treated with BGD as second or subsequent line of chemotherapy
Fig. 6 Overall survival (OS) for patients treated with BGD as second or subsequent line of chemotherapy
Fig. 7 Progression-free survival (PFS) for the subgroup of elderly patients (≥ 60 years)
Fig. 8 Overall survival (OS) for the subgroup of elderly patients (≥ 60 years)
Toxicity of BGD
The treatment-related AEs, mainly grade 1 or 2, were observed in 64 (69.6%) patients. Among grade ≥ 3 hematological toxicities, anemia was reported in 15.2% cases, thrombocytopenia in 20.7%, and neutropenia in 22.8% individuals. Severe non-hematological toxicities included infections (10.9%), alanine and/or aspartate aminotransferase (ALT or AST) increase (2.2%), and skin rush (1.1%). We recorded one death from unknown reasons during BGD therapy. All AEs reported during BGD therapy are shown in Table 4. In the subgroup of elderly patients (≥ 60 years), anemia and thrombocytopenia of grade 3 or 4 occurred in 2 (22.2%) patients, while neutropenia was found in 1 (11.1%) patient. Moreover, 2 (22.2%) patients experienced grade ≥ 3 infection, and 1 (11.1%) grade 3 skin rash in this subgroup. Table 4 Toxicity of BGD therapy
Toxicity Grade 1–2
No. (%) Grade 3–4
No. (%)
Hematological:
- Anemia 37 (40.2) 14 (15.2)
- Thrombocytopenia 25 (27.2) 19 (20.7)
- Neutropenia 19 (20.7) 21 (22.8)
Non-hematological:
- Infection 20 (21.7) 10 (10.9)
- ALT/ASTa increase 0 2 (2.2)
- Skin rush 7 (7.6) 1 (1.1)
- Fatigue 4 (4.3) 0
- Diarrhea 1 (1.1) 0
- Thrombotic events 2 (2.2) 0
- Guillain-Barré syndrome 1 (1.1) 0
- Autoimmune thyroiditis 1 (1.1) 0
Death from unknown reasons 1 (1.1)
aAlanine/aspartate aminotransferase
Discussion
Despite the significant progress in the management of patients with HL, relapsed and refractory disease constitutes a big challenge. According to the current treatment standards, high-dose chemotherapy followed by autoHCT has to be regarded as treatment of choice in the first relapse or primary progressive disease. However, even in the era of new agents such as brentuximab vedotin (BV) or immune checkpoint inhibitors, there are no accepted standards for salvage treatment before autoHCT. In the PLRG allied centers BGD was used since 2012 when the first cases of successful outcome of heavily pretreated patients were reported [16]. We had started to use BGD since both bendamustine and gemcitabine were effective in monotherapy as well as in combination with other agents.
Gemcitabine, a cytidine analog, was assessed in several studies. Kuruvilla et al. showed satisfactory (62%) response rate to GDP (gemcitabine, dexamethasone, and cisplatin) as a second-line therapy in patients with R/R HL [19]. Gemcitabine and vinerolbine combination showed ORR of 72% and 35% of CR [20]. In similar population, four-agent combination of gemcitabine with ifosfamide, vinorelbine, and prednisolone (IGEV) or double-agent schema of vinorelbine and pegylated liposomal doxorubicin (GVD) resulted in ORR of 81.3% and 70%, respectively [8, 9]. Bendamustine, another component of BGD, is a molecule containing the purine analog and the alkylating group. It was assessed in a phase II trial in heavily pretreated patients with HL (including those with relapse after auto- or alloHCT) at the dose of 120 mg/m2 and resulted in the intent-to-treat ORR of 53%, with CRs of 33% [11].
The combination of bendamustine with gemcitabine and vinorelbine (BeGEV) was first assessed in a multicenter phase II study by Santoro et al. [14]. The authors have demonstrated high efficacy of BeGEV as a second-line treatment in autoHCT-eligible patients (ORR 83%, CR 75%). In our retrospective analysis, ORR of BGD was similar to BeGEV although patient characteristics with regard to age and number of prior treatment regimens differ [14]. Moreover, almost one-fourth of patients in our study had been treated using autoHCT. This also most likely explains slightly higher rate of hematological toxicities at grade 3 or 4 in comparison to BeGEV. In contrast, severe non-hematological AEs occurred at similar incidence rates. We did not observe increased pulmonary toxicity which was reported by Cohen et al. in his cohort of patients. This might be due to the use of high dose of steroids (dexamethasone) in our regimen [21]. However, in spite of high efficacy of BGD in relation to ORR and CMR rate, estimated PFS in our study seems to be rather short (21 months). Most likely, this is a consequence of the large group of heavily pretreated patients (up to 6 previous line of therapy) including those after auto- and alloHCT and the subgroup of elderly patients in this cohort.
DHAP and ICE are among of the most commonly used salvage chemotherapy regimens in HL. Similar efficacy of these regimens as the second-line treatment was shown resulting in ORR of 88% for both, while CRs of 21% for DHAP and of 26.2% for ICE [5, 6]. Despite more heavily pretreated patients in our study, we report comparable ORR (80.4%) and much higher CMR rate (55.4%). Moreover, the difference in relation to CR rate increases in sub-analysis restricted to patients treated with BGD as the second line of chemotherapy (64.7%). The optimal number of BGD cycles is four, since about 40% of patients improved their response at the end of treatment compared to the interim assessment.
Most patients (80.4%) in this study were treated with ABVD as the first line of chemotherapy. Out of 13 patients being initially treated with BEACOPP, 5 (38.5%) patients were refractory to this regimen and all these patients achieved ORR after BGD therapy with CMR rate of 40%. In view of the fact that there are not many effective treatment options to overcome the BEACOPP refractoriness, this finding seems very interesting and encouraging for further studies.
In recent years, there have been many new agents evaluated for patients with R/R HL such as BV and immune checkpoint inhibitors. Brentuximab vedotin—an anti-CD30 antibody conjugated to antimicrotubule agent, monomethyl auristatin E—showed ORR of 75% and CR rate of 34% in heavily pretreated patients with HL after autoHCT [22]. Furthermore, BV showed similar efficacy as a second-line therapy in R/R HL (ORR 68%, CR 35%), and 89% of the subjects were able to proceed to autoHCT [23]. Addition of bendamustine to BV seems to increase its efficacy [12, 13]. However, in comparison to BGD regimen, BV does not appear to be superior both in monotherapy and in combination with bendamustine. Immune checkpoint inhibitors, mainly antibodies against programmed cell death protein 1 (PD-1) such as nivolumab or pembrolizumab, showed high efficacy as a salvage therapy for patients with R/R HL [24–27]. Ansell et al. reported ORR 87% in the heavily pretreated HL patients although CR rate was relatively low (17%) compared to BGD [24]. The authors reported similar incidence of AEs of any grade (78% vs. 69.6%) but relatively fewer cases of grade ≥ 3 AEs (22% vs. 38%) during nivolumab therapy when compared to BGD therapy [24].
The high efficacy of BGD in patients after failure of autoHCT is worth noting. This is a very challenging group, in which effective chemotherapy followed by alloHCT is the only option to achieve long-lasting remission. In this population checkpoint inhibitors, nivolumab and pembrolizumab resulted in high ORR rate (69% and 73%, respectively). However, once again, CR rates (16% and 14%, respectively) appear lower compared to BGD in our study (55.4%) and there are still some concerns about the increased incidence of immune complications after alloHCT in patients treated with immune checkpoint inhibitors before transplant [25, 26, 28, 29].
Another interesting finding of this study refers to elderly HL patients. We showed that in the patients at or above the age of 60 years BGD regimen has a similar efficacy (ORR 77.8%, CMR 55.6%) than in younger patients. Moreover, BGD-related toxicity seems to be acceptable in this subgroup.
Relatively small number of subjects included in the analysis as well as its retrospective nature and the lack of metabolic assessment in all patients are the major limitations of this study. Another important limitation of our study is a long accrual time. However, during this period, most of our patients were treated uniformly since novel therapies were not available due to reimbursement hurdles. Addition limitation may pose a large number of accruing centers. However, most of PLRG allied centers are reference centers with good-quality data management which somehow mitigate this flaw. However, our data clearly indicate that BGD which has a high rate of obtaining ORR and a relatively good time in response maintaining (5–6 months in 80% of patients) and an acceptable toxicity profile seems to provide a very good option for R/R HL patients even after BEACOPP first-line chemotherapy. In several patients, it opened a window to perform either autologous or allogeneic transplantation. Despite the fact that in recent years new treatment options, including BV and checkpoint inhibitors, showed promising results in treatment of patients with R/R HL, neither of them as yet is formally approved in the second-line treatment for HL. In addition, although pharmaco-economy was not a subject of this study, we speculate that BGD treatment may be a relatively cheap option. Therefore, we conclude that the BGD should be considered a viable option for patients with R/R HL and may serve as a bridge for individuals being candidates for auto- or alloHCT.
Author contributions
WKP, JMZ, and SG designed the study; all authors except for JMZ, AK, and AW enrolled patients; SG, RS, AK, and AW performed the bioinformatics and statistical analysis; RS and JMZ wrote the paper. All authors read and revised the manuscript critically.
Data availability
Not applicable
Code availability
Not applicable
Declarations
Ethics approval
According to Polish regulations, this was a retrospective study and it does not require approval of the bioethical committee. The study was approved by the board of The Polish Lymphoma Research Group.
Consent to participate
Not applicable
Consent for publication
Not applicable
Conflict of interest
The authors declare no conflict of interest.
The original version of this article was revised: This article was originally published with an incorrect affiliation. It should be 9 ( Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wrocław Medical University, Wrocław, Poland).
Wojciech Spychałowicz passed away during the writing of this article.
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Change history
3/24/2021
A Correction to this paper has been published: 10.1007/s00277-021-04503-1 | 90 MILLIGRAM/SQ. METER, Q28D (EVERY 4 WEEKS (ON DAY 1 AND 2) FOR 60 MINS) | DrugDosageText | CC BY | 33625572 | 19,756,838 | 2021-07 |
What was the dosage of drug 'DEXAMETHASONE'? | High efficacy of BGD (bendamustine, gemcitabine, and dexamethasone) in relapsed/refractory Hodgkin Lymphoma.
The optimal salvage therapy in relapsed/refractory Hodgkin lymphoma (R/R HL) has not been defined so far. The goal of this multicenter retrospective study was to evaluate efficacy and safety of BGD (bendamustine, gemcitabine, dexamethasone) as a second or subsequent line of therapy in classical R/R HL. We have evaluated 92 consecutive R/R HL patients treated with BGD. Median age was 34.5 (19-82) years. Fifty-eight patients (63%) had received 2 or more lines of chemotherapy, 32 patients (34.8%) radiotherapy, and 21 patients (22.8%) an autologous hematopoietic stem cell transplantation (autoHCT). Forty-four patients (47.8%) were resistant to first line of chemotherapy. BGD therapy consisted of bendamustine 90 mg/m2 on days 1 and 2, gemcitabine 800 mg/m2 on days 1 and 4, dexamethasone 40 mg on days 1-4. Median number of BGD cycles was 4 (2-7). The following adverse events ≥ 3 grade were noted: neutropenia (22.8%), thrombocytopenia (20.7%), anemia (15.2%), infections (10.9%), AST/ALT increase (2.2%), and skin rush (1.1%). After BGD therapy, 51 (55.4%) patients achieved complete remission, 23 (25%)-partial response, 7 (7.6%)-stable disease, and 11 (12%) patients experienced progression disease. AutoHCT was conducted in 42 (45.7%) patients after BGD therapy, and allogeneic HCT (alloHCT) in 16 (17.4%) patients. Median progression-free survival was 21 months. BGD is a highly effective, well-tolerated salvage regimen for patients with R/R HL, providing an excellent bridge to auto- or alloHCT.
Introduction
Hodgkin lymphoma (HL), accounting for approximately 10% of all lymphomas, is one of the most curable malignancies. However, up to 30% of patients do not respond to the first-line therapy or relapse after initial response [1]. For patients with relapsed or refractory disease, salvage chemotherapy followed by high-dose chemotherapy with autologous hematopoietic stem cell transplantation (autoHCT) is still the treatment of choice [2, 3]. The long-term cure can be obtained in up to 80% of patients provided a complete metabolic remission (CMR) is achieved before transplant [4]. Consequently, the optimal salvage regimen should be highly effective but also should have a high mobilization rate. However, the standard for salvage chemotherapy before autoHCT is still not established. The most commonly used are platinum-based ICE (ifosfamide, carboplatin, etoposide); DHAP (dexamethasone, cytarabine, cisplatin); ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin); and gemcitabine-based GDP (gemcitabine, dexamethasone, cisplatin), GVD (gemcitabine, vinorelbine, liposomal doxorubicin), IGEV (ifosfamide, gemcitabine, vinorelbine), and GCD (gemcitabine, carboplatin, dexamethasone) combination chemotherapy with response rates ranging between 54 and 88% and mobilization rate of 86–100% [5–10]. Due to rather low rate of complete responses (CRs) achieved with the most frequently used salvage regimens, there is the persisting need to develop new salvage regimens especially in the second-line treatment. Recently, bendamustine both in monotherapy and in combination with other drugs was shown to induce high response rates with an acceptable toxicity profile in third or more line in patients with relapsed/refractory (R/R) HL [11–13]. Experience with bendamustine in the second line is very limited. Santoro et al. modified their original IGEV protocol substituting ifosfamide with bendamustine achieving a very high efficacy as a second-line therapy in patients with R/R HL [9, 14]. The Polish Lymphoma Research Group (PLRG) proposed replacement of vinorelbine with dexamethasone (bendamustine, gemcitabine, dexamethasone; BGD regimen) and is carrying out a prospective, multicenter study in patients with progressive disease during or after ABVD treatment [15] based on the very good preliminary results obtained with BGD in heavily pretreated R/R HL patients [16]. Here we report long-term outcome of these patients enrolled to the multicenter retrospective PLRG study aiming at evaluating the efficacy and toxicity of BGD in a real-life setting.
Methods
Study design
We retrospectively reviewed the data of all patients aged ≥ 18 years with R/R HL who were treated with BGD regimen between April 2012 and December 2018 in 15 centers allied within the PLRG. Primary refractory HL was defined as no CMR achieved after the first line or if progression occurred within 3 months after completion of the first-line chemotherapy. In patients with relapsed HL, the disease reappeared later after achieving CMR. Patients’ records were reviewed to obtain patient characteristics at diagnosis and the start of BGD treatment, including clinical stage according to the Lugano system, presence of B symptoms, extranodal site involvement, and bulky disease.
Treatment and response criteria
The dosage and administration schedule of BGD is shown in Table 1. The interim imaging assessment was performed after second or third cycle of BGD in 86 patients (93.5%). Patients could continue BGD treatment up to 4 cycles or longer at the discretion of a treating physician. The metabolic response to BGD treatment at the end of the therapy was assessed according to the Lugano treatment response criteria using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) [17]. The 18F-FDG uptake less than in the liver was defined as CMR. The higher 18F-FDG uptake, but decreased from baseline, was defined as partial metabolic response (PMR). In case of no significant change in 18F-FDG uptake from baseline or new FDG-avid foci, stable or progressive disease (SD or PD) were diagnosed, respectively. The overall response rate (ORR) was defined as the sum of CMR and PMR. Table 1 BGD regimen repeated every 4 weeks
Drug Dose Route of administrationa Day of administration
Bendamustine 90 mg/m2 i.v. 60 min 1 and 2
Gemcitabine 800 mg/m2 i.v. 30 min 1 and 4
Dexamethasone 40 mg i.v. or p.o. 1, 2, 3, and 4
ai.v., intravenous; p.o., per os
Study end-points and statistical analysis
Primary end-point was the percentage of CMR and ORR whereas progression-free survival (PFS) and overall survival (OS) as well as adverse events (AEs) were secondary end-points. PFS was defined as the time from start of BGD treatment to the date of documented disease progression, death from any cause, or start of new anticancer therapy. The patients at the time of autoHCT or allogeneic hematopoietic stem cell transplantation (alloHCT) were censored for PFS since transplants were not considered a new anticancer therapy. OS was defined as the time from the first BGD administration to death for any reason. AEs were evaluated using Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 [18]. PFS and OS were estimated using the Kaplan-Meier method. Ninety-five percent confidence intervals (CIs) for the survival curves were calculated for chosen times. The log-rank test was performed to compare survival curves between groups. Two-sided P values ≤ 0.05 were considered statistically significant. The statistics were performed descriptively. Statistical analysis was performed using Statistica software (version 13.1, Tulsa, OK, USA) and R statistical software package version 4.0.1. (R Foundation for Statistical Computing, http://www.r-project.org).
Results
Patients’ characteristics
The median age of 92 analyzed patients was 34.5 (range from 19 to 82 years) years with 9 patients at the age or above 60 years. More than 60% of patients were in advanced stages of HL at the time of diagnosis (III and IV according to the Lugano classification). Median number of prior chemotherapy lines was 2 (range from 1 to 6 lines). Thirty-four patients (37%) had previously been treated with only one line of chemotherapy. ABVD was the first-line therapy in 80.4% cases. Forty-four patients (47.8%) were primary refractory to the first-line chemotherapy. Almost 35% of patients had received radiotherapy prior to BGD treatment. Twenty-one patients (22.8%) underwent autoHCT, and three patients (3.3%) underwent alloHCT prior to BGD treatment. The median number of BGD cycles was 4 (range from 2 to 7 cycles). Demographic and clinical data are shown in Table 2. Table 2 Demographics and clinical characteristics of 92 subjects
Characteristic No. %
Age, years
- Median (range) 34.5 (19–82)
- ≥ 60 years 9 9.7
Sex
- Male 44 47.8
- Female 48 52.2
Lugano classification at diagnosis/before BGDa
- I 0/3 0/3.3
- II 33/38 35.9/41.3
- III 25/9 27.2/9.8
- IV 34/42 37/45.7
B-symptoms at diagnosis/before BGDa 67/27 72.9/29.3
Extranodal site involvement at diagnosis/before BGDa 32/39 34.8/42.4
Bulky disease at diagnosis/before BGDa 32/10 34.8/10.9
First-line treatment
ABVDb 74 80.4
BEACOPPc 13 14.1
Otherd 5 5.4
No. of previous treatment lines
- 1. 34 37
- 2. 26 28.3
- 3. 16 17.4
- 4. 9 9.8
- 5. 3 3.3
- 6. 4 4.3
Primary refractory to 1st-line treatment 44 47.8
Patents with late (> 12 months) relapse 20 21.7
No. of BGDa courses
- Median (range) 4 (2–7)
Radiotherapy prior to BGDa 32 34.8
Prior autoHCTe 21 22.8
Prior alloHCTf 3 3.3
aBGD, bendamustine, gemcitabine, dexamethasone
bABVD, adriamycin, bleomycin, vinblastine, dacarbazine
cBEACOPP, bleomycin, cyclophosphamide, doxorubicin, etoposide, prednisone, procarbazine, vincristine
dOther: PVAG, prednisone, vincristine, adriamycin, gemcitabine; OEPA/COPDAC, vincristine, etoposide, prednisone, doxorubicin/ cyclophosphamide, vincristine, prednisone, dacarbazine
eautoHCT, autologous hematopoietic cell transplantation
falloHCT, allogeneic hematopoietic cell transplantation
Efficacy of BGD
Out of 86 patients who were assessed by interim PET/CT after 2 or 3 cycles of BGD, 67 (77.9%) patients achieved overall response, including 33 (38.4%) CMRs. At the end of BGD therapy, ORR and CMR rate increased to 80.4% and 55.4%, respectively. Eleven patients (12%) experienced disease progression, and seven patients (7.6%) had stable disease. Among 34 patients who achieved PMR in the interim imaging test, 14 (41.2%) patients achieved CMR at the end of BGD treatment. In the subgroup of patients treated with BGD only as a second line of chemotherapy (n = 34), ORR was 79.4% while CMR rate was 64.7%. Out of 44 patients being refractory to the first line of chemotherapy, 30 (68.2%) patients achieved overall response and 34.1% achieved CMR. Among the whole study population, five patients were refractory to BEACOPP given as the first line of chemotherapy. All these patients achieved response and two of them (40%) achieved CMR after BGD. The autoHCT was successfully performed after BGD therapy in 42 (45.7%) patients. Furthermore, 16 (17.4%) patients underwent alloHCT after BGD therapy (Table 3). Among 21 patients treated with autoHCT before BGD therapy, 18 (85.7%) achieved response, 11 (52.4%) CMR, and 9 (42.9%) patients proceeded to alloHCT. PFS and OS are shown as Kaplan-Meier curves in Figs. 1 and 2. With a median follow-up of 18 months (range from 3 to 51 months), the median PFS for the overall population was 21 months while the median OS was not reached. PFS and OS rates at 2 years were 44.5% (95%CI: 33.7–58.8) and 75% (95%CI: 64.8–86.7), respectively. There were no differences between patients with relapsed or primary refractory HL in terms of PFS and OS (Figs. 3 and 4, P > 0.05). Similarly, no statistical differences in PFS and OS were noted between patients in whom BGD was used after first line or subsequent line of chemotherapy (Figs. 5 and 6, P > 0.05). Of note, most of the patients (80%) who responded to BGD maintain their response for at least 6 months (Fig. 1). In a subgroup of 9 patients ≥ 60 years old, 5 (55.6%) patients achieved CMR, 2 (22.2%)—PMR (ORR 77.8%), and 2 patients progressed during BGD treatment. PFS at 18 months was 62.2% (95%CI: 35.5–100) and OS at 23 months was 87.5% (95%CI: 67.3–100) (Figs. 7 and 8). Table 3 Response to BGD therapy
No. % (95%CI)
Interim (after 2–3 courses) n = 86
- PMDa 6 7 (1.6–12.4)
- SMDb 13 15.1 (7.5–22.7)
- PMRc 34 39.5 (29.2–49.9)
- CMRd 33 38.4 (28.1–48.6)
- ORRe 67 77.9 (69.1–86.7)
End of BGDf therapy n = 92
- PMDa 11 12 (5.3–18.6)
- SMDb 7 7.6 (2.2–13.0)
- PMRc 23 25 (16.2–33.8)
- CMRd 51 55.4 (45.3–65.6)
- ORRe 74 80.4 (2.3–88.5)
AutoHCTg after BGD therapy
- Yes 42 45.7
- No 50 54.3
AlloHCTh after BGD therapy
- Yes 16 17.4
- No 76 82.6
aPMD, progressive metabolic disease
bSMD, stable metabolic disease
cPMR, partial metabolic response
dCMR, complete metabolic response
eORR, overall response rate
fBGD, bendamustine, gemcitabine, dexamethasone
gautoHCT, autologous hematopoietic cell transplantation
halloHCT, allogeneic hematopoietic cell transplantation
Fig. 1 Progression-free survival (PFS) for the entire population
Fig. 2 Overall survival (OS) for the entire population
Fig. 3 Progression-free survival (PFS) for the subjects with relapsed or primary refractory Hodgkin lymphoma (HL)
Fig. 4 Overall survival (OS) for the subjects with relapsed or primary refractory Hodgkin lymphoma (HL)
Fig. 5 Progression-free survival (PFS) for patients treated with BGD as second or subsequent line of chemotherapy
Fig. 6 Overall survival (OS) for patients treated with BGD as second or subsequent line of chemotherapy
Fig. 7 Progression-free survival (PFS) for the subgroup of elderly patients (≥ 60 years)
Fig. 8 Overall survival (OS) for the subgroup of elderly patients (≥ 60 years)
Toxicity of BGD
The treatment-related AEs, mainly grade 1 or 2, were observed in 64 (69.6%) patients. Among grade ≥ 3 hematological toxicities, anemia was reported in 15.2% cases, thrombocytopenia in 20.7%, and neutropenia in 22.8% individuals. Severe non-hematological toxicities included infections (10.9%), alanine and/or aspartate aminotransferase (ALT or AST) increase (2.2%), and skin rush (1.1%). We recorded one death from unknown reasons during BGD therapy. All AEs reported during BGD therapy are shown in Table 4. In the subgroup of elderly patients (≥ 60 years), anemia and thrombocytopenia of grade 3 or 4 occurred in 2 (22.2%) patients, while neutropenia was found in 1 (11.1%) patient. Moreover, 2 (22.2%) patients experienced grade ≥ 3 infection, and 1 (11.1%) grade 3 skin rash in this subgroup. Table 4 Toxicity of BGD therapy
Toxicity Grade 1–2
No. (%) Grade 3–4
No. (%)
Hematological:
- Anemia 37 (40.2) 14 (15.2)
- Thrombocytopenia 25 (27.2) 19 (20.7)
- Neutropenia 19 (20.7) 21 (22.8)
Non-hematological:
- Infection 20 (21.7) 10 (10.9)
- ALT/ASTa increase 0 2 (2.2)
- Skin rush 7 (7.6) 1 (1.1)
- Fatigue 4 (4.3) 0
- Diarrhea 1 (1.1) 0
- Thrombotic events 2 (2.2) 0
- Guillain-Barré syndrome 1 (1.1) 0
- Autoimmune thyroiditis 1 (1.1) 0
Death from unknown reasons 1 (1.1)
aAlanine/aspartate aminotransferase
Discussion
Despite the significant progress in the management of patients with HL, relapsed and refractory disease constitutes a big challenge. According to the current treatment standards, high-dose chemotherapy followed by autoHCT has to be regarded as treatment of choice in the first relapse or primary progressive disease. However, even in the era of new agents such as brentuximab vedotin (BV) or immune checkpoint inhibitors, there are no accepted standards for salvage treatment before autoHCT. In the PLRG allied centers BGD was used since 2012 when the first cases of successful outcome of heavily pretreated patients were reported [16]. We had started to use BGD since both bendamustine and gemcitabine were effective in monotherapy as well as in combination with other agents.
Gemcitabine, a cytidine analog, was assessed in several studies. Kuruvilla et al. showed satisfactory (62%) response rate to GDP (gemcitabine, dexamethasone, and cisplatin) as a second-line therapy in patients with R/R HL [19]. Gemcitabine and vinerolbine combination showed ORR of 72% and 35% of CR [20]. In similar population, four-agent combination of gemcitabine with ifosfamide, vinorelbine, and prednisolone (IGEV) or double-agent schema of vinorelbine and pegylated liposomal doxorubicin (GVD) resulted in ORR of 81.3% and 70%, respectively [8, 9]. Bendamustine, another component of BGD, is a molecule containing the purine analog and the alkylating group. It was assessed in a phase II trial in heavily pretreated patients with HL (including those with relapse after auto- or alloHCT) at the dose of 120 mg/m2 and resulted in the intent-to-treat ORR of 53%, with CRs of 33% [11].
The combination of bendamustine with gemcitabine and vinorelbine (BeGEV) was first assessed in a multicenter phase II study by Santoro et al. [14]. The authors have demonstrated high efficacy of BeGEV as a second-line treatment in autoHCT-eligible patients (ORR 83%, CR 75%). In our retrospective analysis, ORR of BGD was similar to BeGEV although patient characteristics with regard to age and number of prior treatment regimens differ [14]. Moreover, almost one-fourth of patients in our study had been treated using autoHCT. This also most likely explains slightly higher rate of hematological toxicities at grade 3 or 4 in comparison to BeGEV. In contrast, severe non-hematological AEs occurred at similar incidence rates. We did not observe increased pulmonary toxicity which was reported by Cohen et al. in his cohort of patients. This might be due to the use of high dose of steroids (dexamethasone) in our regimen [21]. However, in spite of high efficacy of BGD in relation to ORR and CMR rate, estimated PFS in our study seems to be rather short (21 months). Most likely, this is a consequence of the large group of heavily pretreated patients (up to 6 previous line of therapy) including those after auto- and alloHCT and the subgroup of elderly patients in this cohort.
DHAP and ICE are among of the most commonly used salvage chemotherapy regimens in HL. Similar efficacy of these regimens as the second-line treatment was shown resulting in ORR of 88% for both, while CRs of 21% for DHAP and of 26.2% for ICE [5, 6]. Despite more heavily pretreated patients in our study, we report comparable ORR (80.4%) and much higher CMR rate (55.4%). Moreover, the difference in relation to CR rate increases in sub-analysis restricted to patients treated with BGD as the second line of chemotherapy (64.7%). The optimal number of BGD cycles is four, since about 40% of patients improved their response at the end of treatment compared to the interim assessment.
Most patients (80.4%) in this study were treated with ABVD as the first line of chemotherapy. Out of 13 patients being initially treated with BEACOPP, 5 (38.5%) patients were refractory to this regimen and all these patients achieved ORR after BGD therapy with CMR rate of 40%. In view of the fact that there are not many effective treatment options to overcome the BEACOPP refractoriness, this finding seems very interesting and encouraging for further studies.
In recent years, there have been many new agents evaluated for patients with R/R HL such as BV and immune checkpoint inhibitors. Brentuximab vedotin—an anti-CD30 antibody conjugated to antimicrotubule agent, monomethyl auristatin E—showed ORR of 75% and CR rate of 34% in heavily pretreated patients with HL after autoHCT [22]. Furthermore, BV showed similar efficacy as a second-line therapy in R/R HL (ORR 68%, CR 35%), and 89% of the subjects were able to proceed to autoHCT [23]. Addition of bendamustine to BV seems to increase its efficacy [12, 13]. However, in comparison to BGD regimen, BV does not appear to be superior both in monotherapy and in combination with bendamustine. Immune checkpoint inhibitors, mainly antibodies against programmed cell death protein 1 (PD-1) such as nivolumab or pembrolizumab, showed high efficacy as a salvage therapy for patients with R/R HL [24–27]. Ansell et al. reported ORR 87% in the heavily pretreated HL patients although CR rate was relatively low (17%) compared to BGD [24]. The authors reported similar incidence of AEs of any grade (78% vs. 69.6%) but relatively fewer cases of grade ≥ 3 AEs (22% vs. 38%) during nivolumab therapy when compared to BGD therapy [24].
The high efficacy of BGD in patients after failure of autoHCT is worth noting. This is a very challenging group, in which effective chemotherapy followed by alloHCT is the only option to achieve long-lasting remission. In this population checkpoint inhibitors, nivolumab and pembrolizumab resulted in high ORR rate (69% and 73%, respectively). However, once again, CR rates (16% and 14%, respectively) appear lower compared to BGD in our study (55.4%) and there are still some concerns about the increased incidence of immune complications after alloHCT in patients treated with immune checkpoint inhibitors before transplant [25, 26, 28, 29].
Another interesting finding of this study refers to elderly HL patients. We showed that in the patients at or above the age of 60 years BGD regimen has a similar efficacy (ORR 77.8%, CMR 55.6%) than in younger patients. Moreover, BGD-related toxicity seems to be acceptable in this subgroup.
Relatively small number of subjects included in the analysis as well as its retrospective nature and the lack of metabolic assessment in all patients are the major limitations of this study. Another important limitation of our study is a long accrual time. However, during this period, most of our patients were treated uniformly since novel therapies were not available due to reimbursement hurdles. Addition limitation may pose a large number of accruing centers. However, most of PLRG allied centers are reference centers with good-quality data management which somehow mitigate this flaw. However, our data clearly indicate that BGD which has a high rate of obtaining ORR and a relatively good time in response maintaining (5–6 months in 80% of patients) and an acceptable toxicity profile seems to provide a very good option for R/R HL patients even after BEACOPP first-line chemotherapy. In several patients, it opened a window to perform either autologous or allogeneic transplantation. Despite the fact that in recent years new treatment options, including BV and checkpoint inhibitors, showed promising results in treatment of patients with R/R HL, neither of them as yet is formally approved in the second-line treatment for HL. In addition, although pharmaco-economy was not a subject of this study, we speculate that BGD treatment may be a relatively cheap option. Therefore, we conclude that the BGD should be considered a viable option for patients with R/R HL and may serve as a bridge for individuals being candidates for auto- or alloHCT.
Author contributions
WKP, JMZ, and SG designed the study; all authors except for JMZ, AK, and AW enrolled patients; SG, RS, AK, and AW performed the bioinformatics and statistical analysis; RS and JMZ wrote the paper. All authors read and revised the manuscript critically.
Data availability
Not applicable
Code availability
Not applicable
Declarations
Ethics approval
According to Polish regulations, this was a retrospective study and it does not require approval of the bioethical committee. The study was approved by the board of The Polish Lymphoma Research Group.
Consent to participate
Not applicable
Consent for publication
Not applicable
Conflict of interest
The authors declare no conflict of interest.
The original version of this article was revised: This article was originally published with an incorrect affiliation. It should be 9 ( Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wrocław Medical University, Wrocław, Poland).
Wojciech Spychałowicz passed away during the writing of this article.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Change history
3/24/2021
A Correction to this paper has been published: 10.1007/s00277-021-04503-1 | 40 MILLIGRAM, Q28D (40 MG, EVERY 4 WEEKS FROM DAYS 1?4) | DrugDosageText | CC BY | 33625572 | 19,756,838 | 2021-07 |
What was the dosage of drug 'GEMCITABINE'? | High efficacy of BGD (bendamustine, gemcitabine, and dexamethasone) in relapsed/refractory Hodgkin Lymphoma.
The optimal salvage therapy in relapsed/refractory Hodgkin lymphoma (R/R HL) has not been defined so far. The goal of this multicenter retrospective study was to evaluate efficacy and safety of BGD (bendamustine, gemcitabine, dexamethasone) as a second or subsequent line of therapy in classical R/R HL. We have evaluated 92 consecutive R/R HL patients treated with BGD. Median age was 34.5 (19-82) years. Fifty-eight patients (63%) had received 2 or more lines of chemotherapy, 32 patients (34.8%) radiotherapy, and 21 patients (22.8%) an autologous hematopoietic stem cell transplantation (autoHCT). Forty-four patients (47.8%) were resistant to first line of chemotherapy. BGD therapy consisted of bendamustine 90 mg/m2 on days 1 and 2, gemcitabine 800 mg/m2 on days 1 and 4, dexamethasone 40 mg on days 1-4. Median number of BGD cycles was 4 (2-7). The following adverse events ≥ 3 grade were noted: neutropenia (22.8%), thrombocytopenia (20.7%), anemia (15.2%), infections (10.9%), AST/ALT increase (2.2%), and skin rush (1.1%). After BGD therapy, 51 (55.4%) patients achieved complete remission, 23 (25%)-partial response, 7 (7.6%)-stable disease, and 11 (12%) patients experienced progression disease. AutoHCT was conducted in 42 (45.7%) patients after BGD therapy, and allogeneic HCT (alloHCT) in 16 (17.4%) patients. Median progression-free survival was 21 months. BGD is a highly effective, well-tolerated salvage regimen for patients with R/R HL, providing an excellent bridge to auto- or alloHCT.
Introduction
Hodgkin lymphoma (HL), accounting for approximately 10% of all lymphomas, is one of the most curable malignancies. However, up to 30% of patients do not respond to the first-line therapy or relapse after initial response [1]. For patients with relapsed or refractory disease, salvage chemotherapy followed by high-dose chemotherapy with autologous hematopoietic stem cell transplantation (autoHCT) is still the treatment of choice [2, 3]. The long-term cure can be obtained in up to 80% of patients provided a complete metabolic remission (CMR) is achieved before transplant [4]. Consequently, the optimal salvage regimen should be highly effective but also should have a high mobilization rate. However, the standard for salvage chemotherapy before autoHCT is still not established. The most commonly used are platinum-based ICE (ifosfamide, carboplatin, etoposide); DHAP (dexamethasone, cytarabine, cisplatin); ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin); and gemcitabine-based GDP (gemcitabine, dexamethasone, cisplatin), GVD (gemcitabine, vinorelbine, liposomal doxorubicin), IGEV (ifosfamide, gemcitabine, vinorelbine), and GCD (gemcitabine, carboplatin, dexamethasone) combination chemotherapy with response rates ranging between 54 and 88% and mobilization rate of 86–100% [5–10]. Due to rather low rate of complete responses (CRs) achieved with the most frequently used salvage regimens, there is the persisting need to develop new salvage regimens especially in the second-line treatment. Recently, bendamustine both in monotherapy and in combination with other drugs was shown to induce high response rates with an acceptable toxicity profile in third or more line in patients with relapsed/refractory (R/R) HL [11–13]. Experience with bendamustine in the second line is very limited. Santoro et al. modified their original IGEV protocol substituting ifosfamide with bendamustine achieving a very high efficacy as a second-line therapy in patients with R/R HL [9, 14]. The Polish Lymphoma Research Group (PLRG) proposed replacement of vinorelbine with dexamethasone (bendamustine, gemcitabine, dexamethasone; BGD regimen) and is carrying out a prospective, multicenter study in patients with progressive disease during or after ABVD treatment [15] based on the very good preliminary results obtained with BGD in heavily pretreated R/R HL patients [16]. Here we report long-term outcome of these patients enrolled to the multicenter retrospective PLRG study aiming at evaluating the efficacy and toxicity of BGD in a real-life setting.
Methods
Study design
We retrospectively reviewed the data of all patients aged ≥ 18 years with R/R HL who were treated with BGD regimen between April 2012 and December 2018 in 15 centers allied within the PLRG. Primary refractory HL was defined as no CMR achieved after the first line or if progression occurred within 3 months after completion of the first-line chemotherapy. In patients with relapsed HL, the disease reappeared later after achieving CMR. Patients’ records were reviewed to obtain patient characteristics at diagnosis and the start of BGD treatment, including clinical stage according to the Lugano system, presence of B symptoms, extranodal site involvement, and bulky disease.
Treatment and response criteria
The dosage and administration schedule of BGD is shown in Table 1. The interim imaging assessment was performed after second or third cycle of BGD in 86 patients (93.5%). Patients could continue BGD treatment up to 4 cycles or longer at the discretion of a treating physician. The metabolic response to BGD treatment at the end of the therapy was assessed according to the Lugano treatment response criteria using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) [17]. The 18F-FDG uptake less than in the liver was defined as CMR. The higher 18F-FDG uptake, but decreased from baseline, was defined as partial metabolic response (PMR). In case of no significant change in 18F-FDG uptake from baseline or new FDG-avid foci, stable or progressive disease (SD or PD) were diagnosed, respectively. The overall response rate (ORR) was defined as the sum of CMR and PMR. Table 1 BGD regimen repeated every 4 weeks
Drug Dose Route of administrationa Day of administration
Bendamustine 90 mg/m2 i.v. 60 min 1 and 2
Gemcitabine 800 mg/m2 i.v. 30 min 1 and 4
Dexamethasone 40 mg i.v. or p.o. 1, 2, 3, and 4
ai.v., intravenous; p.o., per os
Study end-points and statistical analysis
Primary end-point was the percentage of CMR and ORR whereas progression-free survival (PFS) and overall survival (OS) as well as adverse events (AEs) were secondary end-points. PFS was defined as the time from start of BGD treatment to the date of documented disease progression, death from any cause, or start of new anticancer therapy. The patients at the time of autoHCT or allogeneic hematopoietic stem cell transplantation (alloHCT) were censored for PFS since transplants were not considered a new anticancer therapy. OS was defined as the time from the first BGD administration to death for any reason. AEs were evaluated using Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 [18]. PFS and OS were estimated using the Kaplan-Meier method. Ninety-five percent confidence intervals (CIs) for the survival curves were calculated for chosen times. The log-rank test was performed to compare survival curves between groups. Two-sided P values ≤ 0.05 were considered statistically significant. The statistics were performed descriptively. Statistical analysis was performed using Statistica software (version 13.1, Tulsa, OK, USA) and R statistical software package version 4.0.1. (R Foundation for Statistical Computing, http://www.r-project.org).
Results
Patients’ characteristics
The median age of 92 analyzed patients was 34.5 (range from 19 to 82 years) years with 9 patients at the age or above 60 years. More than 60% of patients were in advanced stages of HL at the time of diagnosis (III and IV according to the Lugano classification). Median number of prior chemotherapy lines was 2 (range from 1 to 6 lines). Thirty-four patients (37%) had previously been treated with only one line of chemotherapy. ABVD was the first-line therapy in 80.4% cases. Forty-four patients (47.8%) were primary refractory to the first-line chemotherapy. Almost 35% of patients had received radiotherapy prior to BGD treatment. Twenty-one patients (22.8%) underwent autoHCT, and three patients (3.3%) underwent alloHCT prior to BGD treatment. The median number of BGD cycles was 4 (range from 2 to 7 cycles). Demographic and clinical data are shown in Table 2. Table 2 Demographics and clinical characteristics of 92 subjects
Characteristic No. %
Age, years
- Median (range) 34.5 (19–82)
- ≥ 60 years 9 9.7
Sex
- Male 44 47.8
- Female 48 52.2
Lugano classification at diagnosis/before BGDa
- I 0/3 0/3.3
- II 33/38 35.9/41.3
- III 25/9 27.2/9.8
- IV 34/42 37/45.7
B-symptoms at diagnosis/before BGDa 67/27 72.9/29.3
Extranodal site involvement at diagnosis/before BGDa 32/39 34.8/42.4
Bulky disease at diagnosis/before BGDa 32/10 34.8/10.9
First-line treatment
ABVDb 74 80.4
BEACOPPc 13 14.1
Otherd 5 5.4
No. of previous treatment lines
- 1. 34 37
- 2. 26 28.3
- 3. 16 17.4
- 4. 9 9.8
- 5. 3 3.3
- 6. 4 4.3
Primary refractory to 1st-line treatment 44 47.8
Patents with late (> 12 months) relapse 20 21.7
No. of BGDa courses
- Median (range) 4 (2–7)
Radiotherapy prior to BGDa 32 34.8
Prior autoHCTe 21 22.8
Prior alloHCTf 3 3.3
aBGD, bendamustine, gemcitabine, dexamethasone
bABVD, adriamycin, bleomycin, vinblastine, dacarbazine
cBEACOPP, bleomycin, cyclophosphamide, doxorubicin, etoposide, prednisone, procarbazine, vincristine
dOther: PVAG, prednisone, vincristine, adriamycin, gemcitabine; OEPA/COPDAC, vincristine, etoposide, prednisone, doxorubicin/ cyclophosphamide, vincristine, prednisone, dacarbazine
eautoHCT, autologous hematopoietic cell transplantation
falloHCT, allogeneic hematopoietic cell transplantation
Efficacy of BGD
Out of 86 patients who were assessed by interim PET/CT after 2 or 3 cycles of BGD, 67 (77.9%) patients achieved overall response, including 33 (38.4%) CMRs. At the end of BGD therapy, ORR and CMR rate increased to 80.4% and 55.4%, respectively. Eleven patients (12%) experienced disease progression, and seven patients (7.6%) had stable disease. Among 34 patients who achieved PMR in the interim imaging test, 14 (41.2%) patients achieved CMR at the end of BGD treatment. In the subgroup of patients treated with BGD only as a second line of chemotherapy (n = 34), ORR was 79.4% while CMR rate was 64.7%. Out of 44 patients being refractory to the first line of chemotherapy, 30 (68.2%) patients achieved overall response and 34.1% achieved CMR. Among the whole study population, five patients were refractory to BEACOPP given as the first line of chemotherapy. All these patients achieved response and two of them (40%) achieved CMR after BGD. The autoHCT was successfully performed after BGD therapy in 42 (45.7%) patients. Furthermore, 16 (17.4%) patients underwent alloHCT after BGD therapy (Table 3). Among 21 patients treated with autoHCT before BGD therapy, 18 (85.7%) achieved response, 11 (52.4%) CMR, and 9 (42.9%) patients proceeded to alloHCT. PFS and OS are shown as Kaplan-Meier curves in Figs. 1 and 2. With a median follow-up of 18 months (range from 3 to 51 months), the median PFS for the overall population was 21 months while the median OS was not reached. PFS and OS rates at 2 years were 44.5% (95%CI: 33.7–58.8) and 75% (95%CI: 64.8–86.7), respectively. There were no differences between patients with relapsed or primary refractory HL in terms of PFS and OS (Figs. 3 and 4, P > 0.05). Similarly, no statistical differences in PFS and OS were noted between patients in whom BGD was used after first line or subsequent line of chemotherapy (Figs. 5 and 6, P > 0.05). Of note, most of the patients (80%) who responded to BGD maintain their response for at least 6 months (Fig. 1). In a subgroup of 9 patients ≥ 60 years old, 5 (55.6%) patients achieved CMR, 2 (22.2%)—PMR (ORR 77.8%), and 2 patients progressed during BGD treatment. PFS at 18 months was 62.2% (95%CI: 35.5–100) and OS at 23 months was 87.5% (95%CI: 67.3–100) (Figs. 7 and 8). Table 3 Response to BGD therapy
No. % (95%CI)
Interim (after 2–3 courses) n = 86
- PMDa 6 7 (1.6–12.4)
- SMDb 13 15.1 (7.5–22.7)
- PMRc 34 39.5 (29.2–49.9)
- CMRd 33 38.4 (28.1–48.6)
- ORRe 67 77.9 (69.1–86.7)
End of BGDf therapy n = 92
- PMDa 11 12 (5.3–18.6)
- SMDb 7 7.6 (2.2–13.0)
- PMRc 23 25 (16.2–33.8)
- CMRd 51 55.4 (45.3–65.6)
- ORRe 74 80.4 (2.3–88.5)
AutoHCTg after BGD therapy
- Yes 42 45.7
- No 50 54.3
AlloHCTh after BGD therapy
- Yes 16 17.4
- No 76 82.6
aPMD, progressive metabolic disease
bSMD, stable metabolic disease
cPMR, partial metabolic response
dCMR, complete metabolic response
eORR, overall response rate
fBGD, bendamustine, gemcitabine, dexamethasone
gautoHCT, autologous hematopoietic cell transplantation
halloHCT, allogeneic hematopoietic cell transplantation
Fig. 1 Progression-free survival (PFS) for the entire population
Fig. 2 Overall survival (OS) for the entire population
Fig. 3 Progression-free survival (PFS) for the subjects with relapsed or primary refractory Hodgkin lymphoma (HL)
Fig. 4 Overall survival (OS) for the subjects with relapsed or primary refractory Hodgkin lymphoma (HL)
Fig. 5 Progression-free survival (PFS) for patients treated with BGD as second or subsequent line of chemotherapy
Fig. 6 Overall survival (OS) for patients treated with BGD as second or subsequent line of chemotherapy
Fig. 7 Progression-free survival (PFS) for the subgroup of elderly patients (≥ 60 years)
Fig. 8 Overall survival (OS) for the subgroup of elderly patients (≥ 60 years)
Toxicity of BGD
The treatment-related AEs, mainly grade 1 or 2, were observed in 64 (69.6%) patients. Among grade ≥ 3 hematological toxicities, anemia was reported in 15.2% cases, thrombocytopenia in 20.7%, and neutropenia in 22.8% individuals. Severe non-hematological toxicities included infections (10.9%), alanine and/or aspartate aminotransferase (ALT or AST) increase (2.2%), and skin rush (1.1%). We recorded one death from unknown reasons during BGD therapy. All AEs reported during BGD therapy are shown in Table 4. In the subgroup of elderly patients (≥ 60 years), anemia and thrombocytopenia of grade 3 or 4 occurred in 2 (22.2%) patients, while neutropenia was found in 1 (11.1%) patient. Moreover, 2 (22.2%) patients experienced grade ≥ 3 infection, and 1 (11.1%) grade 3 skin rash in this subgroup. Table 4 Toxicity of BGD therapy
Toxicity Grade 1–2
No. (%) Grade 3–4
No. (%)
Hematological:
- Anemia 37 (40.2) 14 (15.2)
- Thrombocytopenia 25 (27.2) 19 (20.7)
- Neutropenia 19 (20.7) 21 (22.8)
Non-hematological:
- Infection 20 (21.7) 10 (10.9)
- ALT/ASTa increase 0 2 (2.2)
- Skin rush 7 (7.6) 1 (1.1)
- Fatigue 4 (4.3) 0
- Diarrhea 1 (1.1) 0
- Thrombotic events 2 (2.2) 0
- Guillain-Barré syndrome 1 (1.1) 0
- Autoimmune thyroiditis 1 (1.1) 0
Death from unknown reasons 1 (1.1)
aAlanine/aspartate aminotransferase
Discussion
Despite the significant progress in the management of patients with HL, relapsed and refractory disease constitutes a big challenge. According to the current treatment standards, high-dose chemotherapy followed by autoHCT has to be regarded as treatment of choice in the first relapse or primary progressive disease. However, even in the era of new agents such as brentuximab vedotin (BV) or immune checkpoint inhibitors, there are no accepted standards for salvage treatment before autoHCT. In the PLRG allied centers BGD was used since 2012 when the first cases of successful outcome of heavily pretreated patients were reported [16]. We had started to use BGD since both bendamustine and gemcitabine were effective in monotherapy as well as in combination with other agents.
Gemcitabine, a cytidine analog, was assessed in several studies. Kuruvilla et al. showed satisfactory (62%) response rate to GDP (gemcitabine, dexamethasone, and cisplatin) as a second-line therapy in patients with R/R HL [19]. Gemcitabine and vinerolbine combination showed ORR of 72% and 35% of CR [20]. In similar population, four-agent combination of gemcitabine with ifosfamide, vinorelbine, and prednisolone (IGEV) or double-agent schema of vinorelbine and pegylated liposomal doxorubicin (GVD) resulted in ORR of 81.3% and 70%, respectively [8, 9]. Bendamustine, another component of BGD, is a molecule containing the purine analog and the alkylating group. It was assessed in a phase II trial in heavily pretreated patients with HL (including those with relapse after auto- or alloHCT) at the dose of 120 mg/m2 and resulted in the intent-to-treat ORR of 53%, with CRs of 33% [11].
The combination of bendamustine with gemcitabine and vinorelbine (BeGEV) was first assessed in a multicenter phase II study by Santoro et al. [14]. The authors have demonstrated high efficacy of BeGEV as a second-line treatment in autoHCT-eligible patients (ORR 83%, CR 75%). In our retrospective analysis, ORR of BGD was similar to BeGEV although patient characteristics with regard to age and number of prior treatment regimens differ [14]. Moreover, almost one-fourth of patients in our study had been treated using autoHCT. This also most likely explains slightly higher rate of hematological toxicities at grade 3 or 4 in comparison to BeGEV. In contrast, severe non-hematological AEs occurred at similar incidence rates. We did not observe increased pulmonary toxicity which was reported by Cohen et al. in his cohort of patients. This might be due to the use of high dose of steroids (dexamethasone) in our regimen [21]. However, in spite of high efficacy of BGD in relation to ORR and CMR rate, estimated PFS in our study seems to be rather short (21 months). Most likely, this is a consequence of the large group of heavily pretreated patients (up to 6 previous line of therapy) including those after auto- and alloHCT and the subgroup of elderly patients in this cohort.
DHAP and ICE are among of the most commonly used salvage chemotherapy regimens in HL. Similar efficacy of these regimens as the second-line treatment was shown resulting in ORR of 88% for both, while CRs of 21% for DHAP and of 26.2% for ICE [5, 6]. Despite more heavily pretreated patients in our study, we report comparable ORR (80.4%) and much higher CMR rate (55.4%). Moreover, the difference in relation to CR rate increases in sub-analysis restricted to patients treated with BGD as the second line of chemotherapy (64.7%). The optimal number of BGD cycles is four, since about 40% of patients improved their response at the end of treatment compared to the interim assessment.
Most patients (80.4%) in this study were treated with ABVD as the first line of chemotherapy. Out of 13 patients being initially treated with BEACOPP, 5 (38.5%) patients were refractory to this regimen and all these patients achieved ORR after BGD therapy with CMR rate of 40%. In view of the fact that there are not many effective treatment options to overcome the BEACOPP refractoriness, this finding seems very interesting and encouraging for further studies.
In recent years, there have been many new agents evaluated for patients with R/R HL such as BV and immune checkpoint inhibitors. Brentuximab vedotin—an anti-CD30 antibody conjugated to antimicrotubule agent, monomethyl auristatin E—showed ORR of 75% and CR rate of 34% in heavily pretreated patients with HL after autoHCT [22]. Furthermore, BV showed similar efficacy as a second-line therapy in R/R HL (ORR 68%, CR 35%), and 89% of the subjects were able to proceed to autoHCT [23]. Addition of bendamustine to BV seems to increase its efficacy [12, 13]. However, in comparison to BGD regimen, BV does not appear to be superior both in monotherapy and in combination with bendamustine. Immune checkpoint inhibitors, mainly antibodies against programmed cell death protein 1 (PD-1) such as nivolumab or pembrolizumab, showed high efficacy as a salvage therapy for patients with R/R HL [24–27]. Ansell et al. reported ORR 87% in the heavily pretreated HL patients although CR rate was relatively low (17%) compared to BGD [24]. The authors reported similar incidence of AEs of any grade (78% vs. 69.6%) but relatively fewer cases of grade ≥ 3 AEs (22% vs. 38%) during nivolumab therapy when compared to BGD therapy [24].
The high efficacy of BGD in patients after failure of autoHCT is worth noting. This is a very challenging group, in which effective chemotherapy followed by alloHCT is the only option to achieve long-lasting remission. In this population checkpoint inhibitors, nivolumab and pembrolizumab resulted in high ORR rate (69% and 73%, respectively). However, once again, CR rates (16% and 14%, respectively) appear lower compared to BGD in our study (55.4%) and there are still some concerns about the increased incidence of immune complications after alloHCT in patients treated with immune checkpoint inhibitors before transplant [25, 26, 28, 29].
Another interesting finding of this study refers to elderly HL patients. We showed that in the patients at or above the age of 60 years BGD regimen has a similar efficacy (ORR 77.8%, CMR 55.6%) than in younger patients. Moreover, BGD-related toxicity seems to be acceptable in this subgroup.
Relatively small number of subjects included in the analysis as well as its retrospective nature and the lack of metabolic assessment in all patients are the major limitations of this study. Another important limitation of our study is a long accrual time. However, during this period, most of our patients were treated uniformly since novel therapies were not available due to reimbursement hurdles. Addition limitation may pose a large number of accruing centers. However, most of PLRG allied centers are reference centers with good-quality data management which somehow mitigate this flaw. However, our data clearly indicate that BGD which has a high rate of obtaining ORR and a relatively good time in response maintaining (5–6 months in 80% of patients) and an acceptable toxicity profile seems to provide a very good option for R/R HL patients even after BEACOPP first-line chemotherapy. In several patients, it opened a window to perform either autologous or allogeneic transplantation. Despite the fact that in recent years new treatment options, including BV and checkpoint inhibitors, showed promising results in treatment of patients with R/R HL, neither of them as yet is formally approved in the second-line treatment for HL. In addition, although pharmaco-economy was not a subject of this study, we speculate that BGD treatment may be a relatively cheap option. Therefore, we conclude that the BGD should be considered a viable option for patients with R/R HL and may serve as a bridge for individuals being candidates for auto- or alloHCT.
Author contributions
WKP, JMZ, and SG designed the study; all authors except for JMZ, AK, and AW enrolled patients; SG, RS, AK, and AW performed the bioinformatics and statistical analysis; RS and JMZ wrote the paper. All authors read and revised the manuscript critically.
Data availability
Not applicable
Code availability
Not applicable
Declarations
Ethics approval
According to Polish regulations, this was a retrospective study and it does not require approval of the bioethical committee. The study was approved by the board of The Polish Lymphoma Research Group.
Consent to participate
Not applicable
Consent for publication
Not applicable
Conflict of interest
The authors declare no conflict of interest.
The original version of this article was revised: This article was originally published with an incorrect affiliation. It should be 9 ( Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wrocław Medical University, Wrocław, Poland).
Wojciech Spychałowicz passed away during the writing of this article.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Change history
3/24/2021
A Correction to this paper has been published: 10.1007/s00277-021-04503-1 | 800 MILLIGRAM/SQ. METER, Q28D (EVERY 4 WEEKS ON DAYS 1 AND 4 FOR 30 MINS) | DrugDosageText | CC BY | 33625572 | 19,756,838 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Case Report: Prolonged Viral Shedding in Six COVID-19 Patients.
COVID-19 has surfaced as a multi-organ disease predominantly affecting the respiratory system. Detection of the viral RNA through reverse transcriptase-PCR (RT-PCR) from a nasopharyngeal or throat sample is the preferred method of diagnosis. Recent evidence has suggested that COVID-19 patients can shed the SARS-CoV-2 for several weeks. Herein, we report six cases of COVID-19 who had persistently positive SARS-CoV-2 on repeat RT-PCR testing reaching up to 9 weeks. The spectrum of cases described ranges from asymptomatic infection to severe COVID-19 pneumonia. A full understanding of the virus's transmission dynamics needs further research. Prolonged viral shedding currently has unclear implications on the management and isolation decisions-the role of the cycle threshold (Ct) value in guiding therapeutic decisions is yet to be clarified. More data on the relationship between Ct values and viral cultivation are needed, especially in patients with prolonged viral shedding, to understand the virus's viability and infectivity.
INTRODUCTION
Although SARS-CoV-2 infection most often presents as asymptomatic or as mild upper respiratory tract infection (URTI), almost 14% of patients develop severe disease requiring hospitalization, including 5% needing intensive care unit (ICU) admission.1 COVID-19 can result in serious injuries, including acute respiratory distress syndrome, sepsis, acute kidney, heart failure, and multi-organ failure. Older age and increasing comorbidities are risks for higher mortality.1,2 Currently, many diagnostic tests are available for COVID-19 with variable sensitivities.3 Nonetheless, viral RNA detection by reverse transcription–PCR remains the preferred method to establish the diagnosis. Serological detection of IgM and IgG antibodies against the virus using ELISA is also used for screening purposes and to identify past infection or immunity. However, its diagnostic value and accuracy are being evaluated.3
Recent studies showed that patients could asymptomatically shed SARS-CoV-2 for weeks.4,5 Herein, we report six cases of COVID-19 who showed persistent positive SARS-CoV-2 on repeated RT-PCR nasopharyngeal swab testing for varying durations, reaching 9 weeks after the initial diagnosis.
CASE PRESENTATION
Case 1.
The first case is a 74-year-old man known to have asthma, diabetes mellitus (DM), hypertension (HTN), coronary artery disease (CAD), and dyslipidemia (Table 1). He was admitted to a quarantine facility because of an asymptomatic COVID-19 infection identified through screening (RT-PCR). The local guideline at the time warranted two negative PCR swabs before discharge. SARS-CoV-2 was repeatedly positive for 49 days. He showed clinical improvement and was discharged after negative results (Table 1).
Table 1 Summary of baseline characteristics, clinical features, and laboratory test results, diagnoses, treatments, and outcomes of six cases with prolonged viral shedding
Characteristic Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6
Demographics
Age (years) 74 19 46 53 35 65
Gender (M: male) M M M M M M
Comorbid conditions DM2, HTN, Coronary artery disease, and BA None None DM2, HTN, and end-stage renal disease Pulmonary tuberculosis Chronic myeloid leukemia on active immunosuppressive therapy
Presenting symptoms, and clinical and radiological features on admission
Symptoms NA Fever and sore throat Fever, cough, and SOB Fever, diarrhea and abdominal pain Fever, headache, and cough Fever, cough, and SOB
Symptoms’ duration before admission (days) NA 2–3 7 4–5 10 5–6
Oxygen saturation (%) on room air 99 99 100 96 99 97
Chest X-ray Normal Normal Bilateral consolidations Bilateral patchy infiltrates Left lung opacity/cavitary lesion Bilateral lower lobes collapse with effusion
Laboratory tests on admission
White blood cell count (4–10 × 103/µL) NA 9.7 7.4 6.3 8.6 3.8
Hemoglobin (13–17 gm/dL) NA 17.4 11.7 14.8 11.3 7.5
Platelet count (150–400 × 103/µL) NA 260 181 152 511 42
Absolute neutrophil count (2–7 × 103/µL) NA 7.32 4.9 4.5 7 0.4
Lymphocyte count (1–3 × 103/µL) NA 1.68 2.2 1.22 1 0.9
C-reactive protein (0–5 mg/L) NA NA 49.9 30 225 74.6
Lactate dehydrogenase (135–225 U/L) NA NA 282 NA NA 201
Ferritin (30–490 µg/L) NA NA 664 NA 3,439 286
D-dimer (< 0.4 mcg/mL) NA NA NA NA NA 3.41
Creatinine (63.6–110.5 µmol/L) NA 81 86 1,112 61 80
Alanine aminotransferase (0–55 U/L) NA 26.4 32 12.6 42 10
Aspartate aminotransferase (5–34 U/L) NA 22 35 24 92 17
Diagnosis
Asymptomatic Upper respiratory tract infection Pneumonia Pneumonia Pneumonia Pneumonia
Treatment
Hydroxychloroquine No No Yes Yes Yes No
Antivirals No No Yes Yes Yes Yes
Antibiotics No No Yes Yes Yes Yes
Corticosteroid No No No No No No
Tocilizumab No No No No No Yes
Outcome
Intensive care unit admission No No No No No Yes
Invasive ventilation No No No No No No
Noninvasive ventilation No No No No No Yes
Supplemental oxygen No No No Yes No Yes
Total symptoms’ duration (days) NA 4 NA 15 20 35
Time to radiologic recovery (days) NA NA NA 14 46 47
AST = aspartate aminotransferase; BA = bronchial asthma; DM 2 = diabetes mellites type II; HD = hemodialysis; HTN = hypertension; NA = not available; SOB = shortness of breath.
Case 2.
A healthy 19-year-old man presented with a short history of fever and sore throat. The examination was remarkable for low-grade fever and tachycardia, and laboratory investigations and chest X-ray were unremarkable. He was diagnosed as a case of COVID-19 mild URTI and did not require hospital admission but transited through quarantine. His PCR swab remained positive for 48 days.
Case 3.
A previously healthy 46-year-old man presented with a 7-day history of fever, dry cough, and mild dyspnea. On examination, he was febrile, mildly tachypneic, tachycardic, but maintained oxygen saturation on room air. His chest X-ray revealed consolidation involving the left mid and lower zones. SARS-CoV-2 PCR tested positive, and he was started on COVID-19 management for pneumonia following local protocols. The repeated PCR tests were persistently positive for 47 days. The patient was discharged home, asymptomatic after negative PCR.
Case 4.
A 53-year-old man, known to have HTN, DM, and end-stage renal disease (ESRD), presented with fever, abdominal pain, diarrhea, nausea, and vomiting. Physical examination revealed a tired-looking man with mild abdominal tenderness but was otherwise unremarkable. Abdominal computed tomography (CT) scan was performed to rule out causes of acute abdomen. It showed no abdominal pathology but numerous bilateral lungs’ basal patchy consolidations and ground-glass opacities. Subsequently, nasopharyngeal PCR confirmed COVID-19. He received the treatment guided by the local protocol, and he became symptom-free and was discharged home following negative swab PCR after 28 days. Eighteen days later, he again presented with fever, chest pain, and mild dyspnea. The chest X-ray showed bilateral lung infiltrates increasing compared with the previous Images. The initial test for COVID-19 was inconclusive; then, the repeat test was positive 2 days after the second hospital admission. He was restarted on the treatment protocol and continued to improve with an unremarkable hospital stay. The repeated test was negative after 1 week from the second presentation. The patient had 48 days elapsing from the first positive PCR result until the last positive sample.
Case 5.
A 35-year-old man presented with a 10-day history of fever, headache, and dry cough. Physical examination was unremarkable. His baseline blood investigation was remarkable for high inflammatory markers and mild transaminitis. Chest X-ray revealed left mid-zone consolidation with a cavitary lesion. He was found to be positive for SARS-CoV-2 from nasopharyngeal swab PCR. Given the cavitary lesion, tuberculosis (TB) was suspected, and sputum smear acid-fast bacilli confirmed the presence of mycobacterial infection. Thus, the patient was treated as a case of COVID-19 pneumonia and active pulmonary TB. TB culture showed Mycobacterium tuberculosis sensitive for first-line anti-TB drugs. He later developed a rise in liver enzymes suspected to be either secondary to TB drugs versus COVID-19–related hepatitis. Subsequently, he was shifted temporarily to second-line antituberculosis therapy until improvement in his liver enzymes. Re-swabbing was performed as per the protocol, and the patient tested persistently positive for a total of 62 days.
Case 6.
This is a 65-year-old man known to have chronic myeloid leukemia (CML) on dasatinib. He presented with a short history of fever, productive cough, and dyspnea. The examination revealed low-grade fever, tachycardia, and bilateral rhonchi on chest examination. Chest X-ray showed bilateral lower lobe consolidation with effusion. SARS-CoV-2 PCR was positive, and he was subsequently diagnosed as a severe case of COVID-19 pneumonia and received antibiotics and antiviral drugs. His condition deteriorated further during his stay, requiring noninvasive ventilation and ICU admission for 7 days. He eventually improved and was stepped down to the general medical wards for post-ICU care. He continued to have positive PCR for 54 days from the initial positive test.
DISCUSSION
Coronaviruses have structural proteins, including envelope (E), nucleocapsid (N), and spike (S) proteins. Their replication and transcription are expressed from an open reading frame called ORF1ab, and RNA dependent on the RNA polymerase gene (RdRp). The ORF1ab, E, RdRp, N, and S genes are the targets used for the detection of SARS-CoV-2 by RT-PCR.6
SARS-CoV-2 may be detected via an upper respiratory tract PCR sample a few days before symptom onset. Viral shedding persists for varying periods after symptoms’ onset, with a study reporting a median duration of 11 days.7 Newer evidence suggested the long-term shedding of SARS-CoV-2 in the urine and stool of infected patients even when their nasopharyngeal swabs were negative.8,9 Factors independently associated with prolonged respiratory viral shedding include fever (> 38.5°C), severe disease, old age (> 60), male gender, concomitant HTN, steroid use, invasive ventilation, ICU admission, and lack of antiviral drugs.7,10–13
Although some investigators observed a longer duration of viral shedding in symptomatic patients,14 our patients ranged from having an asymptomatic infection (case 1) to severe COVID-19 pneumonia (case 6). All had prolonged viral shedding ranging between 6 and 9 weeks, as depicted by PCR (Figure 1). The periods reported in our series are an underrepresentation of the exact shedding window. The shedding likely exceeded these periods as we calculated only from the first positive test till the last positive test; this excludes shedding before diagnosis and between the last positive and first negative tests. Interestingly, cases 5 and 6 had the most extended shedding window, which may be attributed to their immunosuppressed status (active pulmonary tuberculosis and CML on active chemotherapy, respectively). Two recently reported leukemia and lymphoma cases shed the virus for 70 and 60 days, respectively.15,16 The mechanism by which immunosuppressed status affects SARS-CoV-2 shedding is not well elucidated.16 Nonetheless, derangement of T-cell immune function, which has a strong role in COVID-19 pathophysiology, is likely involved.17 Similarly, impaired immunity and the accompanying increased viral load might have delayed resolution in diabetic patients in cases 1 and 4.18
Figure 1. Schematic presentation of SARS-CoV-2 PCR results. This figure appears in color at www.ajtmh.org.
Bullard et al.19 tried to describe the infectiousness through viral cultures and found that viable SARS-CoV-2 was cultured when the RT-PCR cycle threshold (Ct) value was < 24 and within less than 8 days from symptoms onset. Singanayagam et al.20 also found a strong correlation between the Ct value and viral load with a probability of retrieving viable virus, declining to 8% in samples with Ct > 35, and 6% 10 days after symptoms onset. In line with these findings, multiple Ct value cutoffs were used by different guidelines generating bodies to define the infectivity and guide isolation decisions, which has led to differences in reported COVID-19 prevalence. Nonetheless, RT-PCR positivity is a surrogate that does not necessarily indicate that an individual is infectious or is shedding live viruses. Moreover, the optimal Ct value cutoff is unknown. The CDC and the WHO do not recommend using a test-based strategy guided by the Ct value to ascertain infectivity, at least at this stage.21,22 At the time of this series, our local protocol initially mandated two negative PCR results, and it was revised later in the mid of our patient’s observation to a single negative test. The adopted Ct value cutoff was 33 to guide isolation discontinuation decisions in hospitalized patients. Time lines of the nasopharyngeal PCR Ct value in our cases showed that multiple gene loci fall under the infectious range (Supplemental Table 1). Median Ct values at 2 weeks and even above 6 weeks showed a CT value of less than 33, possibly suggesting high viral load. Most patients had persistent shedding despite symptoms’ resolution; this could imply a carrier state and prolonged infectivity possibly exceeding 6 weeks. To review the possibility of reinfection or relapse in case 4, we analyzed his Ct values chronologically and assessed his Ct values using different genes. When this patient was discharged at 28 days, he had two negative results with the Thermo Fisher kit showing a Ct value > 40 on all gene locus (N, Orf, and S). After 18 days, he presented to the hospital again with clinical and radiological worsening with a Ct value of 32 in Roche E-gene. It is not clear whether this represents a relapse with the same virus with prolonged viral shedding or reinfection with a new virus from the community.
CONCLUSION
In this case series, we observe a persistent viral shedding in patients with immunosuppressive conditions such as DM, leukemia, tuberculosis, and severe COVID-19 pneumonia. SARS-CoV-2 prolonged shedding currently has unclear implications on the management and isolation decisions—the role of the Ct value in guiding infection control decisions is yet to be clarified. More data on the relationship between viral and Ct values are needed, especially in patients with prolonged viral shedding, to assess the virus’s viability and infectivity.
Supplemental table
Supplemental materials
ACKNOWLEDGMENTS
We thank Hamad Medical Corporation for supporting academic research and the medical staff involved in the care of COVID-19 patients. Publication charges for this article were waived due to the ongoing pandemic of COVID-19. | HYDROXYCHLOROQUINE | DrugsGivenReaction | CC BY-NC | 33626020 | 20,155,688 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dermatitis allergic'. | Development and desensitization therapy of high-response factor VIII inhibitors with severe allergic reaction in a moderate hemophilia A patient.
Neutralizing antibodies (inhibitors) against factor VIII/IX (FVIII/FIX) poses a serious and challenging complication in the hemophilia treatment. Allergic reaction is more common in hemophilia B and always companion with FIX inhibitors, but it is rare in hemophilia A (HA). So far only few cases demonstrated FVIII-specific allergic response in hemophilia A. Coexistence of allergic reactions with inhibitors was contraindicated for immune tolerance induction (ITI) regimen which is the only proven therapy to eliminate inhibitor. We report a rare case of a 11-year-old boy with moderate HA who developed high titer inhibitor and severe allergic reaction to both plasma derived and recombinant FVIII concentrates. Inhibitor was eliminated with the use of prednisone. Further desensitization protocol by administering rFVIII of increasing does from 0.01 IU/kg to 40 IU/kg with a pre-determined time schedule allowed patient tolerance to the normal dose and infusion time to FVIII.
Introduction
Hemophilia A (HA) is a congenital bleeding disorder characterized by coagulation factor VIII (FVIII) deficiency.1,2 Prophylactic replacement therapy with FVIII remained as mainstay of the management of HA.3 Further, 30% of severe and 5% of mild and moderate HA patients will develop inhibitors (FVIII neutralizing antibodies) which inhibit the activity of infused FVIII.4–6 Allergic manifestations are rare complications in HA patients,7 and only evidenced by a few cases which suggested to be mediated by IgE.8,9 Here, we report a rare case in a moderate HA patient developed high-titer inhibitor and severe allergic reaction to both plasma derived FVIII (pdFVIII) and recombinant FVIII (rFVIII) concentrates, but controlled by desensitization therapy.
Case report
The patient was a 11-year-old boy, diagnosed with moderate HA (FVIII coagulant activity of 2.6%) and impaired FVIII protein secretion due to F8 missense mutations (c.5590A>G) at the age of 2 years after intracranial hemorrhage for which he received continuous fresh frozen plasma infusion and completely recovered. Later, at the age of 9-year-old, he suffered a gastrointestinal bleeding for which he received FVIII (Xyntha) at a dose of 36 IU/kg/day for 5 days and 18 IU/kg/day for 2 days without using tranexamic acid. After that, prophylaxis with FVIII (Xyntha) was initiated at a dose of 18 IU/kg/three times weekly (TiW) and no bleeding episodes appeared during the first 1.5 months. However, three bleeding episodes (one time in muscle and two times in knee) occurred after 25 exposure days. At this point inhibitor was considered developing and confirmed with 8 Bethesda Unit (BU) mL−1 at the 48 exposure days. Further, inhibitor titer measured after 1 month exhibited 6.8 BU mL−1 and the patient was not tested for FVIII level at this time.
Following this, the patient received ITI therapy to eradicate inhibitors with domestic plasma derived FVIII (pdFVIII) containing full length pdFVIII, von Willebrand factor (VWF) (1:1 ratio), albumin and other proteins at a dose of FVIII 50 IU/kg/QOD. Immediately after the first infusion, he developed allergic reaction (rash and pruritus) with Immunoglobulin E (IgE) level of 727 IU/mL. Further, pdFVIII was replaced by rFVIII (Advate and Kogenate) however, rFVIII led to more severe allergic reactions as respiratory compromise requiring ventilatory support and symptomatic treatment (dexchlorpheniramine and methylprednisolone). The allergic reaction (manifested as skin rash) occurred immediately after rFVIII infusion and infusion was stopped. In consideration of his allergic reaction and poor knee status, prednisone 1mg/kg/day for 4 weeks was prescribed initially and then tapered gradually with domestic plasma derived prothrombin complex concentrates (pdPCC) (30 IU/kg/QoD) prophylaxis. Eleven weeks after, he had a negative inhibitor without any clinical manifestations of allergic reactions (rash, laryngeal edema, etc.). However, it occurred again after rFVIII (Xyntha) infusion where he developed allergic reaction that manifested as increased heart rate and laryngeal edema. The IgE level was detected on the next day of allergic reaction as 329 IU/mL (Figure 1).
Figure 1. Inhibitor titer and Immunoglobulin E (IgE) level during FVIII infusion and desensitization therapy.
pdFVIII, plasma derived factor VIII; rFVIII, combinant factor VIII; PCC, prothrombin complex concentrate.
Further, the patient received desensitization treatment to FVIII which was initiated with prednisone infusion at a dose of 40 mg (1 mg/kg) 30 min−1, an hour before each rFVIII (ADVATE) infusion (Table 1). On the first day of desensitization treatment, rFVIII (ADVATE) was given from 0.01 IU/kg increased to 10 IU/kg i.v. gradually with total amount of 31.15 IU/kg in 8 h. From the second day to the 18th day, FVIII was given as 40 IU/kg daily with a gradually decreasing infusion time from 10 h to 20 min which was a normal dose and speed of FVIII infusion. The total course of desensitization treatment is 22 days. Allergic reactions appeared at the 5th and 11th days manifested with the increasing heart rate and rash which could relief after prolonging the infusion time. Further, upon more than 1 year of follow-up, the patient did not suffer any joint bleeds and other serious bleeding episodes and his inhibitor titer remained negative. However, the patient did not test FVIII recovery. The FVIII level had not been measured during the time the patient with inhibitor. Therefore, we do not know whether there is an antibody against endogenous FVIII. He only confirmed with negative inhibitor and the similar FVIII:C (3.3%) to baseline level (2.6%).
Table 1. FVIII desensitization protocol.
Dose (U/kg) Cumulative dose (U/kg) Actual dose (U) Infusion time (min) Interval from previous dose (min)
Day 1 0.01 0.01 0.48 5 0
0.02 0.03 0.96 5 10
0.04 0.07 1.92 5 10
0.08 0.15 3.84 5 10
0.1 0.25 4.8 5 10
0.2 0.45 9.6 5 20
0.4 0.85 19.2 5 20
0.8 1.65 38.4 5 20
1.5 3.15 72 5 20
3 6.15 144 30 –
6 12.15 288 30 –
9 21.15 432 60 –
10 31.15 480 60 –
Day 2 40 1920 1920 600 –
Day 3 40 1920 1920 480 –
Day 4 40 1920 1920 360 –
Day 5 40 40 1920 600 –
Day 6 40 40 1920 600 –
Day 7 40 40 1920 480 –
Day 8 40 40 1920 360 –
Day 9 40 40 1920 240 –
Day 10 40 40 1920 120 –
Day 11 40 40 1920 180 –
Day 12 40 40 1920 120 –
Day 13 40 40 1920 60 –
Day 14 40 40 1920 30 –
Day 15 40 40 1920 30 –
Day 16 40 40 1920 60 –
Day 17 40 40 1920 30 –
Day 18 40 40 1920 20 –
Day 19 40 40 1920 20 –
Day 20 40 40 1920 20 –
Day 21 40 40 1920 20 –
Day 22 40 40 1920 20 –
Discussion
Patients with hemophilia A are rarely to develop anti-FVIII allergic reaction coexisted with anti-FVIII inhibitors, which was reported to be induced either by FVIII itself or by other proteins in FVIII products only in a few case reports.10–13 In this case, the patient was not allergic to rFVIII until inhibitor development. ITI therapy with pdFVIII lead to allergic reactions with elevated IgE levels and did not subside even after switching back to rFVIII suggesting that the allergic reaction could be caused by FVIII or also by other proteins like albumin or by both. We cannot ensure which substance the patient against with because he did not try pdFVIII before inhibitor development to prove no allergic reaction to it. The patient was a moderate HA child and FVIII:C was 2.6%, and the patient was without other immune diseases when the inhibitor is produced. So we speculate the FVIII antibodies was caused by the exogenous FVIII.
Further, the patient turned to prophylaxis using domestic pdPCC and with prednisolone to cool down immune system. No allergic reactions or inhibitors development was observed even though the pdPCC had a trace amount of FVIII, other proteins similar to pdFVIII. We considered that the trace amount of allergen would induce allergic reaction, but the prednisone would lower the anamnestic response thereby his inhibitor titer remained negative. We anticipate that trace amounts of FVIII in the pdPCC and endogenous FVIII could have been part of the immune tolerance induction. Afterward, the patient infused rFVIII again, however, the infusion still led to respiratory compromise. Thus, the allergic response was inferred causing by FVIII. Although the IgE level (329 IU/mL) detected was much lower than the last detection, the allergic response could still exist for the following two reasons. Firstly, IgE level was monitored on the next day of rFVIII infusion instead of at the time of allergic reaction occurrence, in which it should be much higher. Secondly, IgE level was not investigated while receiving prednisone. Therefore, the trough level of IgE was unknowable which was possible to lower than that we detected this time. However, we still cannot exclude the reason for allergic reaction by other components of pd products because the patient never tried pdFVIII or pdPCC before allergic reaction with inhibitor development or after successful desensitization.
Inhibitors can hardly be tolerized without FVIII.14 However, the present case eliminated inhibitor by prednisone alone which has a general immunosuppressive effect instead of inducing antigen-FVIII tolerance. Although inhibitor turned to negative, FVIII was not tolerated by the patient. Earlier, Kadar et al, reported IgE mediated grade 3 anaphylactic reaction in 51-year-old HA patient that triggered by rFVIII.13 Similarly, with the observation of the high serum IgE level in patient during treatment, we consider his inhibitor for FVIII antigen is probably triggered by an anti-FVIII IgE, but very regrettable, we have not been able to detect the type of antibody to confirm. Desensitization protocol is the other inhibitor eradication strategy found effective in a few patients with allergic reactions.10 In current case, patient achieved tolerance to FVIII through the desensitization protocol where it downregulates the expression of mast cells and basophils thereby inhibiting the release of inflammatory mediators (β-hexosaminidase, prostaglandins and leukotrienes), however the exact mechanism underlying this still remained elusive.15 Further, the current report cannot be generalized as this was a single case report therefore the potential role of desensitization regimen in eliminating the inhibitor and allergic reaction to FVIII still need to be confirmed.
All previously reported cases with inhibitor and allergic reaction were severe hemophilia A/B, which were desensitized successfully. But this case refers to a moderate HA patient the inhibitors and allergic reactions developed could be either due to endogenous or exogenous FVII. However, after desensitization therapy, the allergic reaction toward FVIII disappeared, the inhibitor turned negative, and the FVIII:C recovered to normal.
Conclusion
In summary, we report a rare case of coexistence of high-titer inhibitor and severe allergic reaction to both pdFVIII and rFVIII concentrates in moderate HA patient which was contraindicated for ITI treatment but controlled with the adoption of desensitization therapy.
The authors acknowledge Dr Zekun Li (MD) from Beijing Children’s Hospital for drawing the figure and providing revision of the manuscript for intellectual content. Dr Vengal Rao Pachava (PhD) and Dr Anuradha Nalli (PhD) from Indegene Pvt. Ltd., Bangalore, India, for providing medical writing support in the development of this manuscript.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from Beijing Municipal Science and Technology Commission (code Z181100001718182).
Ethical approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed consent: Written informed consent was obtained from the parent for their anonymized information to be published in this article.
ORCID iD: Runhui Wu https://orcid.org/0000-0002-8397-7057 | ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT, ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT RESIDUES 743-1636 DELETED | DrugsGivenReaction | CC BY-NC | 33626954 | 19,004,972 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug hypersensitivity'. | Development and desensitization therapy of high-response factor VIII inhibitors with severe allergic reaction in a moderate hemophilia A patient.
Neutralizing antibodies (inhibitors) against factor VIII/IX (FVIII/FIX) poses a serious and challenging complication in the hemophilia treatment. Allergic reaction is more common in hemophilia B and always companion with FIX inhibitors, but it is rare in hemophilia A (HA). So far only few cases demonstrated FVIII-specific allergic response in hemophilia A. Coexistence of allergic reactions with inhibitors was contraindicated for immune tolerance induction (ITI) regimen which is the only proven therapy to eliminate inhibitor. We report a rare case of a 11-year-old boy with moderate HA who developed high titer inhibitor and severe allergic reaction to both plasma derived and recombinant FVIII concentrates. Inhibitor was eliminated with the use of prednisone. Further desensitization protocol by administering rFVIII of increasing does from 0.01 IU/kg to 40 IU/kg with a pre-determined time schedule allowed patient tolerance to the normal dose and infusion time to FVIII.
Introduction
Hemophilia A (HA) is a congenital bleeding disorder characterized by coagulation factor VIII (FVIII) deficiency.1,2 Prophylactic replacement therapy with FVIII remained as mainstay of the management of HA.3 Further, 30% of severe and 5% of mild and moderate HA patients will develop inhibitors (FVIII neutralizing antibodies) which inhibit the activity of infused FVIII.4–6 Allergic manifestations are rare complications in HA patients,7 and only evidenced by a few cases which suggested to be mediated by IgE.8,9 Here, we report a rare case in a moderate HA patient developed high-titer inhibitor and severe allergic reaction to both plasma derived FVIII (pdFVIII) and recombinant FVIII (rFVIII) concentrates, but controlled by desensitization therapy.
Case report
The patient was a 11-year-old boy, diagnosed with moderate HA (FVIII coagulant activity of 2.6%) and impaired FVIII protein secretion due to F8 missense mutations (c.5590A>G) at the age of 2 years after intracranial hemorrhage for which he received continuous fresh frozen plasma infusion and completely recovered. Later, at the age of 9-year-old, he suffered a gastrointestinal bleeding for which he received FVIII (Xyntha) at a dose of 36 IU/kg/day for 5 days and 18 IU/kg/day for 2 days without using tranexamic acid. After that, prophylaxis with FVIII (Xyntha) was initiated at a dose of 18 IU/kg/three times weekly (TiW) and no bleeding episodes appeared during the first 1.5 months. However, three bleeding episodes (one time in muscle and two times in knee) occurred after 25 exposure days. At this point inhibitor was considered developing and confirmed with 8 Bethesda Unit (BU) mL−1 at the 48 exposure days. Further, inhibitor titer measured after 1 month exhibited 6.8 BU mL−1 and the patient was not tested for FVIII level at this time.
Following this, the patient received ITI therapy to eradicate inhibitors with domestic plasma derived FVIII (pdFVIII) containing full length pdFVIII, von Willebrand factor (VWF) (1:1 ratio), albumin and other proteins at a dose of FVIII 50 IU/kg/QOD. Immediately after the first infusion, he developed allergic reaction (rash and pruritus) with Immunoglobulin E (IgE) level of 727 IU/mL. Further, pdFVIII was replaced by rFVIII (Advate and Kogenate) however, rFVIII led to more severe allergic reactions as respiratory compromise requiring ventilatory support and symptomatic treatment (dexchlorpheniramine and methylprednisolone). The allergic reaction (manifested as skin rash) occurred immediately after rFVIII infusion and infusion was stopped. In consideration of his allergic reaction and poor knee status, prednisone 1mg/kg/day for 4 weeks was prescribed initially and then tapered gradually with domestic plasma derived prothrombin complex concentrates (pdPCC) (30 IU/kg/QoD) prophylaxis. Eleven weeks after, he had a negative inhibitor without any clinical manifestations of allergic reactions (rash, laryngeal edema, etc.). However, it occurred again after rFVIII (Xyntha) infusion where he developed allergic reaction that manifested as increased heart rate and laryngeal edema. The IgE level was detected on the next day of allergic reaction as 329 IU/mL (Figure 1).
Figure 1. Inhibitor titer and Immunoglobulin E (IgE) level during FVIII infusion and desensitization therapy.
pdFVIII, plasma derived factor VIII; rFVIII, combinant factor VIII; PCC, prothrombin complex concentrate.
Further, the patient received desensitization treatment to FVIII which was initiated with prednisone infusion at a dose of 40 mg (1 mg/kg) 30 min−1, an hour before each rFVIII (ADVATE) infusion (Table 1). On the first day of desensitization treatment, rFVIII (ADVATE) was given from 0.01 IU/kg increased to 10 IU/kg i.v. gradually with total amount of 31.15 IU/kg in 8 h. From the second day to the 18th day, FVIII was given as 40 IU/kg daily with a gradually decreasing infusion time from 10 h to 20 min which was a normal dose and speed of FVIII infusion. The total course of desensitization treatment is 22 days. Allergic reactions appeared at the 5th and 11th days manifested with the increasing heart rate and rash which could relief after prolonging the infusion time. Further, upon more than 1 year of follow-up, the patient did not suffer any joint bleeds and other serious bleeding episodes and his inhibitor titer remained negative. However, the patient did not test FVIII recovery. The FVIII level had not been measured during the time the patient with inhibitor. Therefore, we do not know whether there is an antibody against endogenous FVIII. He only confirmed with negative inhibitor and the similar FVIII:C (3.3%) to baseline level (2.6%).
Table 1. FVIII desensitization protocol.
Dose (U/kg) Cumulative dose (U/kg) Actual dose (U) Infusion time (min) Interval from previous dose (min)
Day 1 0.01 0.01 0.48 5 0
0.02 0.03 0.96 5 10
0.04 0.07 1.92 5 10
0.08 0.15 3.84 5 10
0.1 0.25 4.8 5 10
0.2 0.45 9.6 5 20
0.4 0.85 19.2 5 20
0.8 1.65 38.4 5 20
1.5 3.15 72 5 20
3 6.15 144 30 –
6 12.15 288 30 –
9 21.15 432 60 –
10 31.15 480 60 –
Day 2 40 1920 1920 600 –
Day 3 40 1920 1920 480 –
Day 4 40 1920 1920 360 –
Day 5 40 40 1920 600 –
Day 6 40 40 1920 600 –
Day 7 40 40 1920 480 –
Day 8 40 40 1920 360 –
Day 9 40 40 1920 240 –
Day 10 40 40 1920 120 –
Day 11 40 40 1920 180 –
Day 12 40 40 1920 120 –
Day 13 40 40 1920 60 –
Day 14 40 40 1920 30 –
Day 15 40 40 1920 30 –
Day 16 40 40 1920 60 –
Day 17 40 40 1920 30 –
Day 18 40 40 1920 20 –
Day 19 40 40 1920 20 –
Day 20 40 40 1920 20 –
Day 21 40 40 1920 20 –
Day 22 40 40 1920 20 –
Discussion
Patients with hemophilia A are rarely to develop anti-FVIII allergic reaction coexisted with anti-FVIII inhibitors, which was reported to be induced either by FVIII itself or by other proteins in FVIII products only in a few case reports.10–13 In this case, the patient was not allergic to rFVIII until inhibitor development. ITI therapy with pdFVIII lead to allergic reactions with elevated IgE levels and did not subside even after switching back to rFVIII suggesting that the allergic reaction could be caused by FVIII or also by other proteins like albumin or by both. We cannot ensure which substance the patient against with because he did not try pdFVIII before inhibitor development to prove no allergic reaction to it. The patient was a moderate HA child and FVIII:C was 2.6%, and the patient was without other immune diseases when the inhibitor is produced. So we speculate the FVIII antibodies was caused by the exogenous FVIII.
Further, the patient turned to prophylaxis using domestic pdPCC and with prednisolone to cool down immune system. No allergic reactions or inhibitors development was observed even though the pdPCC had a trace amount of FVIII, other proteins similar to pdFVIII. We considered that the trace amount of allergen would induce allergic reaction, but the prednisone would lower the anamnestic response thereby his inhibitor titer remained negative. We anticipate that trace amounts of FVIII in the pdPCC and endogenous FVIII could have been part of the immune tolerance induction. Afterward, the patient infused rFVIII again, however, the infusion still led to respiratory compromise. Thus, the allergic response was inferred causing by FVIII. Although the IgE level (329 IU/mL) detected was much lower than the last detection, the allergic response could still exist for the following two reasons. Firstly, IgE level was monitored on the next day of rFVIII infusion instead of at the time of allergic reaction occurrence, in which it should be much higher. Secondly, IgE level was not investigated while receiving prednisone. Therefore, the trough level of IgE was unknowable which was possible to lower than that we detected this time. However, we still cannot exclude the reason for allergic reaction by other components of pd products because the patient never tried pdFVIII or pdPCC before allergic reaction with inhibitor development or after successful desensitization.
Inhibitors can hardly be tolerized without FVIII.14 However, the present case eliminated inhibitor by prednisone alone which has a general immunosuppressive effect instead of inducing antigen-FVIII tolerance. Although inhibitor turned to negative, FVIII was not tolerated by the patient. Earlier, Kadar et al, reported IgE mediated grade 3 anaphylactic reaction in 51-year-old HA patient that triggered by rFVIII.13 Similarly, with the observation of the high serum IgE level in patient during treatment, we consider his inhibitor for FVIII antigen is probably triggered by an anti-FVIII IgE, but very regrettable, we have not been able to detect the type of antibody to confirm. Desensitization protocol is the other inhibitor eradication strategy found effective in a few patients with allergic reactions.10 In current case, patient achieved tolerance to FVIII through the desensitization protocol where it downregulates the expression of mast cells and basophils thereby inhibiting the release of inflammatory mediators (β-hexosaminidase, prostaglandins and leukotrienes), however the exact mechanism underlying this still remained elusive.15 Further, the current report cannot be generalized as this was a single case report therefore the potential role of desensitization regimen in eliminating the inhibitor and allergic reaction to FVIII still need to be confirmed.
All previously reported cases with inhibitor and allergic reaction were severe hemophilia A/B, which were desensitized successfully. But this case refers to a moderate HA patient the inhibitors and allergic reactions developed could be either due to endogenous or exogenous FVII. However, after desensitization therapy, the allergic reaction toward FVIII disappeared, the inhibitor turned negative, and the FVIII:C recovered to normal.
Conclusion
In summary, we report a rare case of coexistence of high-titer inhibitor and severe allergic reaction to both pdFVIII and rFVIII concentrates in moderate HA patient which was contraindicated for ITI treatment but controlled with the adoption of desensitization therapy.
The authors acknowledge Dr Zekun Li (MD) from Beijing Children’s Hospital for drawing the figure and providing revision of the manuscript for intellectual content. Dr Vengal Rao Pachava (PhD) and Dr Anuradha Nalli (PhD) from Indegene Pvt. Ltd., Bangalore, India, for providing medical writing support in the development of this manuscript.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from Beijing Municipal Science and Technology Commission (code Z181100001718182).
Ethical approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed consent: Written informed consent was obtained from the parent for their anonymized information to be published in this article.
ORCID iD: Runhui Wu https://orcid.org/0000-0002-8397-7057 | ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT | DrugsGivenReaction | CC BY-NC | 33626954 | 19,057,183 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Inhibiting antibodies positive'. | Development and desensitization therapy of high-response factor VIII inhibitors with severe allergic reaction in a moderate hemophilia A patient.
Neutralizing antibodies (inhibitors) against factor VIII/IX (FVIII/FIX) poses a serious and challenging complication in the hemophilia treatment. Allergic reaction is more common in hemophilia B and always companion with FIX inhibitors, but it is rare in hemophilia A (HA). So far only few cases demonstrated FVIII-specific allergic response in hemophilia A. Coexistence of allergic reactions with inhibitors was contraindicated for immune tolerance induction (ITI) regimen which is the only proven therapy to eliminate inhibitor. We report a rare case of a 11-year-old boy with moderate HA who developed high titer inhibitor and severe allergic reaction to both plasma derived and recombinant FVIII concentrates. Inhibitor was eliminated with the use of prednisone. Further desensitization protocol by administering rFVIII of increasing does from 0.01 IU/kg to 40 IU/kg with a pre-determined time schedule allowed patient tolerance to the normal dose and infusion time to FVIII.
Introduction
Hemophilia A (HA) is a congenital bleeding disorder characterized by coagulation factor VIII (FVIII) deficiency.1,2 Prophylactic replacement therapy with FVIII remained as mainstay of the management of HA.3 Further, 30% of severe and 5% of mild and moderate HA patients will develop inhibitors (FVIII neutralizing antibodies) which inhibit the activity of infused FVIII.4–6 Allergic manifestations are rare complications in HA patients,7 and only evidenced by a few cases which suggested to be mediated by IgE.8,9 Here, we report a rare case in a moderate HA patient developed high-titer inhibitor and severe allergic reaction to both plasma derived FVIII (pdFVIII) and recombinant FVIII (rFVIII) concentrates, but controlled by desensitization therapy.
Case report
The patient was a 11-year-old boy, diagnosed with moderate HA (FVIII coagulant activity of 2.6%) and impaired FVIII protein secretion due to F8 missense mutations (c.5590A>G) at the age of 2 years after intracranial hemorrhage for which he received continuous fresh frozen plasma infusion and completely recovered. Later, at the age of 9-year-old, he suffered a gastrointestinal bleeding for which he received FVIII (Xyntha) at a dose of 36 IU/kg/day for 5 days and 18 IU/kg/day for 2 days without using tranexamic acid. After that, prophylaxis with FVIII (Xyntha) was initiated at a dose of 18 IU/kg/three times weekly (TiW) and no bleeding episodes appeared during the first 1.5 months. However, three bleeding episodes (one time in muscle and two times in knee) occurred after 25 exposure days. At this point inhibitor was considered developing and confirmed with 8 Bethesda Unit (BU) mL−1 at the 48 exposure days. Further, inhibitor titer measured after 1 month exhibited 6.8 BU mL−1 and the patient was not tested for FVIII level at this time.
Following this, the patient received ITI therapy to eradicate inhibitors with domestic plasma derived FVIII (pdFVIII) containing full length pdFVIII, von Willebrand factor (VWF) (1:1 ratio), albumin and other proteins at a dose of FVIII 50 IU/kg/QOD. Immediately after the first infusion, he developed allergic reaction (rash and pruritus) with Immunoglobulin E (IgE) level of 727 IU/mL. Further, pdFVIII was replaced by rFVIII (Advate and Kogenate) however, rFVIII led to more severe allergic reactions as respiratory compromise requiring ventilatory support and symptomatic treatment (dexchlorpheniramine and methylprednisolone). The allergic reaction (manifested as skin rash) occurred immediately after rFVIII infusion and infusion was stopped. In consideration of his allergic reaction and poor knee status, prednisone 1mg/kg/day for 4 weeks was prescribed initially and then tapered gradually with domestic plasma derived prothrombin complex concentrates (pdPCC) (30 IU/kg/QoD) prophylaxis. Eleven weeks after, he had a negative inhibitor without any clinical manifestations of allergic reactions (rash, laryngeal edema, etc.). However, it occurred again after rFVIII (Xyntha) infusion where he developed allergic reaction that manifested as increased heart rate and laryngeal edema. The IgE level was detected on the next day of allergic reaction as 329 IU/mL (Figure 1).
Figure 1. Inhibitor titer and Immunoglobulin E (IgE) level during FVIII infusion and desensitization therapy.
pdFVIII, plasma derived factor VIII; rFVIII, combinant factor VIII; PCC, prothrombin complex concentrate.
Further, the patient received desensitization treatment to FVIII which was initiated with prednisone infusion at a dose of 40 mg (1 mg/kg) 30 min−1, an hour before each rFVIII (ADVATE) infusion (Table 1). On the first day of desensitization treatment, rFVIII (ADVATE) was given from 0.01 IU/kg increased to 10 IU/kg i.v. gradually with total amount of 31.15 IU/kg in 8 h. From the second day to the 18th day, FVIII was given as 40 IU/kg daily with a gradually decreasing infusion time from 10 h to 20 min which was a normal dose and speed of FVIII infusion. The total course of desensitization treatment is 22 days. Allergic reactions appeared at the 5th and 11th days manifested with the increasing heart rate and rash which could relief after prolonging the infusion time. Further, upon more than 1 year of follow-up, the patient did not suffer any joint bleeds and other serious bleeding episodes and his inhibitor titer remained negative. However, the patient did not test FVIII recovery. The FVIII level had not been measured during the time the patient with inhibitor. Therefore, we do not know whether there is an antibody against endogenous FVIII. He only confirmed with negative inhibitor and the similar FVIII:C (3.3%) to baseline level (2.6%).
Table 1. FVIII desensitization protocol.
Dose (U/kg) Cumulative dose (U/kg) Actual dose (U) Infusion time (min) Interval from previous dose (min)
Day 1 0.01 0.01 0.48 5 0
0.02 0.03 0.96 5 10
0.04 0.07 1.92 5 10
0.08 0.15 3.84 5 10
0.1 0.25 4.8 5 10
0.2 0.45 9.6 5 20
0.4 0.85 19.2 5 20
0.8 1.65 38.4 5 20
1.5 3.15 72 5 20
3 6.15 144 30 –
6 12.15 288 30 –
9 21.15 432 60 –
10 31.15 480 60 –
Day 2 40 1920 1920 600 –
Day 3 40 1920 1920 480 –
Day 4 40 1920 1920 360 –
Day 5 40 40 1920 600 –
Day 6 40 40 1920 600 –
Day 7 40 40 1920 480 –
Day 8 40 40 1920 360 –
Day 9 40 40 1920 240 –
Day 10 40 40 1920 120 –
Day 11 40 40 1920 180 –
Day 12 40 40 1920 120 –
Day 13 40 40 1920 60 –
Day 14 40 40 1920 30 –
Day 15 40 40 1920 30 –
Day 16 40 40 1920 60 –
Day 17 40 40 1920 30 –
Day 18 40 40 1920 20 –
Day 19 40 40 1920 20 –
Day 20 40 40 1920 20 –
Day 21 40 40 1920 20 –
Day 22 40 40 1920 20 –
Discussion
Patients with hemophilia A are rarely to develop anti-FVIII allergic reaction coexisted with anti-FVIII inhibitors, which was reported to be induced either by FVIII itself or by other proteins in FVIII products only in a few case reports.10–13 In this case, the patient was not allergic to rFVIII until inhibitor development. ITI therapy with pdFVIII lead to allergic reactions with elevated IgE levels and did not subside even after switching back to rFVIII suggesting that the allergic reaction could be caused by FVIII or also by other proteins like albumin or by both. We cannot ensure which substance the patient against with because he did not try pdFVIII before inhibitor development to prove no allergic reaction to it. The patient was a moderate HA child and FVIII:C was 2.6%, and the patient was without other immune diseases when the inhibitor is produced. So we speculate the FVIII antibodies was caused by the exogenous FVIII.
Further, the patient turned to prophylaxis using domestic pdPCC and with prednisolone to cool down immune system. No allergic reactions or inhibitors development was observed even though the pdPCC had a trace amount of FVIII, other proteins similar to pdFVIII. We considered that the trace amount of allergen would induce allergic reaction, but the prednisone would lower the anamnestic response thereby his inhibitor titer remained negative. We anticipate that trace amounts of FVIII in the pdPCC and endogenous FVIII could have been part of the immune tolerance induction. Afterward, the patient infused rFVIII again, however, the infusion still led to respiratory compromise. Thus, the allergic response was inferred causing by FVIII. Although the IgE level (329 IU/mL) detected was much lower than the last detection, the allergic response could still exist for the following two reasons. Firstly, IgE level was monitored on the next day of rFVIII infusion instead of at the time of allergic reaction occurrence, in which it should be much higher. Secondly, IgE level was not investigated while receiving prednisone. Therefore, the trough level of IgE was unknowable which was possible to lower than that we detected this time. However, we still cannot exclude the reason for allergic reaction by other components of pd products because the patient never tried pdFVIII or pdPCC before allergic reaction with inhibitor development or after successful desensitization.
Inhibitors can hardly be tolerized without FVIII.14 However, the present case eliminated inhibitor by prednisone alone which has a general immunosuppressive effect instead of inducing antigen-FVIII tolerance. Although inhibitor turned to negative, FVIII was not tolerated by the patient. Earlier, Kadar et al, reported IgE mediated grade 3 anaphylactic reaction in 51-year-old HA patient that triggered by rFVIII.13 Similarly, with the observation of the high serum IgE level in patient during treatment, we consider his inhibitor for FVIII antigen is probably triggered by an anti-FVIII IgE, but very regrettable, we have not been able to detect the type of antibody to confirm. Desensitization protocol is the other inhibitor eradication strategy found effective in a few patients with allergic reactions.10 In current case, patient achieved tolerance to FVIII through the desensitization protocol where it downregulates the expression of mast cells and basophils thereby inhibiting the release of inflammatory mediators (β-hexosaminidase, prostaglandins and leukotrienes), however the exact mechanism underlying this still remained elusive.15 Further, the current report cannot be generalized as this was a single case report therefore the potential role of desensitization regimen in eliminating the inhibitor and allergic reaction to FVIII still need to be confirmed.
All previously reported cases with inhibitor and allergic reaction were severe hemophilia A/B, which were desensitized successfully. But this case refers to a moderate HA patient the inhibitors and allergic reactions developed could be either due to endogenous or exogenous FVII. However, after desensitization therapy, the allergic reaction toward FVIII disappeared, the inhibitor turned negative, and the FVIII:C recovered to normal.
Conclusion
In summary, we report a rare case of coexistence of high-titer inhibitor and severe allergic reaction to both pdFVIII and rFVIII concentrates in moderate HA patient which was contraindicated for ITI treatment but controlled with the adoption of desensitization therapy.
The authors acknowledge Dr Zekun Li (MD) from Beijing Children’s Hospital for drawing the figure and providing revision of the manuscript for intellectual content. Dr Vengal Rao Pachava (PhD) and Dr Anuradha Nalli (PhD) from Indegene Pvt. Ltd., Bangalore, India, for providing medical writing support in the development of this manuscript.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from Beijing Municipal Science and Technology Commission (code Z181100001718182).
Ethical approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed consent: Written informed consent was obtained from the parent for their anonymized information to be published in this article.
ORCID iD: Runhui Wu https://orcid.org/0000-0002-8397-7057 | ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT, ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT RESIDUES 743-1636 DELETED | DrugsGivenReaction | CC BY-NC | 33626954 | 19,004,972 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pruritus allergic'. | Development and desensitization therapy of high-response factor VIII inhibitors with severe allergic reaction in a moderate hemophilia A patient.
Neutralizing antibodies (inhibitors) against factor VIII/IX (FVIII/FIX) poses a serious and challenging complication in the hemophilia treatment. Allergic reaction is more common in hemophilia B and always companion with FIX inhibitors, but it is rare in hemophilia A (HA). So far only few cases demonstrated FVIII-specific allergic response in hemophilia A. Coexistence of allergic reactions with inhibitors was contraindicated for immune tolerance induction (ITI) regimen which is the only proven therapy to eliminate inhibitor. We report a rare case of a 11-year-old boy with moderate HA who developed high titer inhibitor and severe allergic reaction to both plasma derived and recombinant FVIII concentrates. Inhibitor was eliminated with the use of prednisone. Further desensitization protocol by administering rFVIII of increasing does from 0.01 IU/kg to 40 IU/kg with a pre-determined time schedule allowed patient tolerance to the normal dose and infusion time to FVIII.
Introduction
Hemophilia A (HA) is a congenital bleeding disorder characterized by coagulation factor VIII (FVIII) deficiency.1,2 Prophylactic replacement therapy with FVIII remained as mainstay of the management of HA.3 Further, 30% of severe and 5% of mild and moderate HA patients will develop inhibitors (FVIII neutralizing antibodies) which inhibit the activity of infused FVIII.4–6 Allergic manifestations are rare complications in HA patients,7 and only evidenced by a few cases which suggested to be mediated by IgE.8,9 Here, we report a rare case in a moderate HA patient developed high-titer inhibitor and severe allergic reaction to both plasma derived FVIII (pdFVIII) and recombinant FVIII (rFVIII) concentrates, but controlled by desensitization therapy.
Case report
The patient was a 11-year-old boy, diagnosed with moderate HA (FVIII coagulant activity of 2.6%) and impaired FVIII protein secretion due to F8 missense mutations (c.5590A>G) at the age of 2 years after intracranial hemorrhage for which he received continuous fresh frozen plasma infusion and completely recovered. Later, at the age of 9-year-old, he suffered a gastrointestinal bleeding for which he received FVIII (Xyntha) at a dose of 36 IU/kg/day for 5 days and 18 IU/kg/day for 2 days without using tranexamic acid. After that, prophylaxis with FVIII (Xyntha) was initiated at a dose of 18 IU/kg/three times weekly (TiW) and no bleeding episodes appeared during the first 1.5 months. However, three bleeding episodes (one time in muscle and two times in knee) occurred after 25 exposure days. At this point inhibitor was considered developing and confirmed with 8 Bethesda Unit (BU) mL−1 at the 48 exposure days. Further, inhibitor titer measured after 1 month exhibited 6.8 BU mL−1 and the patient was not tested for FVIII level at this time.
Following this, the patient received ITI therapy to eradicate inhibitors with domestic plasma derived FVIII (pdFVIII) containing full length pdFVIII, von Willebrand factor (VWF) (1:1 ratio), albumin and other proteins at a dose of FVIII 50 IU/kg/QOD. Immediately after the first infusion, he developed allergic reaction (rash and pruritus) with Immunoglobulin E (IgE) level of 727 IU/mL. Further, pdFVIII was replaced by rFVIII (Advate and Kogenate) however, rFVIII led to more severe allergic reactions as respiratory compromise requiring ventilatory support and symptomatic treatment (dexchlorpheniramine and methylprednisolone). The allergic reaction (manifested as skin rash) occurred immediately after rFVIII infusion and infusion was stopped. In consideration of his allergic reaction and poor knee status, prednisone 1mg/kg/day for 4 weeks was prescribed initially and then tapered gradually with domestic plasma derived prothrombin complex concentrates (pdPCC) (30 IU/kg/QoD) prophylaxis. Eleven weeks after, he had a negative inhibitor without any clinical manifestations of allergic reactions (rash, laryngeal edema, etc.). However, it occurred again after rFVIII (Xyntha) infusion where he developed allergic reaction that manifested as increased heart rate and laryngeal edema. The IgE level was detected on the next day of allergic reaction as 329 IU/mL (Figure 1).
Figure 1. Inhibitor titer and Immunoglobulin E (IgE) level during FVIII infusion and desensitization therapy.
pdFVIII, plasma derived factor VIII; rFVIII, combinant factor VIII; PCC, prothrombin complex concentrate.
Further, the patient received desensitization treatment to FVIII which was initiated with prednisone infusion at a dose of 40 mg (1 mg/kg) 30 min−1, an hour before each rFVIII (ADVATE) infusion (Table 1). On the first day of desensitization treatment, rFVIII (ADVATE) was given from 0.01 IU/kg increased to 10 IU/kg i.v. gradually with total amount of 31.15 IU/kg in 8 h. From the second day to the 18th day, FVIII was given as 40 IU/kg daily with a gradually decreasing infusion time from 10 h to 20 min which was a normal dose and speed of FVIII infusion. The total course of desensitization treatment is 22 days. Allergic reactions appeared at the 5th and 11th days manifested with the increasing heart rate and rash which could relief after prolonging the infusion time. Further, upon more than 1 year of follow-up, the patient did not suffer any joint bleeds and other serious bleeding episodes and his inhibitor titer remained negative. However, the patient did not test FVIII recovery. The FVIII level had not been measured during the time the patient with inhibitor. Therefore, we do not know whether there is an antibody against endogenous FVIII. He only confirmed with negative inhibitor and the similar FVIII:C (3.3%) to baseline level (2.6%).
Table 1. FVIII desensitization protocol.
Dose (U/kg) Cumulative dose (U/kg) Actual dose (U) Infusion time (min) Interval from previous dose (min)
Day 1 0.01 0.01 0.48 5 0
0.02 0.03 0.96 5 10
0.04 0.07 1.92 5 10
0.08 0.15 3.84 5 10
0.1 0.25 4.8 5 10
0.2 0.45 9.6 5 20
0.4 0.85 19.2 5 20
0.8 1.65 38.4 5 20
1.5 3.15 72 5 20
3 6.15 144 30 –
6 12.15 288 30 –
9 21.15 432 60 –
10 31.15 480 60 –
Day 2 40 1920 1920 600 –
Day 3 40 1920 1920 480 –
Day 4 40 1920 1920 360 –
Day 5 40 40 1920 600 –
Day 6 40 40 1920 600 –
Day 7 40 40 1920 480 –
Day 8 40 40 1920 360 –
Day 9 40 40 1920 240 –
Day 10 40 40 1920 120 –
Day 11 40 40 1920 180 –
Day 12 40 40 1920 120 –
Day 13 40 40 1920 60 –
Day 14 40 40 1920 30 –
Day 15 40 40 1920 30 –
Day 16 40 40 1920 60 –
Day 17 40 40 1920 30 –
Day 18 40 40 1920 20 –
Day 19 40 40 1920 20 –
Day 20 40 40 1920 20 –
Day 21 40 40 1920 20 –
Day 22 40 40 1920 20 –
Discussion
Patients with hemophilia A are rarely to develop anti-FVIII allergic reaction coexisted with anti-FVIII inhibitors, which was reported to be induced either by FVIII itself or by other proteins in FVIII products only in a few case reports.10–13 In this case, the patient was not allergic to rFVIII until inhibitor development. ITI therapy with pdFVIII lead to allergic reactions with elevated IgE levels and did not subside even after switching back to rFVIII suggesting that the allergic reaction could be caused by FVIII or also by other proteins like albumin or by both. We cannot ensure which substance the patient against with because he did not try pdFVIII before inhibitor development to prove no allergic reaction to it. The patient was a moderate HA child and FVIII:C was 2.6%, and the patient was without other immune diseases when the inhibitor is produced. So we speculate the FVIII antibodies was caused by the exogenous FVIII.
Further, the patient turned to prophylaxis using domestic pdPCC and with prednisolone to cool down immune system. No allergic reactions or inhibitors development was observed even though the pdPCC had a trace amount of FVIII, other proteins similar to pdFVIII. We considered that the trace amount of allergen would induce allergic reaction, but the prednisone would lower the anamnestic response thereby his inhibitor titer remained negative. We anticipate that trace amounts of FVIII in the pdPCC and endogenous FVIII could have been part of the immune tolerance induction. Afterward, the patient infused rFVIII again, however, the infusion still led to respiratory compromise. Thus, the allergic response was inferred causing by FVIII. Although the IgE level (329 IU/mL) detected was much lower than the last detection, the allergic response could still exist for the following two reasons. Firstly, IgE level was monitored on the next day of rFVIII infusion instead of at the time of allergic reaction occurrence, in which it should be much higher. Secondly, IgE level was not investigated while receiving prednisone. Therefore, the trough level of IgE was unknowable which was possible to lower than that we detected this time. However, we still cannot exclude the reason for allergic reaction by other components of pd products because the patient never tried pdFVIII or pdPCC before allergic reaction with inhibitor development or after successful desensitization.
Inhibitors can hardly be tolerized without FVIII.14 However, the present case eliminated inhibitor by prednisone alone which has a general immunosuppressive effect instead of inducing antigen-FVIII tolerance. Although inhibitor turned to negative, FVIII was not tolerated by the patient. Earlier, Kadar et al, reported IgE mediated grade 3 anaphylactic reaction in 51-year-old HA patient that triggered by rFVIII.13 Similarly, with the observation of the high serum IgE level in patient during treatment, we consider his inhibitor for FVIII antigen is probably triggered by an anti-FVIII IgE, but very regrettable, we have not been able to detect the type of antibody to confirm. Desensitization protocol is the other inhibitor eradication strategy found effective in a few patients with allergic reactions.10 In current case, patient achieved tolerance to FVIII through the desensitization protocol where it downregulates the expression of mast cells and basophils thereby inhibiting the release of inflammatory mediators (β-hexosaminidase, prostaglandins and leukotrienes), however the exact mechanism underlying this still remained elusive.15 Further, the current report cannot be generalized as this was a single case report therefore the potential role of desensitization regimen in eliminating the inhibitor and allergic reaction to FVIII still need to be confirmed.
All previously reported cases with inhibitor and allergic reaction were severe hemophilia A/B, which were desensitized successfully. But this case refers to a moderate HA patient the inhibitors and allergic reactions developed could be either due to endogenous or exogenous FVII. However, after desensitization therapy, the allergic reaction toward FVIII disappeared, the inhibitor turned negative, and the FVIII:C recovered to normal.
Conclusion
In summary, we report a rare case of coexistence of high-titer inhibitor and severe allergic reaction to both pdFVIII and rFVIII concentrates in moderate HA patient which was contraindicated for ITI treatment but controlled with the adoption of desensitization therapy.
The authors acknowledge Dr Zekun Li (MD) from Beijing Children’s Hospital for drawing the figure and providing revision of the manuscript for intellectual content. Dr Vengal Rao Pachava (PhD) and Dr Anuradha Nalli (PhD) from Indegene Pvt. Ltd., Bangalore, India, for providing medical writing support in the development of this manuscript.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from Beijing Municipal Science and Technology Commission (code Z181100001718182).
Ethical approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed consent: Written informed consent was obtained from the parent for their anonymized information to be published in this article.
ORCID iD: Runhui Wu https://orcid.org/0000-0002-8397-7057 | ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT, ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT RESIDUES 743-1636 DELETED | DrugsGivenReaction | CC BY-NC | 33626954 | 19,004,972 | 2021 |
What was the administration route of drug 'ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT'? | Development and desensitization therapy of high-response factor VIII inhibitors with severe allergic reaction in a moderate hemophilia A patient.
Neutralizing antibodies (inhibitors) against factor VIII/IX (FVIII/FIX) poses a serious and challenging complication in the hemophilia treatment. Allergic reaction is more common in hemophilia B and always companion with FIX inhibitors, but it is rare in hemophilia A (HA). So far only few cases demonstrated FVIII-specific allergic response in hemophilia A. Coexistence of allergic reactions with inhibitors was contraindicated for immune tolerance induction (ITI) regimen which is the only proven therapy to eliminate inhibitor. We report a rare case of a 11-year-old boy with moderate HA who developed high titer inhibitor and severe allergic reaction to both plasma derived and recombinant FVIII concentrates. Inhibitor was eliminated with the use of prednisone. Further desensitization protocol by administering rFVIII of increasing does from 0.01 IU/kg to 40 IU/kg with a pre-determined time schedule allowed patient tolerance to the normal dose and infusion time to FVIII.
Introduction
Hemophilia A (HA) is a congenital bleeding disorder characterized by coagulation factor VIII (FVIII) deficiency.1,2 Prophylactic replacement therapy with FVIII remained as mainstay of the management of HA.3 Further, 30% of severe and 5% of mild and moderate HA patients will develop inhibitors (FVIII neutralizing antibodies) which inhibit the activity of infused FVIII.4–6 Allergic manifestations are rare complications in HA patients,7 and only evidenced by a few cases which suggested to be mediated by IgE.8,9 Here, we report a rare case in a moderate HA patient developed high-titer inhibitor and severe allergic reaction to both plasma derived FVIII (pdFVIII) and recombinant FVIII (rFVIII) concentrates, but controlled by desensitization therapy.
Case report
The patient was a 11-year-old boy, diagnosed with moderate HA (FVIII coagulant activity of 2.6%) and impaired FVIII protein secretion due to F8 missense mutations (c.5590A>G) at the age of 2 years after intracranial hemorrhage for which he received continuous fresh frozen plasma infusion and completely recovered. Later, at the age of 9-year-old, he suffered a gastrointestinal bleeding for which he received FVIII (Xyntha) at a dose of 36 IU/kg/day for 5 days and 18 IU/kg/day for 2 days without using tranexamic acid. After that, prophylaxis with FVIII (Xyntha) was initiated at a dose of 18 IU/kg/three times weekly (TiW) and no bleeding episodes appeared during the first 1.5 months. However, three bleeding episodes (one time in muscle and two times in knee) occurred after 25 exposure days. At this point inhibitor was considered developing and confirmed with 8 Bethesda Unit (BU) mL−1 at the 48 exposure days. Further, inhibitor titer measured after 1 month exhibited 6.8 BU mL−1 and the patient was not tested for FVIII level at this time.
Following this, the patient received ITI therapy to eradicate inhibitors with domestic plasma derived FVIII (pdFVIII) containing full length pdFVIII, von Willebrand factor (VWF) (1:1 ratio), albumin and other proteins at a dose of FVIII 50 IU/kg/QOD. Immediately after the first infusion, he developed allergic reaction (rash and pruritus) with Immunoglobulin E (IgE) level of 727 IU/mL. Further, pdFVIII was replaced by rFVIII (Advate and Kogenate) however, rFVIII led to more severe allergic reactions as respiratory compromise requiring ventilatory support and symptomatic treatment (dexchlorpheniramine and methylprednisolone). The allergic reaction (manifested as skin rash) occurred immediately after rFVIII infusion and infusion was stopped. In consideration of his allergic reaction and poor knee status, prednisone 1mg/kg/day for 4 weeks was prescribed initially and then tapered gradually with domestic plasma derived prothrombin complex concentrates (pdPCC) (30 IU/kg/QoD) prophylaxis. Eleven weeks after, he had a negative inhibitor without any clinical manifestations of allergic reactions (rash, laryngeal edema, etc.). However, it occurred again after rFVIII (Xyntha) infusion where he developed allergic reaction that manifested as increased heart rate and laryngeal edema. The IgE level was detected on the next day of allergic reaction as 329 IU/mL (Figure 1).
Figure 1. Inhibitor titer and Immunoglobulin E (IgE) level during FVIII infusion and desensitization therapy.
pdFVIII, plasma derived factor VIII; rFVIII, combinant factor VIII; PCC, prothrombin complex concentrate.
Further, the patient received desensitization treatment to FVIII which was initiated with prednisone infusion at a dose of 40 mg (1 mg/kg) 30 min−1, an hour before each rFVIII (ADVATE) infusion (Table 1). On the first day of desensitization treatment, rFVIII (ADVATE) was given from 0.01 IU/kg increased to 10 IU/kg i.v. gradually with total amount of 31.15 IU/kg in 8 h. From the second day to the 18th day, FVIII was given as 40 IU/kg daily with a gradually decreasing infusion time from 10 h to 20 min which was a normal dose and speed of FVIII infusion. The total course of desensitization treatment is 22 days. Allergic reactions appeared at the 5th and 11th days manifested with the increasing heart rate and rash which could relief after prolonging the infusion time. Further, upon more than 1 year of follow-up, the patient did not suffer any joint bleeds and other serious bleeding episodes and his inhibitor titer remained negative. However, the patient did not test FVIII recovery. The FVIII level had not been measured during the time the patient with inhibitor. Therefore, we do not know whether there is an antibody against endogenous FVIII. He only confirmed with negative inhibitor and the similar FVIII:C (3.3%) to baseline level (2.6%).
Table 1. FVIII desensitization protocol.
Dose (U/kg) Cumulative dose (U/kg) Actual dose (U) Infusion time (min) Interval from previous dose (min)
Day 1 0.01 0.01 0.48 5 0
0.02 0.03 0.96 5 10
0.04 0.07 1.92 5 10
0.08 0.15 3.84 5 10
0.1 0.25 4.8 5 10
0.2 0.45 9.6 5 20
0.4 0.85 19.2 5 20
0.8 1.65 38.4 5 20
1.5 3.15 72 5 20
3 6.15 144 30 –
6 12.15 288 30 –
9 21.15 432 60 –
10 31.15 480 60 –
Day 2 40 1920 1920 600 –
Day 3 40 1920 1920 480 –
Day 4 40 1920 1920 360 –
Day 5 40 40 1920 600 –
Day 6 40 40 1920 600 –
Day 7 40 40 1920 480 –
Day 8 40 40 1920 360 –
Day 9 40 40 1920 240 –
Day 10 40 40 1920 120 –
Day 11 40 40 1920 180 –
Day 12 40 40 1920 120 –
Day 13 40 40 1920 60 –
Day 14 40 40 1920 30 –
Day 15 40 40 1920 30 –
Day 16 40 40 1920 60 –
Day 17 40 40 1920 30 –
Day 18 40 40 1920 20 –
Day 19 40 40 1920 20 –
Day 20 40 40 1920 20 –
Day 21 40 40 1920 20 –
Day 22 40 40 1920 20 –
Discussion
Patients with hemophilia A are rarely to develop anti-FVIII allergic reaction coexisted with anti-FVIII inhibitors, which was reported to be induced either by FVIII itself or by other proteins in FVIII products only in a few case reports.10–13 In this case, the patient was not allergic to rFVIII until inhibitor development. ITI therapy with pdFVIII lead to allergic reactions with elevated IgE levels and did not subside even after switching back to rFVIII suggesting that the allergic reaction could be caused by FVIII or also by other proteins like albumin or by both. We cannot ensure which substance the patient against with because he did not try pdFVIII before inhibitor development to prove no allergic reaction to it. The patient was a moderate HA child and FVIII:C was 2.6%, and the patient was without other immune diseases when the inhibitor is produced. So we speculate the FVIII antibodies was caused by the exogenous FVIII.
Further, the patient turned to prophylaxis using domestic pdPCC and with prednisolone to cool down immune system. No allergic reactions or inhibitors development was observed even though the pdPCC had a trace amount of FVIII, other proteins similar to pdFVIII. We considered that the trace amount of allergen would induce allergic reaction, but the prednisone would lower the anamnestic response thereby his inhibitor titer remained negative. We anticipate that trace amounts of FVIII in the pdPCC and endogenous FVIII could have been part of the immune tolerance induction. Afterward, the patient infused rFVIII again, however, the infusion still led to respiratory compromise. Thus, the allergic response was inferred causing by FVIII. Although the IgE level (329 IU/mL) detected was much lower than the last detection, the allergic response could still exist for the following two reasons. Firstly, IgE level was monitored on the next day of rFVIII infusion instead of at the time of allergic reaction occurrence, in which it should be much higher. Secondly, IgE level was not investigated while receiving prednisone. Therefore, the trough level of IgE was unknowable which was possible to lower than that we detected this time. However, we still cannot exclude the reason for allergic reaction by other components of pd products because the patient never tried pdFVIII or pdPCC before allergic reaction with inhibitor development or after successful desensitization.
Inhibitors can hardly be tolerized without FVIII.14 However, the present case eliminated inhibitor by prednisone alone which has a general immunosuppressive effect instead of inducing antigen-FVIII tolerance. Although inhibitor turned to negative, FVIII was not tolerated by the patient. Earlier, Kadar et al, reported IgE mediated grade 3 anaphylactic reaction in 51-year-old HA patient that triggered by rFVIII.13 Similarly, with the observation of the high serum IgE level in patient during treatment, we consider his inhibitor for FVIII antigen is probably triggered by an anti-FVIII IgE, but very regrettable, we have not been able to detect the type of antibody to confirm. Desensitization protocol is the other inhibitor eradication strategy found effective in a few patients with allergic reactions.10 In current case, patient achieved tolerance to FVIII through the desensitization protocol where it downregulates the expression of mast cells and basophils thereby inhibiting the release of inflammatory mediators (β-hexosaminidase, prostaglandins and leukotrienes), however the exact mechanism underlying this still remained elusive.15 Further, the current report cannot be generalized as this was a single case report therefore the potential role of desensitization regimen in eliminating the inhibitor and allergic reaction to FVIII still need to be confirmed.
All previously reported cases with inhibitor and allergic reaction were severe hemophilia A/B, which were desensitized successfully. But this case refers to a moderate HA patient the inhibitors and allergic reactions developed could be either due to endogenous or exogenous FVII. However, after desensitization therapy, the allergic reaction toward FVIII disappeared, the inhibitor turned negative, and the FVIII:C recovered to normal.
Conclusion
In summary, we report a rare case of coexistence of high-titer inhibitor and severe allergic reaction to both pdFVIII and rFVIII concentrates in moderate HA patient which was contraindicated for ITI treatment but controlled with the adoption of desensitization therapy.
The authors acknowledge Dr Zekun Li (MD) from Beijing Children’s Hospital for drawing the figure and providing revision of the manuscript for intellectual content. Dr Vengal Rao Pachava (PhD) and Dr Anuradha Nalli (PhD) from Indegene Pvt. Ltd., Bangalore, India, for providing medical writing support in the development of this manuscript.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from Beijing Municipal Science and Technology Commission (code Z181100001718182).
Ethical approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed consent: Written informed consent was obtained from the parent for their anonymized information to be published in this article.
ORCID iD: Runhui Wu https://orcid.org/0000-0002-8397-7057 | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33626954 | 19,004,972 | 2021 |
What was the outcome of reaction 'Drug hypersensitivity'? | Development and desensitization therapy of high-response factor VIII inhibitors with severe allergic reaction in a moderate hemophilia A patient.
Neutralizing antibodies (inhibitors) against factor VIII/IX (FVIII/FIX) poses a serious and challenging complication in the hemophilia treatment. Allergic reaction is more common in hemophilia B and always companion with FIX inhibitors, but it is rare in hemophilia A (HA). So far only few cases demonstrated FVIII-specific allergic response in hemophilia A. Coexistence of allergic reactions with inhibitors was contraindicated for immune tolerance induction (ITI) regimen which is the only proven therapy to eliminate inhibitor. We report a rare case of a 11-year-old boy with moderate HA who developed high titer inhibitor and severe allergic reaction to both plasma derived and recombinant FVIII concentrates. Inhibitor was eliminated with the use of prednisone. Further desensitization protocol by administering rFVIII of increasing does from 0.01 IU/kg to 40 IU/kg with a pre-determined time schedule allowed patient tolerance to the normal dose and infusion time to FVIII.
Introduction
Hemophilia A (HA) is a congenital bleeding disorder characterized by coagulation factor VIII (FVIII) deficiency.1,2 Prophylactic replacement therapy with FVIII remained as mainstay of the management of HA.3 Further, 30% of severe and 5% of mild and moderate HA patients will develop inhibitors (FVIII neutralizing antibodies) which inhibit the activity of infused FVIII.4–6 Allergic manifestations are rare complications in HA patients,7 and only evidenced by a few cases which suggested to be mediated by IgE.8,9 Here, we report a rare case in a moderate HA patient developed high-titer inhibitor and severe allergic reaction to both plasma derived FVIII (pdFVIII) and recombinant FVIII (rFVIII) concentrates, but controlled by desensitization therapy.
Case report
The patient was a 11-year-old boy, diagnosed with moderate HA (FVIII coagulant activity of 2.6%) and impaired FVIII protein secretion due to F8 missense mutations (c.5590A>G) at the age of 2 years after intracranial hemorrhage for which he received continuous fresh frozen plasma infusion and completely recovered. Later, at the age of 9-year-old, he suffered a gastrointestinal bleeding for which he received FVIII (Xyntha) at a dose of 36 IU/kg/day for 5 days and 18 IU/kg/day for 2 days without using tranexamic acid. After that, prophylaxis with FVIII (Xyntha) was initiated at a dose of 18 IU/kg/three times weekly (TiW) and no bleeding episodes appeared during the first 1.5 months. However, three bleeding episodes (one time in muscle and two times in knee) occurred after 25 exposure days. At this point inhibitor was considered developing and confirmed with 8 Bethesda Unit (BU) mL−1 at the 48 exposure days. Further, inhibitor titer measured after 1 month exhibited 6.8 BU mL−1 and the patient was not tested for FVIII level at this time.
Following this, the patient received ITI therapy to eradicate inhibitors with domestic plasma derived FVIII (pdFVIII) containing full length pdFVIII, von Willebrand factor (VWF) (1:1 ratio), albumin and other proteins at a dose of FVIII 50 IU/kg/QOD. Immediately after the first infusion, he developed allergic reaction (rash and pruritus) with Immunoglobulin E (IgE) level of 727 IU/mL. Further, pdFVIII was replaced by rFVIII (Advate and Kogenate) however, rFVIII led to more severe allergic reactions as respiratory compromise requiring ventilatory support and symptomatic treatment (dexchlorpheniramine and methylprednisolone). The allergic reaction (manifested as skin rash) occurred immediately after rFVIII infusion and infusion was stopped. In consideration of his allergic reaction and poor knee status, prednisone 1mg/kg/day for 4 weeks was prescribed initially and then tapered gradually with domestic plasma derived prothrombin complex concentrates (pdPCC) (30 IU/kg/QoD) prophylaxis. Eleven weeks after, he had a negative inhibitor without any clinical manifestations of allergic reactions (rash, laryngeal edema, etc.). However, it occurred again after rFVIII (Xyntha) infusion where he developed allergic reaction that manifested as increased heart rate and laryngeal edema. The IgE level was detected on the next day of allergic reaction as 329 IU/mL (Figure 1).
Figure 1. Inhibitor titer and Immunoglobulin E (IgE) level during FVIII infusion and desensitization therapy.
pdFVIII, plasma derived factor VIII; rFVIII, combinant factor VIII; PCC, prothrombin complex concentrate.
Further, the patient received desensitization treatment to FVIII which was initiated with prednisone infusion at a dose of 40 mg (1 mg/kg) 30 min−1, an hour before each rFVIII (ADVATE) infusion (Table 1). On the first day of desensitization treatment, rFVIII (ADVATE) was given from 0.01 IU/kg increased to 10 IU/kg i.v. gradually with total amount of 31.15 IU/kg in 8 h. From the second day to the 18th day, FVIII was given as 40 IU/kg daily with a gradually decreasing infusion time from 10 h to 20 min which was a normal dose and speed of FVIII infusion. The total course of desensitization treatment is 22 days. Allergic reactions appeared at the 5th and 11th days manifested with the increasing heart rate and rash which could relief after prolonging the infusion time. Further, upon more than 1 year of follow-up, the patient did not suffer any joint bleeds and other serious bleeding episodes and his inhibitor titer remained negative. However, the patient did not test FVIII recovery. The FVIII level had not been measured during the time the patient with inhibitor. Therefore, we do not know whether there is an antibody against endogenous FVIII. He only confirmed with negative inhibitor and the similar FVIII:C (3.3%) to baseline level (2.6%).
Table 1. FVIII desensitization protocol.
Dose (U/kg) Cumulative dose (U/kg) Actual dose (U) Infusion time (min) Interval from previous dose (min)
Day 1 0.01 0.01 0.48 5 0
0.02 0.03 0.96 5 10
0.04 0.07 1.92 5 10
0.08 0.15 3.84 5 10
0.1 0.25 4.8 5 10
0.2 0.45 9.6 5 20
0.4 0.85 19.2 5 20
0.8 1.65 38.4 5 20
1.5 3.15 72 5 20
3 6.15 144 30 –
6 12.15 288 30 –
9 21.15 432 60 –
10 31.15 480 60 –
Day 2 40 1920 1920 600 –
Day 3 40 1920 1920 480 –
Day 4 40 1920 1920 360 –
Day 5 40 40 1920 600 –
Day 6 40 40 1920 600 –
Day 7 40 40 1920 480 –
Day 8 40 40 1920 360 –
Day 9 40 40 1920 240 –
Day 10 40 40 1920 120 –
Day 11 40 40 1920 180 –
Day 12 40 40 1920 120 –
Day 13 40 40 1920 60 –
Day 14 40 40 1920 30 –
Day 15 40 40 1920 30 –
Day 16 40 40 1920 60 –
Day 17 40 40 1920 30 –
Day 18 40 40 1920 20 –
Day 19 40 40 1920 20 –
Day 20 40 40 1920 20 –
Day 21 40 40 1920 20 –
Day 22 40 40 1920 20 –
Discussion
Patients with hemophilia A are rarely to develop anti-FVIII allergic reaction coexisted with anti-FVIII inhibitors, which was reported to be induced either by FVIII itself or by other proteins in FVIII products only in a few case reports.10–13 In this case, the patient was not allergic to rFVIII until inhibitor development. ITI therapy with pdFVIII lead to allergic reactions with elevated IgE levels and did not subside even after switching back to rFVIII suggesting that the allergic reaction could be caused by FVIII or also by other proteins like albumin or by both. We cannot ensure which substance the patient against with because he did not try pdFVIII before inhibitor development to prove no allergic reaction to it. The patient was a moderate HA child and FVIII:C was 2.6%, and the patient was without other immune diseases when the inhibitor is produced. So we speculate the FVIII antibodies was caused by the exogenous FVIII.
Further, the patient turned to prophylaxis using domestic pdPCC and with prednisolone to cool down immune system. No allergic reactions or inhibitors development was observed even though the pdPCC had a trace amount of FVIII, other proteins similar to pdFVIII. We considered that the trace amount of allergen would induce allergic reaction, but the prednisone would lower the anamnestic response thereby his inhibitor titer remained negative. We anticipate that trace amounts of FVIII in the pdPCC and endogenous FVIII could have been part of the immune tolerance induction. Afterward, the patient infused rFVIII again, however, the infusion still led to respiratory compromise. Thus, the allergic response was inferred causing by FVIII. Although the IgE level (329 IU/mL) detected was much lower than the last detection, the allergic response could still exist for the following two reasons. Firstly, IgE level was monitored on the next day of rFVIII infusion instead of at the time of allergic reaction occurrence, in which it should be much higher. Secondly, IgE level was not investigated while receiving prednisone. Therefore, the trough level of IgE was unknowable which was possible to lower than that we detected this time. However, we still cannot exclude the reason for allergic reaction by other components of pd products because the patient never tried pdFVIII or pdPCC before allergic reaction with inhibitor development or after successful desensitization.
Inhibitors can hardly be tolerized without FVIII.14 However, the present case eliminated inhibitor by prednisone alone which has a general immunosuppressive effect instead of inducing antigen-FVIII tolerance. Although inhibitor turned to negative, FVIII was not tolerated by the patient. Earlier, Kadar et al, reported IgE mediated grade 3 anaphylactic reaction in 51-year-old HA patient that triggered by rFVIII.13 Similarly, with the observation of the high serum IgE level in patient during treatment, we consider his inhibitor for FVIII antigen is probably triggered by an anti-FVIII IgE, but very regrettable, we have not been able to detect the type of antibody to confirm. Desensitization protocol is the other inhibitor eradication strategy found effective in a few patients with allergic reactions.10 In current case, patient achieved tolerance to FVIII through the desensitization protocol where it downregulates the expression of mast cells and basophils thereby inhibiting the release of inflammatory mediators (β-hexosaminidase, prostaglandins and leukotrienes), however the exact mechanism underlying this still remained elusive.15 Further, the current report cannot be generalized as this was a single case report therefore the potential role of desensitization regimen in eliminating the inhibitor and allergic reaction to FVIII still need to be confirmed.
All previously reported cases with inhibitor and allergic reaction were severe hemophilia A/B, which were desensitized successfully. But this case refers to a moderate HA patient the inhibitors and allergic reactions developed could be either due to endogenous or exogenous FVII. However, after desensitization therapy, the allergic reaction toward FVIII disappeared, the inhibitor turned negative, and the FVIII:C recovered to normal.
Conclusion
In summary, we report a rare case of coexistence of high-titer inhibitor and severe allergic reaction to both pdFVIII and rFVIII concentrates in moderate HA patient which was contraindicated for ITI treatment but controlled with the adoption of desensitization therapy.
The authors acknowledge Dr Zekun Li (MD) from Beijing Children’s Hospital for drawing the figure and providing revision of the manuscript for intellectual content. Dr Vengal Rao Pachava (PhD) and Dr Anuradha Nalli (PhD) from Indegene Pvt. Ltd., Bangalore, India, for providing medical writing support in the development of this manuscript.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from Beijing Municipal Science and Technology Commission (code Z181100001718182).
Ethical approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed consent: Written informed consent was obtained from the parent for their anonymized information to be published in this article.
ORCID iD: Runhui Wu https://orcid.org/0000-0002-8397-7057 | Recovered | ReactionOutcome | CC BY-NC | 33626954 | 19,057,183 | 2021 |
What was the outcome of reaction 'Respiratory disorder'? | Development and desensitization therapy of high-response factor VIII inhibitors with severe allergic reaction in a moderate hemophilia A patient.
Neutralizing antibodies (inhibitors) against factor VIII/IX (FVIII/FIX) poses a serious and challenging complication in the hemophilia treatment. Allergic reaction is more common in hemophilia B and always companion with FIX inhibitors, but it is rare in hemophilia A (HA). So far only few cases demonstrated FVIII-specific allergic response in hemophilia A. Coexistence of allergic reactions with inhibitors was contraindicated for immune tolerance induction (ITI) regimen which is the only proven therapy to eliminate inhibitor. We report a rare case of a 11-year-old boy with moderate HA who developed high titer inhibitor and severe allergic reaction to both plasma derived and recombinant FVIII concentrates. Inhibitor was eliminated with the use of prednisone. Further desensitization protocol by administering rFVIII of increasing does from 0.01 IU/kg to 40 IU/kg with a pre-determined time schedule allowed patient tolerance to the normal dose and infusion time to FVIII.
Introduction
Hemophilia A (HA) is a congenital bleeding disorder characterized by coagulation factor VIII (FVIII) deficiency.1,2 Prophylactic replacement therapy with FVIII remained as mainstay of the management of HA.3 Further, 30% of severe and 5% of mild and moderate HA patients will develop inhibitors (FVIII neutralizing antibodies) which inhibit the activity of infused FVIII.4–6 Allergic manifestations are rare complications in HA patients,7 and only evidenced by a few cases which suggested to be mediated by IgE.8,9 Here, we report a rare case in a moderate HA patient developed high-titer inhibitor and severe allergic reaction to both plasma derived FVIII (pdFVIII) and recombinant FVIII (rFVIII) concentrates, but controlled by desensitization therapy.
Case report
The patient was a 11-year-old boy, diagnosed with moderate HA (FVIII coagulant activity of 2.6%) and impaired FVIII protein secretion due to F8 missense mutations (c.5590A>G) at the age of 2 years after intracranial hemorrhage for which he received continuous fresh frozen plasma infusion and completely recovered. Later, at the age of 9-year-old, he suffered a gastrointestinal bleeding for which he received FVIII (Xyntha) at a dose of 36 IU/kg/day for 5 days and 18 IU/kg/day for 2 days without using tranexamic acid. After that, prophylaxis with FVIII (Xyntha) was initiated at a dose of 18 IU/kg/three times weekly (TiW) and no bleeding episodes appeared during the first 1.5 months. However, three bleeding episodes (one time in muscle and two times in knee) occurred after 25 exposure days. At this point inhibitor was considered developing and confirmed with 8 Bethesda Unit (BU) mL−1 at the 48 exposure days. Further, inhibitor titer measured after 1 month exhibited 6.8 BU mL−1 and the patient was not tested for FVIII level at this time.
Following this, the patient received ITI therapy to eradicate inhibitors with domestic plasma derived FVIII (pdFVIII) containing full length pdFVIII, von Willebrand factor (VWF) (1:1 ratio), albumin and other proteins at a dose of FVIII 50 IU/kg/QOD. Immediately after the first infusion, he developed allergic reaction (rash and pruritus) with Immunoglobulin E (IgE) level of 727 IU/mL. Further, pdFVIII was replaced by rFVIII (Advate and Kogenate) however, rFVIII led to more severe allergic reactions as respiratory compromise requiring ventilatory support and symptomatic treatment (dexchlorpheniramine and methylprednisolone). The allergic reaction (manifested as skin rash) occurred immediately after rFVIII infusion and infusion was stopped. In consideration of his allergic reaction and poor knee status, prednisone 1mg/kg/day for 4 weeks was prescribed initially and then tapered gradually with domestic plasma derived prothrombin complex concentrates (pdPCC) (30 IU/kg/QoD) prophylaxis. Eleven weeks after, he had a negative inhibitor without any clinical manifestations of allergic reactions (rash, laryngeal edema, etc.). However, it occurred again after rFVIII (Xyntha) infusion where he developed allergic reaction that manifested as increased heart rate and laryngeal edema. The IgE level was detected on the next day of allergic reaction as 329 IU/mL (Figure 1).
Figure 1. Inhibitor titer and Immunoglobulin E (IgE) level during FVIII infusion and desensitization therapy.
pdFVIII, plasma derived factor VIII; rFVIII, combinant factor VIII; PCC, prothrombin complex concentrate.
Further, the patient received desensitization treatment to FVIII which was initiated with prednisone infusion at a dose of 40 mg (1 mg/kg) 30 min−1, an hour before each rFVIII (ADVATE) infusion (Table 1). On the first day of desensitization treatment, rFVIII (ADVATE) was given from 0.01 IU/kg increased to 10 IU/kg i.v. gradually with total amount of 31.15 IU/kg in 8 h. From the second day to the 18th day, FVIII was given as 40 IU/kg daily with a gradually decreasing infusion time from 10 h to 20 min which was a normal dose and speed of FVIII infusion. The total course of desensitization treatment is 22 days. Allergic reactions appeared at the 5th and 11th days manifested with the increasing heart rate and rash which could relief after prolonging the infusion time. Further, upon more than 1 year of follow-up, the patient did not suffer any joint bleeds and other serious bleeding episodes and his inhibitor titer remained negative. However, the patient did not test FVIII recovery. The FVIII level had not been measured during the time the patient with inhibitor. Therefore, we do not know whether there is an antibody against endogenous FVIII. He only confirmed with negative inhibitor and the similar FVIII:C (3.3%) to baseline level (2.6%).
Table 1. FVIII desensitization protocol.
Dose (U/kg) Cumulative dose (U/kg) Actual dose (U) Infusion time (min) Interval from previous dose (min)
Day 1 0.01 0.01 0.48 5 0
0.02 0.03 0.96 5 10
0.04 0.07 1.92 5 10
0.08 0.15 3.84 5 10
0.1 0.25 4.8 5 10
0.2 0.45 9.6 5 20
0.4 0.85 19.2 5 20
0.8 1.65 38.4 5 20
1.5 3.15 72 5 20
3 6.15 144 30 –
6 12.15 288 30 –
9 21.15 432 60 –
10 31.15 480 60 –
Day 2 40 1920 1920 600 –
Day 3 40 1920 1920 480 –
Day 4 40 1920 1920 360 –
Day 5 40 40 1920 600 –
Day 6 40 40 1920 600 –
Day 7 40 40 1920 480 –
Day 8 40 40 1920 360 –
Day 9 40 40 1920 240 –
Day 10 40 40 1920 120 –
Day 11 40 40 1920 180 –
Day 12 40 40 1920 120 –
Day 13 40 40 1920 60 –
Day 14 40 40 1920 30 –
Day 15 40 40 1920 30 –
Day 16 40 40 1920 60 –
Day 17 40 40 1920 30 –
Day 18 40 40 1920 20 –
Day 19 40 40 1920 20 –
Day 20 40 40 1920 20 –
Day 21 40 40 1920 20 –
Day 22 40 40 1920 20 –
Discussion
Patients with hemophilia A are rarely to develop anti-FVIII allergic reaction coexisted with anti-FVIII inhibitors, which was reported to be induced either by FVIII itself or by other proteins in FVIII products only in a few case reports.10–13 In this case, the patient was not allergic to rFVIII until inhibitor development. ITI therapy with pdFVIII lead to allergic reactions with elevated IgE levels and did not subside even after switching back to rFVIII suggesting that the allergic reaction could be caused by FVIII or also by other proteins like albumin or by both. We cannot ensure which substance the patient against with because he did not try pdFVIII before inhibitor development to prove no allergic reaction to it. The patient was a moderate HA child and FVIII:C was 2.6%, and the patient was without other immune diseases when the inhibitor is produced. So we speculate the FVIII antibodies was caused by the exogenous FVIII.
Further, the patient turned to prophylaxis using domestic pdPCC and with prednisolone to cool down immune system. No allergic reactions or inhibitors development was observed even though the pdPCC had a trace amount of FVIII, other proteins similar to pdFVIII. We considered that the trace amount of allergen would induce allergic reaction, but the prednisone would lower the anamnestic response thereby his inhibitor titer remained negative. We anticipate that trace amounts of FVIII in the pdPCC and endogenous FVIII could have been part of the immune tolerance induction. Afterward, the patient infused rFVIII again, however, the infusion still led to respiratory compromise. Thus, the allergic response was inferred causing by FVIII. Although the IgE level (329 IU/mL) detected was much lower than the last detection, the allergic response could still exist for the following two reasons. Firstly, IgE level was monitored on the next day of rFVIII infusion instead of at the time of allergic reaction occurrence, in which it should be much higher. Secondly, IgE level was not investigated while receiving prednisone. Therefore, the trough level of IgE was unknowable which was possible to lower than that we detected this time. However, we still cannot exclude the reason for allergic reaction by other components of pd products because the patient never tried pdFVIII or pdPCC before allergic reaction with inhibitor development or after successful desensitization.
Inhibitors can hardly be tolerized without FVIII.14 However, the present case eliminated inhibitor by prednisone alone which has a general immunosuppressive effect instead of inducing antigen-FVIII tolerance. Although inhibitor turned to negative, FVIII was not tolerated by the patient. Earlier, Kadar et al, reported IgE mediated grade 3 anaphylactic reaction in 51-year-old HA patient that triggered by rFVIII.13 Similarly, with the observation of the high serum IgE level in patient during treatment, we consider his inhibitor for FVIII antigen is probably triggered by an anti-FVIII IgE, but very regrettable, we have not been able to detect the type of antibody to confirm. Desensitization protocol is the other inhibitor eradication strategy found effective in a few patients with allergic reactions.10 In current case, patient achieved tolerance to FVIII through the desensitization protocol where it downregulates the expression of mast cells and basophils thereby inhibiting the release of inflammatory mediators (β-hexosaminidase, prostaglandins and leukotrienes), however the exact mechanism underlying this still remained elusive.15 Further, the current report cannot be generalized as this was a single case report therefore the potential role of desensitization regimen in eliminating the inhibitor and allergic reaction to FVIII still need to be confirmed.
All previously reported cases with inhibitor and allergic reaction were severe hemophilia A/B, which were desensitized successfully. But this case refers to a moderate HA patient the inhibitors and allergic reactions developed could be either due to endogenous or exogenous FVII. However, after desensitization therapy, the allergic reaction toward FVIII disappeared, the inhibitor turned negative, and the FVIII:C recovered to normal.
Conclusion
In summary, we report a rare case of coexistence of high-titer inhibitor and severe allergic reaction to both pdFVIII and rFVIII concentrates in moderate HA patient which was contraindicated for ITI treatment but controlled with the adoption of desensitization therapy.
The authors acknowledge Dr Zekun Li (MD) from Beijing Children’s Hospital for drawing the figure and providing revision of the manuscript for intellectual content. Dr Vengal Rao Pachava (PhD) and Dr Anuradha Nalli (PhD) from Indegene Pvt. Ltd., Bangalore, India, for providing medical writing support in the development of this manuscript.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from Beijing Municipal Science and Technology Commission (code Z181100001718182).
Ethical approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed consent: Written informed consent was obtained from the parent for their anonymized information to be published in this article.
ORCID iD: Runhui Wu https://orcid.org/0000-0002-8397-7057 | Recovered | ReactionOutcome | CC BY-NC | 33626954 | 19,057,183 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemoglobin decreased'. | Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension.
The evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.
Among consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan-Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.
Twenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12-47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.
Triple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings.The reviews of this paper are available via the supplemental material section.
Introduction
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by elevated pulmonary arterial pressure (PAP) due to remodeling of the pulmonary arterial bed and right sided-heart failure. Three types of PAH-specific vasodilators targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway have been developed. Combination therapy targeting these different pathways has recently been shown to improve hemodynamics, clinical functions, and even hard endpoints including survival or worsening of PAH in several recent randomized controlled trials and metanalyses.1–5 The effectiveness of triple combination therapy targeting all three of these pathways has also been reported.6–8 However, two such studies analyzed patients who were treated with two types of oral vasodilators and prostacyclin infusion,7,8 and another study was a subgroup analysis of a randomized controlled trial demonstrating a change in the symptom burden by the addition of selexipag, a prostacyclin receptor agonist, to background double combination therapy targeting other pathways.6 Therefore, evidence of the efficacy and safety of triple oral combination therapy remains scarce.
The most recently approved PAH-specific vasodilators targeting each of the three types of pathways are macitentan, which is an endothelin receptor antagonist (ERA); riociguat, which is a soluble guanylate cyclase stimulator targeting the nitric oxide pathway; and selexipag, which is an oral non-prostanoid prostacyclin receptor agonist. All three of these are orally available drugs. The effectiveness of these vasodilators for PAH has recently been proven;2,3,9 however, no clinical trials have been performed to investigate the effectiveness of the combination of these three vasodilators. Furthermore, although the current guideline recommends initial oral therapy for patients with low or intermediate risk,10 how many patients with low or intermediate risk can actually be treated with only oral combination therapy remains poorly documented to date.
Therefore, the purposes of this study were to clarify the clinical effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag and to assess which risk groups can be adequately treated with this combination therapy.
Methods
Study design
This retrospective study was performed in Keio University Hospital in Japan. This study was approved by the Ethics Committee of Keio University Hospital, and written informed consent was obtained from all patients when they received genetic tests or were hospitalized. Patients with PAH who had received triple oral combination therapy with macitentan, riociguat, and selexipag were evaluated among all consecutive patients who were referred to Keio University Hospital from 2009 to 2020.
The diagnosis of PAH was made according to the current guideline.11 Patients who were lost to follow-up or underwent maintenance hemodialysis were excluded. Baseline data were measured at the time of referral to our hospital. If patients were treatment-naïve upon referral to our hospital, the combination of macitentan, riociguat, and selexipag was initiated after diagnosis. The method of up-titration and prioritization of the vasodilators as well as the selection of sequential therapy or upfront therapy was determined at the discretion of the specialized physicians. The doses of the vasodilators were titrated to the maximal tolerated doses. For patients who had already received other PAH-specific vasodilators at the time of enrollment, these drugs targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway were switched to macitentan, riociguat, and selexipag, respectively, with the intention of further improvement of hemodynamics.
Patients received genetic counseling, and genetic tests were performed with informed consent. The methods of the genetic tests, including whole-exome sequencing, are described in our previous reports.12,13
Parameters and outcomes
Dedicated cardiologists performed right-heart catheterization (RHC) without sedation at baseline and follow-up. The right arterial pressure, mean PAP, and pulmonary arterial wedge pressure were measured by RHC. The zero pressure point was set at the level of the midthorax. Cardiac output (CO) was calculated by the Fick technique using oxygen consumption estimated by 125 times the body surface area according to a previous report.14 Pulmonary vascular resistance (PVR) was calculated as the difference between the mean PAP and pulmonary arterial wedge pressure divided by the CO.
The 6-minute walk distance (6MWD), blood concentration of B-type natriuretic peptide (BNP), and World Health Organization functional class (WHO-FC) were measured at the time of hospitalization for RHC.
Standard two-dimensional, M-mode, and Doppler images, including the tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic excursion velocity (RVS’), were obtained by echocardiographers in accordance with the current echocardiography guideline.15 Dedicated cardiologists analyzed the data and measured the right atrial area (RAA), right ventricular end-diastolic area (RVEDA), right ventricular end-systolic area, and right ventricular fractional area change (RVFAC).
Hemodynamic changes measured by RHC, echocardiographic changes, and changes in the 6MWD, BNP concentration, and WHO-FC were assessed from baseline to follow-up.
The events of all-cause death, hospitalization for heart failure, initiation of prostacyclin infusion, and discontinuation of any of the three vasodilators (macitentan, riociguat, and selexipag) because of adverse events since administration of all three vasodilators were collected. The observation period was terminated when patients died, underwent prostacyclin infusion, or stopped taking macitentan, riociguat, or selexipag for any reason.
All patients enrolled in this study were divided into two groups by risk assessment using the three-category REVEAL 2.0 risk score,16 and the prostacyclin infusion-free rate was analyzed in each group. If the value was unmeasured, the value of zero was assigned. According to the three-category REVEAL 2.0 risk score, the high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), and the low-/intermediate-risk group was defined as patients with a predicted 1-year survival rate of ⩾90% (REVEAL 2.0 risk score ⩽8).
Subgroup analysis
Patients who were treatment-naïve at baseline and treated with only macitentan, riociguat, and selexipag for PAH were also independently assessed by subgroup analysis. Their hemodynamics, echocardiography, and clinical function were measured and clinical events were collected similarly to the overall patient analysis.
Statistical analysis
Data are described as median and interquartile range unless otherwise indicated. Wilcoxon’s signed rank test was used to compare the parameters of hemodynamics, echocardiography, 6MWD, and BNP concentration from baseline to the latest follow-up. The cases which had a missing value either at baseline or follow-up were excluded from each analysis. Differences with a p-value of <0.05 were considered statistically significant. All p-values were two-tailed. Event-free rates were analyzed using the Kaplan–Meier method. All analyses were performed using R software (version 3.6.3), and figures were obtained using GraphPad Prism (version 8.0 for Mac; GraphPad Software, La Jolla, CA, USA).
Results
Patient characteristics
The patients’ baseline characteristics and medications are presented in Table 1 and Supplemental material Table 1 online. One patient who was lost to follow-up and one patient who had been undergoing maintenance hemodialysis were excluded; thus, 26 patients were enrolled in this study. The patients were predominantly female (73.1%) with a median age of 38 years. The major etiology of PAH was idiopathic PAH (38.5%) followed by connective tissue disease-associated PAH (26.9%), heritable PAH (19.2%), and congenital heart disease-associated PAH (15.4%). Most patients were treatment-naïve (65.4%), and others were taking some PAH medications at baseline.
Table 1. Demographics and characteristics at baseline.
Variable Triple oral combination therapy
N = 26
Female 19 (73.1)
Age, years 38 (23–48)
WHO-FC
I/II/III/IV 0/9/16/1 (0.0/34.6/61.5/3.8)
BNP, pg/mL 105.25 (36.7–285.5)
6MWD, m 397.5 (312.8–441.8)
PAH etiology
IPAH 10 (38.5)
HPAH 5 (19.2)
CTD-PAH 7 (26.9)
CHD-PAH 4 (15.4)
Medication
Treatment-naïve 17 (65.4)
Single 3 (11.5)
Double 2 (7.7)
Triple 4 (15.4)
Risk assessment*
High risk 12 (46.2)
Intermediate risk 4 (15.4)
Low risk 10 (38.5)
Genetic mutation**
BMPR2 5 (23.8)
ACVRL 1 (4.8)
RNF213 1 (4.8)
Data are expressed as number (%) or median (interquartile range).
* Risk assessment was calculated using the three-category REVEAL 2.0 risk score.16 The high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), the intermediate-risk group was defined as patients with a predicted 1-year survival rate of 90–<95% (REVEAL 2.0 risk score = 7 or 8), and the low-risk group was defined as patients with a predicted 1-year survival rate of ⩾95% (REVEAL 2.0 risk score ⩽6).
** Among 26 patients, 21 were genetically tested and 15 had no genetic mutations related to PAH.
6MWD, 6-minute walk distance; ACVRL1, activin A receptor-like kinase 1; BMPR2, bone morphogenetic protein receptor type 2; BNP, B-type natriuretic peptide; CHD, congenital heart disease; CTD, connective tissue disease; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; RNF213, ring finger protein 213; WHO-FC, World Health Organization functional class.
Ten patients with idiopathic PAH, five with heritable PAH, three with connective tissue disease-associated PAH, and three with congenital heart disease-associated PAH were genetically tested. All five patients with heritable PAH had mutations in known PAH-related genes such as bone morphogenetic protein receptor type 2 (BMPR2) and one patient with idiopathic PAH had a mutation in ring finger protein 213 (RNF213), which we recently reported as a novel PAH-related gene.13,17
Safety and tolerability
Discontinuation of macitentan, riociguat, or selexipag because of adverse events occurred in four of 26 patients (15%). Among these four patients, one had diarrhea with selexipag, one had suspected myelosuppression with macitentan, one had nausea with riociguat, and one had hypotension with riociguat. These patients changed their drug to another drug targeting the same pathway. No adverse events, including death, hospitalization for heart failure, or prostacyclin infusion, were observed after discontinuation of each drug.
The maximum tolerated doses of the vasodilators are summarized in Supplemental Table 2. In detail, 25 (96.2%), 24 (92.3%), and 20 (76.9%) patients were taking the maximum dose of macitentan, riociguat, and selexipag, respectively. Seventeen (65.4%) patients reached the maximum dose of all three vasodilators.
Changes and outcomes after treatment
Hemodynamic data were available for 18 patients. The detailed study flow chart is shown in Supplemental Figure 1. The hemodynamics, WHO-FC, BNP concentration, and 6MWD at baseline and follow-up are presented in Table 2. The median observation period was 441 (229–1103) days. Hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 65% decrease in the mean PVR. The CO significantly increased by 82% from baseline to follow-up. Although >70% of patients had a WHO-FC of III or IV at baseline, 89% of patients had a WHO-FC of I or II at follow-up. The 6MWD and BNP concentration were also significantly improved [Figure 1(a)].
Table 2. Changes in clinical parameters.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 6.5 (4.0–8.0) 4.0 (3.0–5.0) −2.5 (−38) 0.005
Mean PAP, mmHg 56.0 (46.3–65.5) 40.0 (30.0–47.0) −16.0 (−29) <0.001
PAWP, mmHg 7.5 (6.0–9.8) 9.0 (8.0–11.0) 1.5 (20) 0.68
CO, L/min 3.3 (2.4–4.5) 6.0 (5.1–6.7) 2.7 (82) <0.001
CI, L/min per m2 2.2 (1.7–2.7) 3.8 (3.3–4.5) 1.6 (73) <0.001
PVR, WU 13.5 (8.8–21.5) 4.7 (2.8–6.9) −8.8 (−65) <0.001
Echocardiography
TAPSE, cm 1.5 (1.3–1.8) 2.3 (1.9–2.6) 0.8 (53) 0.001
RVS’, cm 9.7 (7.8–11.8) 13.3 (12.4–14.4) 3.6 (37) 0.001
RAA, cm2 17.2 (14.9–21.3) 16.4 (14.1–21.0) −0.8 (−5) 0.49
RVEDA, cm2 26.9 (22.8–33.1) 24.1 (21.0–30.3) −2.8 (−10) 0.21
RVESA, cm2 20.4 (16.3–23.9) 16.4 (13.8–21.1) −4.0 (−20) 0.006
FAC, % 23.6 (16.2–26.9) 32.9 (29.1–35.8) 9.3 (39) <0.001
WHO-FC
I or II 4 (22) 16 (89) – –
III or IV 14 (78) 2 (11) – –
6MWD, m 405.0 (303.0–441.8) 472.0 (439.5–493.5) 67.0 (17) 0.046
BNP, pg/mL 187.8 (36.7–379.5) 17.5 (10.3–27.2) −170.3 (−91) <0.001
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Eighteen patients were analyzed in hemodynamics, and 20 patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 1. Hemodynamic and echocardiographic changes.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Echocardiographic data were available for 20 patients (Supplemental Figure 1). The echocardiographic data are presented in Table 2. The median follow-up period was 737 (256–1179) days. Right ventricular function based on the TAPSE, RVS’, and RVFAC was significantly improved from baseline to follow-up, although the RAA and RVEDA were not [Figure 1(b)].
The Kaplan–Meier curves since administration of all three vasodilators are shown in Figure 2. The 1- and 2-year survival rates were both 93.3%. One patient died of multiple organ failure after femoral neck fracture during the observation period. The overall survival rate was 92.3% with median follow-up period of 33 (24–43) months. No patients were hospitalized for heart failure during the observation period. Prostacyclin infusion was initiated in six patients (25.4%) within 1 year. Among these six patients, selexipag was switched to subcutaneous infusion of treprostinil in one patient, an intravenous infusion of epoprostenol was added to the triple oral combination therapy in another patient, and a subcutaneous infusion of treprostinil was added to the triple oral combination therapy in the remaining four patients. Selexipag was not discontinued in some patients to reduce maintenance dose of the prostacyclin for infusion. No other patients underwent prostacyclin infusion after 1 year. Among six patients who underwent prostacyclin infusion within 1 year, three patients had a BMPR2 mutation, one patient had an RNF213 mutation, and one patient had Eisenmenger syndrome due to an atrial septal defect. Composite events of all-cause death, hospitalization for heart failure, and initiation of prostacyclin infusion occurred in 16.6% of the patients within 6 months and 30.4% of the patients in 1 and 2 years.
Figure 2. Event-free rates in all patients with triple oral combination therapy.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy are shown (n = 26). The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Among 14 patients who were classified as low-/intermediate-risk by the three-category REVEAL 2.0 risk score,16 the prostacyclin-free rate was 92.9% at 3 years, while the rate was 55.0% at 2 years in 12 high-risk patients (Figure 3). The difference was not statistically significant (p = 0.058). Hemodynamic changes from baseline to follow-up in each low/intermediate and high-risk group are summarized in Supplemental Table 3. Among five patients who were classified as high-risk based on the three-category REVEAL 2.0 risk score and needed prostacyclin infusion, three patients had BMPR2 mutations and one patient had a RNF213 mutation.
Figure 3. Kaplan–Meier curve for prostacyclin-free rate in each risk category.
The prostacyclin infusion-free rates in each risk category are shown. The patients were divided into two risk categories by the REVEAL 2.0 risk score.16 The p-values were calculated by the log-rank test.
Subgroup analysis in treatment-naïve patients
Seventeen patients were treatment-naïve at baseline. Six patients were treatment naïve at baseline, but treated with other pulmonary vasodilators. In five out of these six patients, oral medication was switched from beraprost to selexipag, and in one patient, it was switched from ambrisentan and tadalafil to macitentan and riociguat. Thus, these six patients were excluded from the subgroup analysis. Among the remaining 11 patients for the subgroup analysis, the median time from initiation of the first PAH drug to the start of the third PAH drug was 24 (12–47) days. The way of up-titration in treatment naïve patients was as follows. Macitentan 10 mg was initiated at first and followed by riociguat 3.0 mg within 2 weeks. The dose of riociguat was up-titrated by 1.5 mg every 2 weeks with attention to adverse effects. In 36% of treatment naïve patients, selexipag was initiated after riociguat was up-titrated to maximum tolerated dose, whereas selexipag was started within 2 weeks from initiating macitentan in 64% of patients. Selexipag was increased by 0.4 mg every 2 weeks to maximum tolerated dose with attention to side effects. One patient (9.1%) discontinued macitentan because of suspected myelosuppression, and another patient (9.1%) discontinued riociguat because of nausea. RHC data in 10 patients and echocardiographic data in nine patients were available at baseline and at follow-up during the triple oral combination therapy. The patients’ hemodynamic and right ventricular function parameters are presented in Table 3 and Figure 4. The median follow-up period of the hemodynamic analysis was 293 (211–473) days. The hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 66% decrease in the PVR. The CO increased by 90% from baseline to follow-up. The median follow-up period of echocardiography was 385 (230–594) days. The TAPSE, RVS’, and RVFAC, indicating right ventricular function, increased significantly. The WHO-FC, 6MWD, and BNP concentration in this subgroup also improved significantly. In the Kaplan–Meier analysis, no patients died or were hospitalized for heart failure (Figure 5). Prostacyclin infusion was initiated in 31.8% of patients within 7 months, and no patients underwent prostacyclin infusion after 7 months.
Table 3. Changes in clinical parameters among treatment-naïve patients at baseline.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 7.5 (4.3–8.8) 4.0 (3.3–5.0) −3.5 (−47) 0.022
Mean PAP, mmHg 63.0 (55.0–75.8) 44.5 (37.0–51.5) −18.5 (−29) 0.006
PAWP, mmHg 7.5 (6.3–9.8) 8.0 (6.5–10.3) 0.5 (7) 0.61
CO, L/min 3.1 (2.4–4.3) 5.9 (5.1–7.2) 2.8 (90) 0.006
CI, L/min per m2 2.1 (1.7–2.5) 4.2 (3.5–4.6) 2.1 (100) 0.006
PVR, WU 17.5 (13.2–21.9) 5.9 (3.8–9.6) −11.6 (−66) 0.006
Echocardiography
TAPSE, cm 1.4 (1.3–1.5) 2.3 (2.1–2.7) 0.9 (64) 0.009
RVS’, cm 9.3 (7.9–10.8) 13.5 (13.0–14.3) 4.2 (45) 0.035
RAA, cm2 18.5 (15.0–21.1) 15.2 (13.5–16.7) −3.3 (−18) 0.076
RVEDA, cm2 27.0 (25.0–33.2) 23.6 (21.0–24.6) −3.4 (−13) 0.058
RVESA, cm2 22.9 (18.7–25.4) 14.8 (14.0–16.8) −8.1 (−35) 0.009
FAC, % 22.9 (15.9–25.2) 33.1 (29.5–35.0) 10.2 (45) 0.018
WHO-FC
I or II 1 (10) 8 (80)
III or IV 9 (90) 2 (20)
6MWD, m 400.0 (326.5–432.0) 471.5 (451.5–479.2) 71.5 (18) 0.030
BNP, pg/mL 200.8 (41.9–379.5) 20.2 (12.6–24.5) −180.6 (−90) 0.006
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Ten patients were analyzed in hemodynamics, and nine patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 4. Hemodynamic and echocardiographic changes in treatment-naïve patients.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Figure 5. Event-free rates in treatment-naïve patients.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy in treatment-naïve patients are shown. The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite endpoint of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Discussion
In the present study, triple oral combination therapy with macitentan, riociguat, and selexipag improved the hemodynamics, right ventricular function, and clinical function with good tolerability in patients with PAH. Most of the low-/intermediate-risk patients and around half of the high-risk patients could be treated sufficiently with this triple oral combination therapy although it is difficult to generalize these findings.
Two previous studies investigated the efficacy of the combination of prostacyclin infusion, an ERA, and a phosphodiesterase-5 inhibitor (PDE-5i) for PAH,7,8 but data regarding triple oral combination therapy are limited. One study related to triple oral combination therapy is the subgroup analysis of the GRIPHON study, which demonstrated a change in the symptom burden after administration of selexipag in addition to an ERA and PDE-5i.6 Recently, a randomized control study (TRITON study) is also under analysis which investigated the efficacy and safety of triple oral combination therapy with macitentan, tadalafil, and selexipag versus dual oral combination therapy with macitentan and tadalafil.18 The present study is the first to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag using real-world data.
Our results of improved hemodynamics are consistent with previous observational studies that investigated the effectiveness of triple combination therapy including prostacyclin infusion.7 Sitbon et al.7 reported that with intravenous administration of epoprostenol and oral administration of bosentan and sildenafil, the mean PAP, PVR, and cardiac index improved by 33%, 71%, and 119%, respectively. Another observational study involving a combination of ambrisentan, tadalafil, and subcutaneous treprostinil also demonstrated significant improvement of the mean PAP, PVR, and cardiac index by 30%, 66%, and 94%, respectively.8 There are similarities between the results of these previous studies and the results of the present study, suggesting that triple oral combination therapy with macitentan, riociguat, and selexipag can powerfully improve the hemodynamics in patients with PAH. In the TRITON study, triple oral combination therapy improved PVR by 54%, although it was almost the same degree as dual oral combination therapy.18 Improvement of hemodynamic in this study was greater than that of the TRITON study, partly because of the difference of the study design. Although findings from observational study, results in this study provided the possibility that triple oral combination therapy could also improve hemodynamics in the real-world population as well as the randomized controlled trial.
Our study also demonstrated a favorable long-term prognosis as well as improvement of the RVFAC, 6MWD, WHO-FC, and BNP concentration with triple oral combination therapy. In a past retrospective study of the dual combination of an ERA and PDE-5i, the 3-year overall survival rate was nearly 80%.19 In another French registry in which most patients were treated with monotherapy, the 3-year survival rate was <70%.20 The prognosis in the present study appears to be superior to that in previous reports. The low rate of mortality and hospitalization for heart failure was consistent with the TRITON study, in which the risk of first disease progression events was decreased about 41% in the triple oral therapy group.18 These results in this study could verify the efficacy of triple oral combination therapy in preventing disease progression of triple oral combination therapy found in the randomized controlled study.
In the present study, the treatment response in most of the low-/intermediate-risk patients was favorable with administration of the triple oral combination therapy, and around half of the high-risk patients did not need prostacyclin infusion. The current PAH guideline recommends initial oral therapy for low-/intermediate-risk patients, while high-risk patients are recommended to receive initial combination therapy including prostacyclin infusion.10 Patients in this study did not present decompensated heart failure and the urgent initiation of prostacyclin infusion was not necessary. Therefore, the triple oral combination therapy was initiated first and its efficacy was assessed within 6 months. Our data support recommendations in guidelines in low-/intermediate-risk patients and provide a novel possibility that around half of high-risk patients can be treated without prostacyclin infusion. Moreover, 66.7% of the patients who needed prostacyclin infusion had gene mutations, suggesting that the need for prostacyclin infusion can be largely affected by their genetic background. Therefore, we should be especially careful when we use triple oral combination therapy to treat patients with specific etiologies of PAH such as gene mutations.
With respect to safety, a past study investigating the combination of tadalafil as a PDE-5i and ambrisentan as an ERA showed that the discontinuation rate of dual combination therapy because of adverse events was 12% within 2 years of the mean duration of drug use.1 In the subgroup analysis of the GRIPHON study, which investigated the effectiveness of selexipag for the patients of PAH, a triple oral combination therapy with selexipag, ERA, and PDE-5i was discontinued in 19.0% of patients due to adverse events.6 The rate of 15% in the present study was lower than that of the GRIPHON study, suggesting good tolerability in real world data. With regard to the maximum tolerated dose, a past subgroup analysis that investigated the change in the symptom burden after taking selexipag in addition to an ERA and PDE-5i showed that only 27.9% of patients who received selexipag reached the maximum dose of selexipag.6 Another study of the combination of riociguat and macitentan showed that about 70% of patients reached the maximum maintenance dose of riociguat. In the present study, 76.9% and 92.3% of patients could be up-titrated to the maximum dose with selexipag and riociguat, respectively. Thus, this study demonstrated that it is quite possible to up-titrate each drug to the maximum dose, even in patients treated with triple oral combination therapy.
The subgroup analysis showed that the hemodynamics, right ventricular function, and clinical function powerfully improved, and the degree of improvement was similar to those in the overall patient analysis. Moreover, no patients died or were hospitalized for heart failure during the observation period. These results suggest that triple oral combination therapy with macitentan, riociguat, and selexipag can be a promising treatment strategy in treatment-naïve patients.
This study has some limitations. This was a small, single-center, retrospective study that included various types of PAH and some patients were not treatment naïve at baseline. Each etiology of PAH might have affected the results of the study differently. Prostacyclin infusion was initiated within 7 months, and no patients underwent prostacyclin infusion after 7 months, which is towards a bias of an initial high-risk population of patients in which initial triple oral combination treatment was chosen. The drug regimens were decided by the physicians. Furthermore, indirect Fick method was adopted as the measurement of CO. This was not recommended in the European Society of Cardiology/European Respiratory Society Guidelines 2015, but was admitted for use in the practical situation in the Japanese PAH guideline.11 As the results could be affected by the measurement methods of CO, further validation would be warranted.
Conclusion
This study demonstrated the effectiveness of triple oral combination therapy with macitentan, riociguat, and selexipag in patients with PAH. Our data suggest that this triple oral combination therapy is associated with improvement of hemodynamics, right ventricular function, and clinical function with good tolerability. In particular, this triple oral combination therapy can be a promising therapeutic strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further investigation is required to validate these findings.
Supplemental Material
sj-pdf-1-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-1-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-2-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-2-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-3-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-3-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-4-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-4-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-5-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
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Supplemental material, sj-pdf-5-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-7-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
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Supplemental material, sj-pdf-7-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-tif-6-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
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Supplemental material, sj-tif-6-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
We thank all the doctors, nurses, and supporting medical staff members who were involved in the care of the patients enrolled in this study. We also thank Angela Morben, DVM, ELS, from Edanz Group (https://en-author-services.edanzgroup.com/ac), for editing a draft of this manuscript.
Author contribution(s): Mizuki Momoi: Data curation; Formal analysis; Investigation; Writing-original draft.
Takahiro Hiraide: Conceptualization; Methodology; Writing-review & editing.
Yoshiki Shinya: Conceptualization; Validation; Writing-review & editing.
Hiromi Momota: Data curation; Validation; Methodology; Writing-review & editing.
Shogo Fukui: Data curation; Validation; Formal analysis; Writing-review & editing.
Michiyuki Kawakami: Data curation; Validation; Formal analysis; Writing-review & editing.
Yuji Itabashi: Methodology; Data curation; Resources, Writing-review & editing.
Keiichi Fukuda: Supervision; Investigation; Writing-review & editing.
Masaharu Kataoka: Conceptualization; Project administration; Writing-review & editing.
Conflict of interest statement: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Masaharu Kataoka https://orcid.org/0000-0001-8034-1005
Supplemental material: Supplemental material for this article is available online. | AMBRISENTAN, FUROSEMIDE, MACITENTAN, RIOCIGUAT, SELEXIPAG | DrugsGivenReaction | CC BY-NC | 33627044 | 19,134,415 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Headache'. | Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension.
The evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.
Among consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan-Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.
Twenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12-47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.
Triple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings.The reviews of this paper are available via the supplemental material section.
Introduction
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by elevated pulmonary arterial pressure (PAP) due to remodeling of the pulmonary arterial bed and right sided-heart failure. Three types of PAH-specific vasodilators targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway have been developed. Combination therapy targeting these different pathways has recently been shown to improve hemodynamics, clinical functions, and even hard endpoints including survival or worsening of PAH in several recent randomized controlled trials and metanalyses.1–5 The effectiveness of triple combination therapy targeting all three of these pathways has also been reported.6–8 However, two such studies analyzed patients who were treated with two types of oral vasodilators and prostacyclin infusion,7,8 and another study was a subgroup analysis of a randomized controlled trial demonstrating a change in the symptom burden by the addition of selexipag, a prostacyclin receptor agonist, to background double combination therapy targeting other pathways.6 Therefore, evidence of the efficacy and safety of triple oral combination therapy remains scarce.
The most recently approved PAH-specific vasodilators targeting each of the three types of pathways are macitentan, which is an endothelin receptor antagonist (ERA); riociguat, which is a soluble guanylate cyclase stimulator targeting the nitric oxide pathway; and selexipag, which is an oral non-prostanoid prostacyclin receptor agonist. All three of these are orally available drugs. The effectiveness of these vasodilators for PAH has recently been proven;2,3,9 however, no clinical trials have been performed to investigate the effectiveness of the combination of these three vasodilators. Furthermore, although the current guideline recommends initial oral therapy for patients with low or intermediate risk,10 how many patients with low or intermediate risk can actually be treated with only oral combination therapy remains poorly documented to date.
Therefore, the purposes of this study were to clarify the clinical effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag and to assess which risk groups can be adequately treated with this combination therapy.
Methods
Study design
This retrospective study was performed in Keio University Hospital in Japan. This study was approved by the Ethics Committee of Keio University Hospital, and written informed consent was obtained from all patients when they received genetic tests or were hospitalized. Patients with PAH who had received triple oral combination therapy with macitentan, riociguat, and selexipag were evaluated among all consecutive patients who were referred to Keio University Hospital from 2009 to 2020.
The diagnosis of PAH was made according to the current guideline.11 Patients who were lost to follow-up or underwent maintenance hemodialysis were excluded. Baseline data were measured at the time of referral to our hospital. If patients were treatment-naïve upon referral to our hospital, the combination of macitentan, riociguat, and selexipag was initiated after diagnosis. The method of up-titration and prioritization of the vasodilators as well as the selection of sequential therapy or upfront therapy was determined at the discretion of the specialized physicians. The doses of the vasodilators were titrated to the maximal tolerated doses. For patients who had already received other PAH-specific vasodilators at the time of enrollment, these drugs targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway were switched to macitentan, riociguat, and selexipag, respectively, with the intention of further improvement of hemodynamics.
Patients received genetic counseling, and genetic tests were performed with informed consent. The methods of the genetic tests, including whole-exome sequencing, are described in our previous reports.12,13
Parameters and outcomes
Dedicated cardiologists performed right-heart catheterization (RHC) without sedation at baseline and follow-up. The right arterial pressure, mean PAP, and pulmonary arterial wedge pressure were measured by RHC. The zero pressure point was set at the level of the midthorax. Cardiac output (CO) was calculated by the Fick technique using oxygen consumption estimated by 125 times the body surface area according to a previous report.14 Pulmonary vascular resistance (PVR) was calculated as the difference between the mean PAP and pulmonary arterial wedge pressure divided by the CO.
The 6-minute walk distance (6MWD), blood concentration of B-type natriuretic peptide (BNP), and World Health Organization functional class (WHO-FC) were measured at the time of hospitalization for RHC.
Standard two-dimensional, M-mode, and Doppler images, including the tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic excursion velocity (RVS’), were obtained by echocardiographers in accordance with the current echocardiography guideline.15 Dedicated cardiologists analyzed the data and measured the right atrial area (RAA), right ventricular end-diastolic area (RVEDA), right ventricular end-systolic area, and right ventricular fractional area change (RVFAC).
Hemodynamic changes measured by RHC, echocardiographic changes, and changes in the 6MWD, BNP concentration, and WHO-FC were assessed from baseline to follow-up.
The events of all-cause death, hospitalization for heart failure, initiation of prostacyclin infusion, and discontinuation of any of the three vasodilators (macitentan, riociguat, and selexipag) because of adverse events since administration of all three vasodilators were collected. The observation period was terminated when patients died, underwent prostacyclin infusion, or stopped taking macitentan, riociguat, or selexipag for any reason.
All patients enrolled in this study were divided into two groups by risk assessment using the three-category REVEAL 2.0 risk score,16 and the prostacyclin infusion-free rate was analyzed in each group. If the value was unmeasured, the value of zero was assigned. According to the three-category REVEAL 2.0 risk score, the high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), and the low-/intermediate-risk group was defined as patients with a predicted 1-year survival rate of ⩾90% (REVEAL 2.0 risk score ⩽8).
Subgroup analysis
Patients who were treatment-naïve at baseline and treated with only macitentan, riociguat, and selexipag for PAH were also independently assessed by subgroup analysis. Their hemodynamics, echocardiography, and clinical function were measured and clinical events were collected similarly to the overall patient analysis.
Statistical analysis
Data are described as median and interquartile range unless otherwise indicated. Wilcoxon’s signed rank test was used to compare the parameters of hemodynamics, echocardiography, 6MWD, and BNP concentration from baseline to the latest follow-up. The cases which had a missing value either at baseline or follow-up were excluded from each analysis. Differences with a p-value of <0.05 were considered statistically significant. All p-values were two-tailed. Event-free rates were analyzed using the Kaplan–Meier method. All analyses were performed using R software (version 3.6.3), and figures were obtained using GraphPad Prism (version 8.0 for Mac; GraphPad Software, La Jolla, CA, USA).
Results
Patient characteristics
The patients’ baseline characteristics and medications are presented in Table 1 and Supplemental material Table 1 online. One patient who was lost to follow-up and one patient who had been undergoing maintenance hemodialysis were excluded; thus, 26 patients were enrolled in this study. The patients were predominantly female (73.1%) with a median age of 38 years. The major etiology of PAH was idiopathic PAH (38.5%) followed by connective tissue disease-associated PAH (26.9%), heritable PAH (19.2%), and congenital heart disease-associated PAH (15.4%). Most patients were treatment-naïve (65.4%), and others were taking some PAH medications at baseline.
Table 1. Demographics and characteristics at baseline.
Variable Triple oral combination therapy
N = 26
Female 19 (73.1)
Age, years 38 (23–48)
WHO-FC
I/II/III/IV 0/9/16/1 (0.0/34.6/61.5/3.8)
BNP, pg/mL 105.25 (36.7–285.5)
6MWD, m 397.5 (312.8–441.8)
PAH etiology
IPAH 10 (38.5)
HPAH 5 (19.2)
CTD-PAH 7 (26.9)
CHD-PAH 4 (15.4)
Medication
Treatment-naïve 17 (65.4)
Single 3 (11.5)
Double 2 (7.7)
Triple 4 (15.4)
Risk assessment*
High risk 12 (46.2)
Intermediate risk 4 (15.4)
Low risk 10 (38.5)
Genetic mutation**
BMPR2 5 (23.8)
ACVRL 1 (4.8)
RNF213 1 (4.8)
Data are expressed as number (%) or median (interquartile range).
* Risk assessment was calculated using the three-category REVEAL 2.0 risk score.16 The high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), the intermediate-risk group was defined as patients with a predicted 1-year survival rate of 90–<95% (REVEAL 2.0 risk score = 7 or 8), and the low-risk group was defined as patients with a predicted 1-year survival rate of ⩾95% (REVEAL 2.0 risk score ⩽6).
** Among 26 patients, 21 were genetically tested and 15 had no genetic mutations related to PAH.
6MWD, 6-minute walk distance; ACVRL1, activin A receptor-like kinase 1; BMPR2, bone morphogenetic protein receptor type 2; BNP, B-type natriuretic peptide; CHD, congenital heart disease; CTD, connective tissue disease; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; RNF213, ring finger protein 213; WHO-FC, World Health Organization functional class.
Ten patients with idiopathic PAH, five with heritable PAH, three with connective tissue disease-associated PAH, and three with congenital heart disease-associated PAH were genetically tested. All five patients with heritable PAH had mutations in known PAH-related genes such as bone morphogenetic protein receptor type 2 (BMPR2) and one patient with idiopathic PAH had a mutation in ring finger protein 213 (RNF213), which we recently reported as a novel PAH-related gene.13,17
Safety and tolerability
Discontinuation of macitentan, riociguat, or selexipag because of adverse events occurred in four of 26 patients (15%). Among these four patients, one had diarrhea with selexipag, one had suspected myelosuppression with macitentan, one had nausea with riociguat, and one had hypotension with riociguat. These patients changed their drug to another drug targeting the same pathway. No adverse events, including death, hospitalization for heart failure, or prostacyclin infusion, were observed after discontinuation of each drug.
The maximum tolerated doses of the vasodilators are summarized in Supplemental Table 2. In detail, 25 (96.2%), 24 (92.3%), and 20 (76.9%) patients were taking the maximum dose of macitentan, riociguat, and selexipag, respectively. Seventeen (65.4%) patients reached the maximum dose of all three vasodilators.
Changes and outcomes after treatment
Hemodynamic data were available for 18 patients. The detailed study flow chart is shown in Supplemental Figure 1. The hemodynamics, WHO-FC, BNP concentration, and 6MWD at baseline and follow-up are presented in Table 2. The median observation period was 441 (229–1103) days. Hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 65% decrease in the mean PVR. The CO significantly increased by 82% from baseline to follow-up. Although >70% of patients had a WHO-FC of III or IV at baseline, 89% of patients had a WHO-FC of I or II at follow-up. The 6MWD and BNP concentration were also significantly improved [Figure 1(a)].
Table 2. Changes in clinical parameters.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 6.5 (4.0–8.0) 4.0 (3.0–5.0) −2.5 (−38) 0.005
Mean PAP, mmHg 56.0 (46.3–65.5) 40.0 (30.0–47.0) −16.0 (−29) <0.001
PAWP, mmHg 7.5 (6.0–9.8) 9.0 (8.0–11.0) 1.5 (20) 0.68
CO, L/min 3.3 (2.4–4.5) 6.0 (5.1–6.7) 2.7 (82) <0.001
CI, L/min per m2 2.2 (1.7–2.7) 3.8 (3.3–4.5) 1.6 (73) <0.001
PVR, WU 13.5 (8.8–21.5) 4.7 (2.8–6.9) −8.8 (−65) <0.001
Echocardiography
TAPSE, cm 1.5 (1.3–1.8) 2.3 (1.9–2.6) 0.8 (53) 0.001
RVS’, cm 9.7 (7.8–11.8) 13.3 (12.4–14.4) 3.6 (37) 0.001
RAA, cm2 17.2 (14.9–21.3) 16.4 (14.1–21.0) −0.8 (−5) 0.49
RVEDA, cm2 26.9 (22.8–33.1) 24.1 (21.0–30.3) −2.8 (−10) 0.21
RVESA, cm2 20.4 (16.3–23.9) 16.4 (13.8–21.1) −4.0 (−20) 0.006
FAC, % 23.6 (16.2–26.9) 32.9 (29.1–35.8) 9.3 (39) <0.001
WHO-FC
I or II 4 (22) 16 (89) – –
III or IV 14 (78) 2 (11) – –
6MWD, m 405.0 (303.0–441.8) 472.0 (439.5–493.5) 67.0 (17) 0.046
BNP, pg/mL 187.8 (36.7–379.5) 17.5 (10.3–27.2) −170.3 (−91) <0.001
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Eighteen patients were analyzed in hemodynamics, and 20 patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 1. Hemodynamic and echocardiographic changes.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Echocardiographic data were available for 20 patients (Supplemental Figure 1). The echocardiographic data are presented in Table 2. The median follow-up period was 737 (256–1179) days. Right ventricular function based on the TAPSE, RVS’, and RVFAC was significantly improved from baseline to follow-up, although the RAA and RVEDA were not [Figure 1(b)].
The Kaplan–Meier curves since administration of all three vasodilators are shown in Figure 2. The 1- and 2-year survival rates were both 93.3%. One patient died of multiple organ failure after femoral neck fracture during the observation period. The overall survival rate was 92.3% with median follow-up period of 33 (24–43) months. No patients were hospitalized for heart failure during the observation period. Prostacyclin infusion was initiated in six patients (25.4%) within 1 year. Among these six patients, selexipag was switched to subcutaneous infusion of treprostinil in one patient, an intravenous infusion of epoprostenol was added to the triple oral combination therapy in another patient, and a subcutaneous infusion of treprostinil was added to the triple oral combination therapy in the remaining four patients. Selexipag was not discontinued in some patients to reduce maintenance dose of the prostacyclin for infusion. No other patients underwent prostacyclin infusion after 1 year. Among six patients who underwent prostacyclin infusion within 1 year, three patients had a BMPR2 mutation, one patient had an RNF213 mutation, and one patient had Eisenmenger syndrome due to an atrial septal defect. Composite events of all-cause death, hospitalization for heart failure, and initiation of prostacyclin infusion occurred in 16.6% of the patients within 6 months and 30.4% of the patients in 1 and 2 years.
Figure 2. Event-free rates in all patients with triple oral combination therapy.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy are shown (n = 26). The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Among 14 patients who were classified as low-/intermediate-risk by the three-category REVEAL 2.0 risk score,16 the prostacyclin-free rate was 92.9% at 3 years, while the rate was 55.0% at 2 years in 12 high-risk patients (Figure 3). The difference was not statistically significant (p = 0.058). Hemodynamic changes from baseline to follow-up in each low/intermediate and high-risk group are summarized in Supplemental Table 3. Among five patients who were classified as high-risk based on the three-category REVEAL 2.0 risk score and needed prostacyclin infusion, three patients had BMPR2 mutations and one patient had a RNF213 mutation.
Figure 3. Kaplan–Meier curve for prostacyclin-free rate in each risk category.
The prostacyclin infusion-free rates in each risk category are shown. The patients were divided into two risk categories by the REVEAL 2.0 risk score.16 The p-values were calculated by the log-rank test.
Subgroup analysis in treatment-naïve patients
Seventeen patients were treatment-naïve at baseline. Six patients were treatment naïve at baseline, but treated with other pulmonary vasodilators. In five out of these six patients, oral medication was switched from beraprost to selexipag, and in one patient, it was switched from ambrisentan and tadalafil to macitentan and riociguat. Thus, these six patients were excluded from the subgroup analysis. Among the remaining 11 patients for the subgroup analysis, the median time from initiation of the first PAH drug to the start of the third PAH drug was 24 (12–47) days. The way of up-titration in treatment naïve patients was as follows. Macitentan 10 mg was initiated at first and followed by riociguat 3.0 mg within 2 weeks. The dose of riociguat was up-titrated by 1.5 mg every 2 weeks with attention to adverse effects. In 36% of treatment naïve patients, selexipag was initiated after riociguat was up-titrated to maximum tolerated dose, whereas selexipag was started within 2 weeks from initiating macitentan in 64% of patients. Selexipag was increased by 0.4 mg every 2 weeks to maximum tolerated dose with attention to side effects. One patient (9.1%) discontinued macitentan because of suspected myelosuppression, and another patient (9.1%) discontinued riociguat because of nausea. RHC data in 10 patients and echocardiographic data in nine patients were available at baseline and at follow-up during the triple oral combination therapy. The patients’ hemodynamic and right ventricular function parameters are presented in Table 3 and Figure 4. The median follow-up period of the hemodynamic analysis was 293 (211–473) days. The hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 66% decrease in the PVR. The CO increased by 90% from baseline to follow-up. The median follow-up period of echocardiography was 385 (230–594) days. The TAPSE, RVS’, and RVFAC, indicating right ventricular function, increased significantly. The WHO-FC, 6MWD, and BNP concentration in this subgroup also improved significantly. In the Kaplan–Meier analysis, no patients died or were hospitalized for heart failure (Figure 5). Prostacyclin infusion was initiated in 31.8% of patients within 7 months, and no patients underwent prostacyclin infusion after 7 months.
Table 3. Changes in clinical parameters among treatment-naïve patients at baseline.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 7.5 (4.3–8.8) 4.0 (3.3–5.0) −3.5 (−47) 0.022
Mean PAP, mmHg 63.0 (55.0–75.8) 44.5 (37.0–51.5) −18.5 (−29) 0.006
PAWP, mmHg 7.5 (6.3–9.8) 8.0 (6.5–10.3) 0.5 (7) 0.61
CO, L/min 3.1 (2.4–4.3) 5.9 (5.1–7.2) 2.8 (90) 0.006
CI, L/min per m2 2.1 (1.7–2.5) 4.2 (3.5–4.6) 2.1 (100) 0.006
PVR, WU 17.5 (13.2–21.9) 5.9 (3.8–9.6) −11.6 (−66) 0.006
Echocardiography
TAPSE, cm 1.4 (1.3–1.5) 2.3 (2.1–2.7) 0.9 (64) 0.009
RVS’, cm 9.3 (7.9–10.8) 13.5 (13.0–14.3) 4.2 (45) 0.035
RAA, cm2 18.5 (15.0–21.1) 15.2 (13.5–16.7) −3.3 (−18) 0.076
RVEDA, cm2 27.0 (25.0–33.2) 23.6 (21.0–24.6) −3.4 (−13) 0.058
RVESA, cm2 22.9 (18.7–25.4) 14.8 (14.0–16.8) −8.1 (−35) 0.009
FAC, % 22.9 (15.9–25.2) 33.1 (29.5–35.0) 10.2 (45) 0.018
WHO-FC
I or II 1 (10) 8 (80)
III or IV 9 (90) 2 (20)
6MWD, m 400.0 (326.5–432.0) 471.5 (451.5–479.2) 71.5 (18) 0.030
BNP, pg/mL 200.8 (41.9–379.5) 20.2 (12.6–24.5) −180.6 (−90) 0.006
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Ten patients were analyzed in hemodynamics, and nine patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 4. Hemodynamic and echocardiographic changes in treatment-naïve patients.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Figure 5. Event-free rates in treatment-naïve patients.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy in treatment-naïve patients are shown. The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite endpoint of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Discussion
In the present study, triple oral combination therapy with macitentan, riociguat, and selexipag improved the hemodynamics, right ventricular function, and clinical function with good tolerability in patients with PAH. Most of the low-/intermediate-risk patients and around half of the high-risk patients could be treated sufficiently with this triple oral combination therapy although it is difficult to generalize these findings.
Two previous studies investigated the efficacy of the combination of prostacyclin infusion, an ERA, and a phosphodiesterase-5 inhibitor (PDE-5i) for PAH,7,8 but data regarding triple oral combination therapy are limited. One study related to triple oral combination therapy is the subgroup analysis of the GRIPHON study, which demonstrated a change in the symptom burden after administration of selexipag in addition to an ERA and PDE-5i.6 Recently, a randomized control study (TRITON study) is also under analysis which investigated the efficacy and safety of triple oral combination therapy with macitentan, tadalafil, and selexipag versus dual oral combination therapy with macitentan and tadalafil.18 The present study is the first to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag using real-world data.
Our results of improved hemodynamics are consistent with previous observational studies that investigated the effectiveness of triple combination therapy including prostacyclin infusion.7 Sitbon et al.7 reported that with intravenous administration of epoprostenol and oral administration of bosentan and sildenafil, the mean PAP, PVR, and cardiac index improved by 33%, 71%, and 119%, respectively. Another observational study involving a combination of ambrisentan, tadalafil, and subcutaneous treprostinil also demonstrated significant improvement of the mean PAP, PVR, and cardiac index by 30%, 66%, and 94%, respectively.8 There are similarities between the results of these previous studies and the results of the present study, suggesting that triple oral combination therapy with macitentan, riociguat, and selexipag can powerfully improve the hemodynamics in patients with PAH. In the TRITON study, triple oral combination therapy improved PVR by 54%, although it was almost the same degree as dual oral combination therapy.18 Improvement of hemodynamic in this study was greater than that of the TRITON study, partly because of the difference of the study design. Although findings from observational study, results in this study provided the possibility that triple oral combination therapy could also improve hemodynamics in the real-world population as well as the randomized controlled trial.
Our study also demonstrated a favorable long-term prognosis as well as improvement of the RVFAC, 6MWD, WHO-FC, and BNP concentration with triple oral combination therapy. In a past retrospective study of the dual combination of an ERA and PDE-5i, the 3-year overall survival rate was nearly 80%.19 In another French registry in which most patients were treated with monotherapy, the 3-year survival rate was <70%.20 The prognosis in the present study appears to be superior to that in previous reports. The low rate of mortality and hospitalization for heart failure was consistent with the TRITON study, in which the risk of first disease progression events was decreased about 41% in the triple oral therapy group.18 These results in this study could verify the efficacy of triple oral combination therapy in preventing disease progression of triple oral combination therapy found in the randomized controlled study.
In the present study, the treatment response in most of the low-/intermediate-risk patients was favorable with administration of the triple oral combination therapy, and around half of the high-risk patients did not need prostacyclin infusion. The current PAH guideline recommends initial oral therapy for low-/intermediate-risk patients, while high-risk patients are recommended to receive initial combination therapy including prostacyclin infusion.10 Patients in this study did not present decompensated heart failure and the urgent initiation of prostacyclin infusion was not necessary. Therefore, the triple oral combination therapy was initiated first and its efficacy was assessed within 6 months. Our data support recommendations in guidelines in low-/intermediate-risk patients and provide a novel possibility that around half of high-risk patients can be treated without prostacyclin infusion. Moreover, 66.7% of the patients who needed prostacyclin infusion had gene mutations, suggesting that the need for prostacyclin infusion can be largely affected by their genetic background. Therefore, we should be especially careful when we use triple oral combination therapy to treat patients with specific etiologies of PAH such as gene mutations.
With respect to safety, a past study investigating the combination of tadalafil as a PDE-5i and ambrisentan as an ERA showed that the discontinuation rate of dual combination therapy because of adverse events was 12% within 2 years of the mean duration of drug use.1 In the subgroup analysis of the GRIPHON study, which investigated the effectiveness of selexipag for the patients of PAH, a triple oral combination therapy with selexipag, ERA, and PDE-5i was discontinued in 19.0% of patients due to adverse events.6 The rate of 15% in the present study was lower than that of the GRIPHON study, suggesting good tolerability in real world data. With regard to the maximum tolerated dose, a past subgroup analysis that investigated the change in the symptom burden after taking selexipag in addition to an ERA and PDE-5i showed that only 27.9% of patients who received selexipag reached the maximum dose of selexipag.6 Another study of the combination of riociguat and macitentan showed that about 70% of patients reached the maximum maintenance dose of riociguat. In the present study, 76.9% and 92.3% of patients could be up-titrated to the maximum dose with selexipag and riociguat, respectively. Thus, this study demonstrated that it is quite possible to up-titrate each drug to the maximum dose, even in patients treated with triple oral combination therapy.
The subgroup analysis showed that the hemodynamics, right ventricular function, and clinical function powerfully improved, and the degree of improvement was similar to those in the overall patient analysis. Moreover, no patients died or were hospitalized for heart failure during the observation period. These results suggest that triple oral combination therapy with macitentan, riociguat, and selexipag can be a promising treatment strategy in treatment-naïve patients.
This study has some limitations. This was a small, single-center, retrospective study that included various types of PAH and some patients were not treatment naïve at baseline. Each etiology of PAH might have affected the results of the study differently. Prostacyclin infusion was initiated within 7 months, and no patients underwent prostacyclin infusion after 7 months, which is towards a bias of an initial high-risk population of patients in which initial triple oral combination treatment was chosen. The drug regimens were decided by the physicians. Furthermore, indirect Fick method was adopted as the measurement of CO. This was not recommended in the European Society of Cardiology/European Respiratory Society Guidelines 2015, but was admitted for use in the practical situation in the Japanese PAH guideline.11 As the results could be affected by the measurement methods of CO, further validation would be warranted.
Conclusion
This study demonstrated the effectiveness of triple oral combination therapy with macitentan, riociguat, and selexipag in patients with PAH. Our data suggest that this triple oral combination therapy is associated with improvement of hemodynamics, right ventricular function, and clinical function with good tolerability. In particular, this triple oral combination therapy can be a promising therapeutic strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further investigation is required to validate these findings.
Supplemental Material
sj-pdf-1-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-1-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-2-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-2-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-3-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-3-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-4-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-4-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-5-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-7-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-tif-6-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
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Supplemental material, sj-tif-6-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
We thank all the doctors, nurses, and supporting medical staff members who were involved in the care of the patients enrolled in this study. We also thank Angela Morben, DVM, ELS, from Edanz Group (https://en-author-services.edanzgroup.com/ac), for editing a draft of this manuscript.
Author contribution(s): Mizuki Momoi: Data curation; Formal analysis; Investigation; Writing-original draft.
Takahiro Hiraide: Conceptualization; Methodology; Writing-review & editing.
Yoshiki Shinya: Conceptualization; Validation; Writing-review & editing.
Hiromi Momota: Data curation; Validation; Methodology; Writing-review & editing.
Shogo Fukui: Data curation; Validation; Formal analysis; Writing-review & editing.
Michiyuki Kawakami: Data curation; Validation; Formal analysis; Writing-review & editing.
Yuji Itabashi: Methodology; Data curation; Resources, Writing-review & editing.
Keiichi Fukuda: Supervision; Investigation; Writing-review & editing.
Masaharu Kataoka: Conceptualization; Project administration; Writing-review & editing.
Conflict of interest statement: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Masaharu Kataoka https://orcid.org/0000-0001-8034-1005
Supplemental material: Supplemental material for this article is available online. | AMBRISENTAN, FUROSEMIDE, MACITENTAN, RIOCIGUAT, SELEXIPAG | DrugsGivenReaction | CC BY-NC | 33627044 | 19,134,415 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myelosuppression'. | Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension.
The evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.
Among consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan-Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.
Twenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12-47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.
Triple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings.The reviews of this paper are available via the supplemental material section.
Introduction
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by elevated pulmonary arterial pressure (PAP) due to remodeling of the pulmonary arterial bed and right sided-heart failure. Three types of PAH-specific vasodilators targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway have been developed. Combination therapy targeting these different pathways has recently been shown to improve hemodynamics, clinical functions, and even hard endpoints including survival or worsening of PAH in several recent randomized controlled trials and metanalyses.1–5 The effectiveness of triple combination therapy targeting all three of these pathways has also been reported.6–8 However, two such studies analyzed patients who were treated with two types of oral vasodilators and prostacyclin infusion,7,8 and another study was a subgroup analysis of a randomized controlled trial demonstrating a change in the symptom burden by the addition of selexipag, a prostacyclin receptor agonist, to background double combination therapy targeting other pathways.6 Therefore, evidence of the efficacy and safety of triple oral combination therapy remains scarce.
The most recently approved PAH-specific vasodilators targeting each of the three types of pathways are macitentan, which is an endothelin receptor antagonist (ERA); riociguat, which is a soluble guanylate cyclase stimulator targeting the nitric oxide pathway; and selexipag, which is an oral non-prostanoid prostacyclin receptor agonist. All three of these are orally available drugs. The effectiveness of these vasodilators for PAH has recently been proven;2,3,9 however, no clinical trials have been performed to investigate the effectiveness of the combination of these three vasodilators. Furthermore, although the current guideline recommends initial oral therapy for patients with low or intermediate risk,10 how many patients with low or intermediate risk can actually be treated with only oral combination therapy remains poorly documented to date.
Therefore, the purposes of this study were to clarify the clinical effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag and to assess which risk groups can be adequately treated with this combination therapy.
Methods
Study design
This retrospective study was performed in Keio University Hospital in Japan. This study was approved by the Ethics Committee of Keio University Hospital, and written informed consent was obtained from all patients when they received genetic tests or were hospitalized. Patients with PAH who had received triple oral combination therapy with macitentan, riociguat, and selexipag were evaluated among all consecutive patients who were referred to Keio University Hospital from 2009 to 2020.
The diagnosis of PAH was made according to the current guideline.11 Patients who were lost to follow-up or underwent maintenance hemodialysis were excluded. Baseline data were measured at the time of referral to our hospital. If patients were treatment-naïve upon referral to our hospital, the combination of macitentan, riociguat, and selexipag was initiated after diagnosis. The method of up-titration and prioritization of the vasodilators as well as the selection of sequential therapy or upfront therapy was determined at the discretion of the specialized physicians. The doses of the vasodilators were titrated to the maximal tolerated doses. For patients who had already received other PAH-specific vasodilators at the time of enrollment, these drugs targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway were switched to macitentan, riociguat, and selexipag, respectively, with the intention of further improvement of hemodynamics.
Patients received genetic counseling, and genetic tests were performed with informed consent. The methods of the genetic tests, including whole-exome sequencing, are described in our previous reports.12,13
Parameters and outcomes
Dedicated cardiologists performed right-heart catheterization (RHC) without sedation at baseline and follow-up. The right arterial pressure, mean PAP, and pulmonary arterial wedge pressure were measured by RHC. The zero pressure point was set at the level of the midthorax. Cardiac output (CO) was calculated by the Fick technique using oxygen consumption estimated by 125 times the body surface area according to a previous report.14 Pulmonary vascular resistance (PVR) was calculated as the difference between the mean PAP and pulmonary arterial wedge pressure divided by the CO.
The 6-minute walk distance (6MWD), blood concentration of B-type natriuretic peptide (BNP), and World Health Organization functional class (WHO-FC) were measured at the time of hospitalization for RHC.
Standard two-dimensional, M-mode, and Doppler images, including the tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic excursion velocity (RVS’), were obtained by echocardiographers in accordance with the current echocardiography guideline.15 Dedicated cardiologists analyzed the data and measured the right atrial area (RAA), right ventricular end-diastolic area (RVEDA), right ventricular end-systolic area, and right ventricular fractional area change (RVFAC).
Hemodynamic changes measured by RHC, echocardiographic changes, and changes in the 6MWD, BNP concentration, and WHO-FC were assessed from baseline to follow-up.
The events of all-cause death, hospitalization for heart failure, initiation of prostacyclin infusion, and discontinuation of any of the three vasodilators (macitentan, riociguat, and selexipag) because of adverse events since administration of all three vasodilators were collected. The observation period was terminated when patients died, underwent prostacyclin infusion, or stopped taking macitentan, riociguat, or selexipag for any reason.
All patients enrolled in this study were divided into two groups by risk assessment using the three-category REVEAL 2.0 risk score,16 and the prostacyclin infusion-free rate was analyzed in each group. If the value was unmeasured, the value of zero was assigned. According to the three-category REVEAL 2.0 risk score, the high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), and the low-/intermediate-risk group was defined as patients with a predicted 1-year survival rate of ⩾90% (REVEAL 2.0 risk score ⩽8).
Subgroup analysis
Patients who were treatment-naïve at baseline and treated with only macitentan, riociguat, and selexipag for PAH were also independently assessed by subgroup analysis. Their hemodynamics, echocardiography, and clinical function were measured and clinical events were collected similarly to the overall patient analysis.
Statistical analysis
Data are described as median and interquartile range unless otherwise indicated. Wilcoxon’s signed rank test was used to compare the parameters of hemodynamics, echocardiography, 6MWD, and BNP concentration from baseline to the latest follow-up. The cases which had a missing value either at baseline or follow-up were excluded from each analysis. Differences with a p-value of <0.05 were considered statistically significant. All p-values were two-tailed. Event-free rates were analyzed using the Kaplan–Meier method. All analyses were performed using R software (version 3.6.3), and figures were obtained using GraphPad Prism (version 8.0 for Mac; GraphPad Software, La Jolla, CA, USA).
Results
Patient characteristics
The patients’ baseline characteristics and medications are presented in Table 1 and Supplemental material Table 1 online. One patient who was lost to follow-up and one patient who had been undergoing maintenance hemodialysis were excluded; thus, 26 patients were enrolled in this study. The patients were predominantly female (73.1%) with a median age of 38 years. The major etiology of PAH was idiopathic PAH (38.5%) followed by connective tissue disease-associated PAH (26.9%), heritable PAH (19.2%), and congenital heart disease-associated PAH (15.4%). Most patients were treatment-naïve (65.4%), and others were taking some PAH medications at baseline.
Table 1. Demographics and characteristics at baseline.
Variable Triple oral combination therapy
N = 26
Female 19 (73.1)
Age, years 38 (23–48)
WHO-FC
I/II/III/IV 0/9/16/1 (0.0/34.6/61.5/3.8)
BNP, pg/mL 105.25 (36.7–285.5)
6MWD, m 397.5 (312.8–441.8)
PAH etiology
IPAH 10 (38.5)
HPAH 5 (19.2)
CTD-PAH 7 (26.9)
CHD-PAH 4 (15.4)
Medication
Treatment-naïve 17 (65.4)
Single 3 (11.5)
Double 2 (7.7)
Triple 4 (15.4)
Risk assessment*
High risk 12 (46.2)
Intermediate risk 4 (15.4)
Low risk 10 (38.5)
Genetic mutation**
BMPR2 5 (23.8)
ACVRL 1 (4.8)
RNF213 1 (4.8)
Data are expressed as number (%) or median (interquartile range).
* Risk assessment was calculated using the three-category REVEAL 2.0 risk score.16 The high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), the intermediate-risk group was defined as patients with a predicted 1-year survival rate of 90–<95% (REVEAL 2.0 risk score = 7 or 8), and the low-risk group was defined as patients with a predicted 1-year survival rate of ⩾95% (REVEAL 2.0 risk score ⩽6).
** Among 26 patients, 21 were genetically tested and 15 had no genetic mutations related to PAH.
6MWD, 6-minute walk distance; ACVRL1, activin A receptor-like kinase 1; BMPR2, bone morphogenetic protein receptor type 2; BNP, B-type natriuretic peptide; CHD, congenital heart disease; CTD, connective tissue disease; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; RNF213, ring finger protein 213; WHO-FC, World Health Organization functional class.
Ten patients with idiopathic PAH, five with heritable PAH, three with connective tissue disease-associated PAH, and three with congenital heart disease-associated PAH were genetically tested. All five patients with heritable PAH had mutations in known PAH-related genes such as bone morphogenetic protein receptor type 2 (BMPR2) and one patient with idiopathic PAH had a mutation in ring finger protein 213 (RNF213), which we recently reported as a novel PAH-related gene.13,17
Safety and tolerability
Discontinuation of macitentan, riociguat, or selexipag because of adverse events occurred in four of 26 patients (15%). Among these four patients, one had diarrhea with selexipag, one had suspected myelosuppression with macitentan, one had nausea with riociguat, and one had hypotension with riociguat. These patients changed their drug to another drug targeting the same pathway. No adverse events, including death, hospitalization for heart failure, or prostacyclin infusion, were observed after discontinuation of each drug.
The maximum tolerated doses of the vasodilators are summarized in Supplemental Table 2. In detail, 25 (96.2%), 24 (92.3%), and 20 (76.9%) patients were taking the maximum dose of macitentan, riociguat, and selexipag, respectively. Seventeen (65.4%) patients reached the maximum dose of all three vasodilators.
Changes and outcomes after treatment
Hemodynamic data were available for 18 patients. The detailed study flow chart is shown in Supplemental Figure 1. The hemodynamics, WHO-FC, BNP concentration, and 6MWD at baseline and follow-up are presented in Table 2. The median observation period was 441 (229–1103) days. Hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 65% decrease in the mean PVR. The CO significantly increased by 82% from baseline to follow-up. Although >70% of patients had a WHO-FC of III or IV at baseline, 89% of patients had a WHO-FC of I or II at follow-up. The 6MWD and BNP concentration were also significantly improved [Figure 1(a)].
Table 2. Changes in clinical parameters.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 6.5 (4.0–8.0) 4.0 (3.0–5.0) −2.5 (−38) 0.005
Mean PAP, mmHg 56.0 (46.3–65.5) 40.0 (30.0–47.0) −16.0 (−29) <0.001
PAWP, mmHg 7.5 (6.0–9.8) 9.0 (8.0–11.0) 1.5 (20) 0.68
CO, L/min 3.3 (2.4–4.5) 6.0 (5.1–6.7) 2.7 (82) <0.001
CI, L/min per m2 2.2 (1.7–2.7) 3.8 (3.3–4.5) 1.6 (73) <0.001
PVR, WU 13.5 (8.8–21.5) 4.7 (2.8–6.9) −8.8 (−65) <0.001
Echocardiography
TAPSE, cm 1.5 (1.3–1.8) 2.3 (1.9–2.6) 0.8 (53) 0.001
RVS’, cm 9.7 (7.8–11.8) 13.3 (12.4–14.4) 3.6 (37) 0.001
RAA, cm2 17.2 (14.9–21.3) 16.4 (14.1–21.0) −0.8 (−5) 0.49
RVEDA, cm2 26.9 (22.8–33.1) 24.1 (21.0–30.3) −2.8 (−10) 0.21
RVESA, cm2 20.4 (16.3–23.9) 16.4 (13.8–21.1) −4.0 (−20) 0.006
FAC, % 23.6 (16.2–26.9) 32.9 (29.1–35.8) 9.3 (39) <0.001
WHO-FC
I or II 4 (22) 16 (89) – –
III or IV 14 (78) 2 (11) – –
6MWD, m 405.0 (303.0–441.8) 472.0 (439.5–493.5) 67.0 (17) 0.046
BNP, pg/mL 187.8 (36.7–379.5) 17.5 (10.3–27.2) −170.3 (−91) <0.001
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Eighteen patients were analyzed in hemodynamics, and 20 patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 1. Hemodynamic and echocardiographic changes.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Echocardiographic data were available for 20 patients (Supplemental Figure 1). The echocardiographic data are presented in Table 2. The median follow-up period was 737 (256–1179) days. Right ventricular function based on the TAPSE, RVS’, and RVFAC was significantly improved from baseline to follow-up, although the RAA and RVEDA were not [Figure 1(b)].
The Kaplan–Meier curves since administration of all three vasodilators are shown in Figure 2. The 1- and 2-year survival rates were both 93.3%. One patient died of multiple organ failure after femoral neck fracture during the observation period. The overall survival rate was 92.3% with median follow-up period of 33 (24–43) months. No patients were hospitalized for heart failure during the observation period. Prostacyclin infusion was initiated in six patients (25.4%) within 1 year. Among these six patients, selexipag was switched to subcutaneous infusion of treprostinil in one patient, an intravenous infusion of epoprostenol was added to the triple oral combination therapy in another patient, and a subcutaneous infusion of treprostinil was added to the triple oral combination therapy in the remaining four patients. Selexipag was not discontinued in some patients to reduce maintenance dose of the prostacyclin for infusion. No other patients underwent prostacyclin infusion after 1 year. Among six patients who underwent prostacyclin infusion within 1 year, three patients had a BMPR2 mutation, one patient had an RNF213 mutation, and one patient had Eisenmenger syndrome due to an atrial septal defect. Composite events of all-cause death, hospitalization for heart failure, and initiation of prostacyclin infusion occurred in 16.6% of the patients within 6 months and 30.4% of the patients in 1 and 2 years.
Figure 2. Event-free rates in all patients with triple oral combination therapy.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy are shown (n = 26). The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Among 14 patients who were classified as low-/intermediate-risk by the three-category REVEAL 2.0 risk score,16 the prostacyclin-free rate was 92.9% at 3 years, while the rate was 55.0% at 2 years in 12 high-risk patients (Figure 3). The difference was not statistically significant (p = 0.058). Hemodynamic changes from baseline to follow-up in each low/intermediate and high-risk group are summarized in Supplemental Table 3. Among five patients who were classified as high-risk based on the three-category REVEAL 2.0 risk score and needed prostacyclin infusion, three patients had BMPR2 mutations and one patient had a RNF213 mutation.
Figure 3. Kaplan–Meier curve for prostacyclin-free rate in each risk category.
The prostacyclin infusion-free rates in each risk category are shown. The patients were divided into two risk categories by the REVEAL 2.0 risk score.16 The p-values were calculated by the log-rank test.
Subgroup analysis in treatment-naïve patients
Seventeen patients were treatment-naïve at baseline. Six patients were treatment naïve at baseline, but treated with other pulmonary vasodilators. In five out of these six patients, oral medication was switched from beraprost to selexipag, and in one patient, it was switched from ambrisentan and tadalafil to macitentan and riociguat. Thus, these six patients were excluded from the subgroup analysis. Among the remaining 11 patients for the subgroup analysis, the median time from initiation of the first PAH drug to the start of the third PAH drug was 24 (12–47) days. The way of up-titration in treatment naïve patients was as follows. Macitentan 10 mg was initiated at first and followed by riociguat 3.0 mg within 2 weeks. The dose of riociguat was up-titrated by 1.5 mg every 2 weeks with attention to adverse effects. In 36% of treatment naïve patients, selexipag was initiated after riociguat was up-titrated to maximum tolerated dose, whereas selexipag was started within 2 weeks from initiating macitentan in 64% of patients. Selexipag was increased by 0.4 mg every 2 weeks to maximum tolerated dose with attention to side effects. One patient (9.1%) discontinued macitentan because of suspected myelosuppression, and another patient (9.1%) discontinued riociguat because of nausea. RHC data in 10 patients and echocardiographic data in nine patients were available at baseline and at follow-up during the triple oral combination therapy. The patients’ hemodynamic and right ventricular function parameters are presented in Table 3 and Figure 4. The median follow-up period of the hemodynamic analysis was 293 (211–473) days. The hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 66% decrease in the PVR. The CO increased by 90% from baseline to follow-up. The median follow-up period of echocardiography was 385 (230–594) days. The TAPSE, RVS’, and RVFAC, indicating right ventricular function, increased significantly. The WHO-FC, 6MWD, and BNP concentration in this subgroup also improved significantly. In the Kaplan–Meier analysis, no patients died or were hospitalized for heart failure (Figure 5). Prostacyclin infusion was initiated in 31.8% of patients within 7 months, and no patients underwent prostacyclin infusion after 7 months.
Table 3. Changes in clinical parameters among treatment-naïve patients at baseline.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 7.5 (4.3–8.8) 4.0 (3.3–5.0) −3.5 (−47) 0.022
Mean PAP, mmHg 63.0 (55.0–75.8) 44.5 (37.0–51.5) −18.5 (−29) 0.006
PAWP, mmHg 7.5 (6.3–9.8) 8.0 (6.5–10.3) 0.5 (7) 0.61
CO, L/min 3.1 (2.4–4.3) 5.9 (5.1–7.2) 2.8 (90) 0.006
CI, L/min per m2 2.1 (1.7–2.5) 4.2 (3.5–4.6) 2.1 (100) 0.006
PVR, WU 17.5 (13.2–21.9) 5.9 (3.8–9.6) −11.6 (−66) 0.006
Echocardiography
TAPSE, cm 1.4 (1.3–1.5) 2.3 (2.1–2.7) 0.9 (64) 0.009
RVS’, cm 9.3 (7.9–10.8) 13.5 (13.0–14.3) 4.2 (45) 0.035
RAA, cm2 18.5 (15.0–21.1) 15.2 (13.5–16.7) −3.3 (−18) 0.076
RVEDA, cm2 27.0 (25.0–33.2) 23.6 (21.0–24.6) −3.4 (−13) 0.058
RVESA, cm2 22.9 (18.7–25.4) 14.8 (14.0–16.8) −8.1 (−35) 0.009
FAC, % 22.9 (15.9–25.2) 33.1 (29.5–35.0) 10.2 (45) 0.018
WHO-FC
I or II 1 (10) 8 (80)
III or IV 9 (90) 2 (20)
6MWD, m 400.0 (326.5–432.0) 471.5 (451.5–479.2) 71.5 (18) 0.030
BNP, pg/mL 200.8 (41.9–379.5) 20.2 (12.6–24.5) −180.6 (−90) 0.006
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Ten patients were analyzed in hemodynamics, and nine patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 4. Hemodynamic and echocardiographic changes in treatment-naïve patients.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Figure 5. Event-free rates in treatment-naïve patients.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy in treatment-naïve patients are shown. The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite endpoint of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Discussion
In the present study, triple oral combination therapy with macitentan, riociguat, and selexipag improved the hemodynamics, right ventricular function, and clinical function with good tolerability in patients with PAH. Most of the low-/intermediate-risk patients and around half of the high-risk patients could be treated sufficiently with this triple oral combination therapy although it is difficult to generalize these findings.
Two previous studies investigated the efficacy of the combination of prostacyclin infusion, an ERA, and a phosphodiesterase-5 inhibitor (PDE-5i) for PAH,7,8 but data regarding triple oral combination therapy are limited. One study related to triple oral combination therapy is the subgroup analysis of the GRIPHON study, which demonstrated a change in the symptom burden after administration of selexipag in addition to an ERA and PDE-5i.6 Recently, a randomized control study (TRITON study) is also under analysis which investigated the efficacy and safety of triple oral combination therapy with macitentan, tadalafil, and selexipag versus dual oral combination therapy with macitentan and tadalafil.18 The present study is the first to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag using real-world data.
Our results of improved hemodynamics are consistent with previous observational studies that investigated the effectiveness of triple combination therapy including prostacyclin infusion.7 Sitbon et al.7 reported that with intravenous administration of epoprostenol and oral administration of bosentan and sildenafil, the mean PAP, PVR, and cardiac index improved by 33%, 71%, and 119%, respectively. Another observational study involving a combination of ambrisentan, tadalafil, and subcutaneous treprostinil also demonstrated significant improvement of the mean PAP, PVR, and cardiac index by 30%, 66%, and 94%, respectively.8 There are similarities between the results of these previous studies and the results of the present study, suggesting that triple oral combination therapy with macitentan, riociguat, and selexipag can powerfully improve the hemodynamics in patients with PAH. In the TRITON study, triple oral combination therapy improved PVR by 54%, although it was almost the same degree as dual oral combination therapy.18 Improvement of hemodynamic in this study was greater than that of the TRITON study, partly because of the difference of the study design. Although findings from observational study, results in this study provided the possibility that triple oral combination therapy could also improve hemodynamics in the real-world population as well as the randomized controlled trial.
Our study also demonstrated a favorable long-term prognosis as well as improvement of the RVFAC, 6MWD, WHO-FC, and BNP concentration with triple oral combination therapy. In a past retrospective study of the dual combination of an ERA and PDE-5i, the 3-year overall survival rate was nearly 80%.19 In another French registry in which most patients were treated with monotherapy, the 3-year survival rate was <70%.20 The prognosis in the present study appears to be superior to that in previous reports. The low rate of mortality and hospitalization for heart failure was consistent with the TRITON study, in which the risk of first disease progression events was decreased about 41% in the triple oral therapy group.18 These results in this study could verify the efficacy of triple oral combination therapy in preventing disease progression of triple oral combination therapy found in the randomized controlled study.
In the present study, the treatment response in most of the low-/intermediate-risk patients was favorable with administration of the triple oral combination therapy, and around half of the high-risk patients did not need prostacyclin infusion. The current PAH guideline recommends initial oral therapy for low-/intermediate-risk patients, while high-risk patients are recommended to receive initial combination therapy including prostacyclin infusion.10 Patients in this study did not present decompensated heart failure and the urgent initiation of prostacyclin infusion was not necessary. Therefore, the triple oral combination therapy was initiated first and its efficacy was assessed within 6 months. Our data support recommendations in guidelines in low-/intermediate-risk patients and provide a novel possibility that around half of high-risk patients can be treated without prostacyclin infusion. Moreover, 66.7% of the patients who needed prostacyclin infusion had gene mutations, suggesting that the need for prostacyclin infusion can be largely affected by their genetic background. Therefore, we should be especially careful when we use triple oral combination therapy to treat patients with specific etiologies of PAH such as gene mutations.
With respect to safety, a past study investigating the combination of tadalafil as a PDE-5i and ambrisentan as an ERA showed that the discontinuation rate of dual combination therapy because of adverse events was 12% within 2 years of the mean duration of drug use.1 In the subgroup analysis of the GRIPHON study, which investigated the effectiveness of selexipag for the patients of PAH, a triple oral combination therapy with selexipag, ERA, and PDE-5i was discontinued in 19.0% of patients due to adverse events.6 The rate of 15% in the present study was lower than that of the GRIPHON study, suggesting good tolerability in real world data. With regard to the maximum tolerated dose, a past subgroup analysis that investigated the change in the symptom burden after taking selexipag in addition to an ERA and PDE-5i showed that only 27.9% of patients who received selexipag reached the maximum dose of selexipag.6 Another study of the combination of riociguat and macitentan showed that about 70% of patients reached the maximum maintenance dose of riociguat. In the present study, 76.9% and 92.3% of patients could be up-titrated to the maximum dose with selexipag and riociguat, respectively. Thus, this study demonstrated that it is quite possible to up-titrate each drug to the maximum dose, even in patients treated with triple oral combination therapy.
The subgroup analysis showed that the hemodynamics, right ventricular function, and clinical function powerfully improved, and the degree of improvement was similar to those in the overall patient analysis. Moreover, no patients died or were hospitalized for heart failure during the observation period. These results suggest that triple oral combination therapy with macitentan, riociguat, and selexipag can be a promising treatment strategy in treatment-naïve patients.
This study has some limitations. This was a small, single-center, retrospective study that included various types of PAH and some patients were not treatment naïve at baseline. Each etiology of PAH might have affected the results of the study differently. Prostacyclin infusion was initiated within 7 months, and no patients underwent prostacyclin infusion after 7 months, which is towards a bias of an initial high-risk population of patients in which initial triple oral combination treatment was chosen. The drug regimens were decided by the physicians. Furthermore, indirect Fick method was adopted as the measurement of CO. This was not recommended in the European Society of Cardiology/European Respiratory Society Guidelines 2015, but was admitted for use in the practical situation in the Japanese PAH guideline.11 As the results could be affected by the measurement methods of CO, further validation would be warranted.
Conclusion
This study demonstrated the effectiveness of triple oral combination therapy with macitentan, riociguat, and selexipag in patients with PAH. Our data suggest that this triple oral combination therapy is associated with improvement of hemodynamics, right ventricular function, and clinical function with good tolerability. In particular, this triple oral combination therapy can be a promising therapeutic strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further investigation is required to validate these findings.
Supplemental Material
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Supplemental material, sj-pdf-1-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-2-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-3-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-4-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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We thank all the doctors, nurses, and supporting medical staff members who were involved in the care of the patients enrolled in this study. We also thank Angela Morben, DVM, ELS, from Edanz Group (https://en-author-services.edanzgroup.com/ac), for editing a draft of this manuscript.
Author contribution(s): Mizuki Momoi: Data curation; Formal analysis; Investigation; Writing-original draft.
Takahiro Hiraide: Conceptualization; Methodology; Writing-review & editing.
Yoshiki Shinya: Conceptualization; Validation; Writing-review & editing.
Hiromi Momota: Data curation; Validation; Methodology; Writing-review & editing.
Shogo Fukui: Data curation; Validation; Formal analysis; Writing-review & editing.
Michiyuki Kawakami: Data curation; Validation; Formal analysis; Writing-review & editing.
Yuji Itabashi: Methodology; Data curation; Resources, Writing-review & editing.
Keiichi Fukuda: Supervision; Investigation; Writing-review & editing.
Masaharu Kataoka: Conceptualization; Project administration; Writing-review & editing.
Conflict of interest statement: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Masaharu Kataoka https://orcid.org/0000-0001-8034-1005
Supplemental material: Supplemental material for this article is available online. | AMBRISENTAN, FUROSEMIDE, MACITENTAN, RIOCIGUAT, SELEXIPAG | DrugsGivenReaction | CC BY-NC | 33627044 | 19,134,415 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'. | Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension.
The evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.
Among consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan-Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.
Twenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12-47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.
Triple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings.The reviews of this paper are available via the supplemental material section.
Introduction
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by elevated pulmonary arterial pressure (PAP) due to remodeling of the pulmonary arterial bed and right sided-heart failure. Three types of PAH-specific vasodilators targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway have been developed. Combination therapy targeting these different pathways has recently been shown to improve hemodynamics, clinical functions, and even hard endpoints including survival or worsening of PAH in several recent randomized controlled trials and metanalyses.1–5 The effectiveness of triple combination therapy targeting all three of these pathways has also been reported.6–8 However, two such studies analyzed patients who were treated with two types of oral vasodilators and prostacyclin infusion,7,8 and another study was a subgroup analysis of a randomized controlled trial demonstrating a change in the symptom burden by the addition of selexipag, a prostacyclin receptor agonist, to background double combination therapy targeting other pathways.6 Therefore, evidence of the efficacy and safety of triple oral combination therapy remains scarce.
The most recently approved PAH-specific vasodilators targeting each of the three types of pathways are macitentan, which is an endothelin receptor antagonist (ERA); riociguat, which is a soluble guanylate cyclase stimulator targeting the nitric oxide pathway; and selexipag, which is an oral non-prostanoid prostacyclin receptor agonist. All three of these are orally available drugs. The effectiveness of these vasodilators for PAH has recently been proven;2,3,9 however, no clinical trials have been performed to investigate the effectiveness of the combination of these three vasodilators. Furthermore, although the current guideline recommends initial oral therapy for patients with low or intermediate risk,10 how many patients with low or intermediate risk can actually be treated with only oral combination therapy remains poorly documented to date.
Therefore, the purposes of this study were to clarify the clinical effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag and to assess which risk groups can be adequately treated with this combination therapy.
Methods
Study design
This retrospective study was performed in Keio University Hospital in Japan. This study was approved by the Ethics Committee of Keio University Hospital, and written informed consent was obtained from all patients when they received genetic tests or were hospitalized. Patients with PAH who had received triple oral combination therapy with macitentan, riociguat, and selexipag were evaluated among all consecutive patients who were referred to Keio University Hospital from 2009 to 2020.
The diagnosis of PAH was made according to the current guideline.11 Patients who were lost to follow-up or underwent maintenance hemodialysis were excluded. Baseline data were measured at the time of referral to our hospital. If patients were treatment-naïve upon referral to our hospital, the combination of macitentan, riociguat, and selexipag was initiated after diagnosis. The method of up-titration and prioritization of the vasodilators as well as the selection of sequential therapy or upfront therapy was determined at the discretion of the specialized physicians. The doses of the vasodilators were titrated to the maximal tolerated doses. For patients who had already received other PAH-specific vasodilators at the time of enrollment, these drugs targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway were switched to macitentan, riociguat, and selexipag, respectively, with the intention of further improvement of hemodynamics.
Patients received genetic counseling, and genetic tests were performed with informed consent. The methods of the genetic tests, including whole-exome sequencing, are described in our previous reports.12,13
Parameters and outcomes
Dedicated cardiologists performed right-heart catheterization (RHC) without sedation at baseline and follow-up. The right arterial pressure, mean PAP, and pulmonary arterial wedge pressure were measured by RHC. The zero pressure point was set at the level of the midthorax. Cardiac output (CO) was calculated by the Fick technique using oxygen consumption estimated by 125 times the body surface area according to a previous report.14 Pulmonary vascular resistance (PVR) was calculated as the difference between the mean PAP and pulmonary arterial wedge pressure divided by the CO.
The 6-minute walk distance (6MWD), blood concentration of B-type natriuretic peptide (BNP), and World Health Organization functional class (WHO-FC) were measured at the time of hospitalization for RHC.
Standard two-dimensional, M-mode, and Doppler images, including the tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic excursion velocity (RVS’), were obtained by echocardiographers in accordance with the current echocardiography guideline.15 Dedicated cardiologists analyzed the data and measured the right atrial area (RAA), right ventricular end-diastolic area (RVEDA), right ventricular end-systolic area, and right ventricular fractional area change (RVFAC).
Hemodynamic changes measured by RHC, echocardiographic changes, and changes in the 6MWD, BNP concentration, and WHO-FC were assessed from baseline to follow-up.
The events of all-cause death, hospitalization for heart failure, initiation of prostacyclin infusion, and discontinuation of any of the three vasodilators (macitentan, riociguat, and selexipag) because of adverse events since administration of all three vasodilators were collected. The observation period was terminated when patients died, underwent prostacyclin infusion, or stopped taking macitentan, riociguat, or selexipag for any reason.
All patients enrolled in this study were divided into two groups by risk assessment using the three-category REVEAL 2.0 risk score,16 and the prostacyclin infusion-free rate was analyzed in each group. If the value was unmeasured, the value of zero was assigned. According to the three-category REVEAL 2.0 risk score, the high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), and the low-/intermediate-risk group was defined as patients with a predicted 1-year survival rate of ⩾90% (REVEAL 2.0 risk score ⩽8).
Subgroup analysis
Patients who were treatment-naïve at baseline and treated with only macitentan, riociguat, and selexipag for PAH were also independently assessed by subgroup analysis. Their hemodynamics, echocardiography, and clinical function were measured and clinical events were collected similarly to the overall patient analysis.
Statistical analysis
Data are described as median and interquartile range unless otherwise indicated. Wilcoxon’s signed rank test was used to compare the parameters of hemodynamics, echocardiography, 6MWD, and BNP concentration from baseline to the latest follow-up. The cases which had a missing value either at baseline or follow-up were excluded from each analysis. Differences with a p-value of <0.05 were considered statistically significant. All p-values were two-tailed. Event-free rates were analyzed using the Kaplan–Meier method. All analyses were performed using R software (version 3.6.3), and figures were obtained using GraphPad Prism (version 8.0 for Mac; GraphPad Software, La Jolla, CA, USA).
Results
Patient characteristics
The patients’ baseline characteristics and medications are presented in Table 1 and Supplemental material Table 1 online. One patient who was lost to follow-up and one patient who had been undergoing maintenance hemodialysis were excluded; thus, 26 patients were enrolled in this study. The patients were predominantly female (73.1%) with a median age of 38 years. The major etiology of PAH was idiopathic PAH (38.5%) followed by connective tissue disease-associated PAH (26.9%), heritable PAH (19.2%), and congenital heart disease-associated PAH (15.4%). Most patients were treatment-naïve (65.4%), and others were taking some PAH medications at baseline.
Table 1. Demographics and characteristics at baseline.
Variable Triple oral combination therapy
N = 26
Female 19 (73.1)
Age, years 38 (23–48)
WHO-FC
I/II/III/IV 0/9/16/1 (0.0/34.6/61.5/3.8)
BNP, pg/mL 105.25 (36.7–285.5)
6MWD, m 397.5 (312.8–441.8)
PAH etiology
IPAH 10 (38.5)
HPAH 5 (19.2)
CTD-PAH 7 (26.9)
CHD-PAH 4 (15.4)
Medication
Treatment-naïve 17 (65.4)
Single 3 (11.5)
Double 2 (7.7)
Triple 4 (15.4)
Risk assessment*
High risk 12 (46.2)
Intermediate risk 4 (15.4)
Low risk 10 (38.5)
Genetic mutation**
BMPR2 5 (23.8)
ACVRL 1 (4.8)
RNF213 1 (4.8)
Data are expressed as number (%) or median (interquartile range).
* Risk assessment was calculated using the three-category REVEAL 2.0 risk score.16 The high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), the intermediate-risk group was defined as patients with a predicted 1-year survival rate of 90–<95% (REVEAL 2.0 risk score = 7 or 8), and the low-risk group was defined as patients with a predicted 1-year survival rate of ⩾95% (REVEAL 2.0 risk score ⩽6).
** Among 26 patients, 21 were genetically tested and 15 had no genetic mutations related to PAH.
6MWD, 6-minute walk distance; ACVRL1, activin A receptor-like kinase 1; BMPR2, bone morphogenetic protein receptor type 2; BNP, B-type natriuretic peptide; CHD, congenital heart disease; CTD, connective tissue disease; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; RNF213, ring finger protein 213; WHO-FC, World Health Organization functional class.
Ten patients with idiopathic PAH, five with heritable PAH, three with connective tissue disease-associated PAH, and three with congenital heart disease-associated PAH were genetically tested. All five patients with heritable PAH had mutations in known PAH-related genes such as bone morphogenetic protein receptor type 2 (BMPR2) and one patient with idiopathic PAH had a mutation in ring finger protein 213 (RNF213), which we recently reported as a novel PAH-related gene.13,17
Safety and tolerability
Discontinuation of macitentan, riociguat, or selexipag because of adverse events occurred in four of 26 patients (15%). Among these four patients, one had diarrhea with selexipag, one had suspected myelosuppression with macitentan, one had nausea with riociguat, and one had hypotension with riociguat. These patients changed their drug to another drug targeting the same pathway. No adverse events, including death, hospitalization for heart failure, or prostacyclin infusion, were observed after discontinuation of each drug.
The maximum tolerated doses of the vasodilators are summarized in Supplemental Table 2. In detail, 25 (96.2%), 24 (92.3%), and 20 (76.9%) patients were taking the maximum dose of macitentan, riociguat, and selexipag, respectively. Seventeen (65.4%) patients reached the maximum dose of all three vasodilators.
Changes and outcomes after treatment
Hemodynamic data were available for 18 patients. The detailed study flow chart is shown in Supplemental Figure 1. The hemodynamics, WHO-FC, BNP concentration, and 6MWD at baseline and follow-up are presented in Table 2. The median observation period was 441 (229–1103) days. Hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 65% decrease in the mean PVR. The CO significantly increased by 82% from baseline to follow-up. Although >70% of patients had a WHO-FC of III or IV at baseline, 89% of patients had a WHO-FC of I or II at follow-up. The 6MWD and BNP concentration were also significantly improved [Figure 1(a)].
Table 2. Changes in clinical parameters.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 6.5 (4.0–8.0) 4.0 (3.0–5.0) −2.5 (−38) 0.005
Mean PAP, mmHg 56.0 (46.3–65.5) 40.0 (30.0–47.0) −16.0 (−29) <0.001
PAWP, mmHg 7.5 (6.0–9.8) 9.0 (8.0–11.0) 1.5 (20) 0.68
CO, L/min 3.3 (2.4–4.5) 6.0 (5.1–6.7) 2.7 (82) <0.001
CI, L/min per m2 2.2 (1.7–2.7) 3.8 (3.3–4.5) 1.6 (73) <0.001
PVR, WU 13.5 (8.8–21.5) 4.7 (2.8–6.9) −8.8 (−65) <0.001
Echocardiography
TAPSE, cm 1.5 (1.3–1.8) 2.3 (1.9–2.6) 0.8 (53) 0.001
RVS’, cm 9.7 (7.8–11.8) 13.3 (12.4–14.4) 3.6 (37) 0.001
RAA, cm2 17.2 (14.9–21.3) 16.4 (14.1–21.0) −0.8 (−5) 0.49
RVEDA, cm2 26.9 (22.8–33.1) 24.1 (21.0–30.3) −2.8 (−10) 0.21
RVESA, cm2 20.4 (16.3–23.9) 16.4 (13.8–21.1) −4.0 (−20) 0.006
FAC, % 23.6 (16.2–26.9) 32.9 (29.1–35.8) 9.3 (39) <0.001
WHO-FC
I or II 4 (22) 16 (89) – –
III or IV 14 (78) 2 (11) – –
6MWD, m 405.0 (303.0–441.8) 472.0 (439.5–493.5) 67.0 (17) 0.046
BNP, pg/mL 187.8 (36.7–379.5) 17.5 (10.3–27.2) −170.3 (−91) <0.001
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Eighteen patients were analyzed in hemodynamics, and 20 patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 1. Hemodynamic and echocardiographic changes.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Echocardiographic data were available for 20 patients (Supplemental Figure 1). The echocardiographic data are presented in Table 2. The median follow-up period was 737 (256–1179) days. Right ventricular function based on the TAPSE, RVS’, and RVFAC was significantly improved from baseline to follow-up, although the RAA and RVEDA were not [Figure 1(b)].
The Kaplan–Meier curves since administration of all three vasodilators are shown in Figure 2. The 1- and 2-year survival rates were both 93.3%. One patient died of multiple organ failure after femoral neck fracture during the observation period. The overall survival rate was 92.3% with median follow-up period of 33 (24–43) months. No patients were hospitalized for heart failure during the observation period. Prostacyclin infusion was initiated in six patients (25.4%) within 1 year. Among these six patients, selexipag was switched to subcutaneous infusion of treprostinil in one patient, an intravenous infusion of epoprostenol was added to the triple oral combination therapy in another patient, and a subcutaneous infusion of treprostinil was added to the triple oral combination therapy in the remaining four patients. Selexipag was not discontinued in some patients to reduce maintenance dose of the prostacyclin for infusion. No other patients underwent prostacyclin infusion after 1 year. Among six patients who underwent prostacyclin infusion within 1 year, three patients had a BMPR2 mutation, one patient had an RNF213 mutation, and one patient had Eisenmenger syndrome due to an atrial septal defect. Composite events of all-cause death, hospitalization for heart failure, and initiation of prostacyclin infusion occurred in 16.6% of the patients within 6 months and 30.4% of the patients in 1 and 2 years.
Figure 2. Event-free rates in all patients with triple oral combination therapy.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy are shown (n = 26). The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Among 14 patients who were classified as low-/intermediate-risk by the three-category REVEAL 2.0 risk score,16 the prostacyclin-free rate was 92.9% at 3 years, while the rate was 55.0% at 2 years in 12 high-risk patients (Figure 3). The difference was not statistically significant (p = 0.058). Hemodynamic changes from baseline to follow-up in each low/intermediate and high-risk group are summarized in Supplemental Table 3. Among five patients who were classified as high-risk based on the three-category REVEAL 2.0 risk score and needed prostacyclin infusion, three patients had BMPR2 mutations and one patient had a RNF213 mutation.
Figure 3. Kaplan–Meier curve for prostacyclin-free rate in each risk category.
The prostacyclin infusion-free rates in each risk category are shown. The patients were divided into two risk categories by the REVEAL 2.0 risk score.16 The p-values were calculated by the log-rank test.
Subgroup analysis in treatment-naïve patients
Seventeen patients were treatment-naïve at baseline. Six patients were treatment naïve at baseline, but treated with other pulmonary vasodilators. In five out of these six patients, oral medication was switched from beraprost to selexipag, and in one patient, it was switched from ambrisentan and tadalafil to macitentan and riociguat. Thus, these six patients were excluded from the subgroup analysis. Among the remaining 11 patients for the subgroup analysis, the median time from initiation of the first PAH drug to the start of the third PAH drug was 24 (12–47) days. The way of up-titration in treatment naïve patients was as follows. Macitentan 10 mg was initiated at first and followed by riociguat 3.0 mg within 2 weeks. The dose of riociguat was up-titrated by 1.5 mg every 2 weeks with attention to adverse effects. In 36% of treatment naïve patients, selexipag was initiated after riociguat was up-titrated to maximum tolerated dose, whereas selexipag was started within 2 weeks from initiating macitentan in 64% of patients. Selexipag was increased by 0.4 mg every 2 weeks to maximum tolerated dose with attention to side effects. One patient (9.1%) discontinued macitentan because of suspected myelosuppression, and another patient (9.1%) discontinued riociguat because of nausea. RHC data in 10 patients and echocardiographic data in nine patients were available at baseline and at follow-up during the triple oral combination therapy. The patients’ hemodynamic and right ventricular function parameters are presented in Table 3 and Figure 4. The median follow-up period of the hemodynamic analysis was 293 (211–473) days. The hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 66% decrease in the PVR. The CO increased by 90% from baseline to follow-up. The median follow-up period of echocardiography was 385 (230–594) days. The TAPSE, RVS’, and RVFAC, indicating right ventricular function, increased significantly. The WHO-FC, 6MWD, and BNP concentration in this subgroup also improved significantly. In the Kaplan–Meier analysis, no patients died or were hospitalized for heart failure (Figure 5). Prostacyclin infusion was initiated in 31.8% of patients within 7 months, and no patients underwent prostacyclin infusion after 7 months.
Table 3. Changes in clinical parameters among treatment-naïve patients at baseline.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 7.5 (4.3–8.8) 4.0 (3.3–5.0) −3.5 (−47) 0.022
Mean PAP, mmHg 63.0 (55.0–75.8) 44.5 (37.0–51.5) −18.5 (−29) 0.006
PAWP, mmHg 7.5 (6.3–9.8) 8.0 (6.5–10.3) 0.5 (7) 0.61
CO, L/min 3.1 (2.4–4.3) 5.9 (5.1–7.2) 2.8 (90) 0.006
CI, L/min per m2 2.1 (1.7–2.5) 4.2 (3.5–4.6) 2.1 (100) 0.006
PVR, WU 17.5 (13.2–21.9) 5.9 (3.8–9.6) −11.6 (−66) 0.006
Echocardiography
TAPSE, cm 1.4 (1.3–1.5) 2.3 (2.1–2.7) 0.9 (64) 0.009
RVS’, cm 9.3 (7.9–10.8) 13.5 (13.0–14.3) 4.2 (45) 0.035
RAA, cm2 18.5 (15.0–21.1) 15.2 (13.5–16.7) −3.3 (−18) 0.076
RVEDA, cm2 27.0 (25.0–33.2) 23.6 (21.0–24.6) −3.4 (−13) 0.058
RVESA, cm2 22.9 (18.7–25.4) 14.8 (14.0–16.8) −8.1 (−35) 0.009
FAC, % 22.9 (15.9–25.2) 33.1 (29.5–35.0) 10.2 (45) 0.018
WHO-FC
I or II 1 (10) 8 (80)
III or IV 9 (90) 2 (20)
6MWD, m 400.0 (326.5–432.0) 471.5 (451.5–479.2) 71.5 (18) 0.030
BNP, pg/mL 200.8 (41.9–379.5) 20.2 (12.6–24.5) −180.6 (−90) 0.006
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Ten patients were analyzed in hemodynamics, and nine patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 4. Hemodynamic and echocardiographic changes in treatment-naïve patients.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Figure 5. Event-free rates in treatment-naïve patients.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy in treatment-naïve patients are shown. The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite endpoint of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Discussion
In the present study, triple oral combination therapy with macitentan, riociguat, and selexipag improved the hemodynamics, right ventricular function, and clinical function with good tolerability in patients with PAH. Most of the low-/intermediate-risk patients and around half of the high-risk patients could be treated sufficiently with this triple oral combination therapy although it is difficult to generalize these findings.
Two previous studies investigated the efficacy of the combination of prostacyclin infusion, an ERA, and a phosphodiesterase-5 inhibitor (PDE-5i) for PAH,7,8 but data regarding triple oral combination therapy are limited. One study related to triple oral combination therapy is the subgroup analysis of the GRIPHON study, which demonstrated a change in the symptom burden after administration of selexipag in addition to an ERA and PDE-5i.6 Recently, a randomized control study (TRITON study) is also under analysis which investigated the efficacy and safety of triple oral combination therapy with macitentan, tadalafil, and selexipag versus dual oral combination therapy with macitentan and tadalafil.18 The present study is the first to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag using real-world data.
Our results of improved hemodynamics are consistent with previous observational studies that investigated the effectiveness of triple combination therapy including prostacyclin infusion.7 Sitbon et al.7 reported that with intravenous administration of epoprostenol and oral administration of bosentan and sildenafil, the mean PAP, PVR, and cardiac index improved by 33%, 71%, and 119%, respectively. Another observational study involving a combination of ambrisentan, tadalafil, and subcutaneous treprostinil also demonstrated significant improvement of the mean PAP, PVR, and cardiac index by 30%, 66%, and 94%, respectively.8 There are similarities between the results of these previous studies and the results of the present study, suggesting that triple oral combination therapy with macitentan, riociguat, and selexipag can powerfully improve the hemodynamics in patients with PAH. In the TRITON study, triple oral combination therapy improved PVR by 54%, although it was almost the same degree as dual oral combination therapy.18 Improvement of hemodynamic in this study was greater than that of the TRITON study, partly because of the difference of the study design. Although findings from observational study, results in this study provided the possibility that triple oral combination therapy could also improve hemodynamics in the real-world population as well as the randomized controlled trial.
Our study also demonstrated a favorable long-term prognosis as well as improvement of the RVFAC, 6MWD, WHO-FC, and BNP concentration with triple oral combination therapy. In a past retrospective study of the dual combination of an ERA and PDE-5i, the 3-year overall survival rate was nearly 80%.19 In another French registry in which most patients were treated with monotherapy, the 3-year survival rate was <70%.20 The prognosis in the present study appears to be superior to that in previous reports. The low rate of mortality and hospitalization for heart failure was consistent with the TRITON study, in which the risk of first disease progression events was decreased about 41% in the triple oral therapy group.18 These results in this study could verify the efficacy of triple oral combination therapy in preventing disease progression of triple oral combination therapy found in the randomized controlled study.
In the present study, the treatment response in most of the low-/intermediate-risk patients was favorable with administration of the triple oral combination therapy, and around half of the high-risk patients did not need prostacyclin infusion. The current PAH guideline recommends initial oral therapy for low-/intermediate-risk patients, while high-risk patients are recommended to receive initial combination therapy including prostacyclin infusion.10 Patients in this study did not present decompensated heart failure and the urgent initiation of prostacyclin infusion was not necessary. Therefore, the triple oral combination therapy was initiated first and its efficacy was assessed within 6 months. Our data support recommendations in guidelines in low-/intermediate-risk patients and provide a novel possibility that around half of high-risk patients can be treated without prostacyclin infusion. Moreover, 66.7% of the patients who needed prostacyclin infusion had gene mutations, suggesting that the need for prostacyclin infusion can be largely affected by their genetic background. Therefore, we should be especially careful when we use triple oral combination therapy to treat patients with specific etiologies of PAH such as gene mutations.
With respect to safety, a past study investigating the combination of tadalafil as a PDE-5i and ambrisentan as an ERA showed that the discontinuation rate of dual combination therapy because of adverse events was 12% within 2 years of the mean duration of drug use.1 In the subgroup analysis of the GRIPHON study, which investigated the effectiveness of selexipag for the patients of PAH, a triple oral combination therapy with selexipag, ERA, and PDE-5i was discontinued in 19.0% of patients due to adverse events.6 The rate of 15% in the present study was lower than that of the GRIPHON study, suggesting good tolerability in real world data. With regard to the maximum tolerated dose, a past subgroup analysis that investigated the change in the symptom burden after taking selexipag in addition to an ERA and PDE-5i showed that only 27.9% of patients who received selexipag reached the maximum dose of selexipag.6 Another study of the combination of riociguat and macitentan showed that about 70% of patients reached the maximum maintenance dose of riociguat. In the present study, 76.9% and 92.3% of patients could be up-titrated to the maximum dose with selexipag and riociguat, respectively. Thus, this study demonstrated that it is quite possible to up-titrate each drug to the maximum dose, even in patients treated with triple oral combination therapy.
The subgroup analysis showed that the hemodynamics, right ventricular function, and clinical function powerfully improved, and the degree of improvement was similar to those in the overall patient analysis. Moreover, no patients died or were hospitalized for heart failure during the observation period. These results suggest that triple oral combination therapy with macitentan, riociguat, and selexipag can be a promising treatment strategy in treatment-naïve patients.
This study has some limitations. This was a small, single-center, retrospective study that included various types of PAH and some patients were not treatment naïve at baseline. Each etiology of PAH might have affected the results of the study differently. Prostacyclin infusion was initiated within 7 months, and no patients underwent prostacyclin infusion after 7 months, which is towards a bias of an initial high-risk population of patients in which initial triple oral combination treatment was chosen. The drug regimens were decided by the physicians. Furthermore, indirect Fick method was adopted as the measurement of CO. This was not recommended in the European Society of Cardiology/European Respiratory Society Guidelines 2015, but was admitted for use in the practical situation in the Japanese PAH guideline.11 As the results could be affected by the measurement methods of CO, further validation would be warranted.
Conclusion
This study demonstrated the effectiveness of triple oral combination therapy with macitentan, riociguat, and selexipag in patients with PAH. Our data suggest that this triple oral combination therapy is associated with improvement of hemodynamics, right ventricular function, and clinical function with good tolerability. In particular, this triple oral combination therapy can be a promising therapeutic strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further investigation is required to validate these findings.
Supplemental Material
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sj-tif-6-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
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Supplemental material, sj-tif-6-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
We thank all the doctors, nurses, and supporting medical staff members who were involved in the care of the patients enrolled in this study. We also thank Angela Morben, DVM, ELS, from Edanz Group (https://en-author-services.edanzgroup.com/ac), for editing a draft of this manuscript.
Author contribution(s): Mizuki Momoi: Data curation; Formal analysis; Investigation; Writing-original draft.
Takahiro Hiraide: Conceptualization; Methodology; Writing-review & editing.
Yoshiki Shinya: Conceptualization; Validation; Writing-review & editing.
Hiromi Momota: Data curation; Validation; Methodology; Writing-review & editing.
Shogo Fukui: Data curation; Validation; Formal analysis; Writing-review & editing.
Michiyuki Kawakami: Data curation; Validation; Formal analysis; Writing-review & editing.
Yuji Itabashi: Methodology; Data curation; Resources, Writing-review & editing.
Keiichi Fukuda: Supervision; Investigation; Writing-review & editing.
Masaharu Kataoka: Conceptualization; Project administration; Writing-review & editing.
Conflict of interest statement: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Masaharu Kataoka https://orcid.org/0000-0001-8034-1005
Supplemental material: Supplemental material for this article is available online. | AMBRISENTAN, FUROSEMIDE, MACITENTAN, RIOCIGUAT, SELEXIPAG | DrugsGivenReaction | CC BY-NC | 33627044 | 19,134,415 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'White blood cell count decreased'. | Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension.
The evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.
Among consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan-Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.
Twenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12-47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.
Triple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings.The reviews of this paper are available via the supplemental material section.
Introduction
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by elevated pulmonary arterial pressure (PAP) due to remodeling of the pulmonary arterial bed and right sided-heart failure. Three types of PAH-specific vasodilators targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway have been developed. Combination therapy targeting these different pathways has recently been shown to improve hemodynamics, clinical functions, and even hard endpoints including survival or worsening of PAH in several recent randomized controlled trials and metanalyses.1–5 The effectiveness of triple combination therapy targeting all three of these pathways has also been reported.6–8 However, two such studies analyzed patients who were treated with two types of oral vasodilators and prostacyclin infusion,7,8 and another study was a subgroup analysis of a randomized controlled trial demonstrating a change in the symptom burden by the addition of selexipag, a prostacyclin receptor agonist, to background double combination therapy targeting other pathways.6 Therefore, evidence of the efficacy and safety of triple oral combination therapy remains scarce.
The most recently approved PAH-specific vasodilators targeting each of the three types of pathways are macitentan, which is an endothelin receptor antagonist (ERA); riociguat, which is a soluble guanylate cyclase stimulator targeting the nitric oxide pathway; and selexipag, which is an oral non-prostanoid prostacyclin receptor agonist. All three of these are orally available drugs. The effectiveness of these vasodilators for PAH has recently been proven;2,3,9 however, no clinical trials have been performed to investigate the effectiveness of the combination of these three vasodilators. Furthermore, although the current guideline recommends initial oral therapy for patients with low or intermediate risk,10 how many patients with low or intermediate risk can actually be treated with only oral combination therapy remains poorly documented to date.
Therefore, the purposes of this study were to clarify the clinical effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag and to assess which risk groups can be adequately treated with this combination therapy.
Methods
Study design
This retrospective study was performed in Keio University Hospital in Japan. This study was approved by the Ethics Committee of Keio University Hospital, and written informed consent was obtained from all patients when they received genetic tests or were hospitalized. Patients with PAH who had received triple oral combination therapy with macitentan, riociguat, and selexipag were evaluated among all consecutive patients who were referred to Keio University Hospital from 2009 to 2020.
The diagnosis of PAH was made according to the current guideline.11 Patients who were lost to follow-up or underwent maintenance hemodialysis were excluded. Baseline data were measured at the time of referral to our hospital. If patients were treatment-naïve upon referral to our hospital, the combination of macitentan, riociguat, and selexipag was initiated after diagnosis. The method of up-titration and prioritization of the vasodilators as well as the selection of sequential therapy or upfront therapy was determined at the discretion of the specialized physicians. The doses of the vasodilators were titrated to the maximal tolerated doses. For patients who had already received other PAH-specific vasodilators at the time of enrollment, these drugs targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway were switched to macitentan, riociguat, and selexipag, respectively, with the intention of further improvement of hemodynamics.
Patients received genetic counseling, and genetic tests were performed with informed consent. The methods of the genetic tests, including whole-exome sequencing, are described in our previous reports.12,13
Parameters and outcomes
Dedicated cardiologists performed right-heart catheterization (RHC) without sedation at baseline and follow-up. The right arterial pressure, mean PAP, and pulmonary arterial wedge pressure were measured by RHC. The zero pressure point was set at the level of the midthorax. Cardiac output (CO) was calculated by the Fick technique using oxygen consumption estimated by 125 times the body surface area according to a previous report.14 Pulmonary vascular resistance (PVR) was calculated as the difference between the mean PAP and pulmonary arterial wedge pressure divided by the CO.
The 6-minute walk distance (6MWD), blood concentration of B-type natriuretic peptide (BNP), and World Health Organization functional class (WHO-FC) were measured at the time of hospitalization for RHC.
Standard two-dimensional, M-mode, and Doppler images, including the tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic excursion velocity (RVS’), were obtained by echocardiographers in accordance with the current echocardiography guideline.15 Dedicated cardiologists analyzed the data and measured the right atrial area (RAA), right ventricular end-diastolic area (RVEDA), right ventricular end-systolic area, and right ventricular fractional area change (RVFAC).
Hemodynamic changes measured by RHC, echocardiographic changes, and changes in the 6MWD, BNP concentration, and WHO-FC were assessed from baseline to follow-up.
The events of all-cause death, hospitalization for heart failure, initiation of prostacyclin infusion, and discontinuation of any of the three vasodilators (macitentan, riociguat, and selexipag) because of adverse events since administration of all three vasodilators were collected. The observation period was terminated when patients died, underwent prostacyclin infusion, or stopped taking macitentan, riociguat, or selexipag for any reason.
All patients enrolled in this study were divided into two groups by risk assessment using the three-category REVEAL 2.0 risk score,16 and the prostacyclin infusion-free rate was analyzed in each group. If the value was unmeasured, the value of zero was assigned. According to the three-category REVEAL 2.0 risk score, the high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), and the low-/intermediate-risk group was defined as patients with a predicted 1-year survival rate of ⩾90% (REVEAL 2.0 risk score ⩽8).
Subgroup analysis
Patients who were treatment-naïve at baseline and treated with only macitentan, riociguat, and selexipag for PAH were also independently assessed by subgroup analysis. Their hemodynamics, echocardiography, and clinical function were measured and clinical events were collected similarly to the overall patient analysis.
Statistical analysis
Data are described as median and interquartile range unless otherwise indicated. Wilcoxon’s signed rank test was used to compare the parameters of hemodynamics, echocardiography, 6MWD, and BNP concentration from baseline to the latest follow-up. The cases which had a missing value either at baseline or follow-up were excluded from each analysis. Differences with a p-value of <0.05 were considered statistically significant. All p-values were two-tailed. Event-free rates were analyzed using the Kaplan–Meier method. All analyses were performed using R software (version 3.6.3), and figures were obtained using GraphPad Prism (version 8.0 for Mac; GraphPad Software, La Jolla, CA, USA).
Results
Patient characteristics
The patients’ baseline characteristics and medications are presented in Table 1 and Supplemental material Table 1 online. One patient who was lost to follow-up and one patient who had been undergoing maintenance hemodialysis were excluded; thus, 26 patients were enrolled in this study. The patients were predominantly female (73.1%) with a median age of 38 years. The major etiology of PAH was idiopathic PAH (38.5%) followed by connective tissue disease-associated PAH (26.9%), heritable PAH (19.2%), and congenital heart disease-associated PAH (15.4%). Most patients were treatment-naïve (65.4%), and others were taking some PAH medications at baseline.
Table 1. Demographics and characteristics at baseline.
Variable Triple oral combination therapy
N = 26
Female 19 (73.1)
Age, years 38 (23–48)
WHO-FC
I/II/III/IV 0/9/16/1 (0.0/34.6/61.5/3.8)
BNP, pg/mL 105.25 (36.7–285.5)
6MWD, m 397.5 (312.8–441.8)
PAH etiology
IPAH 10 (38.5)
HPAH 5 (19.2)
CTD-PAH 7 (26.9)
CHD-PAH 4 (15.4)
Medication
Treatment-naïve 17 (65.4)
Single 3 (11.5)
Double 2 (7.7)
Triple 4 (15.4)
Risk assessment*
High risk 12 (46.2)
Intermediate risk 4 (15.4)
Low risk 10 (38.5)
Genetic mutation**
BMPR2 5 (23.8)
ACVRL 1 (4.8)
RNF213 1 (4.8)
Data are expressed as number (%) or median (interquartile range).
* Risk assessment was calculated using the three-category REVEAL 2.0 risk score.16 The high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), the intermediate-risk group was defined as patients with a predicted 1-year survival rate of 90–<95% (REVEAL 2.0 risk score = 7 or 8), and the low-risk group was defined as patients with a predicted 1-year survival rate of ⩾95% (REVEAL 2.0 risk score ⩽6).
** Among 26 patients, 21 were genetically tested and 15 had no genetic mutations related to PAH.
6MWD, 6-minute walk distance; ACVRL1, activin A receptor-like kinase 1; BMPR2, bone morphogenetic protein receptor type 2; BNP, B-type natriuretic peptide; CHD, congenital heart disease; CTD, connective tissue disease; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; RNF213, ring finger protein 213; WHO-FC, World Health Organization functional class.
Ten patients with idiopathic PAH, five with heritable PAH, three with connective tissue disease-associated PAH, and three with congenital heart disease-associated PAH were genetically tested. All five patients with heritable PAH had mutations in known PAH-related genes such as bone morphogenetic protein receptor type 2 (BMPR2) and one patient with idiopathic PAH had a mutation in ring finger protein 213 (RNF213), which we recently reported as a novel PAH-related gene.13,17
Safety and tolerability
Discontinuation of macitentan, riociguat, or selexipag because of adverse events occurred in four of 26 patients (15%). Among these four patients, one had diarrhea with selexipag, one had suspected myelosuppression with macitentan, one had nausea with riociguat, and one had hypotension with riociguat. These patients changed their drug to another drug targeting the same pathway. No adverse events, including death, hospitalization for heart failure, or prostacyclin infusion, were observed after discontinuation of each drug.
The maximum tolerated doses of the vasodilators are summarized in Supplemental Table 2. In detail, 25 (96.2%), 24 (92.3%), and 20 (76.9%) patients were taking the maximum dose of macitentan, riociguat, and selexipag, respectively. Seventeen (65.4%) patients reached the maximum dose of all three vasodilators.
Changes and outcomes after treatment
Hemodynamic data were available for 18 patients. The detailed study flow chart is shown in Supplemental Figure 1. The hemodynamics, WHO-FC, BNP concentration, and 6MWD at baseline and follow-up are presented in Table 2. The median observation period was 441 (229–1103) days. Hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 65% decrease in the mean PVR. The CO significantly increased by 82% from baseline to follow-up. Although >70% of patients had a WHO-FC of III or IV at baseline, 89% of patients had a WHO-FC of I or II at follow-up. The 6MWD and BNP concentration were also significantly improved [Figure 1(a)].
Table 2. Changes in clinical parameters.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 6.5 (4.0–8.0) 4.0 (3.0–5.0) −2.5 (−38) 0.005
Mean PAP, mmHg 56.0 (46.3–65.5) 40.0 (30.0–47.0) −16.0 (−29) <0.001
PAWP, mmHg 7.5 (6.0–9.8) 9.0 (8.0–11.0) 1.5 (20) 0.68
CO, L/min 3.3 (2.4–4.5) 6.0 (5.1–6.7) 2.7 (82) <0.001
CI, L/min per m2 2.2 (1.7–2.7) 3.8 (3.3–4.5) 1.6 (73) <0.001
PVR, WU 13.5 (8.8–21.5) 4.7 (2.8–6.9) −8.8 (−65) <0.001
Echocardiography
TAPSE, cm 1.5 (1.3–1.8) 2.3 (1.9–2.6) 0.8 (53) 0.001
RVS’, cm 9.7 (7.8–11.8) 13.3 (12.4–14.4) 3.6 (37) 0.001
RAA, cm2 17.2 (14.9–21.3) 16.4 (14.1–21.0) −0.8 (−5) 0.49
RVEDA, cm2 26.9 (22.8–33.1) 24.1 (21.0–30.3) −2.8 (−10) 0.21
RVESA, cm2 20.4 (16.3–23.9) 16.4 (13.8–21.1) −4.0 (−20) 0.006
FAC, % 23.6 (16.2–26.9) 32.9 (29.1–35.8) 9.3 (39) <0.001
WHO-FC
I or II 4 (22) 16 (89) – –
III or IV 14 (78) 2 (11) – –
6MWD, m 405.0 (303.0–441.8) 472.0 (439.5–493.5) 67.0 (17) 0.046
BNP, pg/mL 187.8 (36.7–379.5) 17.5 (10.3–27.2) −170.3 (−91) <0.001
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Eighteen patients were analyzed in hemodynamics, and 20 patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 1. Hemodynamic and echocardiographic changes.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Echocardiographic data were available for 20 patients (Supplemental Figure 1). The echocardiographic data are presented in Table 2. The median follow-up period was 737 (256–1179) days. Right ventricular function based on the TAPSE, RVS’, and RVFAC was significantly improved from baseline to follow-up, although the RAA and RVEDA were not [Figure 1(b)].
The Kaplan–Meier curves since administration of all three vasodilators are shown in Figure 2. The 1- and 2-year survival rates were both 93.3%. One patient died of multiple organ failure after femoral neck fracture during the observation period. The overall survival rate was 92.3% with median follow-up period of 33 (24–43) months. No patients were hospitalized for heart failure during the observation period. Prostacyclin infusion was initiated in six patients (25.4%) within 1 year. Among these six patients, selexipag was switched to subcutaneous infusion of treprostinil in one patient, an intravenous infusion of epoprostenol was added to the triple oral combination therapy in another patient, and a subcutaneous infusion of treprostinil was added to the triple oral combination therapy in the remaining four patients. Selexipag was not discontinued in some patients to reduce maintenance dose of the prostacyclin for infusion. No other patients underwent prostacyclin infusion after 1 year. Among six patients who underwent prostacyclin infusion within 1 year, three patients had a BMPR2 mutation, one patient had an RNF213 mutation, and one patient had Eisenmenger syndrome due to an atrial septal defect. Composite events of all-cause death, hospitalization for heart failure, and initiation of prostacyclin infusion occurred in 16.6% of the patients within 6 months and 30.4% of the patients in 1 and 2 years.
Figure 2. Event-free rates in all patients with triple oral combination therapy.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy are shown (n = 26). The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Among 14 patients who were classified as low-/intermediate-risk by the three-category REVEAL 2.0 risk score,16 the prostacyclin-free rate was 92.9% at 3 years, while the rate was 55.0% at 2 years in 12 high-risk patients (Figure 3). The difference was not statistically significant (p = 0.058). Hemodynamic changes from baseline to follow-up in each low/intermediate and high-risk group are summarized in Supplemental Table 3. Among five patients who were classified as high-risk based on the three-category REVEAL 2.0 risk score and needed prostacyclin infusion, three patients had BMPR2 mutations and one patient had a RNF213 mutation.
Figure 3. Kaplan–Meier curve for prostacyclin-free rate in each risk category.
The prostacyclin infusion-free rates in each risk category are shown. The patients were divided into two risk categories by the REVEAL 2.0 risk score.16 The p-values were calculated by the log-rank test.
Subgroup analysis in treatment-naïve patients
Seventeen patients were treatment-naïve at baseline. Six patients were treatment naïve at baseline, but treated with other pulmonary vasodilators. In five out of these six patients, oral medication was switched from beraprost to selexipag, and in one patient, it was switched from ambrisentan and tadalafil to macitentan and riociguat. Thus, these six patients were excluded from the subgroup analysis. Among the remaining 11 patients for the subgroup analysis, the median time from initiation of the first PAH drug to the start of the third PAH drug was 24 (12–47) days. The way of up-titration in treatment naïve patients was as follows. Macitentan 10 mg was initiated at first and followed by riociguat 3.0 mg within 2 weeks. The dose of riociguat was up-titrated by 1.5 mg every 2 weeks with attention to adverse effects. In 36% of treatment naïve patients, selexipag was initiated after riociguat was up-titrated to maximum tolerated dose, whereas selexipag was started within 2 weeks from initiating macitentan in 64% of patients. Selexipag was increased by 0.4 mg every 2 weeks to maximum tolerated dose with attention to side effects. One patient (9.1%) discontinued macitentan because of suspected myelosuppression, and another patient (9.1%) discontinued riociguat because of nausea. RHC data in 10 patients and echocardiographic data in nine patients were available at baseline and at follow-up during the triple oral combination therapy. The patients’ hemodynamic and right ventricular function parameters are presented in Table 3 and Figure 4. The median follow-up period of the hemodynamic analysis was 293 (211–473) days. The hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 66% decrease in the PVR. The CO increased by 90% from baseline to follow-up. The median follow-up period of echocardiography was 385 (230–594) days. The TAPSE, RVS’, and RVFAC, indicating right ventricular function, increased significantly. The WHO-FC, 6MWD, and BNP concentration in this subgroup also improved significantly. In the Kaplan–Meier analysis, no patients died or were hospitalized for heart failure (Figure 5). Prostacyclin infusion was initiated in 31.8% of patients within 7 months, and no patients underwent prostacyclin infusion after 7 months.
Table 3. Changes in clinical parameters among treatment-naïve patients at baseline.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 7.5 (4.3–8.8) 4.0 (3.3–5.0) −3.5 (−47) 0.022
Mean PAP, mmHg 63.0 (55.0–75.8) 44.5 (37.0–51.5) −18.5 (−29) 0.006
PAWP, mmHg 7.5 (6.3–9.8) 8.0 (6.5–10.3) 0.5 (7) 0.61
CO, L/min 3.1 (2.4–4.3) 5.9 (5.1–7.2) 2.8 (90) 0.006
CI, L/min per m2 2.1 (1.7–2.5) 4.2 (3.5–4.6) 2.1 (100) 0.006
PVR, WU 17.5 (13.2–21.9) 5.9 (3.8–9.6) −11.6 (−66) 0.006
Echocardiography
TAPSE, cm 1.4 (1.3–1.5) 2.3 (2.1–2.7) 0.9 (64) 0.009
RVS’, cm 9.3 (7.9–10.8) 13.5 (13.0–14.3) 4.2 (45) 0.035
RAA, cm2 18.5 (15.0–21.1) 15.2 (13.5–16.7) −3.3 (−18) 0.076
RVEDA, cm2 27.0 (25.0–33.2) 23.6 (21.0–24.6) −3.4 (−13) 0.058
RVESA, cm2 22.9 (18.7–25.4) 14.8 (14.0–16.8) −8.1 (−35) 0.009
FAC, % 22.9 (15.9–25.2) 33.1 (29.5–35.0) 10.2 (45) 0.018
WHO-FC
I or II 1 (10) 8 (80)
III or IV 9 (90) 2 (20)
6MWD, m 400.0 (326.5–432.0) 471.5 (451.5–479.2) 71.5 (18) 0.030
BNP, pg/mL 200.8 (41.9–379.5) 20.2 (12.6–24.5) −180.6 (−90) 0.006
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Ten patients were analyzed in hemodynamics, and nine patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 4. Hemodynamic and echocardiographic changes in treatment-naïve patients.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Figure 5. Event-free rates in treatment-naïve patients.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy in treatment-naïve patients are shown. The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite endpoint of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Discussion
In the present study, triple oral combination therapy with macitentan, riociguat, and selexipag improved the hemodynamics, right ventricular function, and clinical function with good tolerability in patients with PAH. Most of the low-/intermediate-risk patients and around half of the high-risk patients could be treated sufficiently with this triple oral combination therapy although it is difficult to generalize these findings.
Two previous studies investigated the efficacy of the combination of prostacyclin infusion, an ERA, and a phosphodiesterase-5 inhibitor (PDE-5i) for PAH,7,8 but data regarding triple oral combination therapy are limited. One study related to triple oral combination therapy is the subgroup analysis of the GRIPHON study, which demonstrated a change in the symptom burden after administration of selexipag in addition to an ERA and PDE-5i.6 Recently, a randomized control study (TRITON study) is also under analysis which investigated the efficacy and safety of triple oral combination therapy with macitentan, tadalafil, and selexipag versus dual oral combination therapy with macitentan and tadalafil.18 The present study is the first to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag using real-world data.
Our results of improved hemodynamics are consistent with previous observational studies that investigated the effectiveness of triple combination therapy including prostacyclin infusion.7 Sitbon et al.7 reported that with intravenous administration of epoprostenol and oral administration of bosentan and sildenafil, the mean PAP, PVR, and cardiac index improved by 33%, 71%, and 119%, respectively. Another observational study involving a combination of ambrisentan, tadalafil, and subcutaneous treprostinil also demonstrated significant improvement of the mean PAP, PVR, and cardiac index by 30%, 66%, and 94%, respectively.8 There are similarities between the results of these previous studies and the results of the present study, suggesting that triple oral combination therapy with macitentan, riociguat, and selexipag can powerfully improve the hemodynamics in patients with PAH. In the TRITON study, triple oral combination therapy improved PVR by 54%, although it was almost the same degree as dual oral combination therapy.18 Improvement of hemodynamic in this study was greater than that of the TRITON study, partly because of the difference of the study design. Although findings from observational study, results in this study provided the possibility that triple oral combination therapy could also improve hemodynamics in the real-world population as well as the randomized controlled trial.
Our study also demonstrated a favorable long-term prognosis as well as improvement of the RVFAC, 6MWD, WHO-FC, and BNP concentration with triple oral combination therapy. In a past retrospective study of the dual combination of an ERA and PDE-5i, the 3-year overall survival rate was nearly 80%.19 In another French registry in which most patients were treated with monotherapy, the 3-year survival rate was <70%.20 The prognosis in the present study appears to be superior to that in previous reports. The low rate of mortality and hospitalization for heart failure was consistent with the TRITON study, in which the risk of first disease progression events was decreased about 41% in the triple oral therapy group.18 These results in this study could verify the efficacy of triple oral combination therapy in preventing disease progression of triple oral combination therapy found in the randomized controlled study.
In the present study, the treatment response in most of the low-/intermediate-risk patients was favorable with administration of the triple oral combination therapy, and around half of the high-risk patients did not need prostacyclin infusion. The current PAH guideline recommends initial oral therapy for low-/intermediate-risk patients, while high-risk patients are recommended to receive initial combination therapy including prostacyclin infusion.10 Patients in this study did not present decompensated heart failure and the urgent initiation of prostacyclin infusion was not necessary. Therefore, the triple oral combination therapy was initiated first and its efficacy was assessed within 6 months. Our data support recommendations in guidelines in low-/intermediate-risk patients and provide a novel possibility that around half of high-risk patients can be treated without prostacyclin infusion. Moreover, 66.7% of the patients who needed prostacyclin infusion had gene mutations, suggesting that the need for prostacyclin infusion can be largely affected by their genetic background. Therefore, we should be especially careful when we use triple oral combination therapy to treat patients with specific etiologies of PAH such as gene mutations.
With respect to safety, a past study investigating the combination of tadalafil as a PDE-5i and ambrisentan as an ERA showed that the discontinuation rate of dual combination therapy because of adverse events was 12% within 2 years of the mean duration of drug use.1 In the subgroup analysis of the GRIPHON study, which investigated the effectiveness of selexipag for the patients of PAH, a triple oral combination therapy with selexipag, ERA, and PDE-5i was discontinued in 19.0% of patients due to adverse events.6 The rate of 15% in the present study was lower than that of the GRIPHON study, suggesting good tolerability in real world data. With regard to the maximum tolerated dose, a past subgroup analysis that investigated the change in the symptom burden after taking selexipag in addition to an ERA and PDE-5i showed that only 27.9% of patients who received selexipag reached the maximum dose of selexipag.6 Another study of the combination of riociguat and macitentan showed that about 70% of patients reached the maximum maintenance dose of riociguat. In the present study, 76.9% and 92.3% of patients could be up-titrated to the maximum dose with selexipag and riociguat, respectively. Thus, this study demonstrated that it is quite possible to up-titrate each drug to the maximum dose, even in patients treated with triple oral combination therapy.
The subgroup analysis showed that the hemodynamics, right ventricular function, and clinical function powerfully improved, and the degree of improvement was similar to those in the overall patient analysis. Moreover, no patients died or were hospitalized for heart failure during the observation period. These results suggest that triple oral combination therapy with macitentan, riociguat, and selexipag can be a promising treatment strategy in treatment-naïve patients.
This study has some limitations. This was a small, single-center, retrospective study that included various types of PAH and some patients were not treatment naïve at baseline. Each etiology of PAH might have affected the results of the study differently. Prostacyclin infusion was initiated within 7 months, and no patients underwent prostacyclin infusion after 7 months, which is towards a bias of an initial high-risk population of patients in which initial triple oral combination treatment was chosen. The drug regimens were decided by the physicians. Furthermore, indirect Fick method was adopted as the measurement of CO. This was not recommended in the European Society of Cardiology/European Respiratory Society Guidelines 2015, but was admitted for use in the practical situation in the Japanese PAH guideline.11 As the results could be affected by the measurement methods of CO, further validation would be warranted.
Conclusion
This study demonstrated the effectiveness of triple oral combination therapy with macitentan, riociguat, and selexipag in patients with PAH. Our data suggest that this triple oral combination therapy is associated with improvement of hemodynamics, right ventricular function, and clinical function with good tolerability. In particular, this triple oral combination therapy can be a promising therapeutic strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further investigation is required to validate these findings.
Supplemental Material
sj-pdf-1-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-1-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-2-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Click here for additional data file.
Supplemental material, sj-pdf-3-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-4-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-5-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-7-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-tif-6-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
We thank all the doctors, nurses, and supporting medical staff members who were involved in the care of the patients enrolled in this study. We also thank Angela Morben, DVM, ELS, from Edanz Group (https://en-author-services.edanzgroup.com/ac), for editing a draft of this manuscript.
Author contribution(s): Mizuki Momoi: Data curation; Formal analysis; Investigation; Writing-original draft.
Takahiro Hiraide: Conceptualization; Methodology; Writing-review & editing.
Yoshiki Shinya: Conceptualization; Validation; Writing-review & editing.
Hiromi Momota: Data curation; Validation; Methodology; Writing-review & editing.
Shogo Fukui: Data curation; Validation; Formal analysis; Writing-review & editing.
Michiyuki Kawakami: Data curation; Validation; Formal analysis; Writing-review & editing.
Yuji Itabashi: Methodology; Data curation; Resources, Writing-review & editing.
Keiichi Fukuda: Supervision; Investigation; Writing-review & editing.
Masaharu Kataoka: Conceptualization; Project administration; Writing-review & editing.
Conflict of interest statement: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Masaharu Kataoka https://orcid.org/0000-0001-8034-1005
Supplemental material: Supplemental material for this article is available online. | AMBRISENTAN, FUROSEMIDE, MACITENTAN, RIOCIGUAT, SELEXIPAG | DrugsGivenReaction | CC BY-NC | 33627044 | 19,134,415 | 2021 |
What was the administration route of drug 'FUROSEMIDE'? | Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension.
The evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.
Among consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan-Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.
Twenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12-47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.
Triple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings.The reviews of this paper are available via the supplemental material section.
Introduction
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by elevated pulmonary arterial pressure (PAP) due to remodeling of the pulmonary arterial bed and right sided-heart failure. Three types of PAH-specific vasodilators targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway have been developed. Combination therapy targeting these different pathways has recently been shown to improve hemodynamics, clinical functions, and even hard endpoints including survival or worsening of PAH in several recent randomized controlled trials and metanalyses.1–5 The effectiveness of triple combination therapy targeting all three of these pathways has also been reported.6–8 However, two such studies analyzed patients who were treated with two types of oral vasodilators and prostacyclin infusion,7,8 and another study was a subgroup analysis of a randomized controlled trial demonstrating a change in the symptom burden by the addition of selexipag, a prostacyclin receptor agonist, to background double combination therapy targeting other pathways.6 Therefore, evidence of the efficacy and safety of triple oral combination therapy remains scarce.
The most recently approved PAH-specific vasodilators targeting each of the three types of pathways are macitentan, which is an endothelin receptor antagonist (ERA); riociguat, which is a soluble guanylate cyclase stimulator targeting the nitric oxide pathway; and selexipag, which is an oral non-prostanoid prostacyclin receptor agonist. All three of these are orally available drugs. The effectiveness of these vasodilators for PAH has recently been proven;2,3,9 however, no clinical trials have been performed to investigate the effectiveness of the combination of these three vasodilators. Furthermore, although the current guideline recommends initial oral therapy for patients with low or intermediate risk,10 how many patients with low or intermediate risk can actually be treated with only oral combination therapy remains poorly documented to date.
Therefore, the purposes of this study were to clarify the clinical effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag and to assess which risk groups can be adequately treated with this combination therapy.
Methods
Study design
This retrospective study was performed in Keio University Hospital in Japan. This study was approved by the Ethics Committee of Keio University Hospital, and written informed consent was obtained from all patients when they received genetic tests or were hospitalized. Patients with PAH who had received triple oral combination therapy with macitentan, riociguat, and selexipag were evaluated among all consecutive patients who were referred to Keio University Hospital from 2009 to 2020.
The diagnosis of PAH was made according to the current guideline.11 Patients who were lost to follow-up or underwent maintenance hemodialysis were excluded. Baseline data were measured at the time of referral to our hospital. If patients were treatment-naïve upon referral to our hospital, the combination of macitentan, riociguat, and selexipag was initiated after diagnosis. The method of up-titration and prioritization of the vasodilators as well as the selection of sequential therapy or upfront therapy was determined at the discretion of the specialized physicians. The doses of the vasodilators were titrated to the maximal tolerated doses. For patients who had already received other PAH-specific vasodilators at the time of enrollment, these drugs targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway were switched to macitentan, riociguat, and selexipag, respectively, with the intention of further improvement of hemodynamics.
Patients received genetic counseling, and genetic tests were performed with informed consent. The methods of the genetic tests, including whole-exome sequencing, are described in our previous reports.12,13
Parameters and outcomes
Dedicated cardiologists performed right-heart catheterization (RHC) without sedation at baseline and follow-up. The right arterial pressure, mean PAP, and pulmonary arterial wedge pressure were measured by RHC. The zero pressure point was set at the level of the midthorax. Cardiac output (CO) was calculated by the Fick technique using oxygen consumption estimated by 125 times the body surface area according to a previous report.14 Pulmonary vascular resistance (PVR) was calculated as the difference between the mean PAP and pulmonary arterial wedge pressure divided by the CO.
The 6-minute walk distance (6MWD), blood concentration of B-type natriuretic peptide (BNP), and World Health Organization functional class (WHO-FC) were measured at the time of hospitalization for RHC.
Standard two-dimensional, M-mode, and Doppler images, including the tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic excursion velocity (RVS’), were obtained by echocardiographers in accordance with the current echocardiography guideline.15 Dedicated cardiologists analyzed the data and measured the right atrial area (RAA), right ventricular end-diastolic area (RVEDA), right ventricular end-systolic area, and right ventricular fractional area change (RVFAC).
Hemodynamic changes measured by RHC, echocardiographic changes, and changes in the 6MWD, BNP concentration, and WHO-FC were assessed from baseline to follow-up.
The events of all-cause death, hospitalization for heart failure, initiation of prostacyclin infusion, and discontinuation of any of the three vasodilators (macitentan, riociguat, and selexipag) because of adverse events since administration of all three vasodilators were collected. The observation period was terminated when patients died, underwent prostacyclin infusion, or stopped taking macitentan, riociguat, or selexipag for any reason.
All patients enrolled in this study were divided into two groups by risk assessment using the three-category REVEAL 2.0 risk score,16 and the prostacyclin infusion-free rate was analyzed in each group. If the value was unmeasured, the value of zero was assigned. According to the three-category REVEAL 2.0 risk score, the high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), and the low-/intermediate-risk group was defined as patients with a predicted 1-year survival rate of ⩾90% (REVEAL 2.0 risk score ⩽8).
Subgroup analysis
Patients who were treatment-naïve at baseline and treated with only macitentan, riociguat, and selexipag for PAH were also independently assessed by subgroup analysis. Their hemodynamics, echocardiography, and clinical function were measured and clinical events were collected similarly to the overall patient analysis.
Statistical analysis
Data are described as median and interquartile range unless otherwise indicated. Wilcoxon’s signed rank test was used to compare the parameters of hemodynamics, echocardiography, 6MWD, and BNP concentration from baseline to the latest follow-up. The cases which had a missing value either at baseline or follow-up were excluded from each analysis. Differences with a p-value of <0.05 were considered statistically significant. All p-values were two-tailed. Event-free rates were analyzed using the Kaplan–Meier method. All analyses were performed using R software (version 3.6.3), and figures were obtained using GraphPad Prism (version 8.0 for Mac; GraphPad Software, La Jolla, CA, USA).
Results
Patient characteristics
The patients’ baseline characteristics and medications are presented in Table 1 and Supplemental material Table 1 online. One patient who was lost to follow-up and one patient who had been undergoing maintenance hemodialysis were excluded; thus, 26 patients were enrolled in this study. The patients were predominantly female (73.1%) with a median age of 38 years. The major etiology of PAH was idiopathic PAH (38.5%) followed by connective tissue disease-associated PAH (26.9%), heritable PAH (19.2%), and congenital heart disease-associated PAH (15.4%). Most patients were treatment-naïve (65.4%), and others were taking some PAH medications at baseline.
Table 1. Demographics and characteristics at baseline.
Variable Triple oral combination therapy
N = 26
Female 19 (73.1)
Age, years 38 (23–48)
WHO-FC
I/II/III/IV 0/9/16/1 (0.0/34.6/61.5/3.8)
BNP, pg/mL 105.25 (36.7–285.5)
6MWD, m 397.5 (312.8–441.8)
PAH etiology
IPAH 10 (38.5)
HPAH 5 (19.2)
CTD-PAH 7 (26.9)
CHD-PAH 4 (15.4)
Medication
Treatment-naïve 17 (65.4)
Single 3 (11.5)
Double 2 (7.7)
Triple 4 (15.4)
Risk assessment*
High risk 12 (46.2)
Intermediate risk 4 (15.4)
Low risk 10 (38.5)
Genetic mutation**
BMPR2 5 (23.8)
ACVRL 1 (4.8)
RNF213 1 (4.8)
Data are expressed as number (%) or median (interquartile range).
* Risk assessment was calculated using the three-category REVEAL 2.0 risk score.16 The high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), the intermediate-risk group was defined as patients with a predicted 1-year survival rate of 90–<95% (REVEAL 2.0 risk score = 7 or 8), and the low-risk group was defined as patients with a predicted 1-year survival rate of ⩾95% (REVEAL 2.0 risk score ⩽6).
** Among 26 patients, 21 were genetically tested and 15 had no genetic mutations related to PAH.
6MWD, 6-minute walk distance; ACVRL1, activin A receptor-like kinase 1; BMPR2, bone morphogenetic protein receptor type 2; BNP, B-type natriuretic peptide; CHD, congenital heart disease; CTD, connective tissue disease; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; RNF213, ring finger protein 213; WHO-FC, World Health Organization functional class.
Ten patients with idiopathic PAH, five with heritable PAH, three with connective tissue disease-associated PAH, and three with congenital heart disease-associated PAH were genetically tested. All five patients with heritable PAH had mutations in known PAH-related genes such as bone morphogenetic protein receptor type 2 (BMPR2) and one patient with idiopathic PAH had a mutation in ring finger protein 213 (RNF213), which we recently reported as a novel PAH-related gene.13,17
Safety and tolerability
Discontinuation of macitentan, riociguat, or selexipag because of adverse events occurred in four of 26 patients (15%). Among these four patients, one had diarrhea with selexipag, one had suspected myelosuppression with macitentan, one had nausea with riociguat, and one had hypotension with riociguat. These patients changed their drug to another drug targeting the same pathway. No adverse events, including death, hospitalization for heart failure, or prostacyclin infusion, were observed after discontinuation of each drug.
The maximum tolerated doses of the vasodilators are summarized in Supplemental Table 2. In detail, 25 (96.2%), 24 (92.3%), and 20 (76.9%) patients were taking the maximum dose of macitentan, riociguat, and selexipag, respectively. Seventeen (65.4%) patients reached the maximum dose of all three vasodilators.
Changes and outcomes after treatment
Hemodynamic data were available for 18 patients. The detailed study flow chart is shown in Supplemental Figure 1. The hemodynamics, WHO-FC, BNP concentration, and 6MWD at baseline and follow-up are presented in Table 2. The median observation period was 441 (229–1103) days. Hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 65% decrease in the mean PVR. The CO significantly increased by 82% from baseline to follow-up. Although >70% of patients had a WHO-FC of III or IV at baseline, 89% of patients had a WHO-FC of I or II at follow-up. The 6MWD and BNP concentration were also significantly improved [Figure 1(a)].
Table 2. Changes in clinical parameters.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 6.5 (4.0–8.0) 4.0 (3.0–5.0) −2.5 (−38) 0.005
Mean PAP, mmHg 56.0 (46.3–65.5) 40.0 (30.0–47.0) −16.0 (−29) <0.001
PAWP, mmHg 7.5 (6.0–9.8) 9.0 (8.0–11.0) 1.5 (20) 0.68
CO, L/min 3.3 (2.4–4.5) 6.0 (5.1–6.7) 2.7 (82) <0.001
CI, L/min per m2 2.2 (1.7–2.7) 3.8 (3.3–4.5) 1.6 (73) <0.001
PVR, WU 13.5 (8.8–21.5) 4.7 (2.8–6.9) −8.8 (−65) <0.001
Echocardiography
TAPSE, cm 1.5 (1.3–1.8) 2.3 (1.9–2.6) 0.8 (53) 0.001
RVS’, cm 9.7 (7.8–11.8) 13.3 (12.4–14.4) 3.6 (37) 0.001
RAA, cm2 17.2 (14.9–21.3) 16.4 (14.1–21.0) −0.8 (−5) 0.49
RVEDA, cm2 26.9 (22.8–33.1) 24.1 (21.0–30.3) −2.8 (−10) 0.21
RVESA, cm2 20.4 (16.3–23.9) 16.4 (13.8–21.1) −4.0 (−20) 0.006
FAC, % 23.6 (16.2–26.9) 32.9 (29.1–35.8) 9.3 (39) <0.001
WHO-FC
I or II 4 (22) 16 (89) – –
III or IV 14 (78) 2 (11) – –
6MWD, m 405.0 (303.0–441.8) 472.0 (439.5–493.5) 67.0 (17) 0.046
BNP, pg/mL 187.8 (36.7–379.5) 17.5 (10.3–27.2) −170.3 (−91) <0.001
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Eighteen patients were analyzed in hemodynamics, and 20 patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 1. Hemodynamic and echocardiographic changes.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Echocardiographic data were available for 20 patients (Supplemental Figure 1). The echocardiographic data are presented in Table 2. The median follow-up period was 737 (256–1179) days. Right ventricular function based on the TAPSE, RVS’, and RVFAC was significantly improved from baseline to follow-up, although the RAA and RVEDA were not [Figure 1(b)].
The Kaplan–Meier curves since administration of all three vasodilators are shown in Figure 2. The 1- and 2-year survival rates were both 93.3%. One patient died of multiple organ failure after femoral neck fracture during the observation period. The overall survival rate was 92.3% with median follow-up period of 33 (24–43) months. No patients were hospitalized for heart failure during the observation period. Prostacyclin infusion was initiated in six patients (25.4%) within 1 year. Among these six patients, selexipag was switched to subcutaneous infusion of treprostinil in one patient, an intravenous infusion of epoprostenol was added to the triple oral combination therapy in another patient, and a subcutaneous infusion of treprostinil was added to the triple oral combination therapy in the remaining four patients. Selexipag was not discontinued in some patients to reduce maintenance dose of the prostacyclin for infusion. No other patients underwent prostacyclin infusion after 1 year. Among six patients who underwent prostacyclin infusion within 1 year, three patients had a BMPR2 mutation, one patient had an RNF213 mutation, and one patient had Eisenmenger syndrome due to an atrial septal defect. Composite events of all-cause death, hospitalization for heart failure, and initiation of prostacyclin infusion occurred in 16.6% of the patients within 6 months and 30.4% of the patients in 1 and 2 years.
Figure 2. Event-free rates in all patients with triple oral combination therapy.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy are shown (n = 26). The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Among 14 patients who were classified as low-/intermediate-risk by the three-category REVEAL 2.0 risk score,16 the prostacyclin-free rate was 92.9% at 3 years, while the rate was 55.0% at 2 years in 12 high-risk patients (Figure 3). The difference was not statistically significant (p = 0.058). Hemodynamic changes from baseline to follow-up in each low/intermediate and high-risk group are summarized in Supplemental Table 3. Among five patients who were classified as high-risk based on the three-category REVEAL 2.0 risk score and needed prostacyclin infusion, three patients had BMPR2 mutations and one patient had a RNF213 mutation.
Figure 3. Kaplan–Meier curve for prostacyclin-free rate in each risk category.
The prostacyclin infusion-free rates in each risk category are shown. The patients were divided into two risk categories by the REVEAL 2.0 risk score.16 The p-values were calculated by the log-rank test.
Subgroup analysis in treatment-naïve patients
Seventeen patients were treatment-naïve at baseline. Six patients were treatment naïve at baseline, but treated with other pulmonary vasodilators. In five out of these six patients, oral medication was switched from beraprost to selexipag, and in one patient, it was switched from ambrisentan and tadalafil to macitentan and riociguat. Thus, these six patients were excluded from the subgroup analysis. Among the remaining 11 patients for the subgroup analysis, the median time from initiation of the first PAH drug to the start of the third PAH drug was 24 (12–47) days. The way of up-titration in treatment naïve patients was as follows. Macitentan 10 mg was initiated at first and followed by riociguat 3.0 mg within 2 weeks. The dose of riociguat was up-titrated by 1.5 mg every 2 weeks with attention to adverse effects. In 36% of treatment naïve patients, selexipag was initiated after riociguat was up-titrated to maximum tolerated dose, whereas selexipag was started within 2 weeks from initiating macitentan in 64% of patients. Selexipag was increased by 0.4 mg every 2 weeks to maximum tolerated dose with attention to side effects. One patient (9.1%) discontinued macitentan because of suspected myelosuppression, and another patient (9.1%) discontinued riociguat because of nausea. RHC data in 10 patients and echocardiographic data in nine patients were available at baseline and at follow-up during the triple oral combination therapy. The patients’ hemodynamic and right ventricular function parameters are presented in Table 3 and Figure 4. The median follow-up period of the hemodynamic analysis was 293 (211–473) days. The hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 66% decrease in the PVR. The CO increased by 90% from baseline to follow-up. The median follow-up period of echocardiography was 385 (230–594) days. The TAPSE, RVS’, and RVFAC, indicating right ventricular function, increased significantly. The WHO-FC, 6MWD, and BNP concentration in this subgroup also improved significantly. In the Kaplan–Meier analysis, no patients died or were hospitalized for heart failure (Figure 5). Prostacyclin infusion was initiated in 31.8% of patients within 7 months, and no patients underwent prostacyclin infusion after 7 months.
Table 3. Changes in clinical parameters among treatment-naïve patients at baseline.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 7.5 (4.3–8.8) 4.0 (3.3–5.0) −3.5 (−47) 0.022
Mean PAP, mmHg 63.0 (55.0–75.8) 44.5 (37.0–51.5) −18.5 (−29) 0.006
PAWP, mmHg 7.5 (6.3–9.8) 8.0 (6.5–10.3) 0.5 (7) 0.61
CO, L/min 3.1 (2.4–4.3) 5.9 (5.1–7.2) 2.8 (90) 0.006
CI, L/min per m2 2.1 (1.7–2.5) 4.2 (3.5–4.6) 2.1 (100) 0.006
PVR, WU 17.5 (13.2–21.9) 5.9 (3.8–9.6) −11.6 (−66) 0.006
Echocardiography
TAPSE, cm 1.4 (1.3–1.5) 2.3 (2.1–2.7) 0.9 (64) 0.009
RVS’, cm 9.3 (7.9–10.8) 13.5 (13.0–14.3) 4.2 (45) 0.035
RAA, cm2 18.5 (15.0–21.1) 15.2 (13.5–16.7) −3.3 (−18) 0.076
RVEDA, cm2 27.0 (25.0–33.2) 23.6 (21.0–24.6) −3.4 (−13) 0.058
RVESA, cm2 22.9 (18.7–25.4) 14.8 (14.0–16.8) −8.1 (−35) 0.009
FAC, % 22.9 (15.9–25.2) 33.1 (29.5–35.0) 10.2 (45) 0.018
WHO-FC
I or II 1 (10) 8 (80)
III or IV 9 (90) 2 (20)
6MWD, m 400.0 (326.5–432.0) 471.5 (451.5–479.2) 71.5 (18) 0.030
BNP, pg/mL 200.8 (41.9–379.5) 20.2 (12.6–24.5) −180.6 (−90) 0.006
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Ten patients were analyzed in hemodynamics, and nine patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 4. Hemodynamic and echocardiographic changes in treatment-naïve patients.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Figure 5. Event-free rates in treatment-naïve patients.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy in treatment-naïve patients are shown. The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite endpoint of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Discussion
In the present study, triple oral combination therapy with macitentan, riociguat, and selexipag improved the hemodynamics, right ventricular function, and clinical function with good tolerability in patients with PAH. Most of the low-/intermediate-risk patients and around half of the high-risk patients could be treated sufficiently with this triple oral combination therapy although it is difficult to generalize these findings.
Two previous studies investigated the efficacy of the combination of prostacyclin infusion, an ERA, and a phosphodiesterase-5 inhibitor (PDE-5i) for PAH,7,8 but data regarding triple oral combination therapy are limited. One study related to triple oral combination therapy is the subgroup analysis of the GRIPHON study, which demonstrated a change in the symptom burden after administration of selexipag in addition to an ERA and PDE-5i.6 Recently, a randomized control study (TRITON study) is also under analysis which investigated the efficacy and safety of triple oral combination therapy with macitentan, tadalafil, and selexipag versus dual oral combination therapy with macitentan and tadalafil.18 The present study is the first to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag using real-world data.
Our results of improved hemodynamics are consistent with previous observational studies that investigated the effectiveness of triple combination therapy including prostacyclin infusion.7 Sitbon et al.7 reported that with intravenous administration of epoprostenol and oral administration of bosentan and sildenafil, the mean PAP, PVR, and cardiac index improved by 33%, 71%, and 119%, respectively. Another observational study involving a combination of ambrisentan, tadalafil, and subcutaneous treprostinil also demonstrated significant improvement of the mean PAP, PVR, and cardiac index by 30%, 66%, and 94%, respectively.8 There are similarities between the results of these previous studies and the results of the present study, suggesting that triple oral combination therapy with macitentan, riociguat, and selexipag can powerfully improve the hemodynamics in patients with PAH. In the TRITON study, triple oral combination therapy improved PVR by 54%, although it was almost the same degree as dual oral combination therapy.18 Improvement of hemodynamic in this study was greater than that of the TRITON study, partly because of the difference of the study design. Although findings from observational study, results in this study provided the possibility that triple oral combination therapy could also improve hemodynamics in the real-world population as well as the randomized controlled trial.
Our study also demonstrated a favorable long-term prognosis as well as improvement of the RVFAC, 6MWD, WHO-FC, and BNP concentration with triple oral combination therapy. In a past retrospective study of the dual combination of an ERA and PDE-5i, the 3-year overall survival rate was nearly 80%.19 In another French registry in which most patients were treated with monotherapy, the 3-year survival rate was <70%.20 The prognosis in the present study appears to be superior to that in previous reports. The low rate of mortality and hospitalization for heart failure was consistent with the TRITON study, in which the risk of first disease progression events was decreased about 41% in the triple oral therapy group.18 These results in this study could verify the efficacy of triple oral combination therapy in preventing disease progression of triple oral combination therapy found in the randomized controlled study.
In the present study, the treatment response in most of the low-/intermediate-risk patients was favorable with administration of the triple oral combination therapy, and around half of the high-risk patients did not need prostacyclin infusion. The current PAH guideline recommends initial oral therapy for low-/intermediate-risk patients, while high-risk patients are recommended to receive initial combination therapy including prostacyclin infusion.10 Patients in this study did not present decompensated heart failure and the urgent initiation of prostacyclin infusion was not necessary. Therefore, the triple oral combination therapy was initiated first and its efficacy was assessed within 6 months. Our data support recommendations in guidelines in low-/intermediate-risk patients and provide a novel possibility that around half of high-risk patients can be treated without prostacyclin infusion. Moreover, 66.7% of the patients who needed prostacyclin infusion had gene mutations, suggesting that the need for prostacyclin infusion can be largely affected by their genetic background. Therefore, we should be especially careful when we use triple oral combination therapy to treat patients with specific etiologies of PAH such as gene mutations.
With respect to safety, a past study investigating the combination of tadalafil as a PDE-5i and ambrisentan as an ERA showed that the discontinuation rate of dual combination therapy because of adverse events was 12% within 2 years of the mean duration of drug use.1 In the subgroup analysis of the GRIPHON study, which investigated the effectiveness of selexipag for the patients of PAH, a triple oral combination therapy with selexipag, ERA, and PDE-5i was discontinued in 19.0% of patients due to adverse events.6 The rate of 15% in the present study was lower than that of the GRIPHON study, suggesting good tolerability in real world data. With regard to the maximum tolerated dose, a past subgroup analysis that investigated the change in the symptom burden after taking selexipag in addition to an ERA and PDE-5i showed that only 27.9% of patients who received selexipag reached the maximum dose of selexipag.6 Another study of the combination of riociguat and macitentan showed that about 70% of patients reached the maximum maintenance dose of riociguat. In the present study, 76.9% and 92.3% of patients could be up-titrated to the maximum dose with selexipag and riociguat, respectively. Thus, this study demonstrated that it is quite possible to up-titrate each drug to the maximum dose, even in patients treated with triple oral combination therapy.
The subgroup analysis showed that the hemodynamics, right ventricular function, and clinical function powerfully improved, and the degree of improvement was similar to those in the overall patient analysis. Moreover, no patients died or were hospitalized for heart failure during the observation period. These results suggest that triple oral combination therapy with macitentan, riociguat, and selexipag can be a promising treatment strategy in treatment-naïve patients.
This study has some limitations. This was a small, single-center, retrospective study that included various types of PAH and some patients were not treatment naïve at baseline. Each etiology of PAH might have affected the results of the study differently. Prostacyclin infusion was initiated within 7 months, and no patients underwent prostacyclin infusion after 7 months, which is towards a bias of an initial high-risk population of patients in which initial triple oral combination treatment was chosen. The drug regimens were decided by the physicians. Furthermore, indirect Fick method was adopted as the measurement of CO. This was not recommended in the European Society of Cardiology/European Respiratory Society Guidelines 2015, but was admitted for use in the practical situation in the Japanese PAH guideline.11 As the results could be affected by the measurement methods of CO, further validation would be warranted.
Conclusion
This study demonstrated the effectiveness of triple oral combination therapy with macitentan, riociguat, and selexipag in patients with PAH. Our data suggest that this triple oral combination therapy is associated with improvement of hemodynamics, right ventricular function, and clinical function with good tolerability. In particular, this triple oral combination therapy can be a promising therapeutic strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further investigation is required to validate these findings.
Supplemental Material
sj-pdf-1-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
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Supplemental material, sj-pdf-1-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-2-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Click here for additional data file.
Supplemental material, sj-pdf-3-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Click here for additional data file.
Supplemental material, sj-pdf-4-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-5-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-7-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-tif-6-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
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Supplemental material, sj-tif-6-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
We thank all the doctors, nurses, and supporting medical staff members who were involved in the care of the patients enrolled in this study. We also thank Angela Morben, DVM, ELS, from Edanz Group (https://en-author-services.edanzgroup.com/ac), for editing a draft of this manuscript.
Author contribution(s): Mizuki Momoi: Data curation; Formal analysis; Investigation; Writing-original draft.
Takahiro Hiraide: Conceptualization; Methodology; Writing-review & editing.
Yoshiki Shinya: Conceptualization; Validation; Writing-review & editing.
Hiromi Momota: Data curation; Validation; Methodology; Writing-review & editing.
Shogo Fukui: Data curation; Validation; Formal analysis; Writing-review & editing.
Michiyuki Kawakami: Data curation; Validation; Formal analysis; Writing-review & editing.
Yuji Itabashi: Methodology; Data curation; Resources, Writing-review & editing.
Keiichi Fukuda: Supervision; Investigation; Writing-review & editing.
Masaharu Kataoka: Conceptualization; Project administration; Writing-review & editing.
Conflict of interest statement: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Masaharu Kataoka https://orcid.org/0000-0001-8034-1005
Supplemental material: Supplemental material for this article is available online. | Oral | DrugAdministrationRoute | CC BY-NC | 33627044 | 19,134,415 | 2021 |
What was the administration route of drug 'MACITENTAN'? | Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension.
The evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.
Among consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan-Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.
Twenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12-47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.
Triple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings.The reviews of this paper are available via the supplemental material section.
Introduction
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by elevated pulmonary arterial pressure (PAP) due to remodeling of the pulmonary arterial bed and right sided-heart failure. Three types of PAH-specific vasodilators targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway have been developed. Combination therapy targeting these different pathways has recently been shown to improve hemodynamics, clinical functions, and even hard endpoints including survival or worsening of PAH in several recent randomized controlled trials and metanalyses.1–5 The effectiveness of triple combination therapy targeting all three of these pathways has also been reported.6–8 However, two such studies analyzed patients who were treated with two types of oral vasodilators and prostacyclin infusion,7,8 and another study was a subgroup analysis of a randomized controlled trial demonstrating a change in the symptom burden by the addition of selexipag, a prostacyclin receptor agonist, to background double combination therapy targeting other pathways.6 Therefore, evidence of the efficacy and safety of triple oral combination therapy remains scarce.
The most recently approved PAH-specific vasodilators targeting each of the three types of pathways are macitentan, which is an endothelin receptor antagonist (ERA); riociguat, which is a soluble guanylate cyclase stimulator targeting the nitric oxide pathway; and selexipag, which is an oral non-prostanoid prostacyclin receptor agonist. All three of these are orally available drugs. The effectiveness of these vasodilators for PAH has recently been proven;2,3,9 however, no clinical trials have been performed to investigate the effectiveness of the combination of these three vasodilators. Furthermore, although the current guideline recommends initial oral therapy for patients with low or intermediate risk,10 how many patients with low or intermediate risk can actually be treated with only oral combination therapy remains poorly documented to date.
Therefore, the purposes of this study were to clarify the clinical effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag and to assess which risk groups can be adequately treated with this combination therapy.
Methods
Study design
This retrospective study was performed in Keio University Hospital in Japan. This study was approved by the Ethics Committee of Keio University Hospital, and written informed consent was obtained from all patients when they received genetic tests or were hospitalized. Patients with PAH who had received triple oral combination therapy with macitentan, riociguat, and selexipag were evaluated among all consecutive patients who were referred to Keio University Hospital from 2009 to 2020.
The diagnosis of PAH was made according to the current guideline.11 Patients who were lost to follow-up or underwent maintenance hemodialysis were excluded. Baseline data were measured at the time of referral to our hospital. If patients were treatment-naïve upon referral to our hospital, the combination of macitentan, riociguat, and selexipag was initiated after diagnosis. The method of up-titration and prioritization of the vasodilators as well as the selection of sequential therapy or upfront therapy was determined at the discretion of the specialized physicians. The doses of the vasodilators were titrated to the maximal tolerated doses. For patients who had already received other PAH-specific vasodilators at the time of enrollment, these drugs targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway were switched to macitentan, riociguat, and selexipag, respectively, with the intention of further improvement of hemodynamics.
Patients received genetic counseling, and genetic tests were performed with informed consent. The methods of the genetic tests, including whole-exome sequencing, are described in our previous reports.12,13
Parameters and outcomes
Dedicated cardiologists performed right-heart catheterization (RHC) without sedation at baseline and follow-up. The right arterial pressure, mean PAP, and pulmonary arterial wedge pressure were measured by RHC. The zero pressure point was set at the level of the midthorax. Cardiac output (CO) was calculated by the Fick technique using oxygen consumption estimated by 125 times the body surface area according to a previous report.14 Pulmonary vascular resistance (PVR) was calculated as the difference between the mean PAP and pulmonary arterial wedge pressure divided by the CO.
The 6-minute walk distance (6MWD), blood concentration of B-type natriuretic peptide (BNP), and World Health Organization functional class (WHO-FC) were measured at the time of hospitalization for RHC.
Standard two-dimensional, M-mode, and Doppler images, including the tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic excursion velocity (RVS’), were obtained by echocardiographers in accordance with the current echocardiography guideline.15 Dedicated cardiologists analyzed the data and measured the right atrial area (RAA), right ventricular end-diastolic area (RVEDA), right ventricular end-systolic area, and right ventricular fractional area change (RVFAC).
Hemodynamic changes measured by RHC, echocardiographic changes, and changes in the 6MWD, BNP concentration, and WHO-FC were assessed from baseline to follow-up.
The events of all-cause death, hospitalization for heart failure, initiation of prostacyclin infusion, and discontinuation of any of the three vasodilators (macitentan, riociguat, and selexipag) because of adverse events since administration of all three vasodilators were collected. The observation period was terminated when patients died, underwent prostacyclin infusion, or stopped taking macitentan, riociguat, or selexipag for any reason.
All patients enrolled in this study were divided into two groups by risk assessment using the three-category REVEAL 2.0 risk score,16 and the prostacyclin infusion-free rate was analyzed in each group. If the value was unmeasured, the value of zero was assigned. According to the three-category REVEAL 2.0 risk score, the high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), and the low-/intermediate-risk group was defined as patients with a predicted 1-year survival rate of ⩾90% (REVEAL 2.0 risk score ⩽8).
Subgroup analysis
Patients who were treatment-naïve at baseline and treated with only macitentan, riociguat, and selexipag for PAH were also independently assessed by subgroup analysis. Their hemodynamics, echocardiography, and clinical function were measured and clinical events were collected similarly to the overall patient analysis.
Statistical analysis
Data are described as median and interquartile range unless otherwise indicated. Wilcoxon’s signed rank test was used to compare the parameters of hemodynamics, echocardiography, 6MWD, and BNP concentration from baseline to the latest follow-up. The cases which had a missing value either at baseline or follow-up were excluded from each analysis. Differences with a p-value of <0.05 were considered statistically significant. All p-values were two-tailed. Event-free rates were analyzed using the Kaplan–Meier method. All analyses were performed using R software (version 3.6.3), and figures were obtained using GraphPad Prism (version 8.0 for Mac; GraphPad Software, La Jolla, CA, USA).
Results
Patient characteristics
The patients’ baseline characteristics and medications are presented in Table 1 and Supplemental material Table 1 online. One patient who was lost to follow-up and one patient who had been undergoing maintenance hemodialysis were excluded; thus, 26 patients were enrolled in this study. The patients were predominantly female (73.1%) with a median age of 38 years. The major etiology of PAH was idiopathic PAH (38.5%) followed by connective tissue disease-associated PAH (26.9%), heritable PAH (19.2%), and congenital heart disease-associated PAH (15.4%). Most patients were treatment-naïve (65.4%), and others were taking some PAH medications at baseline.
Table 1. Demographics and characteristics at baseline.
Variable Triple oral combination therapy
N = 26
Female 19 (73.1)
Age, years 38 (23–48)
WHO-FC
I/II/III/IV 0/9/16/1 (0.0/34.6/61.5/3.8)
BNP, pg/mL 105.25 (36.7–285.5)
6MWD, m 397.5 (312.8–441.8)
PAH etiology
IPAH 10 (38.5)
HPAH 5 (19.2)
CTD-PAH 7 (26.9)
CHD-PAH 4 (15.4)
Medication
Treatment-naïve 17 (65.4)
Single 3 (11.5)
Double 2 (7.7)
Triple 4 (15.4)
Risk assessment*
High risk 12 (46.2)
Intermediate risk 4 (15.4)
Low risk 10 (38.5)
Genetic mutation**
BMPR2 5 (23.8)
ACVRL 1 (4.8)
RNF213 1 (4.8)
Data are expressed as number (%) or median (interquartile range).
* Risk assessment was calculated using the three-category REVEAL 2.0 risk score.16 The high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), the intermediate-risk group was defined as patients with a predicted 1-year survival rate of 90–<95% (REVEAL 2.0 risk score = 7 or 8), and the low-risk group was defined as patients with a predicted 1-year survival rate of ⩾95% (REVEAL 2.0 risk score ⩽6).
** Among 26 patients, 21 were genetically tested and 15 had no genetic mutations related to PAH.
6MWD, 6-minute walk distance; ACVRL1, activin A receptor-like kinase 1; BMPR2, bone morphogenetic protein receptor type 2; BNP, B-type natriuretic peptide; CHD, congenital heart disease; CTD, connective tissue disease; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; RNF213, ring finger protein 213; WHO-FC, World Health Organization functional class.
Ten patients with idiopathic PAH, five with heritable PAH, three with connective tissue disease-associated PAH, and three with congenital heart disease-associated PAH were genetically tested. All five patients with heritable PAH had mutations in known PAH-related genes such as bone morphogenetic protein receptor type 2 (BMPR2) and one patient with idiopathic PAH had a mutation in ring finger protein 213 (RNF213), which we recently reported as a novel PAH-related gene.13,17
Safety and tolerability
Discontinuation of macitentan, riociguat, or selexipag because of adverse events occurred in four of 26 patients (15%). Among these four patients, one had diarrhea with selexipag, one had suspected myelosuppression with macitentan, one had nausea with riociguat, and one had hypotension with riociguat. These patients changed their drug to another drug targeting the same pathway. No adverse events, including death, hospitalization for heart failure, or prostacyclin infusion, were observed after discontinuation of each drug.
The maximum tolerated doses of the vasodilators are summarized in Supplemental Table 2. In detail, 25 (96.2%), 24 (92.3%), and 20 (76.9%) patients were taking the maximum dose of macitentan, riociguat, and selexipag, respectively. Seventeen (65.4%) patients reached the maximum dose of all three vasodilators.
Changes and outcomes after treatment
Hemodynamic data were available for 18 patients. The detailed study flow chart is shown in Supplemental Figure 1. The hemodynamics, WHO-FC, BNP concentration, and 6MWD at baseline and follow-up are presented in Table 2. The median observation period was 441 (229–1103) days. Hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 65% decrease in the mean PVR. The CO significantly increased by 82% from baseline to follow-up. Although >70% of patients had a WHO-FC of III or IV at baseline, 89% of patients had a WHO-FC of I or II at follow-up. The 6MWD and BNP concentration were also significantly improved [Figure 1(a)].
Table 2. Changes in clinical parameters.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 6.5 (4.0–8.0) 4.0 (3.0–5.0) −2.5 (−38) 0.005
Mean PAP, mmHg 56.0 (46.3–65.5) 40.0 (30.0–47.0) −16.0 (−29) <0.001
PAWP, mmHg 7.5 (6.0–9.8) 9.0 (8.0–11.0) 1.5 (20) 0.68
CO, L/min 3.3 (2.4–4.5) 6.0 (5.1–6.7) 2.7 (82) <0.001
CI, L/min per m2 2.2 (1.7–2.7) 3.8 (3.3–4.5) 1.6 (73) <0.001
PVR, WU 13.5 (8.8–21.5) 4.7 (2.8–6.9) −8.8 (−65) <0.001
Echocardiography
TAPSE, cm 1.5 (1.3–1.8) 2.3 (1.9–2.6) 0.8 (53) 0.001
RVS’, cm 9.7 (7.8–11.8) 13.3 (12.4–14.4) 3.6 (37) 0.001
RAA, cm2 17.2 (14.9–21.3) 16.4 (14.1–21.0) −0.8 (−5) 0.49
RVEDA, cm2 26.9 (22.8–33.1) 24.1 (21.0–30.3) −2.8 (−10) 0.21
RVESA, cm2 20.4 (16.3–23.9) 16.4 (13.8–21.1) −4.0 (−20) 0.006
FAC, % 23.6 (16.2–26.9) 32.9 (29.1–35.8) 9.3 (39) <0.001
WHO-FC
I or II 4 (22) 16 (89) – –
III or IV 14 (78) 2 (11) – –
6MWD, m 405.0 (303.0–441.8) 472.0 (439.5–493.5) 67.0 (17) 0.046
BNP, pg/mL 187.8 (36.7–379.5) 17.5 (10.3–27.2) −170.3 (−91) <0.001
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Eighteen patients were analyzed in hemodynamics, and 20 patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 1. Hemodynamic and echocardiographic changes.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Echocardiographic data were available for 20 patients (Supplemental Figure 1). The echocardiographic data are presented in Table 2. The median follow-up period was 737 (256–1179) days. Right ventricular function based on the TAPSE, RVS’, and RVFAC was significantly improved from baseline to follow-up, although the RAA and RVEDA were not [Figure 1(b)].
The Kaplan–Meier curves since administration of all three vasodilators are shown in Figure 2. The 1- and 2-year survival rates were both 93.3%. One patient died of multiple organ failure after femoral neck fracture during the observation period. The overall survival rate was 92.3% with median follow-up period of 33 (24–43) months. No patients were hospitalized for heart failure during the observation period. Prostacyclin infusion was initiated in six patients (25.4%) within 1 year. Among these six patients, selexipag was switched to subcutaneous infusion of treprostinil in one patient, an intravenous infusion of epoprostenol was added to the triple oral combination therapy in another patient, and a subcutaneous infusion of treprostinil was added to the triple oral combination therapy in the remaining four patients. Selexipag was not discontinued in some patients to reduce maintenance dose of the prostacyclin for infusion. No other patients underwent prostacyclin infusion after 1 year. Among six patients who underwent prostacyclin infusion within 1 year, three patients had a BMPR2 mutation, one patient had an RNF213 mutation, and one patient had Eisenmenger syndrome due to an atrial septal defect. Composite events of all-cause death, hospitalization for heart failure, and initiation of prostacyclin infusion occurred in 16.6% of the patients within 6 months and 30.4% of the patients in 1 and 2 years.
Figure 2. Event-free rates in all patients with triple oral combination therapy.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy are shown (n = 26). The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Among 14 patients who were classified as low-/intermediate-risk by the three-category REVEAL 2.0 risk score,16 the prostacyclin-free rate was 92.9% at 3 years, while the rate was 55.0% at 2 years in 12 high-risk patients (Figure 3). The difference was not statistically significant (p = 0.058). Hemodynamic changes from baseline to follow-up in each low/intermediate and high-risk group are summarized in Supplemental Table 3. Among five patients who were classified as high-risk based on the three-category REVEAL 2.0 risk score and needed prostacyclin infusion, three patients had BMPR2 mutations and one patient had a RNF213 mutation.
Figure 3. Kaplan–Meier curve for prostacyclin-free rate in each risk category.
The prostacyclin infusion-free rates in each risk category are shown. The patients were divided into two risk categories by the REVEAL 2.0 risk score.16 The p-values were calculated by the log-rank test.
Subgroup analysis in treatment-naïve patients
Seventeen patients were treatment-naïve at baseline. Six patients were treatment naïve at baseline, but treated with other pulmonary vasodilators. In five out of these six patients, oral medication was switched from beraprost to selexipag, and in one patient, it was switched from ambrisentan and tadalafil to macitentan and riociguat. Thus, these six patients were excluded from the subgroup analysis. Among the remaining 11 patients for the subgroup analysis, the median time from initiation of the first PAH drug to the start of the third PAH drug was 24 (12–47) days. The way of up-titration in treatment naïve patients was as follows. Macitentan 10 mg was initiated at first and followed by riociguat 3.0 mg within 2 weeks. The dose of riociguat was up-titrated by 1.5 mg every 2 weeks with attention to adverse effects. In 36% of treatment naïve patients, selexipag was initiated after riociguat was up-titrated to maximum tolerated dose, whereas selexipag was started within 2 weeks from initiating macitentan in 64% of patients. Selexipag was increased by 0.4 mg every 2 weeks to maximum tolerated dose with attention to side effects. One patient (9.1%) discontinued macitentan because of suspected myelosuppression, and another patient (9.1%) discontinued riociguat because of nausea. RHC data in 10 patients and echocardiographic data in nine patients were available at baseline and at follow-up during the triple oral combination therapy. The patients’ hemodynamic and right ventricular function parameters are presented in Table 3 and Figure 4. The median follow-up period of the hemodynamic analysis was 293 (211–473) days. The hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 66% decrease in the PVR. The CO increased by 90% from baseline to follow-up. The median follow-up period of echocardiography was 385 (230–594) days. The TAPSE, RVS’, and RVFAC, indicating right ventricular function, increased significantly. The WHO-FC, 6MWD, and BNP concentration in this subgroup also improved significantly. In the Kaplan–Meier analysis, no patients died or were hospitalized for heart failure (Figure 5). Prostacyclin infusion was initiated in 31.8% of patients within 7 months, and no patients underwent prostacyclin infusion after 7 months.
Table 3. Changes in clinical parameters among treatment-naïve patients at baseline.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 7.5 (4.3–8.8) 4.0 (3.3–5.0) −3.5 (−47) 0.022
Mean PAP, mmHg 63.0 (55.0–75.8) 44.5 (37.0–51.5) −18.5 (−29) 0.006
PAWP, mmHg 7.5 (6.3–9.8) 8.0 (6.5–10.3) 0.5 (7) 0.61
CO, L/min 3.1 (2.4–4.3) 5.9 (5.1–7.2) 2.8 (90) 0.006
CI, L/min per m2 2.1 (1.7–2.5) 4.2 (3.5–4.6) 2.1 (100) 0.006
PVR, WU 17.5 (13.2–21.9) 5.9 (3.8–9.6) −11.6 (−66) 0.006
Echocardiography
TAPSE, cm 1.4 (1.3–1.5) 2.3 (2.1–2.7) 0.9 (64) 0.009
RVS’, cm 9.3 (7.9–10.8) 13.5 (13.0–14.3) 4.2 (45) 0.035
RAA, cm2 18.5 (15.0–21.1) 15.2 (13.5–16.7) −3.3 (−18) 0.076
RVEDA, cm2 27.0 (25.0–33.2) 23.6 (21.0–24.6) −3.4 (−13) 0.058
RVESA, cm2 22.9 (18.7–25.4) 14.8 (14.0–16.8) −8.1 (−35) 0.009
FAC, % 22.9 (15.9–25.2) 33.1 (29.5–35.0) 10.2 (45) 0.018
WHO-FC
I or II 1 (10) 8 (80)
III or IV 9 (90) 2 (20)
6MWD, m 400.0 (326.5–432.0) 471.5 (451.5–479.2) 71.5 (18) 0.030
BNP, pg/mL 200.8 (41.9–379.5) 20.2 (12.6–24.5) −180.6 (−90) 0.006
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Ten patients were analyzed in hemodynamics, and nine patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 4. Hemodynamic and echocardiographic changes in treatment-naïve patients.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Figure 5. Event-free rates in treatment-naïve patients.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy in treatment-naïve patients are shown. The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite endpoint of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Discussion
In the present study, triple oral combination therapy with macitentan, riociguat, and selexipag improved the hemodynamics, right ventricular function, and clinical function with good tolerability in patients with PAH. Most of the low-/intermediate-risk patients and around half of the high-risk patients could be treated sufficiently with this triple oral combination therapy although it is difficult to generalize these findings.
Two previous studies investigated the efficacy of the combination of prostacyclin infusion, an ERA, and a phosphodiesterase-5 inhibitor (PDE-5i) for PAH,7,8 but data regarding triple oral combination therapy are limited. One study related to triple oral combination therapy is the subgroup analysis of the GRIPHON study, which demonstrated a change in the symptom burden after administration of selexipag in addition to an ERA and PDE-5i.6 Recently, a randomized control study (TRITON study) is also under analysis which investigated the efficacy and safety of triple oral combination therapy with macitentan, tadalafil, and selexipag versus dual oral combination therapy with macitentan and tadalafil.18 The present study is the first to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag using real-world data.
Our results of improved hemodynamics are consistent with previous observational studies that investigated the effectiveness of triple combination therapy including prostacyclin infusion.7 Sitbon et al.7 reported that with intravenous administration of epoprostenol and oral administration of bosentan and sildenafil, the mean PAP, PVR, and cardiac index improved by 33%, 71%, and 119%, respectively. Another observational study involving a combination of ambrisentan, tadalafil, and subcutaneous treprostinil also demonstrated significant improvement of the mean PAP, PVR, and cardiac index by 30%, 66%, and 94%, respectively.8 There are similarities between the results of these previous studies and the results of the present study, suggesting that triple oral combination therapy with macitentan, riociguat, and selexipag can powerfully improve the hemodynamics in patients with PAH. In the TRITON study, triple oral combination therapy improved PVR by 54%, although it was almost the same degree as dual oral combination therapy.18 Improvement of hemodynamic in this study was greater than that of the TRITON study, partly because of the difference of the study design. Although findings from observational study, results in this study provided the possibility that triple oral combination therapy could also improve hemodynamics in the real-world population as well as the randomized controlled trial.
Our study also demonstrated a favorable long-term prognosis as well as improvement of the RVFAC, 6MWD, WHO-FC, and BNP concentration with triple oral combination therapy. In a past retrospective study of the dual combination of an ERA and PDE-5i, the 3-year overall survival rate was nearly 80%.19 In another French registry in which most patients were treated with monotherapy, the 3-year survival rate was <70%.20 The prognosis in the present study appears to be superior to that in previous reports. The low rate of mortality and hospitalization for heart failure was consistent with the TRITON study, in which the risk of first disease progression events was decreased about 41% in the triple oral therapy group.18 These results in this study could verify the efficacy of triple oral combination therapy in preventing disease progression of triple oral combination therapy found in the randomized controlled study.
In the present study, the treatment response in most of the low-/intermediate-risk patients was favorable with administration of the triple oral combination therapy, and around half of the high-risk patients did not need prostacyclin infusion. The current PAH guideline recommends initial oral therapy for low-/intermediate-risk patients, while high-risk patients are recommended to receive initial combination therapy including prostacyclin infusion.10 Patients in this study did not present decompensated heart failure and the urgent initiation of prostacyclin infusion was not necessary. Therefore, the triple oral combination therapy was initiated first and its efficacy was assessed within 6 months. Our data support recommendations in guidelines in low-/intermediate-risk patients and provide a novel possibility that around half of high-risk patients can be treated without prostacyclin infusion. Moreover, 66.7% of the patients who needed prostacyclin infusion had gene mutations, suggesting that the need for prostacyclin infusion can be largely affected by their genetic background. Therefore, we should be especially careful when we use triple oral combination therapy to treat patients with specific etiologies of PAH such as gene mutations.
With respect to safety, a past study investigating the combination of tadalafil as a PDE-5i and ambrisentan as an ERA showed that the discontinuation rate of dual combination therapy because of adverse events was 12% within 2 years of the mean duration of drug use.1 In the subgroup analysis of the GRIPHON study, which investigated the effectiveness of selexipag for the patients of PAH, a triple oral combination therapy with selexipag, ERA, and PDE-5i was discontinued in 19.0% of patients due to adverse events.6 The rate of 15% in the present study was lower than that of the GRIPHON study, suggesting good tolerability in real world data. With regard to the maximum tolerated dose, a past subgroup analysis that investigated the change in the symptom burden after taking selexipag in addition to an ERA and PDE-5i showed that only 27.9% of patients who received selexipag reached the maximum dose of selexipag.6 Another study of the combination of riociguat and macitentan showed that about 70% of patients reached the maximum maintenance dose of riociguat. In the present study, 76.9% and 92.3% of patients could be up-titrated to the maximum dose with selexipag and riociguat, respectively. Thus, this study demonstrated that it is quite possible to up-titrate each drug to the maximum dose, even in patients treated with triple oral combination therapy.
The subgroup analysis showed that the hemodynamics, right ventricular function, and clinical function powerfully improved, and the degree of improvement was similar to those in the overall patient analysis. Moreover, no patients died or were hospitalized for heart failure during the observation period. These results suggest that triple oral combination therapy with macitentan, riociguat, and selexipag can be a promising treatment strategy in treatment-naïve patients.
This study has some limitations. This was a small, single-center, retrospective study that included various types of PAH and some patients were not treatment naïve at baseline. Each etiology of PAH might have affected the results of the study differently. Prostacyclin infusion was initiated within 7 months, and no patients underwent prostacyclin infusion after 7 months, which is towards a bias of an initial high-risk population of patients in which initial triple oral combination treatment was chosen. The drug regimens were decided by the physicians. Furthermore, indirect Fick method was adopted as the measurement of CO. This was not recommended in the European Society of Cardiology/European Respiratory Society Guidelines 2015, but was admitted for use in the practical situation in the Japanese PAH guideline.11 As the results could be affected by the measurement methods of CO, further validation would be warranted.
Conclusion
This study demonstrated the effectiveness of triple oral combination therapy with macitentan, riociguat, and selexipag in patients with PAH. Our data suggest that this triple oral combination therapy is associated with improvement of hemodynamics, right ventricular function, and clinical function with good tolerability. In particular, this triple oral combination therapy can be a promising therapeutic strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further investigation is required to validate these findings.
Supplemental Material
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Supplemental material, sj-pdf-1-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-2-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-3-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-4-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-7-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-tif-6-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
We thank all the doctors, nurses, and supporting medical staff members who were involved in the care of the patients enrolled in this study. We also thank Angela Morben, DVM, ELS, from Edanz Group (https://en-author-services.edanzgroup.com/ac), for editing a draft of this manuscript.
Author contribution(s): Mizuki Momoi: Data curation; Formal analysis; Investigation; Writing-original draft.
Takahiro Hiraide: Conceptualization; Methodology; Writing-review & editing.
Yoshiki Shinya: Conceptualization; Validation; Writing-review & editing.
Hiromi Momota: Data curation; Validation; Methodology; Writing-review & editing.
Shogo Fukui: Data curation; Validation; Formal analysis; Writing-review & editing.
Michiyuki Kawakami: Data curation; Validation; Formal analysis; Writing-review & editing.
Yuji Itabashi: Methodology; Data curation; Resources, Writing-review & editing.
Keiichi Fukuda: Supervision; Investigation; Writing-review & editing.
Masaharu Kataoka: Conceptualization; Project administration; Writing-review & editing.
Conflict of interest statement: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Masaharu Kataoka https://orcid.org/0000-0001-8034-1005
Supplemental material: Supplemental material for this article is available online. | Oral | DrugAdministrationRoute | CC BY-NC | 33627044 | 18,982,738 | 2021 |
What was the administration route of drug 'RIOCIGUAT'? | Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension.
The evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.
Among consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan-Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.
Twenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12-47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.
Triple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings.The reviews of this paper are available via the supplemental material section.
Introduction
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by elevated pulmonary arterial pressure (PAP) due to remodeling of the pulmonary arterial bed and right sided-heart failure. Three types of PAH-specific vasodilators targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway have been developed. Combination therapy targeting these different pathways has recently been shown to improve hemodynamics, clinical functions, and even hard endpoints including survival or worsening of PAH in several recent randomized controlled trials and metanalyses.1–5 The effectiveness of triple combination therapy targeting all three of these pathways has also been reported.6–8 However, two such studies analyzed patients who were treated with two types of oral vasodilators and prostacyclin infusion,7,8 and another study was a subgroup analysis of a randomized controlled trial demonstrating a change in the symptom burden by the addition of selexipag, a prostacyclin receptor agonist, to background double combination therapy targeting other pathways.6 Therefore, evidence of the efficacy and safety of triple oral combination therapy remains scarce.
The most recently approved PAH-specific vasodilators targeting each of the three types of pathways are macitentan, which is an endothelin receptor antagonist (ERA); riociguat, which is a soluble guanylate cyclase stimulator targeting the nitric oxide pathway; and selexipag, which is an oral non-prostanoid prostacyclin receptor agonist. All three of these are orally available drugs. The effectiveness of these vasodilators for PAH has recently been proven;2,3,9 however, no clinical trials have been performed to investigate the effectiveness of the combination of these three vasodilators. Furthermore, although the current guideline recommends initial oral therapy for patients with low or intermediate risk,10 how many patients with low or intermediate risk can actually be treated with only oral combination therapy remains poorly documented to date.
Therefore, the purposes of this study were to clarify the clinical effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag and to assess which risk groups can be adequately treated with this combination therapy.
Methods
Study design
This retrospective study was performed in Keio University Hospital in Japan. This study was approved by the Ethics Committee of Keio University Hospital, and written informed consent was obtained from all patients when they received genetic tests or were hospitalized. Patients with PAH who had received triple oral combination therapy with macitentan, riociguat, and selexipag were evaluated among all consecutive patients who were referred to Keio University Hospital from 2009 to 2020.
The diagnosis of PAH was made according to the current guideline.11 Patients who were lost to follow-up or underwent maintenance hemodialysis were excluded. Baseline data were measured at the time of referral to our hospital. If patients were treatment-naïve upon referral to our hospital, the combination of macitentan, riociguat, and selexipag was initiated after diagnosis. The method of up-titration and prioritization of the vasodilators as well as the selection of sequential therapy or upfront therapy was determined at the discretion of the specialized physicians. The doses of the vasodilators were titrated to the maximal tolerated doses. For patients who had already received other PAH-specific vasodilators at the time of enrollment, these drugs targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway were switched to macitentan, riociguat, and selexipag, respectively, with the intention of further improvement of hemodynamics.
Patients received genetic counseling, and genetic tests were performed with informed consent. The methods of the genetic tests, including whole-exome sequencing, are described in our previous reports.12,13
Parameters and outcomes
Dedicated cardiologists performed right-heart catheterization (RHC) without sedation at baseline and follow-up. The right arterial pressure, mean PAP, and pulmonary arterial wedge pressure were measured by RHC. The zero pressure point was set at the level of the midthorax. Cardiac output (CO) was calculated by the Fick technique using oxygen consumption estimated by 125 times the body surface area according to a previous report.14 Pulmonary vascular resistance (PVR) was calculated as the difference between the mean PAP and pulmonary arterial wedge pressure divided by the CO.
The 6-minute walk distance (6MWD), blood concentration of B-type natriuretic peptide (BNP), and World Health Organization functional class (WHO-FC) were measured at the time of hospitalization for RHC.
Standard two-dimensional, M-mode, and Doppler images, including the tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic excursion velocity (RVS’), were obtained by echocardiographers in accordance with the current echocardiography guideline.15 Dedicated cardiologists analyzed the data and measured the right atrial area (RAA), right ventricular end-diastolic area (RVEDA), right ventricular end-systolic area, and right ventricular fractional area change (RVFAC).
Hemodynamic changes measured by RHC, echocardiographic changes, and changes in the 6MWD, BNP concentration, and WHO-FC were assessed from baseline to follow-up.
The events of all-cause death, hospitalization for heart failure, initiation of prostacyclin infusion, and discontinuation of any of the three vasodilators (macitentan, riociguat, and selexipag) because of adverse events since administration of all three vasodilators were collected. The observation period was terminated when patients died, underwent prostacyclin infusion, or stopped taking macitentan, riociguat, or selexipag for any reason.
All patients enrolled in this study were divided into two groups by risk assessment using the three-category REVEAL 2.0 risk score,16 and the prostacyclin infusion-free rate was analyzed in each group. If the value was unmeasured, the value of zero was assigned. According to the three-category REVEAL 2.0 risk score, the high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), and the low-/intermediate-risk group was defined as patients with a predicted 1-year survival rate of ⩾90% (REVEAL 2.0 risk score ⩽8).
Subgroup analysis
Patients who were treatment-naïve at baseline and treated with only macitentan, riociguat, and selexipag for PAH were also independently assessed by subgroup analysis. Their hemodynamics, echocardiography, and clinical function were measured and clinical events were collected similarly to the overall patient analysis.
Statistical analysis
Data are described as median and interquartile range unless otherwise indicated. Wilcoxon’s signed rank test was used to compare the parameters of hemodynamics, echocardiography, 6MWD, and BNP concentration from baseline to the latest follow-up. The cases which had a missing value either at baseline or follow-up were excluded from each analysis. Differences with a p-value of <0.05 were considered statistically significant. All p-values were two-tailed. Event-free rates were analyzed using the Kaplan–Meier method. All analyses were performed using R software (version 3.6.3), and figures were obtained using GraphPad Prism (version 8.0 for Mac; GraphPad Software, La Jolla, CA, USA).
Results
Patient characteristics
The patients’ baseline characteristics and medications are presented in Table 1 and Supplemental material Table 1 online. One patient who was lost to follow-up and one patient who had been undergoing maintenance hemodialysis were excluded; thus, 26 patients were enrolled in this study. The patients were predominantly female (73.1%) with a median age of 38 years. The major etiology of PAH was idiopathic PAH (38.5%) followed by connective tissue disease-associated PAH (26.9%), heritable PAH (19.2%), and congenital heart disease-associated PAH (15.4%). Most patients were treatment-naïve (65.4%), and others were taking some PAH medications at baseline.
Table 1. Demographics and characteristics at baseline.
Variable Triple oral combination therapy
N = 26
Female 19 (73.1)
Age, years 38 (23–48)
WHO-FC
I/II/III/IV 0/9/16/1 (0.0/34.6/61.5/3.8)
BNP, pg/mL 105.25 (36.7–285.5)
6MWD, m 397.5 (312.8–441.8)
PAH etiology
IPAH 10 (38.5)
HPAH 5 (19.2)
CTD-PAH 7 (26.9)
CHD-PAH 4 (15.4)
Medication
Treatment-naïve 17 (65.4)
Single 3 (11.5)
Double 2 (7.7)
Triple 4 (15.4)
Risk assessment*
High risk 12 (46.2)
Intermediate risk 4 (15.4)
Low risk 10 (38.5)
Genetic mutation**
BMPR2 5 (23.8)
ACVRL 1 (4.8)
RNF213 1 (4.8)
Data are expressed as number (%) or median (interquartile range).
* Risk assessment was calculated using the three-category REVEAL 2.0 risk score.16 The high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), the intermediate-risk group was defined as patients with a predicted 1-year survival rate of 90–<95% (REVEAL 2.0 risk score = 7 or 8), and the low-risk group was defined as patients with a predicted 1-year survival rate of ⩾95% (REVEAL 2.0 risk score ⩽6).
** Among 26 patients, 21 were genetically tested and 15 had no genetic mutations related to PAH.
6MWD, 6-minute walk distance; ACVRL1, activin A receptor-like kinase 1; BMPR2, bone morphogenetic protein receptor type 2; BNP, B-type natriuretic peptide; CHD, congenital heart disease; CTD, connective tissue disease; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; RNF213, ring finger protein 213; WHO-FC, World Health Organization functional class.
Ten patients with idiopathic PAH, five with heritable PAH, three with connective tissue disease-associated PAH, and three with congenital heart disease-associated PAH were genetically tested. All five patients with heritable PAH had mutations in known PAH-related genes such as bone morphogenetic protein receptor type 2 (BMPR2) and one patient with idiopathic PAH had a mutation in ring finger protein 213 (RNF213), which we recently reported as a novel PAH-related gene.13,17
Safety and tolerability
Discontinuation of macitentan, riociguat, or selexipag because of adverse events occurred in four of 26 patients (15%). Among these four patients, one had diarrhea with selexipag, one had suspected myelosuppression with macitentan, one had nausea with riociguat, and one had hypotension with riociguat. These patients changed their drug to another drug targeting the same pathway. No adverse events, including death, hospitalization for heart failure, or prostacyclin infusion, were observed after discontinuation of each drug.
The maximum tolerated doses of the vasodilators are summarized in Supplemental Table 2. In detail, 25 (96.2%), 24 (92.3%), and 20 (76.9%) patients were taking the maximum dose of macitentan, riociguat, and selexipag, respectively. Seventeen (65.4%) patients reached the maximum dose of all three vasodilators.
Changes and outcomes after treatment
Hemodynamic data were available for 18 patients. The detailed study flow chart is shown in Supplemental Figure 1. The hemodynamics, WHO-FC, BNP concentration, and 6MWD at baseline and follow-up are presented in Table 2. The median observation period was 441 (229–1103) days. Hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 65% decrease in the mean PVR. The CO significantly increased by 82% from baseline to follow-up. Although >70% of patients had a WHO-FC of III or IV at baseline, 89% of patients had a WHO-FC of I or II at follow-up. The 6MWD and BNP concentration were also significantly improved [Figure 1(a)].
Table 2. Changes in clinical parameters.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 6.5 (4.0–8.0) 4.0 (3.0–5.0) −2.5 (−38) 0.005
Mean PAP, mmHg 56.0 (46.3–65.5) 40.0 (30.0–47.0) −16.0 (−29) <0.001
PAWP, mmHg 7.5 (6.0–9.8) 9.0 (8.0–11.0) 1.5 (20) 0.68
CO, L/min 3.3 (2.4–4.5) 6.0 (5.1–6.7) 2.7 (82) <0.001
CI, L/min per m2 2.2 (1.7–2.7) 3.8 (3.3–4.5) 1.6 (73) <0.001
PVR, WU 13.5 (8.8–21.5) 4.7 (2.8–6.9) −8.8 (−65) <0.001
Echocardiography
TAPSE, cm 1.5 (1.3–1.8) 2.3 (1.9–2.6) 0.8 (53) 0.001
RVS’, cm 9.7 (7.8–11.8) 13.3 (12.4–14.4) 3.6 (37) 0.001
RAA, cm2 17.2 (14.9–21.3) 16.4 (14.1–21.0) −0.8 (−5) 0.49
RVEDA, cm2 26.9 (22.8–33.1) 24.1 (21.0–30.3) −2.8 (−10) 0.21
RVESA, cm2 20.4 (16.3–23.9) 16.4 (13.8–21.1) −4.0 (−20) 0.006
FAC, % 23.6 (16.2–26.9) 32.9 (29.1–35.8) 9.3 (39) <0.001
WHO-FC
I or II 4 (22) 16 (89) – –
III or IV 14 (78) 2 (11) – –
6MWD, m 405.0 (303.0–441.8) 472.0 (439.5–493.5) 67.0 (17) 0.046
BNP, pg/mL 187.8 (36.7–379.5) 17.5 (10.3–27.2) −170.3 (−91) <0.001
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Eighteen patients were analyzed in hemodynamics, and 20 patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 1. Hemodynamic and echocardiographic changes.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Echocardiographic data were available for 20 patients (Supplemental Figure 1). The echocardiographic data are presented in Table 2. The median follow-up period was 737 (256–1179) days. Right ventricular function based on the TAPSE, RVS’, and RVFAC was significantly improved from baseline to follow-up, although the RAA and RVEDA were not [Figure 1(b)].
The Kaplan–Meier curves since administration of all three vasodilators are shown in Figure 2. The 1- and 2-year survival rates were both 93.3%. One patient died of multiple organ failure after femoral neck fracture during the observation period. The overall survival rate was 92.3% with median follow-up period of 33 (24–43) months. No patients were hospitalized for heart failure during the observation period. Prostacyclin infusion was initiated in six patients (25.4%) within 1 year. Among these six patients, selexipag was switched to subcutaneous infusion of treprostinil in one patient, an intravenous infusion of epoprostenol was added to the triple oral combination therapy in another patient, and a subcutaneous infusion of treprostinil was added to the triple oral combination therapy in the remaining four patients. Selexipag was not discontinued in some patients to reduce maintenance dose of the prostacyclin for infusion. No other patients underwent prostacyclin infusion after 1 year. Among six patients who underwent prostacyclin infusion within 1 year, three patients had a BMPR2 mutation, one patient had an RNF213 mutation, and one patient had Eisenmenger syndrome due to an atrial septal defect. Composite events of all-cause death, hospitalization for heart failure, and initiation of prostacyclin infusion occurred in 16.6% of the patients within 6 months and 30.4% of the patients in 1 and 2 years.
Figure 2. Event-free rates in all patients with triple oral combination therapy.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy are shown (n = 26). The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Among 14 patients who were classified as low-/intermediate-risk by the three-category REVEAL 2.0 risk score,16 the prostacyclin-free rate was 92.9% at 3 years, while the rate was 55.0% at 2 years in 12 high-risk patients (Figure 3). The difference was not statistically significant (p = 0.058). Hemodynamic changes from baseline to follow-up in each low/intermediate and high-risk group are summarized in Supplemental Table 3. Among five patients who were classified as high-risk based on the three-category REVEAL 2.0 risk score and needed prostacyclin infusion, three patients had BMPR2 mutations and one patient had a RNF213 mutation.
Figure 3. Kaplan–Meier curve for prostacyclin-free rate in each risk category.
The prostacyclin infusion-free rates in each risk category are shown. The patients were divided into two risk categories by the REVEAL 2.0 risk score.16 The p-values were calculated by the log-rank test.
Subgroup analysis in treatment-naïve patients
Seventeen patients were treatment-naïve at baseline. Six patients were treatment naïve at baseline, but treated with other pulmonary vasodilators. In five out of these six patients, oral medication was switched from beraprost to selexipag, and in one patient, it was switched from ambrisentan and tadalafil to macitentan and riociguat. Thus, these six patients were excluded from the subgroup analysis. Among the remaining 11 patients for the subgroup analysis, the median time from initiation of the first PAH drug to the start of the third PAH drug was 24 (12–47) days. The way of up-titration in treatment naïve patients was as follows. Macitentan 10 mg was initiated at first and followed by riociguat 3.0 mg within 2 weeks. The dose of riociguat was up-titrated by 1.5 mg every 2 weeks with attention to adverse effects. In 36% of treatment naïve patients, selexipag was initiated after riociguat was up-titrated to maximum tolerated dose, whereas selexipag was started within 2 weeks from initiating macitentan in 64% of patients. Selexipag was increased by 0.4 mg every 2 weeks to maximum tolerated dose with attention to side effects. One patient (9.1%) discontinued macitentan because of suspected myelosuppression, and another patient (9.1%) discontinued riociguat because of nausea. RHC data in 10 patients and echocardiographic data in nine patients were available at baseline and at follow-up during the triple oral combination therapy. The patients’ hemodynamic and right ventricular function parameters are presented in Table 3 and Figure 4. The median follow-up period of the hemodynamic analysis was 293 (211–473) days. The hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 66% decrease in the PVR. The CO increased by 90% from baseline to follow-up. The median follow-up period of echocardiography was 385 (230–594) days. The TAPSE, RVS’, and RVFAC, indicating right ventricular function, increased significantly. The WHO-FC, 6MWD, and BNP concentration in this subgroup also improved significantly. In the Kaplan–Meier analysis, no patients died or were hospitalized for heart failure (Figure 5). Prostacyclin infusion was initiated in 31.8% of patients within 7 months, and no patients underwent prostacyclin infusion after 7 months.
Table 3. Changes in clinical parameters among treatment-naïve patients at baseline.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 7.5 (4.3–8.8) 4.0 (3.3–5.0) −3.5 (−47) 0.022
Mean PAP, mmHg 63.0 (55.0–75.8) 44.5 (37.0–51.5) −18.5 (−29) 0.006
PAWP, mmHg 7.5 (6.3–9.8) 8.0 (6.5–10.3) 0.5 (7) 0.61
CO, L/min 3.1 (2.4–4.3) 5.9 (5.1–7.2) 2.8 (90) 0.006
CI, L/min per m2 2.1 (1.7–2.5) 4.2 (3.5–4.6) 2.1 (100) 0.006
PVR, WU 17.5 (13.2–21.9) 5.9 (3.8–9.6) −11.6 (−66) 0.006
Echocardiography
TAPSE, cm 1.4 (1.3–1.5) 2.3 (2.1–2.7) 0.9 (64) 0.009
RVS’, cm 9.3 (7.9–10.8) 13.5 (13.0–14.3) 4.2 (45) 0.035
RAA, cm2 18.5 (15.0–21.1) 15.2 (13.5–16.7) −3.3 (−18) 0.076
RVEDA, cm2 27.0 (25.0–33.2) 23.6 (21.0–24.6) −3.4 (−13) 0.058
RVESA, cm2 22.9 (18.7–25.4) 14.8 (14.0–16.8) −8.1 (−35) 0.009
FAC, % 22.9 (15.9–25.2) 33.1 (29.5–35.0) 10.2 (45) 0.018
WHO-FC
I or II 1 (10) 8 (80)
III or IV 9 (90) 2 (20)
6MWD, m 400.0 (326.5–432.0) 471.5 (451.5–479.2) 71.5 (18) 0.030
BNP, pg/mL 200.8 (41.9–379.5) 20.2 (12.6–24.5) −180.6 (−90) 0.006
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Ten patients were analyzed in hemodynamics, and nine patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 4. Hemodynamic and echocardiographic changes in treatment-naïve patients.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Figure 5. Event-free rates in treatment-naïve patients.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy in treatment-naïve patients are shown. The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite endpoint of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Discussion
In the present study, triple oral combination therapy with macitentan, riociguat, and selexipag improved the hemodynamics, right ventricular function, and clinical function with good tolerability in patients with PAH. Most of the low-/intermediate-risk patients and around half of the high-risk patients could be treated sufficiently with this triple oral combination therapy although it is difficult to generalize these findings.
Two previous studies investigated the efficacy of the combination of prostacyclin infusion, an ERA, and a phosphodiesterase-5 inhibitor (PDE-5i) for PAH,7,8 but data regarding triple oral combination therapy are limited. One study related to triple oral combination therapy is the subgroup analysis of the GRIPHON study, which demonstrated a change in the symptom burden after administration of selexipag in addition to an ERA and PDE-5i.6 Recently, a randomized control study (TRITON study) is also under analysis which investigated the efficacy and safety of triple oral combination therapy with macitentan, tadalafil, and selexipag versus dual oral combination therapy with macitentan and tadalafil.18 The present study is the first to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag using real-world data.
Our results of improved hemodynamics are consistent with previous observational studies that investigated the effectiveness of triple combination therapy including prostacyclin infusion.7 Sitbon et al.7 reported that with intravenous administration of epoprostenol and oral administration of bosentan and sildenafil, the mean PAP, PVR, and cardiac index improved by 33%, 71%, and 119%, respectively. Another observational study involving a combination of ambrisentan, tadalafil, and subcutaneous treprostinil also demonstrated significant improvement of the mean PAP, PVR, and cardiac index by 30%, 66%, and 94%, respectively.8 There are similarities between the results of these previous studies and the results of the present study, suggesting that triple oral combination therapy with macitentan, riociguat, and selexipag can powerfully improve the hemodynamics in patients with PAH. In the TRITON study, triple oral combination therapy improved PVR by 54%, although it was almost the same degree as dual oral combination therapy.18 Improvement of hemodynamic in this study was greater than that of the TRITON study, partly because of the difference of the study design. Although findings from observational study, results in this study provided the possibility that triple oral combination therapy could also improve hemodynamics in the real-world population as well as the randomized controlled trial.
Our study also demonstrated a favorable long-term prognosis as well as improvement of the RVFAC, 6MWD, WHO-FC, and BNP concentration with triple oral combination therapy. In a past retrospective study of the dual combination of an ERA and PDE-5i, the 3-year overall survival rate was nearly 80%.19 In another French registry in which most patients were treated with monotherapy, the 3-year survival rate was <70%.20 The prognosis in the present study appears to be superior to that in previous reports. The low rate of mortality and hospitalization for heart failure was consistent with the TRITON study, in which the risk of first disease progression events was decreased about 41% in the triple oral therapy group.18 These results in this study could verify the efficacy of triple oral combination therapy in preventing disease progression of triple oral combination therapy found in the randomized controlled study.
In the present study, the treatment response in most of the low-/intermediate-risk patients was favorable with administration of the triple oral combination therapy, and around half of the high-risk patients did not need prostacyclin infusion. The current PAH guideline recommends initial oral therapy for low-/intermediate-risk patients, while high-risk patients are recommended to receive initial combination therapy including prostacyclin infusion.10 Patients in this study did not present decompensated heart failure and the urgent initiation of prostacyclin infusion was not necessary. Therefore, the triple oral combination therapy was initiated first and its efficacy was assessed within 6 months. Our data support recommendations in guidelines in low-/intermediate-risk patients and provide a novel possibility that around half of high-risk patients can be treated without prostacyclin infusion. Moreover, 66.7% of the patients who needed prostacyclin infusion had gene mutations, suggesting that the need for prostacyclin infusion can be largely affected by their genetic background. Therefore, we should be especially careful when we use triple oral combination therapy to treat patients with specific etiologies of PAH such as gene mutations.
With respect to safety, a past study investigating the combination of tadalafil as a PDE-5i and ambrisentan as an ERA showed that the discontinuation rate of dual combination therapy because of adverse events was 12% within 2 years of the mean duration of drug use.1 In the subgroup analysis of the GRIPHON study, which investigated the effectiveness of selexipag for the patients of PAH, a triple oral combination therapy with selexipag, ERA, and PDE-5i was discontinued in 19.0% of patients due to adverse events.6 The rate of 15% in the present study was lower than that of the GRIPHON study, suggesting good tolerability in real world data. With regard to the maximum tolerated dose, a past subgroup analysis that investigated the change in the symptom burden after taking selexipag in addition to an ERA and PDE-5i showed that only 27.9% of patients who received selexipag reached the maximum dose of selexipag.6 Another study of the combination of riociguat and macitentan showed that about 70% of patients reached the maximum maintenance dose of riociguat. In the present study, 76.9% and 92.3% of patients could be up-titrated to the maximum dose with selexipag and riociguat, respectively. Thus, this study demonstrated that it is quite possible to up-titrate each drug to the maximum dose, even in patients treated with triple oral combination therapy.
The subgroup analysis showed that the hemodynamics, right ventricular function, and clinical function powerfully improved, and the degree of improvement was similar to those in the overall patient analysis. Moreover, no patients died or were hospitalized for heart failure during the observation period. These results suggest that triple oral combination therapy with macitentan, riociguat, and selexipag can be a promising treatment strategy in treatment-naïve patients.
This study has some limitations. This was a small, single-center, retrospective study that included various types of PAH and some patients were not treatment naïve at baseline. Each etiology of PAH might have affected the results of the study differently. Prostacyclin infusion was initiated within 7 months, and no patients underwent prostacyclin infusion after 7 months, which is towards a bias of an initial high-risk population of patients in which initial triple oral combination treatment was chosen. The drug regimens were decided by the physicians. Furthermore, indirect Fick method was adopted as the measurement of CO. This was not recommended in the European Society of Cardiology/European Respiratory Society Guidelines 2015, but was admitted for use in the practical situation in the Japanese PAH guideline.11 As the results could be affected by the measurement methods of CO, further validation would be warranted.
Conclusion
This study demonstrated the effectiveness of triple oral combination therapy with macitentan, riociguat, and selexipag in patients with PAH. Our data suggest that this triple oral combination therapy is associated with improvement of hemodynamics, right ventricular function, and clinical function with good tolerability. In particular, this triple oral combination therapy can be a promising therapeutic strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further investigation is required to validate these findings.
Supplemental Material
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sj-tif-6-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
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Supplemental material, sj-tif-6-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
We thank all the doctors, nurses, and supporting medical staff members who were involved in the care of the patients enrolled in this study. We also thank Angela Morben, DVM, ELS, from Edanz Group (https://en-author-services.edanzgroup.com/ac), for editing a draft of this manuscript.
Author contribution(s): Mizuki Momoi: Data curation; Formal analysis; Investigation; Writing-original draft.
Takahiro Hiraide: Conceptualization; Methodology; Writing-review & editing.
Yoshiki Shinya: Conceptualization; Validation; Writing-review & editing.
Hiromi Momota: Data curation; Validation; Methodology; Writing-review & editing.
Shogo Fukui: Data curation; Validation; Formal analysis; Writing-review & editing.
Michiyuki Kawakami: Data curation; Validation; Formal analysis; Writing-review & editing.
Yuji Itabashi: Methodology; Data curation; Resources, Writing-review & editing.
Keiichi Fukuda: Supervision; Investigation; Writing-review & editing.
Masaharu Kataoka: Conceptualization; Project administration; Writing-review & editing.
Conflict of interest statement: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Masaharu Kataoka https://orcid.org/0000-0001-8034-1005
Supplemental material: Supplemental material for this article is available online. | Oral | DrugAdministrationRoute | CC BY-NC | 33627044 | 18,982,738 | 2021 |
What was the administration route of drug 'SELEXIPAG'? | Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension.
The evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.
Among consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan-Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.
Twenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12-47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.
Triple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings.The reviews of this paper are available via the supplemental material section.
Introduction
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by elevated pulmonary arterial pressure (PAP) due to remodeling of the pulmonary arterial bed and right sided-heart failure. Three types of PAH-specific vasodilators targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway have been developed. Combination therapy targeting these different pathways has recently been shown to improve hemodynamics, clinical functions, and even hard endpoints including survival or worsening of PAH in several recent randomized controlled trials and metanalyses.1–5 The effectiveness of triple combination therapy targeting all three of these pathways has also been reported.6–8 However, two such studies analyzed patients who were treated with two types of oral vasodilators and prostacyclin infusion,7,8 and another study was a subgroup analysis of a randomized controlled trial demonstrating a change in the symptom burden by the addition of selexipag, a prostacyclin receptor agonist, to background double combination therapy targeting other pathways.6 Therefore, evidence of the efficacy and safety of triple oral combination therapy remains scarce.
The most recently approved PAH-specific vasodilators targeting each of the three types of pathways are macitentan, which is an endothelin receptor antagonist (ERA); riociguat, which is a soluble guanylate cyclase stimulator targeting the nitric oxide pathway; and selexipag, which is an oral non-prostanoid prostacyclin receptor agonist. All three of these are orally available drugs. The effectiveness of these vasodilators for PAH has recently been proven;2,3,9 however, no clinical trials have been performed to investigate the effectiveness of the combination of these three vasodilators. Furthermore, although the current guideline recommends initial oral therapy for patients with low or intermediate risk,10 how many patients with low or intermediate risk can actually be treated with only oral combination therapy remains poorly documented to date.
Therefore, the purposes of this study were to clarify the clinical effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag and to assess which risk groups can be adequately treated with this combination therapy.
Methods
Study design
This retrospective study was performed in Keio University Hospital in Japan. This study was approved by the Ethics Committee of Keio University Hospital, and written informed consent was obtained from all patients when they received genetic tests or were hospitalized. Patients with PAH who had received triple oral combination therapy with macitentan, riociguat, and selexipag were evaluated among all consecutive patients who were referred to Keio University Hospital from 2009 to 2020.
The diagnosis of PAH was made according to the current guideline.11 Patients who were lost to follow-up or underwent maintenance hemodialysis were excluded. Baseline data were measured at the time of referral to our hospital. If patients were treatment-naïve upon referral to our hospital, the combination of macitentan, riociguat, and selexipag was initiated after diagnosis. The method of up-titration and prioritization of the vasodilators as well as the selection of sequential therapy or upfront therapy was determined at the discretion of the specialized physicians. The doses of the vasodilators were titrated to the maximal tolerated doses. For patients who had already received other PAH-specific vasodilators at the time of enrollment, these drugs targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway were switched to macitentan, riociguat, and selexipag, respectively, with the intention of further improvement of hemodynamics.
Patients received genetic counseling, and genetic tests were performed with informed consent. The methods of the genetic tests, including whole-exome sequencing, are described in our previous reports.12,13
Parameters and outcomes
Dedicated cardiologists performed right-heart catheterization (RHC) without sedation at baseline and follow-up. The right arterial pressure, mean PAP, and pulmonary arterial wedge pressure were measured by RHC. The zero pressure point was set at the level of the midthorax. Cardiac output (CO) was calculated by the Fick technique using oxygen consumption estimated by 125 times the body surface area according to a previous report.14 Pulmonary vascular resistance (PVR) was calculated as the difference between the mean PAP and pulmonary arterial wedge pressure divided by the CO.
The 6-minute walk distance (6MWD), blood concentration of B-type natriuretic peptide (BNP), and World Health Organization functional class (WHO-FC) were measured at the time of hospitalization for RHC.
Standard two-dimensional, M-mode, and Doppler images, including the tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic excursion velocity (RVS’), were obtained by echocardiographers in accordance with the current echocardiography guideline.15 Dedicated cardiologists analyzed the data and measured the right atrial area (RAA), right ventricular end-diastolic area (RVEDA), right ventricular end-systolic area, and right ventricular fractional area change (RVFAC).
Hemodynamic changes measured by RHC, echocardiographic changes, and changes in the 6MWD, BNP concentration, and WHO-FC were assessed from baseline to follow-up.
The events of all-cause death, hospitalization for heart failure, initiation of prostacyclin infusion, and discontinuation of any of the three vasodilators (macitentan, riociguat, and selexipag) because of adverse events since administration of all three vasodilators were collected. The observation period was terminated when patients died, underwent prostacyclin infusion, or stopped taking macitentan, riociguat, or selexipag for any reason.
All patients enrolled in this study were divided into two groups by risk assessment using the three-category REVEAL 2.0 risk score,16 and the prostacyclin infusion-free rate was analyzed in each group. If the value was unmeasured, the value of zero was assigned. According to the three-category REVEAL 2.0 risk score, the high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), and the low-/intermediate-risk group was defined as patients with a predicted 1-year survival rate of ⩾90% (REVEAL 2.0 risk score ⩽8).
Subgroup analysis
Patients who were treatment-naïve at baseline and treated with only macitentan, riociguat, and selexipag for PAH were also independently assessed by subgroup analysis. Their hemodynamics, echocardiography, and clinical function were measured and clinical events were collected similarly to the overall patient analysis.
Statistical analysis
Data are described as median and interquartile range unless otherwise indicated. Wilcoxon’s signed rank test was used to compare the parameters of hemodynamics, echocardiography, 6MWD, and BNP concentration from baseline to the latest follow-up. The cases which had a missing value either at baseline or follow-up were excluded from each analysis. Differences with a p-value of <0.05 were considered statistically significant. All p-values were two-tailed. Event-free rates were analyzed using the Kaplan–Meier method. All analyses were performed using R software (version 3.6.3), and figures were obtained using GraphPad Prism (version 8.0 for Mac; GraphPad Software, La Jolla, CA, USA).
Results
Patient characteristics
The patients’ baseline characteristics and medications are presented in Table 1 and Supplemental material Table 1 online. One patient who was lost to follow-up and one patient who had been undergoing maintenance hemodialysis were excluded; thus, 26 patients were enrolled in this study. The patients were predominantly female (73.1%) with a median age of 38 years. The major etiology of PAH was idiopathic PAH (38.5%) followed by connective tissue disease-associated PAH (26.9%), heritable PAH (19.2%), and congenital heart disease-associated PAH (15.4%). Most patients were treatment-naïve (65.4%), and others were taking some PAH medications at baseline.
Table 1. Demographics and characteristics at baseline.
Variable Triple oral combination therapy
N = 26
Female 19 (73.1)
Age, years 38 (23–48)
WHO-FC
I/II/III/IV 0/9/16/1 (0.0/34.6/61.5/3.8)
BNP, pg/mL 105.25 (36.7–285.5)
6MWD, m 397.5 (312.8–441.8)
PAH etiology
IPAH 10 (38.5)
HPAH 5 (19.2)
CTD-PAH 7 (26.9)
CHD-PAH 4 (15.4)
Medication
Treatment-naïve 17 (65.4)
Single 3 (11.5)
Double 2 (7.7)
Triple 4 (15.4)
Risk assessment*
High risk 12 (46.2)
Intermediate risk 4 (15.4)
Low risk 10 (38.5)
Genetic mutation**
BMPR2 5 (23.8)
ACVRL 1 (4.8)
RNF213 1 (4.8)
Data are expressed as number (%) or median (interquartile range).
* Risk assessment was calculated using the three-category REVEAL 2.0 risk score.16 The high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), the intermediate-risk group was defined as patients with a predicted 1-year survival rate of 90–<95% (REVEAL 2.0 risk score = 7 or 8), and the low-risk group was defined as patients with a predicted 1-year survival rate of ⩾95% (REVEAL 2.0 risk score ⩽6).
** Among 26 patients, 21 were genetically tested and 15 had no genetic mutations related to PAH.
6MWD, 6-minute walk distance; ACVRL1, activin A receptor-like kinase 1; BMPR2, bone morphogenetic protein receptor type 2; BNP, B-type natriuretic peptide; CHD, congenital heart disease; CTD, connective tissue disease; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; RNF213, ring finger protein 213; WHO-FC, World Health Organization functional class.
Ten patients with idiopathic PAH, five with heritable PAH, three with connective tissue disease-associated PAH, and three with congenital heart disease-associated PAH were genetically tested. All five patients with heritable PAH had mutations in known PAH-related genes such as bone morphogenetic protein receptor type 2 (BMPR2) and one patient with idiopathic PAH had a mutation in ring finger protein 213 (RNF213), which we recently reported as a novel PAH-related gene.13,17
Safety and tolerability
Discontinuation of macitentan, riociguat, or selexipag because of adverse events occurred in four of 26 patients (15%). Among these four patients, one had diarrhea with selexipag, one had suspected myelosuppression with macitentan, one had nausea with riociguat, and one had hypotension with riociguat. These patients changed their drug to another drug targeting the same pathway. No adverse events, including death, hospitalization for heart failure, or prostacyclin infusion, were observed after discontinuation of each drug.
The maximum tolerated doses of the vasodilators are summarized in Supplemental Table 2. In detail, 25 (96.2%), 24 (92.3%), and 20 (76.9%) patients were taking the maximum dose of macitentan, riociguat, and selexipag, respectively. Seventeen (65.4%) patients reached the maximum dose of all three vasodilators.
Changes and outcomes after treatment
Hemodynamic data were available for 18 patients. The detailed study flow chart is shown in Supplemental Figure 1. The hemodynamics, WHO-FC, BNP concentration, and 6MWD at baseline and follow-up are presented in Table 2. The median observation period was 441 (229–1103) days. Hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 65% decrease in the mean PVR. The CO significantly increased by 82% from baseline to follow-up. Although >70% of patients had a WHO-FC of III or IV at baseline, 89% of patients had a WHO-FC of I or II at follow-up. The 6MWD and BNP concentration were also significantly improved [Figure 1(a)].
Table 2. Changes in clinical parameters.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 6.5 (4.0–8.0) 4.0 (3.0–5.0) −2.5 (−38) 0.005
Mean PAP, mmHg 56.0 (46.3–65.5) 40.0 (30.0–47.0) −16.0 (−29) <0.001
PAWP, mmHg 7.5 (6.0–9.8) 9.0 (8.0–11.0) 1.5 (20) 0.68
CO, L/min 3.3 (2.4–4.5) 6.0 (5.1–6.7) 2.7 (82) <0.001
CI, L/min per m2 2.2 (1.7–2.7) 3.8 (3.3–4.5) 1.6 (73) <0.001
PVR, WU 13.5 (8.8–21.5) 4.7 (2.8–6.9) −8.8 (−65) <0.001
Echocardiography
TAPSE, cm 1.5 (1.3–1.8) 2.3 (1.9–2.6) 0.8 (53) 0.001
RVS’, cm 9.7 (7.8–11.8) 13.3 (12.4–14.4) 3.6 (37) 0.001
RAA, cm2 17.2 (14.9–21.3) 16.4 (14.1–21.0) −0.8 (−5) 0.49
RVEDA, cm2 26.9 (22.8–33.1) 24.1 (21.0–30.3) −2.8 (−10) 0.21
RVESA, cm2 20.4 (16.3–23.9) 16.4 (13.8–21.1) −4.0 (−20) 0.006
FAC, % 23.6 (16.2–26.9) 32.9 (29.1–35.8) 9.3 (39) <0.001
WHO-FC
I or II 4 (22) 16 (89) – –
III or IV 14 (78) 2 (11) – –
6MWD, m 405.0 (303.0–441.8) 472.0 (439.5–493.5) 67.0 (17) 0.046
BNP, pg/mL 187.8 (36.7–379.5) 17.5 (10.3–27.2) −170.3 (−91) <0.001
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Eighteen patients were analyzed in hemodynamics, and 20 patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 1. Hemodynamic and echocardiographic changes.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Echocardiographic data were available for 20 patients (Supplemental Figure 1). The echocardiographic data are presented in Table 2. The median follow-up period was 737 (256–1179) days. Right ventricular function based on the TAPSE, RVS’, and RVFAC was significantly improved from baseline to follow-up, although the RAA and RVEDA were not [Figure 1(b)].
The Kaplan–Meier curves since administration of all three vasodilators are shown in Figure 2. The 1- and 2-year survival rates were both 93.3%. One patient died of multiple organ failure after femoral neck fracture during the observation period. The overall survival rate was 92.3% with median follow-up period of 33 (24–43) months. No patients were hospitalized for heart failure during the observation period. Prostacyclin infusion was initiated in six patients (25.4%) within 1 year. Among these six patients, selexipag was switched to subcutaneous infusion of treprostinil in one patient, an intravenous infusion of epoprostenol was added to the triple oral combination therapy in another patient, and a subcutaneous infusion of treprostinil was added to the triple oral combination therapy in the remaining four patients. Selexipag was not discontinued in some patients to reduce maintenance dose of the prostacyclin for infusion. No other patients underwent prostacyclin infusion after 1 year. Among six patients who underwent prostacyclin infusion within 1 year, three patients had a BMPR2 mutation, one patient had an RNF213 mutation, and one patient had Eisenmenger syndrome due to an atrial septal defect. Composite events of all-cause death, hospitalization for heart failure, and initiation of prostacyclin infusion occurred in 16.6% of the patients within 6 months and 30.4% of the patients in 1 and 2 years.
Figure 2. Event-free rates in all patients with triple oral combination therapy.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy are shown (n = 26). The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Among 14 patients who were classified as low-/intermediate-risk by the three-category REVEAL 2.0 risk score,16 the prostacyclin-free rate was 92.9% at 3 years, while the rate was 55.0% at 2 years in 12 high-risk patients (Figure 3). The difference was not statistically significant (p = 0.058). Hemodynamic changes from baseline to follow-up in each low/intermediate and high-risk group are summarized in Supplemental Table 3. Among five patients who were classified as high-risk based on the three-category REVEAL 2.0 risk score and needed prostacyclin infusion, three patients had BMPR2 mutations and one patient had a RNF213 mutation.
Figure 3. Kaplan–Meier curve for prostacyclin-free rate in each risk category.
The prostacyclin infusion-free rates in each risk category are shown. The patients were divided into two risk categories by the REVEAL 2.0 risk score.16 The p-values were calculated by the log-rank test.
Subgroup analysis in treatment-naïve patients
Seventeen patients were treatment-naïve at baseline. Six patients were treatment naïve at baseline, but treated with other pulmonary vasodilators. In five out of these six patients, oral medication was switched from beraprost to selexipag, and in one patient, it was switched from ambrisentan and tadalafil to macitentan and riociguat. Thus, these six patients were excluded from the subgroup analysis. Among the remaining 11 patients for the subgroup analysis, the median time from initiation of the first PAH drug to the start of the third PAH drug was 24 (12–47) days. The way of up-titration in treatment naïve patients was as follows. Macitentan 10 mg was initiated at first and followed by riociguat 3.0 mg within 2 weeks. The dose of riociguat was up-titrated by 1.5 mg every 2 weeks with attention to adverse effects. In 36% of treatment naïve patients, selexipag was initiated after riociguat was up-titrated to maximum tolerated dose, whereas selexipag was started within 2 weeks from initiating macitentan in 64% of patients. Selexipag was increased by 0.4 mg every 2 weeks to maximum tolerated dose with attention to side effects. One patient (9.1%) discontinued macitentan because of suspected myelosuppression, and another patient (9.1%) discontinued riociguat because of nausea. RHC data in 10 patients and echocardiographic data in nine patients were available at baseline and at follow-up during the triple oral combination therapy. The patients’ hemodynamic and right ventricular function parameters are presented in Table 3 and Figure 4. The median follow-up period of the hemodynamic analysis was 293 (211–473) days. The hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 66% decrease in the PVR. The CO increased by 90% from baseline to follow-up. The median follow-up period of echocardiography was 385 (230–594) days. The TAPSE, RVS’, and RVFAC, indicating right ventricular function, increased significantly. The WHO-FC, 6MWD, and BNP concentration in this subgroup also improved significantly. In the Kaplan–Meier analysis, no patients died or were hospitalized for heart failure (Figure 5). Prostacyclin infusion was initiated in 31.8% of patients within 7 months, and no patients underwent prostacyclin infusion after 7 months.
Table 3. Changes in clinical parameters among treatment-naïve patients at baseline.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 7.5 (4.3–8.8) 4.0 (3.3–5.0) −3.5 (−47) 0.022
Mean PAP, mmHg 63.0 (55.0–75.8) 44.5 (37.0–51.5) −18.5 (−29) 0.006
PAWP, mmHg 7.5 (6.3–9.8) 8.0 (6.5–10.3) 0.5 (7) 0.61
CO, L/min 3.1 (2.4–4.3) 5.9 (5.1–7.2) 2.8 (90) 0.006
CI, L/min per m2 2.1 (1.7–2.5) 4.2 (3.5–4.6) 2.1 (100) 0.006
PVR, WU 17.5 (13.2–21.9) 5.9 (3.8–9.6) −11.6 (−66) 0.006
Echocardiography
TAPSE, cm 1.4 (1.3–1.5) 2.3 (2.1–2.7) 0.9 (64) 0.009
RVS’, cm 9.3 (7.9–10.8) 13.5 (13.0–14.3) 4.2 (45) 0.035
RAA, cm2 18.5 (15.0–21.1) 15.2 (13.5–16.7) −3.3 (−18) 0.076
RVEDA, cm2 27.0 (25.0–33.2) 23.6 (21.0–24.6) −3.4 (−13) 0.058
RVESA, cm2 22.9 (18.7–25.4) 14.8 (14.0–16.8) −8.1 (−35) 0.009
FAC, % 22.9 (15.9–25.2) 33.1 (29.5–35.0) 10.2 (45) 0.018
WHO-FC
I or II 1 (10) 8 (80)
III or IV 9 (90) 2 (20)
6MWD, m 400.0 (326.5–432.0) 471.5 (451.5–479.2) 71.5 (18) 0.030
BNP, pg/mL 200.8 (41.9–379.5) 20.2 (12.6–24.5) −180.6 (−90) 0.006
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Ten patients were analyzed in hemodynamics, and nine patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 4. Hemodynamic and echocardiographic changes in treatment-naïve patients.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Figure 5. Event-free rates in treatment-naïve patients.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy in treatment-naïve patients are shown. The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite endpoint of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Discussion
In the present study, triple oral combination therapy with macitentan, riociguat, and selexipag improved the hemodynamics, right ventricular function, and clinical function with good tolerability in patients with PAH. Most of the low-/intermediate-risk patients and around half of the high-risk patients could be treated sufficiently with this triple oral combination therapy although it is difficult to generalize these findings.
Two previous studies investigated the efficacy of the combination of prostacyclin infusion, an ERA, and a phosphodiesterase-5 inhibitor (PDE-5i) for PAH,7,8 but data regarding triple oral combination therapy are limited. One study related to triple oral combination therapy is the subgroup analysis of the GRIPHON study, which demonstrated a change in the symptom burden after administration of selexipag in addition to an ERA and PDE-5i.6 Recently, a randomized control study (TRITON study) is also under analysis which investigated the efficacy and safety of triple oral combination therapy with macitentan, tadalafil, and selexipag versus dual oral combination therapy with macitentan and tadalafil.18 The present study is the first to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag using real-world data.
Our results of improved hemodynamics are consistent with previous observational studies that investigated the effectiveness of triple combination therapy including prostacyclin infusion.7 Sitbon et al.7 reported that with intravenous administration of epoprostenol and oral administration of bosentan and sildenafil, the mean PAP, PVR, and cardiac index improved by 33%, 71%, and 119%, respectively. Another observational study involving a combination of ambrisentan, tadalafil, and subcutaneous treprostinil also demonstrated significant improvement of the mean PAP, PVR, and cardiac index by 30%, 66%, and 94%, respectively.8 There are similarities between the results of these previous studies and the results of the present study, suggesting that triple oral combination therapy with macitentan, riociguat, and selexipag can powerfully improve the hemodynamics in patients with PAH. In the TRITON study, triple oral combination therapy improved PVR by 54%, although it was almost the same degree as dual oral combination therapy.18 Improvement of hemodynamic in this study was greater than that of the TRITON study, partly because of the difference of the study design. Although findings from observational study, results in this study provided the possibility that triple oral combination therapy could also improve hemodynamics in the real-world population as well as the randomized controlled trial.
Our study also demonstrated a favorable long-term prognosis as well as improvement of the RVFAC, 6MWD, WHO-FC, and BNP concentration with triple oral combination therapy. In a past retrospective study of the dual combination of an ERA and PDE-5i, the 3-year overall survival rate was nearly 80%.19 In another French registry in which most patients were treated with monotherapy, the 3-year survival rate was <70%.20 The prognosis in the present study appears to be superior to that in previous reports. The low rate of mortality and hospitalization for heart failure was consistent with the TRITON study, in which the risk of first disease progression events was decreased about 41% in the triple oral therapy group.18 These results in this study could verify the efficacy of triple oral combination therapy in preventing disease progression of triple oral combination therapy found in the randomized controlled study.
In the present study, the treatment response in most of the low-/intermediate-risk patients was favorable with administration of the triple oral combination therapy, and around half of the high-risk patients did not need prostacyclin infusion. The current PAH guideline recommends initial oral therapy for low-/intermediate-risk patients, while high-risk patients are recommended to receive initial combination therapy including prostacyclin infusion.10 Patients in this study did not present decompensated heart failure and the urgent initiation of prostacyclin infusion was not necessary. Therefore, the triple oral combination therapy was initiated first and its efficacy was assessed within 6 months. Our data support recommendations in guidelines in low-/intermediate-risk patients and provide a novel possibility that around half of high-risk patients can be treated without prostacyclin infusion. Moreover, 66.7% of the patients who needed prostacyclin infusion had gene mutations, suggesting that the need for prostacyclin infusion can be largely affected by their genetic background. Therefore, we should be especially careful when we use triple oral combination therapy to treat patients with specific etiologies of PAH such as gene mutations.
With respect to safety, a past study investigating the combination of tadalafil as a PDE-5i and ambrisentan as an ERA showed that the discontinuation rate of dual combination therapy because of adverse events was 12% within 2 years of the mean duration of drug use.1 In the subgroup analysis of the GRIPHON study, which investigated the effectiveness of selexipag for the patients of PAH, a triple oral combination therapy with selexipag, ERA, and PDE-5i was discontinued in 19.0% of patients due to adverse events.6 The rate of 15% in the present study was lower than that of the GRIPHON study, suggesting good tolerability in real world data. With regard to the maximum tolerated dose, a past subgroup analysis that investigated the change in the symptom burden after taking selexipag in addition to an ERA and PDE-5i showed that only 27.9% of patients who received selexipag reached the maximum dose of selexipag.6 Another study of the combination of riociguat and macitentan showed that about 70% of patients reached the maximum maintenance dose of riociguat. In the present study, 76.9% and 92.3% of patients could be up-titrated to the maximum dose with selexipag and riociguat, respectively. Thus, this study demonstrated that it is quite possible to up-titrate each drug to the maximum dose, even in patients treated with triple oral combination therapy.
The subgroup analysis showed that the hemodynamics, right ventricular function, and clinical function powerfully improved, and the degree of improvement was similar to those in the overall patient analysis. Moreover, no patients died or were hospitalized for heart failure during the observation period. These results suggest that triple oral combination therapy with macitentan, riociguat, and selexipag can be a promising treatment strategy in treatment-naïve patients.
This study has some limitations. This was a small, single-center, retrospective study that included various types of PAH and some patients were not treatment naïve at baseline. Each etiology of PAH might have affected the results of the study differently. Prostacyclin infusion was initiated within 7 months, and no patients underwent prostacyclin infusion after 7 months, which is towards a bias of an initial high-risk population of patients in which initial triple oral combination treatment was chosen. The drug regimens were decided by the physicians. Furthermore, indirect Fick method was adopted as the measurement of CO. This was not recommended in the European Society of Cardiology/European Respiratory Society Guidelines 2015, but was admitted for use in the practical situation in the Japanese PAH guideline.11 As the results could be affected by the measurement methods of CO, further validation would be warranted.
Conclusion
This study demonstrated the effectiveness of triple oral combination therapy with macitentan, riociguat, and selexipag in patients with PAH. Our data suggest that this triple oral combination therapy is associated with improvement of hemodynamics, right ventricular function, and clinical function with good tolerability. In particular, this triple oral combination therapy can be a promising therapeutic strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further investigation is required to validate these findings.
Supplemental Material
sj-pdf-1-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-1-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-2-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-2-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-3-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-3-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-4-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-4-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-5-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-5-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-7-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-7-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-tif-6-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-tif-6-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
We thank all the doctors, nurses, and supporting medical staff members who were involved in the care of the patients enrolled in this study. We also thank Angela Morben, DVM, ELS, from Edanz Group (https://en-author-services.edanzgroup.com/ac), for editing a draft of this manuscript.
Author contribution(s): Mizuki Momoi: Data curation; Formal analysis; Investigation; Writing-original draft.
Takahiro Hiraide: Conceptualization; Methodology; Writing-review & editing.
Yoshiki Shinya: Conceptualization; Validation; Writing-review & editing.
Hiromi Momota: Data curation; Validation; Methodology; Writing-review & editing.
Shogo Fukui: Data curation; Validation; Formal analysis; Writing-review & editing.
Michiyuki Kawakami: Data curation; Validation; Formal analysis; Writing-review & editing.
Yuji Itabashi: Methodology; Data curation; Resources, Writing-review & editing.
Keiichi Fukuda: Supervision; Investigation; Writing-review & editing.
Masaharu Kataoka: Conceptualization; Project administration; Writing-review & editing.
Conflict of interest statement: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Masaharu Kataoka https://orcid.org/0000-0001-8034-1005
Supplemental material: Supplemental material for this article is available online. | Oral | DrugAdministrationRoute | CC BY-NC | 33627044 | 18,982,738 | 2021 |
What was the dosage of drug 'AMBRISENTAN'? | Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension.
The evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.
Among consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan-Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.
Twenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12-47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.
Triple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings.The reviews of this paper are available via the supplemental material section.
Introduction
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by elevated pulmonary arterial pressure (PAP) due to remodeling of the pulmonary arterial bed and right sided-heart failure. Three types of PAH-specific vasodilators targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway have been developed. Combination therapy targeting these different pathways has recently been shown to improve hemodynamics, clinical functions, and even hard endpoints including survival or worsening of PAH in several recent randomized controlled trials and metanalyses.1–5 The effectiveness of triple combination therapy targeting all three of these pathways has also been reported.6–8 However, two such studies analyzed patients who were treated with two types of oral vasodilators and prostacyclin infusion,7,8 and another study was a subgroup analysis of a randomized controlled trial demonstrating a change in the symptom burden by the addition of selexipag, a prostacyclin receptor agonist, to background double combination therapy targeting other pathways.6 Therefore, evidence of the efficacy and safety of triple oral combination therapy remains scarce.
The most recently approved PAH-specific vasodilators targeting each of the three types of pathways are macitentan, which is an endothelin receptor antagonist (ERA); riociguat, which is a soluble guanylate cyclase stimulator targeting the nitric oxide pathway; and selexipag, which is an oral non-prostanoid prostacyclin receptor agonist. All three of these are orally available drugs. The effectiveness of these vasodilators for PAH has recently been proven;2,3,9 however, no clinical trials have been performed to investigate the effectiveness of the combination of these three vasodilators. Furthermore, although the current guideline recommends initial oral therapy for patients with low or intermediate risk,10 how many patients with low or intermediate risk can actually be treated with only oral combination therapy remains poorly documented to date.
Therefore, the purposes of this study were to clarify the clinical effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag and to assess which risk groups can be adequately treated with this combination therapy.
Methods
Study design
This retrospective study was performed in Keio University Hospital in Japan. This study was approved by the Ethics Committee of Keio University Hospital, and written informed consent was obtained from all patients when they received genetic tests or were hospitalized. Patients with PAH who had received triple oral combination therapy with macitentan, riociguat, and selexipag were evaluated among all consecutive patients who were referred to Keio University Hospital from 2009 to 2020.
The diagnosis of PAH was made according to the current guideline.11 Patients who were lost to follow-up or underwent maintenance hemodialysis were excluded. Baseline data were measured at the time of referral to our hospital. If patients were treatment-naïve upon referral to our hospital, the combination of macitentan, riociguat, and selexipag was initiated after diagnosis. The method of up-titration and prioritization of the vasodilators as well as the selection of sequential therapy or upfront therapy was determined at the discretion of the specialized physicians. The doses of the vasodilators were titrated to the maximal tolerated doses. For patients who had already received other PAH-specific vasodilators at the time of enrollment, these drugs targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway were switched to macitentan, riociguat, and selexipag, respectively, with the intention of further improvement of hemodynamics.
Patients received genetic counseling, and genetic tests were performed with informed consent. The methods of the genetic tests, including whole-exome sequencing, are described in our previous reports.12,13
Parameters and outcomes
Dedicated cardiologists performed right-heart catheterization (RHC) without sedation at baseline and follow-up. The right arterial pressure, mean PAP, and pulmonary arterial wedge pressure were measured by RHC. The zero pressure point was set at the level of the midthorax. Cardiac output (CO) was calculated by the Fick technique using oxygen consumption estimated by 125 times the body surface area according to a previous report.14 Pulmonary vascular resistance (PVR) was calculated as the difference between the mean PAP and pulmonary arterial wedge pressure divided by the CO.
The 6-minute walk distance (6MWD), blood concentration of B-type natriuretic peptide (BNP), and World Health Organization functional class (WHO-FC) were measured at the time of hospitalization for RHC.
Standard two-dimensional, M-mode, and Doppler images, including the tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic excursion velocity (RVS’), were obtained by echocardiographers in accordance with the current echocardiography guideline.15 Dedicated cardiologists analyzed the data and measured the right atrial area (RAA), right ventricular end-diastolic area (RVEDA), right ventricular end-systolic area, and right ventricular fractional area change (RVFAC).
Hemodynamic changes measured by RHC, echocardiographic changes, and changes in the 6MWD, BNP concentration, and WHO-FC were assessed from baseline to follow-up.
The events of all-cause death, hospitalization for heart failure, initiation of prostacyclin infusion, and discontinuation of any of the three vasodilators (macitentan, riociguat, and selexipag) because of adverse events since administration of all three vasodilators were collected. The observation period was terminated when patients died, underwent prostacyclin infusion, or stopped taking macitentan, riociguat, or selexipag for any reason.
All patients enrolled in this study were divided into two groups by risk assessment using the three-category REVEAL 2.0 risk score,16 and the prostacyclin infusion-free rate was analyzed in each group. If the value was unmeasured, the value of zero was assigned. According to the three-category REVEAL 2.0 risk score, the high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), and the low-/intermediate-risk group was defined as patients with a predicted 1-year survival rate of ⩾90% (REVEAL 2.0 risk score ⩽8).
Subgroup analysis
Patients who were treatment-naïve at baseline and treated with only macitentan, riociguat, and selexipag for PAH were also independently assessed by subgroup analysis. Their hemodynamics, echocardiography, and clinical function were measured and clinical events were collected similarly to the overall patient analysis.
Statistical analysis
Data are described as median and interquartile range unless otherwise indicated. Wilcoxon’s signed rank test was used to compare the parameters of hemodynamics, echocardiography, 6MWD, and BNP concentration from baseline to the latest follow-up. The cases which had a missing value either at baseline or follow-up were excluded from each analysis. Differences with a p-value of <0.05 were considered statistically significant. All p-values were two-tailed. Event-free rates were analyzed using the Kaplan–Meier method. All analyses were performed using R software (version 3.6.3), and figures were obtained using GraphPad Prism (version 8.0 for Mac; GraphPad Software, La Jolla, CA, USA).
Results
Patient characteristics
The patients’ baseline characteristics and medications are presented in Table 1 and Supplemental material Table 1 online. One patient who was lost to follow-up and one patient who had been undergoing maintenance hemodialysis were excluded; thus, 26 patients were enrolled in this study. The patients were predominantly female (73.1%) with a median age of 38 years. The major etiology of PAH was idiopathic PAH (38.5%) followed by connective tissue disease-associated PAH (26.9%), heritable PAH (19.2%), and congenital heart disease-associated PAH (15.4%). Most patients were treatment-naïve (65.4%), and others were taking some PAH medications at baseline.
Table 1. Demographics and characteristics at baseline.
Variable Triple oral combination therapy
N = 26
Female 19 (73.1)
Age, years 38 (23–48)
WHO-FC
I/II/III/IV 0/9/16/1 (0.0/34.6/61.5/3.8)
BNP, pg/mL 105.25 (36.7–285.5)
6MWD, m 397.5 (312.8–441.8)
PAH etiology
IPAH 10 (38.5)
HPAH 5 (19.2)
CTD-PAH 7 (26.9)
CHD-PAH 4 (15.4)
Medication
Treatment-naïve 17 (65.4)
Single 3 (11.5)
Double 2 (7.7)
Triple 4 (15.4)
Risk assessment*
High risk 12 (46.2)
Intermediate risk 4 (15.4)
Low risk 10 (38.5)
Genetic mutation**
BMPR2 5 (23.8)
ACVRL 1 (4.8)
RNF213 1 (4.8)
Data are expressed as number (%) or median (interquartile range).
* Risk assessment was calculated using the three-category REVEAL 2.0 risk score.16 The high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), the intermediate-risk group was defined as patients with a predicted 1-year survival rate of 90–<95% (REVEAL 2.0 risk score = 7 or 8), and the low-risk group was defined as patients with a predicted 1-year survival rate of ⩾95% (REVEAL 2.0 risk score ⩽6).
** Among 26 patients, 21 were genetically tested and 15 had no genetic mutations related to PAH.
6MWD, 6-minute walk distance; ACVRL1, activin A receptor-like kinase 1; BMPR2, bone morphogenetic protein receptor type 2; BNP, B-type natriuretic peptide; CHD, congenital heart disease; CTD, connective tissue disease; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; RNF213, ring finger protein 213; WHO-FC, World Health Organization functional class.
Ten patients with idiopathic PAH, five with heritable PAH, three with connective tissue disease-associated PAH, and three with congenital heart disease-associated PAH were genetically tested. All five patients with heritable PAH had mutations in known PAH-related genes such as bone morphogenetic protein receptor type 2 (BMPR2) and one patient with idiopathic PAH had a mutation in ring finger protein 213 (RNF213), which we recently reported as a novel PAH-related gene.13,17
Safety and tolerability
Discontinuation of macitentan, riociguat, or selexipag because of adverse events occurred in four of 26 patients (15%). Among these four patients, one had diarrhea with selexipag, one had suspected myelosuppression with macitentan, one had nausea with riociguat, and one had hypotension with riociguat. These patients changed their drug to another drug targeting the same pathway. No adverse events, including death, hospitalization for heart failure, or prostacyclin infusion, were observed after discontinuation of each drug.
The maximum tolerated doses of the vasodilators are summarized in Supplemental Table 2. In detail, 25 (96.2%), 24 (92.3%), and 20 (76.9%) patients were taking the maximum dose of macitentan, riociguat, and selexipag, respectively. Seventeen (65.4%) patients reached the maximum dose of all three vasodilators.
Changes and outcomes after treatment
Hemodynamic data were available for 18 patients. The detailed study flow chart is shown in Supplemental Figure 1. The hemodynamics, WHO-FC, BNP concentration, and 6MWD at baseline and follow-up are presented in Table 2. The median observation period was 441 (229–1103) days. Hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 65% decrease in the mean PVR. The CO significantly increased by 82% from baseline to follow-up. Although >70% of patients had a WHO-FC of III or IV at baseline, 89% of patients had a WHO-FC of I or II at follow-up. The 6MWD and BNP concentration were also significantly improved [Figure 1(a)].
Table 2. Changes in clinical parameters.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 6.5 (4.0–8.0) 4.0 (3.0–5.0) −2.5 (−38) 0.005
Mean PAP, mmHg 56.0 (46.3–65.5) 40.0 (30.0–47.0) −16.0 (−29) <0.001
PAWP, mmHg 7.5 (6.0–9.8) 9.0 (8.0–11.0) 1.5 (20) 0.68
CO, L/min 3.3 (2.4–4.5) 6.0 (5.1–6.7) 2.7 (82) <0.001
CI, L/min per m2 2.2 (1.7–2.7) 3.8 (3.3–4.5) 1.6 (73) <0.001
PVR, WU 13.5 (8.8–21.5) 4.7 (2.8–6.9) −8.8 (−65) <0.001
Echocardiography
TAPSE, cm 1.5 (1.3–1.8) 2.3 (1.9–2.6) 0.8 (53) 0.001
RVS’, cm 9.7 (7.8–11.8) 13.3 (12.4–14.4) 3.6 (37) 0.001
RAA, cm2 17.2 (14.9–21.3) 16.4 (14.1–21.0) −0.8 (−5) 0.49
RVEDA, cm2 26.9 (22.8–33.1) 24.1 (21.0–30.3) −2.8 (−10) 0.21
RVESA, cm2 20.4 (16.3–23.9) 16.4 (13.8–21.1) −4.0 (−20) 0.006
FAC, % 23.6 (16.2–26.9) 32.9 (29.1–35.8) 9.3 (39) <0.001
WHO-FC
I or II 4 (22) 16 (89) – –
III or IV 14 (78) 2 (11) – –
6MWD, m 405.0 (303.0–441.8) 472.0 (439.5–493.5) 67.0 (17) 0.046
BNP, pg/mL 187.8 (36.7–379.5) 17.5 (10.3–27.2) −170.3 (−91) <0.001
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Eighteen patients were analyzed in hemodynamics, and 20 patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 1. Hemodynamic and echocardiographic changes.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Echocardiographic data were available for 20 patients (Supplemental Figure 1). The echocardiographic data are presented in Table 2. The median follow-up period was 737 (256–1179) days. Right ventricular function based on the TAPSE, RVS’, and RVFAC was significantly improved from baseline to follow-up, although the RAA and RVEDA were not [Figure 1(b)].
The Kaplan–Meier curves since administration of all three vasodilators are shown in Figure 2. The 1- and 2-year survival rates were both 93.3%. One patient died of multiple organ failure after femoral neck fracture during the observation period. The overall survival rate was 92.3% with median follow-up period of 33 (24–43) months. No patients were hospitalized for heart failure during the observation period. Prostacyclin infusion was initiated in six patients (25.4%) within 1 year. Among these six patients, selexipag was switched to subcutaneous infusion of treprostinil in one patient, an intravenous infusion of epoprostenol was added to the triple oral combination therapy in another patient, and a subcutaneous infusion of treprostinil was added to the triple oral combination therapy in the remaining four patients. Selexipag was not discontinued in some patients to reduce maintenance dose of the prostacyclin for infusion. No other patients underwent prostacyclin infusion after 1 year. Among six patients who underwent prostacyclin infusion within 1 year, three patients had a BMPR2 mutation, one patient had an RNF213 mutation, and one patient had Eisenmenger syndrome due to an atrial septal defect. Composite events of all-cause death, hospitalization for heart failure, and initiation of prostacyclin infusion occurred in 16.6% of the patients within 6 months and 30.4% of the patients in 1 and 2 years.
Figure 2. Event-free rates in all patients with triple oral combination therapy.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy are shown (n = 26). The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Among 14 patients who were classified as low-/intermediate-risk by the three-category REVEAL 2.0 risk score,16 the prostacyclin-free rate was 92.9% at 3 years, while the rate was 55.0% at 2 years in 12 high-risk patients (Figure 3). The difference was not statistically significant (p = 0.058). Hemodynamic changes from baseline to follow-up in each low/intermediate and high-risk group are summarized in Supplemental Table 3. Among five patients who were classified as high-risk based on the three-category REVEAL 2.0 risk score and needed prostacyclin infusion, three patients had BMPR2 mutations and one patient had a RNF213 mutation.
Figure 3. Kaplan–Meier curve for prostacyclin-free rate in each risk category.
The prostacyclin infusion-free rates in each risk category are shown. The patients were divided into two risk categories by the REVEAL 2.0 risk score.16 The p-values were calculated by the log-rank test.
Subgroup analysis in treatment-naïve patients
Seventeen patients were treatment-naïve at baseline. Six patients were treatment naïve at baseline, but treated with other pulmonary vasodilators. In five out of these six patients, oral medication was switched from beraprost to selexipag, and in one patient, it was switched from ambrisentan and tadalafil to macitentan and riociguat. Thus, these six patients were excluded from the subgroup analysis. Among the remaining 11 patients for the subgroup analysis, the median time from initiation of the first PAH drug to the start of the third PAH drug was 24 (12–47) days. The way of up-titration in treatment naïve patients was as follows. Macitentan 10 mg was initiated at first and followed by riociguat 3.0 mg within 2 weeks. The dose of riociguat was up-titrated by 1.5 mg every 2 weeks with attention to adverse effects. In 36% of treatment naïve patients, selexipag was initiated after riociguat was up-titrated to maximum tolerated dose, whereas selexipag was started within 2 weeks from initiating macitentan in 64% of patients. Selexipag was increased by 0.4 mg every 2 weeks to maximum tolerated dose with attention to side effects. One patient (9.1%) discontinued macitentan because of suspected myelosuppression, and another patient (9.1%) discontinued riociguat because of nausea. RHC data in 10 patients and echocardiographic data in nine patients were available at baseline and at follow-up during the triple oral combination therapy. The patients’ hemodynamic and right ventricular function parameters are presented in Table 3 and Figure 4. The median follow-up period of the hemodynamic analysis was 293 (211–473) days. The hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 66% decrease in the PVR. The CO increased by 90% from baseline to follow-up. The median follow-up period of echocardiography was 385 (230–594) days. The TAPSE, RVS’, and RVFAC, indicating right ventricular function, increased significantly. The WHO-FC, 6MWD, and BNP concentration in this subgroup also improved significantly. In the Kaplan–Meier analysis, no patients died or were hospitalized for heart failure (Figure 5). Prostacyclin infusion was initiated in 31.8% of patients within 7 months, and no patients underwent prostacyclin infusion after 7 months.
Table 3. Changes in clinical parameters among treatment-naïve patients at baseline.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 7.5 (4.3–8.8) 4.0 (3.3–5.0) −3.5 (−47) 0.022
Mean PAP, mmHg 63.0 (55.0–75.8) 44.5 (37.0–51.5) −18.5 (−29) 0.006
PAWP, mmHg 7.5 (6.3–9.8) 8.0 (6.5–10.3) 0.5 (7) 0.61
CO, L/min 3.1 (2.4–4.3) 5.9 (5.1–7.2) 2.8 (90) 0.006
CI, L/min per m2 2.1 (1.7–2.5) 4.2 (3.5–4.6) 2.1 (100) 0.006
PVR, WU 17.5 (13.2–21.9) 5.9 (3.8–9.6) −11.6 (−66) 0.006
Echocardiography
TAPSE, cm 1.4 (1.3–1.5) 2.3 (2.1–2.7) 0.9 (64) 0.009
RVS’, cm 9.3 (7.9–10.8) 13.5 (13.0–14.3) 4.2 (45) 0.035
RAA, cm2 18.5 (15.0–21.1) 15.2 (13.5–16.7) −3.3 (−18) 0.076
RVEDA, cm2 27.0 (25.0–33.2) 23.6 (21.0–24.6) −3.4 (−13) 0.058
RVESA, cm2 22.9 (18.7–25.4) 14.8 (14.0–16.8) −8.1 (−35) 0.009
FAC, % 22.9 (15.9–25.2) 33.1 (29.5–35.0) 10.2 (45) 0.018
WHO-FC
I or II 1 (10) 8 (80)
III or IV 9 (90) 2 (20)
6MWD, m 400.0 (326.5–432.0) 471.5 (451.5–479.2) 71.5 (18) 0.030
BNP, pg/mL 200.8 (41.9–379.5) 20.2 (12.6–24.5) −180.6 (−90) 0.006
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Ten patients were analyzed in hemodynamics, and nine patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 4. Hemodynamic and echocardiographic changes in treatment-naïve patients.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Figure 5. Event-free rates in treatment-naïve patients.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy in treatment-naïve patients are shown. The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite endpoint of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Discussion
In the present study, triple oral combination therapy with macitentan, riociguat, and selexipag improved the hemodynamics, right ventricular function, and clinical function with good tolerability in patients with PAH. Most of the low-/intermediate-risk patients and around half of the high-risk patients could be treated sufficiently with this triple oral combination therapy although it is difficult to generalize these findings.
Two previous studies investigated the efficacy of the combination of prostacyclin infusion, an ERA, and a phosphodiesterase-5 inhibitor (PDE-5i) for PAH,7,8 but data regarding triple oral combination therapy are limited. One study related to triple oral combination therapy is the subgroup analysis of the GRIPHON study, which demonstrated a change in the symptom burden after administration of selexipag in addition to an ERA and PDE-5i.6 Recently, a randomized control study (TRITON study) is also under analysis which investigated the efficacy and safety of triple oral combination therapy with macitentan, tadalafil, and selexipag versus dual oral combination therapy with macitentan and tadalafil.18 The present study is the first to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag using real-world data.
Our results of improved hemodynamics are consistent with previous observational studies that investigated the effectiveness of triple combination therapy including prostacyclin infusion.7 Sitbon et al.7 reported that with intravenous administration of epoprostenol and oral administration of bosentan and sildenafil, the mean PAP, PVR, and cardiac index improved by 33%, 71%, and 119%, respectively. Another observational study involving a combination of ambrisentan, tadalafil, and subcutaneous treprostinil also demonstrated significant improvement of the mean PAP, PVR, and cardiac index by 30%, 66%, and 94%, respectively.8 There are similarities between the results of these previous studies and the results of the present study, suggesting that triple oral combination therapy with macitentan, riociguat, and selexipag can powerfully improve the hemodynamics in patients with PAH. In the TRITON study, triple oral combination therapy improved PVR by 54%, although it was almost the same degree as dual oral combination therapy.18 Improvement of hemodynamic in this study was greater than that of the TRITON study, partly because of the difference of the study design. Although findings from observational study, results in this study provided the possibility that triple oral combination therapy could also improve hemodynamics in the real-world population as well as the randomized controlled trial.
Our study also demonstrated a favorable long-term prognosis as well as improvement of the RVFAC, 6MWD, WHO-FC, and BNP concentration with triple oral combination therapy. In a past retrospective study of the dual combination of an ERA and PDE-5i, the 3-year overall survival rate was nearly 80%.19 In another French registry in which most patients were treated with monotherapy, the 3-year survival rate was <70%.20 The prognosis in the present study appears to be superior to that in previous reports. The low rate of mortality and hospitalization for heart failure was consistent with the TRITON study, in which the risk of first disease progression events was decreased about 41% in the triple oral therapy group.18 These results in this study could verify the efficacy of triple oral combination therapy in preventing disease progression of triple oral combination therapy found in the randomized controlled study.
In the present study, the treatment response in most of the low-/intermediate-risk patients was favorable with administration of the triple oral combination therapy, and around half of the high-risk patients did not need prostacyclin infusion. The current PAH guideline recommends initial oral therapy for low-/intermediate-risk patients, while high-risk patients are recommended to receive initial combination therapy including prostacyclin infusion.10 Patients in this study did not present decompensated heart failure and the urgent initiation of prostacyclin infusion was not necessary. Therefore, the triple oral combination therapy was initiated first and its efficacy was assessed within 6 months. Our data support recommendations in guidelines in low-/intermediate-risk patients and provide a novel possibility that around half of high-risk patients can be treated without prostacyclin infusion. Moreover, 66.7% of the patients who needed prostacyclin infusion had gene mutations, suggesting that the need for prostacyclin infusion can be largely affected by their genetic background. Therefore, we should be especially careful when we use triple oral combination therapy to treat patients with specific etiologies of PAH such as gene mutations.
With respect to safety, a past study investigating the combination of tadalafil as a PDE-5i and ambrisentan as an ERA showed that the discontinuation rate of dual combination therapy because of adverse events was 12% within 2 years of the mean duration of drug use.1 In the subgroup analysis of the GRIPHON study, which investigated the effectiveness of selexipag for the patients of PAH, a triple oral combination therapy with selexipag, ERA, and PDE-5i was discontinued in 19.0% of patients due to adverse events.6 The rate of 15% in the present study was lower than that of the GRIPHON study, suggesting good tolerability in real world data. With regard to the maximum tolerated dose, a past subgroup analysis that investigated the change in the symptom burden after taking selexipag in addition to an ERA and PDE-5i showed that only 27.9% of patients who received selexipag reached the maximum dose of selexipag.6 Another study of the combination of riociguat and macitentan showed that about 70% of patients reached the maximum maintenance dose of riociguat. In the present study, 76.9% and 92.3% of patients could be up-titrated to the maximum dose with selexipag and riociguat, respectively. Thus, this study demonstrated that it is quite possible to up-titrate each drug to the maximum dose, even in patients treated with triple oral combination therapy.
The subgroup analysis showed that the hemodynamics, right ventricular function, and clinical function powerfully improved, and the degree of improvement was similar to those in the overall patient analysis. Moreover, no patients died or were hospitalized for heart failure during the observation period. These results suggest that triple oral combination therapy with macitentan, riociguat, and selexipag can be a promising treatment strategy in treatment-naïve patients.
This study has some limitations. This was a small, single-center, retrospective study that included various types of PAH and some patients were not treatment naïve at baseline. Each etiology of PAH might have affected the results of the study differently. Prostacyclin infusion was initiated within 7 months, and no patients underwent prostacyclin infusion after 7 months, which is towards a bias of an initial high-risk population of patients in which initial triple oral combination treatment was chosen. The drug regimens were decided by the physicians. Furthermore, indirect Fick method was adopted as the measurement of CO. This was not recommended in the European Society of Cardiology/European Respiratory Society Guidelines 2015, but was admitted for use in the practical situation in the Japanese PAH guideline.11 As the results could be affected by the measurement methods of CO, further validation would be warranted.
Conclusion
This study demonstrated the effectiveness of triple oral combination therapy with macitentan, riociguat, and selexipag in patients with PAH. Our data suggest that this triple oral combination therapy is associated with improvement of hemodynamics, right ventricular function, and clinical function with good tolerability. In particular, this triple oral combination therapy can be a promising therapeutic strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further investigation is required to validate these findings.
Supplemental Material
sj-pdf-1-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
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Supplemental material, sj-pdf-1-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-2-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-3-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-3-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-4-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-4-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-5-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Click here for additional data file.
Supplemental material, sj-pdf-7-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-tif-6-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
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Supplemental material, sj-tif-6-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
We thank all the doctors, nurses, and supporting medical staff members who were involved in the care of the patients enrolled in this study. We also thank Angela Morben, DVM, ELS, from Edanz Group (https://en-author-services.edanzgroup.com/ac), for editing a draft of this manuscript.
Author contribution(s): Mizuki Momoi: Data curation; Formal analysis; Investigation; Writing-original draft.
Takahiro Hiraide: Conceptualization; Methodology; Writing-review & editing.
Yoshiki Shinya: Conceptualization; Validation; Writing-review & editing.
Hiromi Momota: Data curation; Validation; Methodology; Writing-review & editing.
Shogo Fukui: Data curation; Validation; Formal analysis; Writing-review & editing.
Michiyuki Kawakami: Data curation; Validation; Formal analysis; Writing-review & editing.
Yuji Itabashi: Methodology; Data curation; Resources, Writing-review & editing.
Keiichi Fukuda: Supervision; Investigation; Writing-review & editing.
Masaharu Kataoka: Conceptualization; Project administration; Writing-review & editing.
Conflict of interest statement: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Masaharu Kataoka https://orcid.org/0000-0001-8034-1005
Supplemental material: Supplemental material for this article is available online. | DOSE UNKNOWN | DrugDosageText | CC BY-NC | 33627044 | 19,134,415 | 2021 |
What was the dosage of drug 'RIOCIGUAT'? | Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension.
The evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.
Among consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan-Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.
Twenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12-47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.
Triple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings.The reviews of this paper are available via the supplemental material section.
Introduction
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by elevated pulmonary arterial pressure (PAP) due to remodeling of the pulmonary arterial bed and right sided-heart failure. Three types of PAH-specific vasodilators targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway have been developed. Combination therapy targeting these different pathways has recently been shown to improve hemodynamics, clinical functions, and even hard endpoints including survival or worsening of PAH in several recent randomized controlled trials and metanalyses.1–5 The effectiveness of triple combination therapy targeting all three of these pathways has also been reported.6–8 However, two such studies analyzed patients who were treated with two types of oral vasodilators and prostacyclin infusion,7,8 and another study was a subgroup analysis of a randomized controlled trial demonstrating a change in the symptom burden by the addition of selexipag, a prostacyclin receptor agonist, to background double combination therapy targeting other pathways.6 Therefore, evidence of the efficacy and safety of triple oral combination therapy remains scarce.
The most recently approved PAH-specific vasodilators targeting each of the three types of pathways are macitentan, which is an endothelin receptor antagonist (ERA); riociguat, which is a soluble guanylate cyclase stimulator targeting the nitric oxide pathway; and selexipag, which is an oral non-prostanoid prostacyclin receptor agonist. All three of these are orally available drugs. The effectiveness of these vasodilators for PAH has recently been proven;2,3,9 however, no clinical trials have been performed to investigate the effectiveness of the combination of these three vasodilators. Furthermore, although the current guideline recommends initial oral therapy for patients with low or intermediate risk,10 how many patients with low or intermediate risk can actually be treated with only oral combination therapy remains poorly documented to date.
Therefore, the purposes of this study were to clarify the clinical effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag and to assess which risk groups can be adequately treated with this combination therapy.
Methods
Study design
This retrospective study was performed in Keio University Hospital in Japan. This study was approved by the Ethics Committee of Keio University Hospital, and written informed consent was obtained from all patients when they received genetic tests or were hospitalized. Patients with PAH who had received triple oral combination therapy with macitentan, riociguat, and selexipag were evaluated among all consecutive patients who were referred to Keio University Hospital from 2009 to 2020.
The diagnosis of PAH was made according to the current guideline.11 Patients who were lost to follow-up or underwent maintenance hemodialysis were excluded. Baseline data were measured at the time of referral to our hospital. If patients were treatment-naïve upon referral to our hospital, the combination of macitentan, riociguat, and selexipag was initiated after diagnosis. The method of up-titration and prioritization of the vasodilators as well as the selection of sequential therapy or upfront therapy was determined at the discretion of the specialized physicians. The doses of the vasodilators were titrated to the maximal tolerated doses. For patients who had already received other PAH-specific vasodilators at the time of enrollment, these drugs targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway were switched to macitentan, riociguat, and selexipag, respectively, with the intention of further improvement of hemodynamics.
Patients received genetic counseling, and genetic tests were performed with informed consent. The methods of the genetic tests, including whole-exome sequencing, are described in our previous reports.12,13
Parameters and outcomes
Dedicated cardiologists performed right-heart catheterization (RHC) without sedation at baseline and follow-up. The right arterial pressure, mean PAP, and pulmonary arterial wedge pressure were measured by RHC. The zero pressure point was set at the level of the midthorax. Cardiac output (CO) was calculated by the Fick technique using oxygen consumption estimated by 125 times the body surface area according to a previous report.14 Pulmonary vascular resistance (PVR) was calculated as the difference between the mean PAP and pulmonary arterial wedge pressure divided by the CO.
The 6-minute walk distance (6MWD), blood concentration of B-type natriuretic peptide (BNP), and World Health Organization functional class (WHO-FC) were measured at the time of hospitalization for RHC.
Standard two-dimensional, M-mode, and Doppler images, including the tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic excursion velocity (RVS’), were obtained by echocardiographers in accordance with the current echocardiography guideline.15 Dedicated cardiologists analyzed the data and measured the right atrial area (RAA), right ventricular end-diastolic area (RVEDA), right ventricular end-systolic area, and right ventricular fractional area change (RVFAC).
Hemodynamic changes measured by RHC, echocardiographic changes, and changes in the 6MWD, BNP concentration, and WHO-FC were assessed from baseline to follow-up.
The events of all-cause death, hospitalization for heart failure, initiation of prostacyclin infusion, and discontinuation of any of the three vasodilators (macitentan, riociguat, and selexipag) because of adverse events since administration of all three vasodilators were collected. The observation period was terminated when patients died, underwent prostacyclin infusion, or stopped taking macitentan, riociguat, or selexipag for any reason.
All patients enrolled in this study were divided into two groups by risk assessment using the three-category REVEAL 2.0 risk score,16 and the prostacyclin infusion-free rate was analyzed in each group. If the value was unmeasured, the value of zero was assigned. According to the three-category REVEAL 2.0 risk score, the high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), and the low-/intermediate-risk group was defined as patients with a predicted 1-year survival rate of ⩾90% (REVEAL 2.0 risk score ⩽8).
Subgroup analysis
Patients who were treatment-naïve at baseline and treated with only macitentan, riociguat, and selexipag for PAH were also independently assessed by subgroup analysis. Their hemodynamics, echocardiography, and clinical function were measured and clinical events were collected similarly to the overall patient analysis.
Statistical analysis
Data are described as median and interquartile range unless otherwise indicated. Wilcoxon’s signed rank test was used to compare the parameters of hemodynamics, echocardiography, 6MWD, and BNP concentration from baseline to the latest follow-up. The cases which had a missing value either at baseline or follow-up were excluded from each analysis. Differences with a p-value of <0.05 were considered statistically significant. All p-values were two-tailed. Event-free rates were analyzed using the Kaplan–Meier method. All analyses were performed using R software (version 3.6.3), and figures were obtained using GraphPad Prism (version 8.0 for Mac; GraphPad Software, La Jolla, CA, USA).
Results
Patient characteristics
The patients’ baseline characteristics and medications are presented in Table 1 and Supplemental material Table 1 online. One patient who was lost to follow-up and one patient who had been undergoing maintenance hemodialysis were excluded; thus, 26 patients were enrolled in this study. The patients were predominantly female (73.1%) with a median age of 38 years. The major etiology of PAH was idiopathic PAH (38.5%) followed by connective tissue disease-associated PAH (26.9%), heritable PAH (19.2%), and congenital heart disease-associated PAH (15.4%). Most patients were treatment-naïve (65.4%), and others were taking some PAH medications at baseline.
Table 1. Demographics and characteristics at baseline.
Variable Triple oral combination therapy
N = 26
Female 19 (73.1)
Age, years 38 (23–48)
WHO-FC
I/II/III/IV 0/9/16/1 (0.0/34.6/61.5/3.8)
BNP, pg/mL 105.25 (36.7–285.5)
6MWD, m 397.5 (312.8–441.8)
PAH etiology
IPAH 10 (38.5)
HPAH 5 (19.2)
CTD-PAH 7 (26.9)
CHD-PAH 4 (15.4)
Medication
Treatment-naïve 17 (65.4)
Single 3 (11.5)
Double 2 (7.7)
Triple 4 (15.4)
Risk assessment*
High risk 12 (46.2)
Intermediate risk 4 (15.4)
Low risk 10 (38.5)
Genetic mutation**
BMPR2 5 (23.8)
ACVRL 1 (4.8)
RNF213 1 (4.8)
Data are expressed as number (%) or median (interquartile range).
* Risk assessment was calculated using the three-category REVEAL 2.0 risk score.16 The high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), the intermediate-risk group was defined as patients with a predicted 1-year survival rate of 90–<95% (REVEAL 2.0 risk score = 7 or 8), and the low-risk group was defined as patients with a predicted 1-year survival rate of ⩾95% (REVEAL 2.0 risk score ⩽6).
** Among 26 patients, 21 were genetically tested and 15 had no genetic mutations related to PAH.
6MWD, 6-minute walk distance; ACVRL1, activin A receptor-like kinase 1; BMPR2, bone morphogenetic protein receptor type 2; BNP, B-type natriuretic peptide; CHD, congenital heart disease; CTD, connective tissue disease; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; RNF213, ring finger protein 213; WHO-FC, World Health Organization functional class.
Ten patients with idiopathic PAH, five with heritable PAH, three with connective tissue disease-associated PAH, and three with congenital heart disease-associated PAH were genetically tested. All five patients with heritable PAH had mutations in known PAH-related genes such as bone morphogenetic protein receptor type 2 (BMPR2) and one patient with idiopathic PAH had a mutation in ring finger protein 213 (RNF213), which we recently reported as a novel PAH-related gene.13,17
Safety and tolerability
Discontinuation of macitentan, riociguat, or selexipag because of adverse events occurred in four of 26 patients (15%). Among these four patients, one had diarrhea with selexipag, one had suspected myelosuppression with macitentan, one had nausea with riociguat, and one had hypotension with riociguat. These patients changed their drug to another drug targeting the same pathway. No adverse events, including death, hospitalization for heart failure, or prostacyclin infusion, were observed after discontinuation of each drug.
The maximum tolerated doses of the vasodilators are summarized in Supplemental Table 2. In detail, 25 (96.2%), 24 (92.3%), and 20 (76.9%) patients were taking the maximum dose of macitentan, riociguat, and selexipag, respectively. Seventeen (65.4%) patients reached the maximum dose of all three vasodilators.
Changes and outcomes after treatment
Hemodynamic data were available for 18 patients. The detailed study flow chart is shown in Supplemental Figure 1. The hemodynamics, WHO-FC, BNP concentration, and 6MWD at baseline and follow-up are presented in Table 2. The median observation period was 441 (229–1103) days. Hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 65% decrease in the mean PVR. The CO significantly increased by 82% from baseline to follow-up. Although >70% of patients had a WHO-FC of III or IV at baseline, 89% of patients had a WHO-FC of I or II at follow-up. The 6MWD and BNP concentration were also significantly improved [Figure 1(a)].
Table 2. Changes in clinical parameters.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 6.5 (4.0–8.0) 4.0 (3.0–5.0) −2.5 (−38) 0.005
Mean PAP, mmHg 56.0 (46.3–65.5) 40.0 (30.0–47.0) −16.0 (−29) <0.001
PAWP, mmHg 7.5 (6.0–9.8) 9.0 (8.0–11.0) 1.5 (20) 0.68
CO, L/min 3.3 (2.4–4.5) 6.0 (5.1–6.7) 2.7 (82) <0.001
CI, L/min per m2 2.2 (1.7–2.7) 3.8 (3.3–4.5) 1.6 (73) <0.001
PVR, WU 13.5 (8.8–21.5) 4.7 (2.8–6.9) −8.8 (−65) <0.001
Echocardiography
TAPSE, cm 1.5 (1.3–1.8) 2.3 (1.9–2.6) 0.8 (53) 0.001
RVS’, cm 9.7 (7.8–11.8) 13.3 (12.4–14.4) 3.6 (37) 0.001
RAA, cm2 17.2 (14.9–21.3) 16.4 (14.1–21.0) −0.8 (−5) 0.49
RVEDA, cm2 26.9 (22.8–33.1) 24.1 (21.0–30.3) −2.8 (−10) 0.21
RVESA, cm2 20.4 (16.3–23.9) 16.4 (13.8–21.1) −4.0 (−20) 0.006
FAC, % 23.6 (16.2–26.9) 32.9 (29.1–35.8) 9.3 (39) <0.001
WHO-FC
I or II 4 (22) 16 (89) – –
III or IV 14 (78) 2 (11) – –
6MWD, m 405.0 (303.0–441.8) 472.0 (439.5–493.5) 67.0 (17) 0.046
BNP, pg/mL 187.8 (36.7–379.5) 17.5 (10.3–27.2) −170.3 (−91) <0.001
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Eighteen patients were analyzed in hemodynamics, and 20 patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 1. Hemodynamic and echocardiographic changes.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Echocardiographic data were available for 20 patients (Supplemental Figure 1). The echocardiographic data are presented in Table 2. The median follow-up period was 737 (256–1179) days. Right ventricular function based on the TAPSE, RVS’, and RVFAC was significantly improved from baseline to follow-up, although the RAA and RVEDA were not [Figure 1(b)].
The Kaplan–Meier curves since administration of all three vasodilators are shown in Figure 2. The 1- and 2-year survival rates were both 93.3%. One patient died of multiple organ failure after femoral neck fracture during the observation period. The overall survival rate was 92.3% with median follow-up period of 33 (24–43) months. No patients were hospitalized for heart failure during the observation period. Prostacyclin infusion was initiated in six patients (25.4%) within 1 year. Among these six patients, selexipag was switched to subcutaneous infusion of treprostinil in one patient, an intravenous infusion of epoprostenol was added to the triple oral combination therapy in another patient, and a subcutaneous infusion of treprostinil was added to the triple oral combination therapy in the remaining four patients. Selexipag was not discontinued in some patients to reduce maintenance dose of the prostacyclin for infusion. No other patients underwent prostacyclin infusion after 1 year. Among six patients who underwent prostacyclin infusion within 1 year, three patients had a BMPR2 mutation, one patient had an RNF213 mutation, and one patient had Eisenmenger syndrome due to an atrial septal defect. Composite events of all-cause death, hospitalization for heart failure, and initiation of prostacyclin infusion occurred in 16.6% of the patients within 6 months and 30.4% of the patients in 1 and 2 years.
Figure 2. Event-free rates in all patients with triple oral combination therapy.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy are shown (n = 26). The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Among 14 patients who were classified as low-/intermediate-risk by the three-category REVEAL 2.0 risk score,16 the prostacyclin-free rate was 92.9% at 3 years, while the rate was 55.0% at 2 years in 12 high-risk patients (Figure 3). The difference was not statistically significant (p = 0.058). Hemodynamic changes from baseline to follow-up in each low/intermediate and high-risk group are summarized in Supplemental Table 3. Among five patients who were classified as high-risk based on the three-category REVEAL 2.0 risk score and needed prostacyclin infusion, three patients had BMPR2 mutations and one patient had a RNF213 mutation.
Figure 3. Kaplan–Meier curve for prostacyclin-free rate in each risk category.
The prostacyclin infusion-free rates in each risk category are shown. The patients were divided into two risk categories by the REVEAL 2.0 risk score.16 The p-values were calculated by the log-rank test.
Subgroup analysis in treatment-naïve patients
Seventeen patients were treatment-naïve at baseline. Six patients were treatment naïve at baseline, but treated with other pulmonary vasodilators. In five out of these six patients, oral medication was switched from beraprost to selexipag, and in one patient, it was switched from ambrisentan and tadalafil to macitentan and riociguat. Thus, these six patients were excluded from the subgroup analysis. Among the remaining 11 patients for the subgroup analysis, the median time from initiation of the first PAH drug to the start of the third PAH drug was 24 (12–47) days. The way of up-titration in treatment naïve patients was as follows. Macitentan 10 mg was initiated at first and followed by riociguat 3.0 mg within 2 weeks. The dose of riociguat was up-titrated by 1.5 mg every 2 weeks with attention to adverse effects. In 36% of treatment naïve patients, selexipag was initiated after riociguat was up-titrated to maximum tolerated dose, whereas selexipag was started within 2 weeks from initiating macitentan in 64% of patients. Selexipag was increased by 0.4 mg every 2 weeks to maximum tolerated dose with attention to side effects. One patient (9.1%) discontinued macitentan because of suspected myelosuppression, and another patient (9.1%) discontinued riociguat because of nausea. RHC data in 10 patients and echocardiographic data in nine patients were available at baseline and at follow-up during the triple oral combination therapy. The patients’ hemodynamic and right ventricular function parameters are presented in Table 3 and Figure 4. The median follow-up period of the hemodynamic analysis was 293 (211–473) days. The hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 66% decrease in the PVR. The CO increased by 90% from baseline to follow-up. The median follow-up period of echocardiography was 385 (230–594) days. The TAPSE, RVS’, and RVFAC, indicating right ventricular function, increased significantly. The WHO-FC, 6MWD, and BNP concentration in this subgroup also improved significantly. In the Kaplan–Meier analysis, no patients died or were hospitalized for heart failure (Figure 5). Prostacyclin infusion was initiated in 31.8% of patients within 7 months, and no patients underwent prostacyclin infusion after 7 months.
Table 3. Changes in clinical parameters among treatment-naïve patients at baseline.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 7.5 (4.3–8.8) 4.0 (3.3–5.0) −3.5 (−47) 0.022
Mean PAP, mmHg 63.0 (55.0–75.8) 44.5 (37.0–51.5) −18.5 (−29) 0.006
PAWP, mmHg 7.5 (6.3–9.8) 8.0 (6.5–10.3) 0.5 (7) 0.61
CO, L/min 3.1 (2.4–4.3) 5.9 (5.1–7.2) 2.8 (90) 0.006
CI, L/min per m2 2.1 (1.7–2.5) 4.2 (3.5–4.6) 2.1 (100) 0.006
PVR, WU 17.5 (13.2–21.9) 5.9 (3.8–9.6) −11.6 (−66) 0.006
Echocardiography
TAPSE, cm 1.4 (1.3–1.5) 2.3 (2.1–2.7) 0.9 (64) 0.009
RVS’, cm 9.3 (7.9–10.8) 13.5 (13.0–14.3) 4.2 (45) 0.035
RAA, cm2 18.5 (15.0–21.1) 15.2 (13.5–16.7) −3.3 (−18) 0.076
RVEDA, cm2 27.0 (25.0–33.2) 23.6 (21.0–24.6) −3.4 (−13) 0.058
RVESA, cm2 22.9 (18.7–25.4) 14.8 (14.0–16.8) −8.1 (−35) 0.009
FAC, % 22.9 (15.9–25.2) 33.1 (29.5–35.0) 10.2 (45) 0.018
WHO-FC
I or II 1 (10) 8 (80)
III or IV 9 (90) 2 (20)
6MWD, m 400.0 (326.5–432.0) 471.5 (451.5–479.2) 71.5 (18) 0.030
BNP, pg/mL 200.8 (41.9–379.5) 20.2 (12.6–24.5) −180.6 (−90) 0.006
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Ten patients were analyzed in hemodynamics, and nine patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 4. Hemodynamic and echocardiographic changes in treatment-naïve patients.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Figure 5. Event-free rates in treatment-naïve patients.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy in treatment-naïve patients are shown. The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite endpoint of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Discussion
In the present study, triple oral combination therapy with macitentan, riociguat, and selexipag improved the hemodynamics, right ventricular function, and clinical function with good tolerability in patients with PAH. Most of the low-/intermediate-risk patients and around half of the high-risk patients could be treated sufficiently with this triple oral combination therapy although it is difficult to generalize these findings.
Two previous studies investigated the efficacy of the combination of prostacyclin infusion, an ERA, and a phosphodiesterase-5 inhibitor (PDE-5i) for PAH,7,8 but data regarding triple oral combination therapy are limited. One study related to triple oral combination therapy is the subgroup analysis of the GRIPHON study, which demonstrated a change in the symptom burden after administration of selexipag in addition to an ERA and PDE-5i.6 Recently, a randomized control study (TRITON study) is also under analysis which investigated the efficacy and safety of triple oral combination therapy with macitentan, tadalafil, and selexipag versus dual oral combination therapy with macitentan and tadalafil.18 The present study is the first to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag using real-world data.
Our results of improved hemodynamics are consistent with previous observational studies that investigated the effectiveness of triple combination therapy including prostacyclin infusion.7 Sitbon et al.7 reported that with intravenous administration of epoprostenol and oral administration of bosentan and sildenafil, the mean PAP, PVR, and cardiac index improved by 33%, 71%, and 119%, respectively. Another observational study involving a combination of ambrisentan, tadalafil, and subcutaneous treprostinil also demonstrated significant improvement of the mean PAP, PVR, and cardiac index by 30%, 66%, and 94%, respectively.8 There are similarities between the results of these previous studies and the results of the present study, suggesting that triple oral combination therapy with macitentan, riociguat, and selexipag can powerfully improve the hemodynamics in patients with PAH. In the TRITON study, triple oral combination therapy improved PVR by 54%, although it was almost the same degree as dual oral combination therapy.18 Improvement of hemodynamic in this study was greater than that of the TRITON study, partly because of the difference of the study design. Although findings from observational study, results in this study provided the possibility that triple oral combination therapy could also improve hemodynamics in the real-world population as well as the randomized controlled trial.
Our study also demonstrated a favorable long-term prognosis as well as improvement of the RVFAC, 6MWD, WHO-FC, and BNP concentration with triple oral combination therapy. In a past retrospective study of the dual combination of an ERA and PDE-5i, the 3-year overall survival rate was nearly 80%.19 In another French registry in which most patients were treated with monotherapy, the 3-year survival rate was <70%.20 The prognosis in the present study appears to be superior to that in previous reports. The low rate of mortality and hospitalization for heart failure was consistent with the TRITON study, in which the risk of first disease progression events was decreased about 41% in the triple oral therapy group.18 These results in this study could verify the efficacy of triple oral combination therapy in preventing disease progression of triple oral combination therapy found in the randomized controlled study.
In the present study, the treatment response in most of the low-/intermediate-risk patients was favorable with administration of the triple oral combination therapy, and around half of the high-risk patients did not need prostacyclin infusion. The current PAH guideline recommends initial oral therapy for low-/intermediate-risk patients, while high-risk patients are recommended to receive initial combination therapy including prostacyclin infusion.10 Patients in this study did not present decompensated heart failure and the urgent initiation of prostacyclin infusion was not necessary. Therefore, the triple oral combination therapy was initiated first and its efficacy was assessed within 6 months. Our data support recommendations in guidelines in low-/intermediate-risk patients and provide a novel possibility that around half of high-risk patients can be treated without prostacyclin infusion. Moreover, 66.7% of the patients who needed prostacyclin infusion had gene mutations, suggesting that the need for prostacyclin infusion can be largely affected by their genetic background. Therefore, we should be especially careful when we use triple oral combination therapy to treat patients with specific etiologies of PAH such as gene mutations.
With respect to safety, a past study investigating the combination of tadalafil as a PDE-5i and ambrisentan as an ERA showed that the discontinuation rate of dual combination therapy because of adverse events was 12% within 2 years of the mean duration of drug use.1 In the subgroup analysis of the GRIPHON study, which investigated the effectiveness of selexipag for the patients of PAH, a triple oral combination therapy with selexipag, ERA, and PDE-5i was discontinued in 19.0% of patients due to adverse events.6 The rate of 15% in the present study was lower than that of the GRIPHON study, suggesting good tolerability in real world data. With regard to the maximum tolerated dose, a past subgroup analysis that investigated the change in the symptom burden after taking selexipag in addition to an ERA and PDE-5i showed that only 27.9% of patients who received selexipag reached the maximum dose of selexipag.6 Another study of the combination of riociguat and macitentan showed that about 70% of patients reached the maximum maintenance dose of riociguat. In the present study, 76.9% and 92.3% of patients could be up-titrated to the maximum dose with selexipag and riociguat, respectively. Thus, this study demonstrated that it is quite possible to up-titrate each drug to the maximum dose, even in patients treated with triple oral combination therapy.
The subgroup analysis showed that the hemodynamics, right ventricular function, and clinical function powerfully improved, and the degree of improvement was similar to those in the overall patient analysis. Moreover, no patients died or were hospitalized for heart failure during the observation period. These results suggest that triple oral combination therapy with macitentan, riociguat, and selexipag can be a promising treatment strategy in treatment-naïve patients.
This study has some limitations. This was a small, single-center, retrospective study that included various types of PAH and some patients were not treatment naïve at baseline. Each etiology of PAH might have affected the results of the study differently. Prostacyclin infusion was initiated within 7 months, and no patients underwent prostacyclin infusion after 7 months, which is towards a bias of an initial high-risk population of patients in which initial triple oral combination treatment was chosen. The drug regimens were decided by the physicians. Furthermore, indirect Fick method was adopted as the measurement of CO. This was not recommended in the European Society of Cardiology/European Respiratory Society Guidelines 2015, but was admitted for use in the practical situation in the Japanese PAH guideline.11 As the results could be affected by the measurement methods of CO, further validation would be warranted.
Conclusion
This study demonstrated the effectiveness of triple oral combination therapy with macitentan, riociguat, and selexipag in patients with PAH. Our data suggest that this triple oral combination therapy is associated with improvement of hemodynamics, right ventricular function, and clinical function with good tolerability. In particular, this triple oral combination therapy can be a promising therapeutic strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further investigation is required to validate these findings.
Supplemental Material
sj-pdf-1-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
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Supplemental material, sj-pdf-1-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-2-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-3-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-4-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-5-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-7-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-tif-6-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
We thank all the doctors, nurses, and supporting medical staff members who were involved in the care of the patients enrolled in this study. We also thank Angela Morben, DVM, ELS, from Edanz Group (https://en-author-services.edanzgroup.com/ac), for editing a draft of this manuscript.
Author contribution(s): Mizuki Momoi: Data curation; Formal analysis; Investigation; Writing-original draft.
Takahiro Hiraide: Conceptualization; Methodology; Writing-review & editing.
Yoshiki Shinya: Conceptualization; Validation; Writing-review & editing.
Hiromi Momota: Data curation; Validation; Methodology; Writing-review & editing.
Shogo Fukui: Data curation; Validation; Formal analysis; Writing-review & editing.
Michiyuki Kawakami: Data curation; Validation; Formal analysis; Writing-review & editing.
Yuji Itabashi: Methodology; Data curation; Resources, Writing-review & editing.
Keiichi Fukuda: Supervision; Investigation; Writing-review & editing.
Masaharu Kataoka: Conceptualization; Project administration; Writing-review & editing.
Conflict of interest statement: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Masaharu Kataoka https://orcid.org/0000-0001-8034-1005
Supplemental material: Supplemental material for this article is available online. | 1.0?2.5 MG T.I.D | DrugDosageText | CC BY-NC | 33627044 | 19,134,415 | 2021 |
What was the outcome of reaction 'Diarrhoea'? | Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension.
The evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.
Among consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan-Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.
Twenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12-47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.
Triple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings.The reviews of this paper are available via the supplemental material section.
Introduction
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by elevated pulmonary arterial pressure (PAP) due to remodeling of the pulmonary arterial bed and right sided-heart failure. Three types of PAH-specific vasodilators targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway have been developed. Combination therapy targeting these different pathways has recently been shown to improve hemodynamics, clinical functions, and even hard endpoints including survival or worsening of PAH in several recent randomized controlled trials and metanalyses.1–5 The effectiveness of triple combination therapy targeting all three of these pathways has also been reported.6–8 However, two such studies analyzed patients who were treated with two types of oral vasodilators and prostacyclin infusion,7,8 and another study was a subgroup analysis of a randomized controlled trial demonstrating a change in the symptom burden by the addition of selexipag, a prostacyclin receptor agonist, to background double combination therapy targeting other pathways.6 Therefore, evidence of the efficacy and safety of triple oral combination therapy remains scarce.
The most recently approved PAH-specific vasodilators targeting each of the three types of pathways are macitentan, which is an endothelin receptor antagonist (ERA); riociguat, which is a soluble guanylate cyclase stimulator targeting the nitric oxide pathway; and selexipag, which is an oral non-prostanoid prostacyclin receptor agonist. All three of these are orally available drugs. The effectiveness of these vasodilators for PAH has recently been proven;2,3,9 however, no clinical trials have been performed to investigate the effectiveness of the combination of these three vasodilators. Furthermore, although the current guideline recommends initial oral therapy for patients with low or intermediate risk,10 how many patients with low or intermediate risk can actually be treated with only oral combination therapy remains poorly documented to date.
Therefore, the purposes of this study were to clarify the clinical effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag and to assess which risk groups can be adequately treated with this combination therapy.
Methods
Study design
This retrospective study was performed in Keio University Hospital in Japan. This study was approved by the Ethics Committee of Keio University Hospital, and written informed consent was obtained from all patients when they received genetic tests or were hospitalized. Patients with PAH who had received triple oral combination therapy with macitentan, riociguat, and selexipag were evaluated among all consecutive patients who were referred to Keio University Hospital from 2009 to 2020.
The diagnosis of PAH was made according to the current guideline.11 Patients who were lost to follow-up or underwent maintenance hemodialysis were excluded. Baseline data were measured at the time of referral to our hospital. If patients were treatment-naïve upon referral to our hospital, the combination of macitentan, riociguat, and selexipag was initiated after diagnosis. The method of up-titration and prioritization of the vasodilators as well as the selection of sequential therapy or upfront therapy was determined at the discretion of the specialized physicians. The doses of the vasodilators were titrated to the maximal tolerated doses. For patients who had already received other PAH-specific vasodilators at the time of enrollment, these drugs targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway were switched to macitentan, riociguat, and selexipag, respectively, with the intention of further improvement of hemodynamics.
Patients received genetic counseling, and genetic tests were performed with informed consent. The methods of the genetic tests, including whole-exome sequencing, are described in our previous reports.12,13
Parameters and outcomes
Dedicated cardiologists performed right-heart catheterization (RHC) without sedation at baseline and follow-up. The right arterial pressure, mean PAP, and pulmonary arterial wedge pressure were measured by RHC. The zero pressure point was set at the level of the midthorax. Cardiac output (CO) was calculated by the Fick technique using oxygen consumption estimated by 125 times the body surface area according to a previous report.14 Pulmonary vascular resistance (PVR) was calculated as the difference between the mean PAP and pulmonary arterial wedge pressure divided by the CO.
The 6-minute walk distance (6MWD), blood concentration of B-type natriuretic peptide (BNP), and World Health Organization functional class (WHO-FC) were measured at the time of hospitalization for RHC.
Standard two-dimensional, M-mode, and Doppler images, including the tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic excursion velocity (RVS’), were obtained by echocardiographers in accordance with the current echocardiography guideline.15 Dedicated cardiologists analyzed the data and measured the right atrial area (RAA), right ventricular end-diastolic area (RVEDA), right ventricular end-systolic area, and right ventricular fractional area change (RVFAC).
Hemodynamic changes measured by RHC, echocardiographic changes, and changes in the 6MWD, BNP concentration, and WHO-FC were assessed from baseline to follow-up.
The events of all-cause death, hospitalization for heart failure, initiation of prostacyclin infusion, and discontinuation of any of the three vasodilators (macitentan, riociguat, and selexipag) because of adverse events since administration of all three vasodilators were collected. The observation period was terminated when patients died, underwent prostacyclin infusion, or stopped taking macitentan, riociguat, or selexipag for any reason.
All patients enrolled in this study were divided into two groups by risk assessment using the three-category REVEAL 2.0 risk score,16 and the prostacyclin infusion-free rate was analyzed in each group. If the value was unmeasured, the value of zero was assigned. According to the three-category REVEAL 2.0 risk score, the high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), and the low-/intermediate-risk group was defined as patients with a predicted 1-year survival rate of ⩾90% (REVEAL 2.0 risk score ⩽8).
Subgroup analysis
Patients who were treatment-naïve at baseline and treated with only macitentan, riociguat, and selexipag for PAH were also independently assessed by subgroup analysis. Their hemodynamics, echocardiography, and clinical function were measured and clinical events were collected similarly to the overall patient analysis.
Statistical analysis
Data are described as median and interquartile range unless otherwise indicated. Wilcoxon’s signed rank test was used to compare the parameters of hemodynamics, echocardiography, 6MWD, and BNP concentration from baseline to the latest follow-up. The cases which had a missing value either at baseline or follow-up were excluded from each analysis. Differences with a p-value of <0.05 were considered statistically significant. All p-values were two-tailed. Event-free rates were analyzed using the Kaplan–Meier method. All analyses were performed using R software (version 3.6.3), and figures were obtained using GraphPad Prism (version 8.0 for Mac; GraphPad Software, La Jolla, CA, USA).
Results
Patient characteristics
The patients’ baseline characteristics and medications are presented in Table 1 and Supplemental material Table 1 online. One patient who was lost to follow-up and one patient who had been undergoing maintenance hemodialysis were excluded; thus, 26 patients were enrolled in this study. The patients were predominantly female (73.1%) with a median age of 38 years. The major etiology of PAH was idiopathic PAH (38.5%) followed by connective tissue disease-associated PAH (26.9%), heritable PAH (19.2%), and congenital heart disease-associated PAH (15.4%). Most patients were treatment-naïve (65.4%), and others were taking some PAH medications at baseline.
Table 1. Demographics and characteristics at baseline.
Variable Triple oral combination therapy
N = 26
Female 19 (73.1)
Age, years 38 (23–48)
WHO-FC
I/II/III/IV 0/9/16/1 (0.0/34.6/61.5/3.8)
BNP, pg/mL 105.25 (36.7–285.5)
6MWD, m 397.5 (312.8–441.8)
PAH etiology
IPAH 10 (38.5)
HPAH 5 (19.2)
CTD-PAH 7 (26.9)
CHD-PAH 4 (15.4)
Medication
Treatment-naïve 17 (65.4)
Single 3 (11.5)
Double 2 (7.7)
Triple 4 (15.4)
Risk assessment*
High risk 12 (46.2)
Intermediate risk 4 (15.4)
Low risk 10 (38.5)
Genetic mutation**
BMPR2 5 (23.8)
ACVRL 1 (4.8)
RNF213 1 (4.8)
Data are expressed as number (%) or median (interquartile range).
* Risk assessment was calculated using the three-category REVEAL 2.0 risk score.16 The high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), the intermediate-risk group was defined as patients with a predicted 1-year survival rate of 90–<95% (REVEAL 2.0 risk score = 7 or 8), and the low-risk group was defined as patients with a predicted 1-year survival rate of ⩾95% (REVEAL 2.0 risk score ⩽6).
** Among 26 patients, 21 were genetically tested and 15 had no genetic mutations related to PAH.
6MWD, 6-minute walk distance; ACVRL1, activin A receptor-like kinase 1; BMPR2, bone morphogenetic protein receptor type 2; BNP, B-type natriuretic peptide; CHD, congenital heart disease; CTD, connective tissue disease; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; RNF213, ring finger protein 213; WHO-FC, World Health Organization functional class.
Ten patients with idiopathic PAH, five with heritable PAH, three with connective tissue disease-associated PAH, and three with congenital heart disease-associated PAH were genetically tested. All five patients with heritable PAH had mutations in known PAH-related genes such as bone morphogenetic protein receptor type 2 (BMPR2) and one patient with idiopathic PAH had a mutation in ring finger protein 213 (RNF213), which we recently reported as a novel PAH-related gene.13,17
Safety and tolerability
Discontinuation of macitentan, riociguat, or selexipag because of adverse events occurred in four of 26 patients (15%). Among these four patients, one had diarrhea with selexipag, one had suspected myelosuppression with macitentan, one had nausea with riociguat, and one had hypotension with riociguat. These patients changed their drug to another drug targeting the same pathway. No adverse events, including death, hospitalization for heart failure, or prostacyclin infusion, were observed after discontinuation of each drug.
The maximum tolerated doses of the vasodilators are summarized in Supplemental Table 2. In detail, 25 (96.2%), 24 (92.3%), and 20 (76.9%) patients were taking the maximum dose of macitentan, riociguat, and selexipag, respectively. Seventeen (65.4%) patients reached the maximum dose of all three vasodilators.
Changes and outcomes after treatment
Hemodynamic data were available for 18 patients. The detailed study flow chart is shown in Supplemental Figure 1. The hemodynamics, WHO-FC, BNP concentration, and 6MWD at baseline and follow-up are presented in Table 2. The median observation period was 441 (229–1103) days. Hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 65% decrease in the mean PVR. The CO significantly increased by 82% from baseline to follow-up. Although >70% of patients had a WHO-FC of III or IV at baseline, 89% of patients had a WHO-FC of I or II at follow-up. The 6MWD and BNP concentration were also significantly improved [Figure 1(a)].
Table 2. Changes in clinical parameters.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 6.5 (4.0–8.0) 4.0 (3.0–5.0) −2.5 (−38) 0.005
Mean PAP, mmHg 56.0 (46.3–65.5) 40.0 (30.0–47.0) −16.0 (−29) <0.001
PAWP, mmHg 7.5 (6.0–9.8) 9.0 (8.0–11.0) 1.5 (20) 0.68
CO, L/min 3.3 (2.4–4.5) 6.0 (5.1–6.7) 2.7 (82) <0.001
CI, L/min per m2 2.2 (1.7–2.7) 3.8 (3.3–4.5) 1.6 (73) <0.001
PVR, WU 13.5 (8.8–21.5) 4.7 (2.8–6.9) −8.8 (−65) <0.001
Echocardiography
TAPSE, cm 1.5 (1.3–1.8) 2.3 (1.9–2.6) 0.8 (53) 0.001
RVS’, cm 9.7 (7.8–11.8) 13.3 (12.4–14.4) 3.6 (37) 0.001
RAA, cm2 17.2 (14.9–21.3) 16.4 (14.1–21.0) −0.8 (−5) 0.49
RVEDA, cm2 26.9 (22.8–33.1) 24.1 (21.0–30.3) −2.8 (−10) 0.21
RVESA, cm2 20.4 (16.3–23.9) 16.4 (13.8–21.1) −4.0 (−20) 0.006
FAC, % 23.6 (16.2–26.9) 32.9 (29.1–35.8) 9.3 (39) <0.001
WHO-FC
I or II 4 (22) 16 (89) – –
III or IV 14 (78) 2 (11) – –
6MWD, m 405.0 (303.0–441.8) 472.0 (439.5–493.5) 67.0 (17) 0.046
BNP, pg/mL 187.8 (36.7–379.5) 17.5 (10.3–27.2) −170.3 (−91) <0.001
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Eighteen patients were analyzed in hemodynamics, and 20 patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 1. Hemodynamic and echocardiographic changes.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Echocardiographic data were available for 20 patients (Supplemental Figure 1). The echocardiographic data are presented in Table 2. The median follow-up period was 737 (256–1179) days. Right ventricular function based on the TAPSE, RVS’, and RVFAC was significantly improved from baseline to follow-up, although the RAA and RVEDA were not [Figure 1(b)].
The Kaplan–Meier curves since administration of all three vasodilators are shown in Figure 2. The 1- and 2-year survival rates were both 93.3%. One patient died of multiple organ failure after femoral neck fracture during the observation period. The overall survival rate was 92.3% with median follow-up period of 33 (24–43) months. No patients were hospitalized for heart failure during the observation period. Prostacyclin infusion was initiated in six patients (25.4%) within 1 year. Among these six patients, selexipag was switched to subcutaneous infusion of treprostinil in one patient, an intravenous infusion of epoprostenol was added to the triple oral combination therapy in another patient, and a subcutaneous infusion of treprostinil was added to the triple oral combination therapy in the remaining four patients. Selexipag was not discontinued in some patients to reduce maintenance dose of the prostacyclin for infusion. No other patients underwent prostacyclin infusion after 1 year. Among six patients who underwent prostacyclin infusion within 1 year, three patients had a BMPR2 mutation, one patient had an RNF213 mutation, and one patient had Eisenmenger syndrome due to an atrial septal defect. Composite events of all-cause death, hospitalization for heart failure, and initiation of prostacyclin infusion occurred in 16.6% of the patients within 6 months and 30.4% of the patients in 1 and 2 years.
Figure 2. Event-free rates in all patients with triple oral combination therapy.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy are shown (n = 26). The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Among 14 patients who were classified as low-/intermediate-risk by the three-category REVEAL 2.0 risk score,16 the prostacyclin-free rate was 92.9% at 3 years, while the rate was 55.0% at 2 years in 12 high-risk patients (Figure 3). The difference was not statistically significant (p = 0.058). Hemodynamic changes from baseline to follow-up in each low/intermediate and high-risk group are summarized in Supplemental Table 3. Among five patients who were classified as high-risk based on the three-category REVEAL 2.0 risk score and needed prostacyclin infusion, three patients had BMPR2 mutations and one patient had a RNF213 mutation.
Figure 3. Kaplan–Meier curve for prostacyclin-free rate in each risk category.
The prostacyclin infusion-free rates in each risk category are shown. The patients were divided into two risk categories by the REVEAL 2.0 risk score.16 The p-values were calculated by the log-rank test.
Subgroup analysis in treatment-naïve patients
Seventeen patients were treatment-naïve at baseline. Six patients were treatment naïve at baseline, but treated with other pulmonary vasodilators. In five out of these six patients, oral medication was switched from beraprost to selexipag, and in one patient, it was switched from ambrisentan and tadalafil to macitentan and riociguat. Thus, these six patients were excluded from the subgroup analysis. Among the remaining 11 patients for the subgroup analysis, the median time from initiation of the first PAH drug to the start of the third PAH drug was 24 (12–47) days. The way of up-titration in treatment naïve patients was as follows. Macitentan 10 mg was initiated at first and followed by riociguat 3.0 mg within 2 weeks. The dose of riociguat was up-titrated by 1.5 mg every 2 weeks with attention to adverse effects. In 36% of treatment naïve patients, selexipag was initiated after riociguat was up-titrated to maximum tolerated dose, whereas selexipag was started within 2 weeks from initiating macitentan in 64% of patients. Selexipag was increased by 0.4 mg every 2 weeks to maximum tolerated dose with attention to side effects. One patient (9.1%) discontinued macitentan because of suspected myelosuppression, and another patient (9.1%) discontinued riociguat because of nausea. RHC data in 10 patients and echocardiographic data in nine patients were available at baseline and at follow-up during the triple oral combination therapy. The patients’ hemodynamic and right ventricular function parameters are presented in Table 3 and Figure 4. The median follow-up period of the hemodynamic analysis was 293 (211–473) days. The hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 66% decrease in the PVR. The CO increased by 90% from baseline to follow-up. The median follow-up period of echocardiography was 385 (230–594) days. The TAPSE, RVS’, and RVFAC, indicating right ventricular function, increased significantly. The WHO-FC, 6MWD, and BNP concentration in this subgroup also improved significantly. In the Kaplan–Meier analysis, no patients died or were hospitalized for heart failure (Figure 5). Prostacyclin infusion was initiated in 31.8% of patients within 7 months, and no patients underwent prostacyclin infusion after 7 months.
Table 3. Changes in clinical parameters among treatment-naïve patients at baseline.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 7.5 (4.3–8.8) 4.0 (3.3–5.0) −3.5 (−47) 0.022
Mean PAP, mmHg 63.0 (55.0–75.8) 44.5 (37.0–51.5) −18.5 (−29) 0.006
PAWP, mmHg 7.5 (6.3–9.8) 8.0 (6.5–10.3) 0.5 (7) 0.61
CO, L/min 3.1 (2.4–4.3) 5.9 (5.1–7.2) 2.8 (90) 0.006
CI, L/min per m2 2.1 (1.7–2.5) 4.2 (3.5–4.6) 2.1 (100) 0.006
PVR, WU 17.5 (13.2–21.9) 5.9 (3.8–9.6) −11.6 (−66) 0.006
Echocardiography
TAPSE, cm 1.4 (1.3–1.5) 2.3 (2.1–2.7) 0.9 (64) 0.009
RVS’, cm 9.3 (7.9–10.8) 13.5 (13.0–14.3) 4.2 (45) 0.035
RAA, cm2 18.5 (15.0–21.1) 15.2 (13.5–16.7) −3.3 (−18) 0.076
RVEDA, cm2 27.0 (25.0–33.2) 23.6 (21.0–24.6) −3.4 (−13) 0.058
RVESA, cm2 22.9 (18.7–25.4) 14.8 (14.0–16.8) −8.1 (−35) 0.009
FAC, % 22.9 (15.9–25.2) 33.1 (29.5–35.0) 10.2 (45) 0.018
WHO-FC
I or II 1 (10) 8 (80)
III or IV 9 (90) 2 (20)
6MWD, m 400.0 (326.5–432.0) 471.5 (451.5–479.2) 71.5 (18) 0.030
BNP, pg/mL 200.8 (41.9–379.5) 20.2 (12.6–24.5) −180.6 (−90) 0.006
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Ten patients were analyzed in hemodynamics, and nine patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 4. Hemodynamic and echocardiographic changes in treatment-naïve patients.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Figure 5. Event-free rates in treatment-naïve patients.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy in treatment-naïve patients are shown. The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite endpoint of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Discussion
In the present study, triple oral combination therapy with macitentan, riociguat, and selexipag improved the hemodynamics, right ventricular function, and clinical function with good tolerability in patients with PAH. Most of the low-/intermediate-risk patients and around half of the high-risk patients could be treated sufficiently with this triple oral combination therapy although it is difficult to generalize these findings.
Two previous studies investigated the efficacy of the combination of prostacyclin infusion, an ERA, and a phosphodiesterase-5 inhibitor (PDE-5i) for PAH,7,8 but data regarding triple oral combination therapy are limited. One study related to triple oral combination therapy is the subgroup analysis of the GRIPHON study, which demonstrated a change in the symptom burden after administration of selexipag in addition to an ERA and PDE-5i.6 Recently, a randomized control study (TRITON study) is also under analysis which investigated the efficacy and safety of triple oral combination therapy with macitentan, tadalafil, and selexipag versus dual oral combination therapy with macitentan and tadalafil.18 The present study is the first to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag using real-world data.
Our results of improved hemodynamics are consistent with previous observational studies that investigated the effectiveness of triple combination therapy including prostacyclin infusion.7 Sitbon et al.7 reported that with intravenous administration of epoprostenol and oral administration of bosentan and sildenafil, the mean PAP, PVR, and cardiac index improved by 33%, 71%, and 119%, respectively. Another observational study involving a combination of ambrisentan, tadalafil, and subcutaneous treprostinil also demonstrated significant improvement of the mean PAP, PVR, and cardiac index by 30%, 66%, and 94%, respectively.8 There are similarities between the results of these previous studies and the results of the present study, suggesting that triple oral combination therapy with macitentan, riociguat, and selexipag can powerfully improve the hemodynamics in patients with PAH. In the TRITON study, triple oral combination therapy improved PVR by 54%, although it was almost the same degree as dual oral combination therapy.18 Improvement of hemodynamic in this study was greater than that of the TRITON study, partly because of the difference of the study design. Although findings from observational study, results in this study provided the possibility that triple oral combination therapy could also improve hemodynamics in the real-world population as well as the randomized controlled trial.
Our study also demonstrated a favorable long-term prognosis as well as improvement of the RVFAC, 6MWD, WHO-FC, and BNP concentration with triple oral combination therapy. In a past retrospective study of the dual combination of an ERA and PDE-5i, the 3-year overall survival rate was nearly 80%.19 In another French registry in which most patients were treated with monotherapy, the 3-year survival rate was <70%.20 The prognosis in the present study appears to be superior to that in previous reports. The low rate of mortality and hospitalization for heart failure was consistent with the TRITON study, in which the risk of first disease progression events was decreased about 41% in the triple oral therapy group.18 These results in this study could verify the efficacy of triple oral combination therapy in preventing disease progression of triple oral combination therapy found in the randomized controlled study.
In the present study, the treatment response in most of the low-/intermediate-risk patients was favorable with administration of the triple oral combination therapy, and around half of the high-risk patients did not need prostacyclin infusion. The current PAH guideline recommends initial oral therapy for low-/intermediate-risk patients, while high-risk patients are recommended to receive initial combination therapy including prostacyclin infusion.10 Patients in this study did not present decompensated heart failure and the urgent initiation of prostacyclin infusion was not necessary. Therefore, the triple oral combination therapy was initiated first and its efficacy was assessed within 6 months. Our data support recommendations in guidelines in low-/intermediate-risk patients and provide a novel possibility that around half of high-risk patients can be treated without prostacyclin infusion. Moreover, 66.7% of the patients who needed prostacyclin infusion had gene mutations, suggesting that the need for prostacyclin infusion can be largely affected by their genetic background. Therefore, we should be especially careful when we use triple oral combination therapy to treat patients with specific etiologies of PAH such as gene mutations.
With respect to safety, a past study investigating the combination of tadalafil as a PDE-5i and ambrisentan as an ERA showed that the discontinuation rate of dual combination therapy because of adverse events was 12% within 2 years of the mean duration of drug use.1 In the subgroup analysis of the GRIPHON study, which investigated the effectiveness of selexipag for the patients of PAH, a triple oral combination therapy with selexipag, ERA, and PDE-5i was discontinued in 19.0% of patients due to adverse events.6 The rate of 15% in the present study was lower than that of the GRIPHON study, suggesting good tolerability in real world data. With regard to the maximum tolerated dose, a past subgroup analysis that investigated the change in the symptom burden after taking selexipag in addition to an ERA and PDE-5i showed that only 27.9% of patients who received selexipag reached the maximum dose of selexipag.6 Another study of the combination of riociguat and macitentan showed that about 70% of patients reached the maximum maintenance dose of riociguat. In the present study, 76.9% and 92.3% of patients could be up-titrated to the maximum dose with selexipag and riociguat, respectively. Thus, this study demonstrated that it is quite possible to up-titrate each drug to the maximum dose, even in patients treated with triple oral combination therapy.
The subgroup analysis showed that the hemodynamics, right ventricular function, and clinical function powerfully improved, and the degree of improvement was similar to those in the overall patient analysis. Moreover, no patients died or were hospitalized for heart failure during the observation period. These results suggest that triple oral combination therapy with macitentan, riociguat, and selexipag can be a promising treatment strategy in treatment-naïve patients.
This study has some limitations. This was a small, single-center, retrospective study that included various types of PAH and some patients were not treatment naïve at baseline. Each etiology of PAH might have affected the results of the study differently. Prostacyclin infusion was initiated within 7 months, and no patients underwent prostacyclin infusion after 7 months, which is towards a bias of an initial high-risk population of patients in which initial triple oral combination treatment was chosen. The drug regimens were decided by the physicians. Furthermore, indirect Fick method was adopted as the measurement of CO. This was not recommended in the European Society of Cardiology/European Respiratory Society Guidelines 2015, but was admitted for use in the practical situation in the Japanese PAH guideline.11 As the results could be affected by the measurement methods of CO, further validation would be warranted.
Conclusion
This study demonstrated the effectiveness of triple oral combination therapy with macitentan, riociguat, and selexipag in patients with PAH. Our data suggest that this triple oral combination therapy is associated with improvement of hemodynamics, right ventricular function, and clinical function with good tolerability. In particular, this triple oral combination therapy can be a promising therapeutic strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further investigation is required to validate these findings.
Supplemental Material
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sj-tif-6-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
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Supplemental material, sj-tif-6-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
We thank all the doctors, nurses, and supporting medical staff members who were involved in the care of the patients enrolled in this study. We also thank Angela Morben, DVM, ELS, from Edanz Group (https://en-author-services.edanzgroup.com/ac), for editing a draft of this manuscript.
Author contribution(s): Mizuki Momoi: Data curation; Formal analysis; Investigation; Writing-original draft.
Takahiro Hiraide: Conceptualization; Methodology; Writing-review & editing.
Yoshiki Shinya: Conceptualization; Validation; Writing-review & editing.
Hiromi Momota: Data curation; Validation; Methodology; Writing-review & editing.
Shogo Fukui: Data curation; Validation; Formal analysis; Writing-review & editing.
Michiyuki Kawakami: Data curation; Validation; Formal analysis; Writing-review & editing.
Yuji Itabashi: Methodology; Data curation; Resources, Writing-review & editing.
Keiichi Fukuda: Supervision; Investigation; Writing-review & editing.
Masaharu Kataoka: Conceptualization; Project administration; Writing-review & editing.
Conflict of interest statement: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Masaharu Kataoka https://orcid.org/0000-0001-8034-1005
Supplemental material: Supplemental material for this article is available online. | Recovering | ReactionOutcome | CC BY-NC | 33627044 | 19,134,415 | 2021 |
What was the outcome of reaction 'Haemoglobin decreased'? | Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension.
The evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.
Among consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan-Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.
Twenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12-47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.
Triple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings.The reviews of this paper are available via the supplemental material section.
Introduction
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by elevated pulmonary arterial pressure (PAP) due to remodeling of the pulmonary arterial bed and right sided-heart failure. Three types of PAH-specific vasodilators targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway have been developed. Combination therapy targeting these different pathways has recently been shown to improve hemodynamics, clinical functions, and even hard endpoints including survival or worsening of PAH in several recent randomized controlled trials and metanalyses.1–5 The effectiveness of triple combination therapy targeting all three of these pathways has also been reported.6–8 However, two such studies analyzed patients who were treated with two types of oral vasodilators and prostacyclin infusion,7,8 and another study was a subgroup analysis of a randomized controlled trial demonstrating a change in the symptom burden by the addition of selexipag, a prostacyclin receptor agonist, to background double combination therapy targeting other pathways.6 Therefore, evidence of the efficacy and safety of triple oral combination therapy remains scarce.
The most recently approved PAH-specific vasodilators targeting each of the three types of pathways are macitentan, which is an endothelin receptor antagonist (ERA); riociguat, which is a soluble guanylate cyclase stimulator targeting the nitric oxide pathway; and selexipag, which is an oral non-prostanoid prostacyclin receptor agonist. All three of these are orally available drugs. The effectiveness of these vasodilators for PAH has recently been proven;2,3,9 however, no clinical trials have been performed to investigate the effectiveness of the combination of these three vasodilators. Furthermore, although the current guideline recommends initial oral therapy for patients with low or intermediate risk,10 how many patients with low or intermediate risk can actually be treated with only oral combination therapy remains poorly documented to date.
Therefore, the purposes of this study were to clarify the clinical effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag and to assess which risk groups can be adequately treated with this combination therapy.
Methods
Study design
This retrospective study was performed in Keio University Hospital in Japan. This study was approved by the Ethics Committee of Keio University Hospital, and written informed consent was obtained from all patients when they received genetic tests or were hospitalized. Patients with PAH who had received triple oral combination therapy with macitentan, riociguat, and selexipag were evaluated among all consecutive patients who were referred to Keio University Hospital from 2009 to 2020.
The diagnosis of PAH was made according to the current guideline.11 Patients who were lost to follow-up or underwent maintenance hemodialysis were excluded. Baseline data were measured at the time of referral to our hospital. If patients were treatment-naïve upon referral to our hospital, the combination of macitentan, riociguat, and selexipag was initiated after diagnosis. The method of up-titration and prioritization of the vasodilators as well as the selection of sequential therapy or upfront therapy was determined at the discretion of the specialized physicians. The doses of the vasodilators were titrated to the maximal tolerated doses. For patients who had already received other PAH-specific vasodilators at the time of enrollment, these drugs targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway were switched to macitentan, riociguat, and selexipag, respectively, with the intention of further improvement of hemodynamics.
Patients received genetic counseling, and genetic tests were performed with informed consent. The methods of the genetic tests, including whole-exome sequencing, are described in our previous reports.12,13
Parameters and outcomes
Dedicated cardiologists performed right-heart catheterization (RHC) without sedation at baseline and follow-up. The right arterial pressure, mean PAP, and pulmonary arterial wedge pressure were measured by RHC. The zero pressure point was set at the level of the midthorax. Cardiac output (CO) was calculated by the Fick technique using oxygen consumption estimated by 125 times the body surface area according to a previous report.14 Pulmonary vascular resistance (PVR) was calculated as the difference between the mean PAP and pulmonary arterial wedge pressure divided by the CO.
The 6-minute walk distance (6MWD), blood concentration of B-type natriuretic peptide (BNP), and World Health Organization functional class (WHO-FC) were measured at the time of hospitalization for RHC.
Standard two-dimensional, M-mode, and Doppler images, including the tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic excursion velocity (RVS’), were obtained by echocardiographers in accordance with the current echocardiography guideline.15 Dedicated cardiologists analyzed the data and measured the right atrial area (RAA), right ventricular end-diastolic area (RVEDA), right ventricular end-systolic area, and right ventricular fractional area change (RVFAC).
Hemodynamic changes measured by RHC, echocardiographic changes, and changes in the 6MWD, BNP concentration, and WHO-FC were assessed from baseline to follow-up.
The events of all-cause death, hospitalization for heart failure, initiation of prostacyclin infusion, and discontinuation of any of the three vasodilators (macitentan, riociguat, and selexipag) because of adverse events since administration of all three vasodilators were collected. The observation period was terminated when patients died, underwent prostacyclin infusion, or stopped taking macitentan, riociguat, or selexipag for any reason.
All patients enrolled in this study were divided into two groups by risk assessment using the three-category REVEAL 2.0 risk score,16 and the prostacyclin infusion-free rate was analyzed in each group. If the value was unmeasured, the value of zero was assigned. According to the three-category REVEAL 2.0 risk score, the high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), and the low-/intermediate-risk group was defined as patients with a predicted 1-year survival rate of ⩾90% (REVEAL 2.0 risk score ⩽8).
Subgroup analysis
Patients who were treatment-naïve at baseline and treated with only macitentan, riociguat, and selexipag for PAH were also independently assessed by subgroup analysis. Their hemodynamics, echocardiography, and clinical function were measured and clinical events were collected similarly to the overall patient analysis.
Statistical analysis
Data are described as median and interquartile range unless otherwise indicated. Wilcoxon’s signed rank test was used to compare the parameters of hemodynamics, echocardiography, 6MWD, and BNP concentration from baseline to the latest follow-up. The cases which had a missing value either at baseline or follow-up were excluded from each analysis. Differences with a p-value of <0.05 were considered statistically significant. All p-values were two-tailed. Event-free rates were analyzed using the Kaplan–Meier method. All analyses were performed using R software (version 3.6.3), and figures were obtained using GraphPad Prism (version 8.0 for Mac; GraphPad Software, La Jolla, CA, USA).
Results
Patient characteristics
The patients’ baseline characteristics and medications are presented in Table 1 and Supplemental material Table 1 online. One patient who was lost to follow-up and one patient who had been undergoing maintenance hemodialysis were excluded; thus, 26 patients were enrolled in this study. The patients were predominantly female (73.1%) with a median age of 38 years. The major etiology of PAH was idiopathic PAH (38.5%) followed by connective tissue disease-associated PAH (26.9%), heritable PAH (19.2%), and congenital heart disease-associated PAH (15.4%). Most patients were treatment-naïve (65.4%), and others were taking some PAH medications at baseline.
Table 1. Demographics and characteristics at baseline.
Variable Triple oral combination therapy
N = 26
Female 19 (73.1)
Age, years 38 (23–48)
WHO-FC
I/II/III/IV 0/9/16/1 (0.0/34.6/61.5/3.8)
BNP, pg/mL 105.25 (36.7–285.5)
6MWD, m 397.5 (312.8–441.8)
PAH etiology
IPAH 10 (38.5)
HPAH 5 (19.2)
CTD-PAH 7 (26.9)
CHD-PAH 4 (15.4)
Medication
Treatment-naïve 17 (65.4)
Single 3 (11.5)
Double 2 (7.7)
Triple 4 (15.4)
Risk assessment*
High risk 12 (46.2)
Intermediate risk 4 (15.4)
Low risk 10 (38.5)
Genetic mutation**
BMPR2 5 (23.8)
ACVRL 1 (4.8)
RNF213 1 (4.8)
Data are expressed as number (%) or median (interquartile range).
* Risk assessment was calculated using the three-category REVEAL 2.0 risk score.16 The high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), the intermediate-risk group was defined as patients with a predicted 1-year survival rate of 90–<95% (REVEAL 2.0 risk score = 7 or 8), and the low-risk group was defined as patients with a predicted 1-year survival rate of ⩾95% (REVEAL 2.0 risk score ⩽6).
** Among 26 patients, 21 were genetically tested and 15 had no genetic mutations related to PAH.
6MWD, 6-minute walk distance; ACVRL1, activin A receptor-like kinase 1; BMPR2, bone morphogenetic protein receptor type 2; BNP, B-type natriuretic peptide; CHD, congenital heart disease; CTD, connective tissue disease; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; RNF213, ring finger protein 213; WHO-FC, World Health Organization functional class.
Ten patients with idiopathic PAH, five with heritable PAH, three with connective tissue disease-associated PAH, and three with congenital heart disease-associated PAH were genetically tested. All five patients with heritable PAH had mutations in known PAH-related genes such as bone morphogenetic protein receptor type 2 (BMPR2) and one patient with idiopathic PAH had a mutation in ring finger protein 213 (RNF213), which we recently reported as a novel PAH-related gene.13,17
Safety and tolerability
Discontinuation of macitentan, riociguat, or selexipag because of adverse events occurred in four of 26 patients (15%). Among these four patients, one had diarrhea with selexipag, one had suspected myelosuppression with macitentan, one had nausea with riociguat, and one had hypotension with riociguat. These patients changed their drug to another drug targeting the same pathway. No adverse events, including death, hospitalization for heart failure, or prostacyclin infusion, were observed after discontinuation of each drug.
The maximum tolerated doses of the vasodilators are summarized in Supplemental Table 2. In detail, 25 (96.2%), 24 (92.3%), and 20 (76.9%) patients were taking the maximum dose of macitentan, riociguat, and selexipag, respectively. Seventeen (65.4%) patients reached the maximum dose of all three vasodilators.
Changes and outcomes after treatment
Hemodynamic data were available for 18 patients. The detailed study flow chart is shown in Supplemental Figure 1. The hemodynamics, WHO-FC, BNP concentration, and 6MWD at baseline and follow-up are presented in Table 2. The median observation period was 441 (229–1103) days. Hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 65% decrease in the mean PVR. The CO significantly increased by 82% from baseline to follow-up. Although >70% of patients had a WHO-FC of III or IV at baseline, 89% of patients had a WHO-FC of I or II at follow-up. The 6MWD and BNP concentration were also significantly improved [Figure 1(a)].
Table 2. Changes in clinical parameters.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 6.5 (4.0–8.0) 4.0 (3.0–5.0) −2.5 (−38) 0.005
Mean PAP, mmHg 56.0 (46.3–65.5) 40.0 (30.0–47.0) −16.0 (−29) <0.001
PAWP, mmHg 7.5 (6.0–9.8) 9.0 (8.0–11.0) 1.5 (20) 0.68
CO, L/min 3.3 (2.4–4.5) 6.0 (5.1–6.7) 2.7 (82) <0.001
CI, L/min per m2 2.2 (1.7–2.7) 3.8 (3.3–4.5) 1.6 (73) <0.001
PVR, WU 13.5 (8.8–21.5) 4.7 (2.8–6.9) −8.8 (−65) <0.001
Echocardiography
TAPSE, cm 1.5 (1.3–1.8) 2.3 (1.9–2.6) 0.8 (53) 0.001
RVS’, cm 9.7 (7.8–11.8) 13.3 (12.4–14.4) 3.6 (37) 0.001
RAA, cm2 17.2 (14.9–21.3) 16.4 (14.1–21.0) −0.8 (−5) 0.49
RVEDA, cm2 26.9 (22.8–33.1) 24.1 (21.0–30.3) −2.8 (−10) 0.21
RVESA, cm2 20.4 (16.3–23.9) 16.4 (13.8–21.1) −4.0 (−20) 0.006
FAC, % 23.6 (16.2–26.9) 32.9 (29.1–35.8) 9.3 (39) <0.001
WHO-FC
I or II 4 (22) 16 (89) – –
III or IV 14 (78) 2 (11) – –
6MWD, m 405.0 (303.0–441.8) 472.0 (439.5–493.5) 67.0 (17) 0.046
BNP, pg/mL 187.8 (36.7–379.5) 17.5 (10.3–27.2) −170.3 (−91) <0.001
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Eighteen patients were analyzed in hemodynamics, and 20 patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 1. Hemodynamic and echocardiographic changes.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Echocardiographic data were available for 20 patients (Supplemental Figure 1). The echocardiographic data are presented in Table 2. The median follow-up period was 737 (256–1179) days. Right ventricular function based on the TAPSE, RVS’, and RVFAC was significantly improved from baseline to follow-up, although the RAA and RVEDA were not [Figure 1(b)].
The Kaplan–Meier curves since administration of all three vasodilators are shown in Figure 2. The 1- and 2-year survival rates were both 93.3%. One patient died of multiple organ failure after femoral neck fracture during the observation period. The overall survival rate was 92.3% with median follow-up period of 33 (24–43) months. No patients were hospitalized for heart failure during the observation period. Prostacyclin infusion was initiated in six patients (25.4%) within 1 year. Among these six patients, selexipag was switched to subcutaneous infusion of treprostinil in one patient, an intravenous infusion of epoprostenol was added to the triple oral combination therapy in another patient, and a subcutaneous infusion of treprostinil was added to the triple oral combination therapy in the remaining four patients. Selexipag was not discontinued in some patients to reduce maintenance dose of the prostacyclin for infusion. No other patients underwent prostacyclin infusion after 1 year. Among six patients who underwent prostacyclin infusion within 1 year, three patients had a BMPR2 mutation, one patient had an RNF213 mutation, and one patient had Eisenmenger syndrome due to an atrial septal defect. Composite events of all-cause death, hospitalization for heart failure, and initiation of prostacyclin infusion occurred in 16.6% of the patients within 6 months and 30.4% of the patients in 1 and 2 years.
Figure 2. Event-free rates in all patients with triple oral combination therapy.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy are shown (n = 26). The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Among 14 patients who were classified as low-/intermediate-risk by the three-category REVEAL 2.0 risk score,16 the prostacyclin-free rate was 92.9% at 3 years, while the rate was 55.0% at 2 years in 12 high-risk patients (Figure 3). The difference was not statistically significant (p = 0.058). Hemodynamic changes from baseline to follow-up in each low/intermediate and high-risk group are summarized in Supplemental Table 3. Among five patients who were classified as high-risk based on the three-category REVEAL 2.0 risk score and needed prostacyclin infusion, three patients had BMPR2 mutations and one patient had a RNF213 mutation.
Figure 3. Kaplan–Meier curve for prostacyclin-free rate in each risk category.
The prostacyclin infusion-free rates in each risk category are shown. The patients were divided into two risk categories by the REVEAL 2.0 risk score.16 The p-values were calculated by the log-rank test.
Subgroup analysis in treatment-naïve patients
Seventeen patients were treatment-naïve at baseline. Six patients were treatment naïve at baseline, but treated with other pulmonary vasodilators. In five out of these six patients, oral medication was switched from beraprost to selexipag, and in one patient, it was switched from ambrisentan and tadalafil to macitentan and riociguat. Thus, these six patients were excluded from the subgroup analysis. Among the remaining 11 patients for the subgroup analysis, the median time from initiation of the first PAH drug to the start of the third PAH drug was 24 (12–47) days. The way of up-titration in treatment naïve patients was as follows. Macitentan 10 mg was initiated at first and followed by riociguat 3.0 mg within 2 weeks. The dose of riociguat was up-titrated by 1.5 mg every 2 weeks with attention to adverse effects. In 36% of treatment naïve patients, selexipag was initiated after riociguat was up-titrated to maximum tolerated dose, whereas selexipag was started within 2 weeks from initiating macitentan in 64% of patients. Selexipag was increased by 0.4 mg every 2 weeks to maximum tolerated dose with attention to side effects. One patient (9.1%) discontinued macitentan because of suspected myelosuppression, and another patient (9.1%) discontinued riociguat because of nausea. RHC data in 10 patients and echocardiographic data in nine patients were available at baseline and at follow-up during the triple oral combination therapy. The patients’ hemodynamic and right ventricular function parameters are presented in Table 3 and Figure 4. The median follow-up period of the hemodynamic analysis was 293 (211–473) days. The hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 66% decrease in the PVR. The CO increased by 90% from baseline to follow-up. The median follow-up period of echocardiography was 385 (230–594) days. The TAPSE, RVS’, and RVFAC, indicating right ventricular function, increased significantly. The WHO-FC, 6MWD, and BNP concentration in this subgroup also improved significantly. In the Kaplan–Meier analysis, no patients died or were hospitalized for heart failure (Figure 5). Prostacyclin infusion was initiated in 31.8% of patients within 7 months, and no patients underwent prostacyclin infusion after 7 months.
Table 3. Changes in clinical parameters among treatment-naïve patients at baseline.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 7.5 (4.3–8.8) 4.0 (3.3–5.0) −3.5 (−47) 0.022
Mean PAP, mmHg 63.0 (55.0–75.8) 44.5 (37.0–51.5) −18.5 (−29) 0.006
PAWP, mmHg 7.5 (6.3–9.8) 8.0 (6.5–10.3) 0.5 (7) 0.61
CO, L/min 3.1 (2.4–4.3) 5.9 (5.1–7.2) 2.8 (90) 0.006
CI, L/min per m2 2.1 (1.7–2.5) 4.2 (3.5–4.6) 2.1 (100) 0.006
PVR, WU 17.5 (13.2–21.9) 5.9 (3.8–9.6) −11.6 (−66) 0.006
Echocardiography
TAPSE, cm 1.4 (1.3–1.5) 2.3 (2.1–2.7) 0.9 (64) 0.009
RVS’, cm 9.3 (7.9–10.8) 13.5 (13.0–14.3) 4.2 (45) 0.035
RAA, cm2 18.5 (15.0–21.1) 15.2 (13.5–16.7) −3.3 (−18) 0.076
RVEDA, cm2 27.0 (25.0–33.2) 23.6 (21.0–24.6) −3.4 (−13) 0.058
RVESA, cm2 22.9 (18.7–25.4) 14.8 (14.0–16.8) −8.1 (−35) 0.009
FAC, % 22.9 (15.9–25.2) 33.1 (29.5–35.0) 10.2 (45) 0.018
WHO-FC
I or II 1 (10) 8 (80)
III or IV 9 (90) 2 (20)
6MWD, m 400.0 (326.5–432.0) 471.5 (451.5–479.2) 71.5 (18) 0.030
BNP, pg/mL 200.8 (41.9–379.5) 20.2 (12.6–24.5) −180.6 (−90) 0.006
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Ten patients were analyzed in hemodynamics, and nine patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 4. Hemodynamic and echocardiographic changes in treatment-naïve patients.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Figure 5. Event-free rates in treatment-naïve patients.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy in treatment-naïve patients are shown. The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite endpoint of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Discussion
In the present study, triple oral combination therapy with macitentan, riociguat, and selexipag improved the hemodynamics, right ventricular function, and clinical function with good tolerability in patients with PAH. Most of the low-/intermediate-risk patients and around half of the high-risk patients could be treated sufficiently with this triple oral combination therapy although it is difficult to generalize these findings.
Two previous studies investigated the efficacy of the combination of prostacyclin infusion, an ERA, and a phosphodiesterase-5 inhibitor (PDE-5i) for PAH,7,8 but data regarding triple oral combination therapy are limited. One study related to triple oral combination therapy is the subgroup analysis of the GRIPHON study, which demonstrated a change in the symptom burden after administration of selexipag in addition to an ERA and PDE-5i.6 Recently, a randomized control study (TRITON study) is also under analysis which investigated the efficacy and safety of triple oral combination therapy with macitentan, tadalafil, and selexipag versus dual oral combination therapy with macitentan and tadalafil.18 The present study is the first to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag using real-world data.
Our results of improved hemodynamics are consistent with previous observational studies that investigated the effectiveness of triple combination therapy including prostacyclin infusion.7 Sitbon et al.7 reported that with intravenous administration of epoprostenol and oral administration of bosentan and sildenafil, the mean PAP, PVR, and cardiac index improved by 33%, 71%, and 119%, respectively. Another observational study involving a combination of ambrisentan, tadalafil, and subcutaneous treprostinil also demonstrated significant improvement of the mean PAP, PVR, and cardiac index by 30%, 66%, and 94%, respectively.8 There are similarities between the results of these previous studies and the results of the present study, suggesting that triple oral combination therapy with macitentan, riociguat, and selexipag can powerfully improve the hemodynamics in patients with PAH. In the TRITON study, triple oral combination therapy improved PVR by 54%, although it was almost the same degree as dual oral combination therapy.18 Improvement of hemodynamic in this study was greater than that of the TRITON study, partly because of the difference of the study design. Although findings from observational study, results in this study provided the possibility that triple oral combination therapy could also improve hemodynamics in the real-world population as well as the randomized controlled trial.
Our study also demonstrated a favorable long-term prognosis as well as improvement of the RVFAC, 6MWD, WHO-FC, and BNP concentration with triple oral combination therapy. In a past retrospective study of the dual combination of an ERA and PDE-5i, the 3-year overall survival rate was nearly 80%.19 In another French registry in which most patients were treated with monotherapy, the 3-year survival rate was <70%.20 The prognosis in the present study appears to be superior to that in previous reports. The low rate of mortality and hospitalization for heart failure was consistent with the TRITON study, in which the risk of first disease progression events was decreased about 41% in the triple oral therapy group.18 These results in this study could verify the efficacy of triple oral combination therapy in preventing disease progression of triple oral combination therapy found in the randomized controlled study.
In the present study, the treatment response in most of the low-/intermediate-risk patients was favorable with administration of the triple oral combination therapy, and around half of the high-risk patients did not need prostacyclin infusion. The current PAH guideline recommends initial oral therapy for low-/intermediate-risk patients, while high-risk patients are recommended to receive initial combination therapy including prostacyclin infusion.10 Patients in this study did not present decompensated heart failure and the urgent initiation of prostacyclin infusion was not necessary. Therefore, the triple oral combination therapy was initiated first and its efficacy was assessed within 6 months. Our data support recommendations in guidelines in low-/intermediate-risk patients and provide a novel possibility that around half of high-risk patients can be treated without prostacyclin infusion. Moreover, 66.7% of the patients who needed prostacyclin infusion had gene mutations, suggesting that the need for prostacyclin infusion can be largely affected by their genetic background. Therefore, we should be especially careful when we use triple oral combination therapy to treat patients with specific etiologies of PAH such as gene mutations.
With respect to safety, a past study investigating the combination of tadalafil as a PDE-5i and ambrisentan as an ERA showed that the discontinuation rate of dual combination therapy because of adverse events was 12% within 2 years of the mean duration of drug use.1 In the subgroup analysis of the GRIPHON study, which investigated the effectiveness of selexipag for the patients of PAH, a triple oral combination therapy with selexipag, ERA, and PDE-5i was discontinued in 19.0% of patients due to adverse events.6 The rate of 15% in the present study was lower than that of the GRIPHON study, suggesting good tolerability in real world data. With regard to the maximum tolerated dose, a past subgroup analysis that investigated the change in the symptom burden after taking selexipag in addition to an ERA and PDE-5i showed that only 27.9% of patients who received selexipag reached the maximum dose of selexipag.6 Another study of the combination of riociguat and macitentan showed that about 70% of patients reached the maximum maintenance dose of riociguat. In the present study, 76.9% and 92.3% of patients could be up-titrated to the maximum dose with selexipag and riociguat, respectively. Thus, this study demonstrated that it is quite possible to up-titrate each drug to the maximum dose, even in patients treated with triple oral combination therapy.
The subgroup analysis showed that the hemodynamics, right ventricular function, and clinical function powerfully improved, and the degree of improvement was similar to those in the overall patient analysis. Moreover, no patients died or were hospitalized for heart failure during the observation period. These results suggest that triple oral combination therapy with macitentan, riociguat, and selexipag can be a promising treatment strategy in treatment-naïve patients.
This study has some limitations. This was a small, single-center, retrospective study that included various types of PAH and some patients were not treatment naïve at baseline. Each etiology of PAH might have affected the results of the study differently. Prostacyclin infusion was initiated within 7 months, and no patients underwent prostacyclin infusion after 7 months, which is towards a bias of an initial high-risk population of patients in which initial triple oral combination treatment was chosen. The drug regimens were decided by the physicians. Furthermore, indirect Fick method was adopted as the measurement of CO. This was not recommended in the European Society of Cardiology/European Respiratory Society Guidelines 2015, but was admitted for use in the practical situation in the Japanese PAH guideline.11 As the results could be affected by the measurement methods of CO, further validation would be warranted.
Conclusion
This study demonstrated the effectiveness of triple oral combination therapy with macitentan, riociguat, and selexipag in patients with PAH. Our data suggest that this triple oral combination therapy is associated with improvement of hemodynamics, right ventricular function, and clinical function with good tolerability. In particular, this triple oral combination therapy can be a promising therapeutic strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further investigation is required to validate these findings.
Supplemental Material
sj-pdf-1-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-1-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-2-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-2-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-3-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-3-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-4-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-4-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-5-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-5-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-7-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-7-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-tif-6-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-tif-6-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
We thank all the doctors, nurses, and supporting medical staff members who were involved in the care of the patients enrolled in this study. We also thank Angela Morben, DVM, ELS, from Edanz Group (https://en-author-services.edanzgroup.com/ac), for editing a draft of this manuscript.
Author contribution(s): Mizuki Momoi: Data curation; Formal analysis; Investigation; Writing-original draft.
Takahiro Hiraide: Conceptualization; Methodology; Writing-review & editing.
Yoshiki Shinya: Conceptualization; Validation; Writing-review & editing.
Hiromi Momota: Data curation; Validation; Methodology; Writing-review & editing.
Shogo Fukui: Data curation; Validation; Formal analysis; Writing-review & editing.
Michiyuki Kawakami: Data curation; Validation; Formal analysis; Writing-review & editing.
Yuji Itabashi: Methodology; Data curation; Resources, Writing-review & editing.
Keiichi Fukuda: Supervision; Investigation; Writing-review & editing.
Masaharu Kataoka: Conceptualization; Project administration; Writing-review & editing.
Conflict of interest statement: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Masaharu Kataoka https://orcid.org/0000-0001-8034-1005
Supplemental material: Supplemental material for this article is available online. | Recovering | ReactionOutcome | CC BY-NC | 33627044 | 19,134,415 | 2021 |
What was the outcome of reaction 'Headache'? | Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension.
The evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.
Among consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan-Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.
Twenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12-47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.
Triple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings.The reviews of this paper are available via the supplemental material section.
Introduction
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by elevated pulmonary arterial pressure (PAP) due to remodeling of the pulmonary arterial bed and right sided-heart failure. Three types of PAH-specific vasodilators targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway have been developed. Combination therapy targeting these different pathways has recently been shown to improve hemodynamics, clinical functions, and even hard endpoints including survival or worsening of PAH in several recent randomized controlled trials and metanalyses.1–5 The effectiveness of triple combination therapy targeting all three of these pathways has also been reported.6–8 However, two such studies analyzed patients who were treated with two types of oral vasodilators and prostacyclin infusion,7,8 and another study was a subgroup analysis of a randomized controlled trial demonstrating a change in the symptom burden by the addition of selexipag, a prostacyclin receptor agonist, to background double combination therapy targeting other pathways.6 Therefore, evidence of the efficacy and safety of triple oral combination therapy remains scarce.
The most recently approved PAH-specific vasodilators targeting each of the three types of pathways are macitentan, which is an endothelin receptor antagonist (ERA); riociguat, which is a soluble guanylate cyclase stimulator targeting the nitric oxide pathway; and selexipag, which is an oral non-prostanoid prostacyclin receptor agonist. All three of these are orally available drugs. The effectiveness of these vasodilators for PAH has recently been proven;2,3,9 however, no clinical trials have been performed to investigate the effectiveness of the combination of these three vasodilators. Furthermore, although the current guideline recommends initial oral therapy for patients with low or intermediate risk,10 how many patients with low or intermediate risk can actually be treated with only oral combination therapy remains poorly documented to date.
Therefore, the purposes of this study were to clarify the clinical effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag and to assess which risk groups can be adequately treated with this combination therapy.
Methods
Study design
This retrospective study was performed in Keio University Hospital in Japan. This study was approved by the Ethics Committee of Keio University Hospital, and written informed consent was obtained from all patients when they received genetic tests or were hospitalized. Patients with PAH who had received triple oral combination therapy with macitentan, riociguat, and selexipag were evaluated among all consecutive patients who were referred to Keio University Hospital from 2009 to 2020.
The diagnosis of PAH was made according to the current guideline.11 Patients who were lost to follow-up or underwent maintenance hemodialysis were excluded. Baseline data were measured at the time of referral to our hospital. If patients were treatment-naïve upon referral to our hospital, the combination of macitentan, riociguat, and selexipag was initiated after diagnosis. The method of up-titration and prioritization of the vasodilators as well as the selection of sequential therapy or upfront therapy was determined at the discretion of the specialized physicians. The doses of the vasodilators were titrated to the maximal tolerated doses. For patients who had already received other PAH-specific vasodilators at the time of enrollment, these drugs targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway were switched to macitentan, riociguat, and selexipag, respectively, with the intention of further improvement of hemodynamics.
Patients received genetic counseling, and genetic tests were performed with informed consent. The methods of the genetic tests, including whole-exome sequencing, are described in our previous reports.12,13
Parameters and outcomes
Dedicated cardiologists performed right-heart catheterization (RHC) without sedation at baseline and follow-up. The right arterial pressure, mean PAP, and pulmonary arterial wedge pressure were measured by RHC. The zero pressure point was set at the level of the midthorax. Cardiac output (CO) was calculated by the Fick technique using oxygen consumption estimated by 125 times the body surface area according to a previous report.14 Pulmonary vascular resistance (PVR) was calculated as the difference between the mean PAP and pulmonary arterial wedge pressure divided by the CO.
The 6-minute walk distance (6MWD), blood concentration of B-type natriuretic peptide (BNP), and World Health Organization functional class (WHO-FC) were measured at the time of hospitalization for RHC.
Standard two-dimensional, M-mode, and Doppler images, including the tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic excursion velocity (RVS’), were obtained by echocardiographers in accordance with the current echocardiography guideline.15 Dedicated cardiologists analyzed the data and measured the right atrial area (RAA), right ventricular end-diastolic area (RVEDA), right ventricular end-systolic area, and right ventricular fractional area change (RVFAC).
Hemodynamic changes measured by RHC, echocardiographic changes, and changes in the 6MWD, BNP concentration, and WHO-FC were assessed from baseline to follow-up.
The events of all-cause death, hospitalization for heart failure, initiation of prostacyclin infusion, and discontinuation of any of the three vasodilators (macitentan, riociguat, and selexipag) because of adverse events since administration of all three vasodilators were collected. The observation period was terminated when patients died, underwent prostacyclin infusion, or stopped taking macitentan, riociguat, or selexipag for any reason.
All patients enrolled in this study were divided into two groups by risk assessment using the three-category REVEAL 2.0 risk score,16 and the prostacyclin infusion-free rate was analyzed in each group. If the value was unmeasured, the value of zero was assigned. According to the three-category REVEAL 2.0 risk score, the high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), and the low-/intermediate-risk group was defined as patients with a predicted 1-year survival rate of ⩾90% (REVEAL 2.0 risk score ⩽8).
Subgroup analysis
Patients who were treatment-naïve at baseline and treated with only macitentan, riociguat, and selexipag for PAH were also independently assessed by subgroup analysis. Their hemodynamics, echocardiography, and clinical function were measured and clinical events were collected similarly to the overall patient analysis.
Statistical analysis
Data are described as median and interquartile range unless otherwise indicated. Wilcoxon’s signed rank test was used to compare the parameters of hemodynamics, echocardiography, 6MWD, and BNP concentration from baseline to the latest follow-up. The cases which had a missing value either at baseline or follow-up were excluded from each analysis. Differences with a p-value of <0.05 were considered statistically significant. All p-values were two-tailed. Event-free rates were analyzed using the Kaplan–Meier method. All analyses were performed using R software (version 3.6.3), and figures were obtained using GraphPad Prism (version 8.0 for Mac; GraphPad Software, La Jolla, CA, USA).
Results
Patient characteristics
The patients’ baseline characteristics and medications are presented in Table 1 and Supplemental material Table 1 online. One patient who was lost to follow-up and one patient who had been undergoing maintenance hemodialysis were excluded; thus, 26 patients were enrolled in this study. The patients were predominantly female (73.1%) with a median age of 38 years. The major etiology of PAH was idiopathic PAH (38.5%) followed by connective tissue disease-associated PAH (26.9%), heritable PAH (19.2%), and congenital heart disease-associated PAH (15.4%). Most patients were treatment-naïve (65.4%), and others were taking some PAH medications at baseline.
Table 1. Demographics and characteristics at baseline.
Variable Triple oral combination therapy
N = 26
Female 19 (73.1)
Age, years 38 (23–48)
WHO-FC
I/II/III/IV 0/9/16/1 (0.0/34.6/61.5/3.8)
BNP, pg/mL 105.25 (36.7–285.5)
6MWD, m 397.5 (312.8–441.8)
PAH etiology
IPAH 10 (38.5)
HPAH 5 (19.2)
CTD-PAH 7 (26.9)
CHD-PAH 4 (15.4)
Medication
Treatment-naïve 17 (65.4)
Single 3 (11.5)
Double 2 (7.7)
Triple 4 (15.4)
Risk assessment*
High risk 12 (46.2)
Intermediate risk 4 (15.4)
Low risk 10 (38.5)
Genetic mutation**
BMPR2 5 (23.8)
ACVRL 1 (4.8)
RNF213 1 (4.8)
Data are expressed as number (%) or median (interquartile range).
* Risk assessment was calculated using the three-category REVEAL 2.0 risk score.16 The high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), the intermediate-risk group was defined as patients with a predicted 1-year survival rate of 90–<95% (REVEAL 2.0 risk score = 7 or 8), and the low-risk group was defined as patients with a predicted 1-year survival rate of ⩾95% (REVEAL 2.0 risk score ⩽6).
** Among 26 patients, 21 were genetically tested and 15 had no genetic mutations related to PAH.
6MWD, 6-minute walk distance; ACVRL1, activin A receptor-like kinase 1; BMPR2, bone morphogenetic protein receptor type 2; BNP, B-type natriuretic peptide; CHD, congenital heart disease; CTD, connective tissue disease; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; RNF213, ring finger protein 213; WHO-FC, World Health Organization functional class.
Ten patients with idiopathic PAH, five with heritable PAH, three with connective tissue disease-associated PAH, and three with congenital heart disease-associated PAH were genetically tested. All five patients with heritable PAH had mutations in known PAH-related genes such as bone morphogenetic protein receptor type 2 (BMPR2) and one patient with idiopathic PAH had a mutation in ring finger protein 213 (RNF213), which we recently reported as a novel PAH-related gene.13,17
Safety and tolerability
Discontinuation of macitentan, riociguat, or selexipag because of adverse events occurred in four of 26 patients (15%). Among these four patients, one had diarrhea with selexipag, one had suspected myelosuppression with macitentan, one had nausea with riociguat, and one had hypotension with riociguat. These patients changed their drug to another drug targeting the same pathway. No adverse events, including death, hospitalization for heart failure, or prostacyclin infusion, were observed after discontinuation of each drug.
The maximum tolerated doses of the vasodilators are summarized in Supplemental Table 2. In detail, 25 (96.2%), 24 (92.3%), and 20 (76.9%) patients were taking the maximum dose of macitentan, riociguat, and selexipag, respectively. Seventeen (65.4%) patients reached the maximum dose of all three vasodilators.
Changes and outcomes after treatment
Hemodynamic data were available for 18 patients. The detailed study flow chart is shown in Supplemental Figure 1. The hemodynamics, WHO-FC, BNP concentration, and 6MWD at baseline and follow-up are presented in Table 2. The median observation period was 441 (229–1103) days. Hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 65% decrease in the mean PVR. The CO significantly increased by 82% from baseline to follow-up. Although >70% of patients had a WHO-FC of III or IV at baseline, 89% of patients had a WHO-FC of I or II at follow-up. The 6MWD and BNP concentration were also significantly improved [Figure 1(a)].
Table 2. Changes in clinical parameters.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 6.5 (4.0–8.0) 4.0 (3.0–5.0) −2.5 (−38) 0.005
Mean PAP, mmHg 56.0 (46.3–65.5) 40.0 (30.0–47.0) −16.0 (−29) <0.001
PAWP, mmHg 7.5 (6.0–9.8) 9.0 (8.0–11.0) 1.5 (20) 0.68
CO, L/min 3.3 (2.4–4.5) 6.0 (5.1–6.7) 2.7 (82) <0.001
CI, L/min per m2 2.2 (1.7–2.7) 3.8 (3.3–4.5) 1.6 (73) <0.001
PVR, WU 13.5 (8.8–21.5) 4.7 (2.8–6.9) −8.8 (−65) <0.001
Echocardiography
TAPSE, cm 1.5 (1.3–1.8) 2.3 (1.9–2.6) 0.8 (53) 0.001
RVS’, cm 9.7 (7.8–11.8) 13.3 (12.4–14.4) 3.6 (37) 0.001
RAA, cm2 17.2 (14.9–21.3) 16.4 (14.1–21.0) −0.8 (−5) 0.49
RVEDA, cm2 26.9 (22.8–33.1) 24.1 (21.0–30.3) −2.8 (−10) 0.21
RVESA, cm2 20.4 (16.3–23.9) 16.4 (13.8–21.1) −4.0 (−20) 0.006
FAC, % 23.6 (16.2–26.9) 32.9 (29.1–35.8) 9.3 (39) <0.001
WHO-FC
I or II 4 (22) 16 (89) – –
III or IV 14 (78) 2 (11) – –
6MWD, m 405.0 (303.0–441.8) 472.0 (439.5–493.5) 67.0 (17) 0.046
BNP, pg/mL 187.8 (36.7–379.5) 17.5 (10.3–27.2) −170.3 (−91) <0.001
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Eighteen patients were analyzed in hemodynamics, and 20 patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 1. Hemodynamic and echocardiographic changes.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Echocardiographic data were available for 20 patients (Supplemental Figure 1). The echocardiographic data are presented in Table 2. The median follow-up period was 737 (256–1179) days. Right ventricular function based on the TAPSE, RVS’, and RVFAC was significantly improved from baseline to follow-up, although the RAA and RVEDA were not [Figure 1(b)].
The Kaplan–Meier curves since administration of all three vasodilators are shown in Figure 2. The 1- and 2-year survival rates were both 93.3%. One patient died of multiple organ failure after femoral neck fracture during the observation period. The overall survival rate was 92.3% with median follow-up period of 33 (24–43) months. No patients were hospitalized for heart failure during the observation period. Prostacyclin infusion was initiated in six patients (25.4%) within 1 year. Among these six patients, selexipag was switched to subcutaneous infusion of treprostinil in one patient, an intravenous infusion of epoprostenol was added to the triple oral combination therapy in another patient, and a subcutaneous infusion of treprostinil was added to the triple oral combination therapy in the remaining four patients. Selexipag was not discontinued in some patients to reduce maintenance dose of the prostacyclin for infusion. No other patients underwent prostacyclin infusion after 1 year. Among six patients who underwent prostacyclin infusion within 1 year, three patients had a BMPR2 mutation, one patient had an RNF213 mutation, and one patient had Eisenmenger syndrome due to an atrial septal defect. Composite events of all-cause death, hospitalization for heart failure, and initiation of prostacyclin infusion occurred in 16.6% of the patients within 6 months and 30.4% of the patients in 1 and 2 years.
Figure 2. Event-free rates in all patients with triple oral combination therapy.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy are shown (n = 26). The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Among 14 patients who were classified as low-/intermediate-risk by the three-category REVEAL 2.0 risk score,16 the prostacyclin-free rate was 92.9% at 3 years, while the rate was 55.0% at 2 years in 12 high-risk patients (Figure 3). The difference was not statistically significant (p = 0.058). Hemodynamic changes from baseline to follow-up in each low/intermediate and high-risk group are summarized in Supplemental Table 3. Among five patients who were classified as high-risk based on the three-category REVEAL 2.0 risk score and needed prostacyclin infusion, three patients had BMPR2 mutations and one patient had a RNF213 mutation.
Figure 3. Kaplan–Meier curve for prostacyclin-free rate in each risk category.
The prostacyclin infusion-free rates in each risk category are shown. The patients were divided into two risk categories by the REVEAL 2.0 risk score.16 The p-values were calculated by the log-rank test.
Subgroup analysis in treatment-naïve patients
Seventeen patients were treatment-naïve at baseline. Six patients were treatment naïve at baseline, but treated with other pulmonary vasodilators. In five out of these six patients, oral medication was switched from beraprost to selexipag, and in one patient, it was switched from ambrisentan and tadalafil to macitentan and riociguat. Thus, these six patients were excluded from the subgroup analysis. Among the remaining 11 patients for the subgroup analysis, the median time from initiation of the first PAH drug to the start of the third PAH drug was 24 (12–47) days. The way of up-titration in treatment naïve patients was as follows. Macitentan 10 mg was initiated at first and followed by riociguat 3.0 mg within 2 weeks. The dose of riociguat was up-titrated by 1.5 mg every 2 weeks with attention to adverse effects. In 36% of treatment naïve patients, selexipag was initiated after riociguat was up-titrated to maximum tolerated dose, whereas selexipag was started within 2 weeks from initiating macitentan in 64% of patients. Selexipag was increased by 0.4 mg every 2 weeks to maximum tolerated dose with attention to side effects. One patient (9.1%) discontinued macitentan because of suspected myelosuppression, and another patient (9.1%) discontinued riociguat because of nausea. RHC data in 10 patients and echocardiographic data in nine patients were available at baseline and at follow-up during the triple oral combination therapy. The patients’ hemodynamic and right ventricular function parameters are presented in Table 3 and Figure 4. The median follow-up period of the hemodynamic analysis was 293 (211–473) days. The hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 66% decrease in the PVR. The CO increased by 90% from baseline to follow-up. The median follow-up period of echocardiography was 385 (230–594) days. The TAPSE, RVS’, and RVFAC, indicating right ventricular function, increased significantly. The WHO-FC, 6MWD, and BNP concentration in this subgroup also improved significantly. In the Kaplan–Meier analysis, no patients died or were hospitalized for heart failure (Figure 5). Prostacyclin infusion was initiated in 31.8% of patients within 7 months, and no patients underwent prostacyclin infusion after 7 months.
Table 3. Changes in clinical parameters among treatment-naïve patients at baseline.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 7.5 (4.3–8.8) 4.0 (3.3–5.0) −3.5 (−47) 0.022
Mean PAP, mmHg 63.0 (55.0–75.8) 44.5 (37.0–51.5) −18.5 (−29) 0.006
PAWP, mmHg 7.5 (6.3–9.8) 8.0 (6.5–10.3) 0.5 (7) 0.61
CO, L/min 3.1 (2.4–4.3) 5.9 (5.1–7.2) 2.8 (90) 0.006
CI, L/min per m2 2.1 (1.7–2.5) 4.2 (3.5–4.6) 2.1 (100) 0.006
PVR, WU 17.5 (13.2–21.9) 5.9 (3.8–9.6) −11.6 (−66) 0.006
Echocardiography
TAPSE, cm 1.4 (1.3–1.5) 2.3 (2.1–2.7) 0.9 (64) 0.009
RVS’, cm 9.3 (7.9–10.8) 13.5 (13.0–14.3) 4.2 (45) 0.035
RAA, cm2 18.5 (15.0–21.1) 15.2 (13.5–16.7) −3.3 (−18) 0.076
RVEDA, cm2 27.0 (25.0–33.2) 23.6 (21.0–24.6) −3.4 (−13) 0.058
RVESA, cm2 22.9 (18.7–25.4) 14.8 (14.0–16.8) −8.1 (−35) 0.009
FAC, % 22.9 (15.9–25.2) 33.1 (29.5–35.0) 10.2 (45) 0.018
WHO-FC
I or II 1 (10) 8 (80)
III or IV 9 (90) 2 (20)
6MWD, m 400.0 (326.5–432.0) 471.5 (451.5–479.2) 71.5 (18) 0.030
BNP, pg/mL 200.8 (41.9–379.5) 20.2 (12.6–24.5) −180.6 (−90) 0.006
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Ten patients were analyzed in hemodynamics, and nine patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 4. Hemodynamic and echocardiographic changes in treatment-naïve patients.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Figure 5. Event-free rates in treatment-naïve patients.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy in treatment-naïve patients are shown. The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite endpoint of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Discussion
In the present study, triple oral combination therapy with macitentan, riociguat, and selexipag improved the hemodynamics, right ventricular function, and clinical function with good tolerability in patients with PAH. Most of the low-/intermediate-risk patients and around half of the high-risk patients could be treated sufficiently with this triple oral combination therapy although it is difficult to generalize these findings.
Two previous studies investigated the efficacy of the combination of prostacyclin infusion, an ERA, and a phosphodiesterase-5 inhibitor (PDE-5i) for PAH,7,8 but data regarding triple oral combination therapy are limited. One study related to triple oral combination therapy is the subgroup analysis of the GRIPHON study, which demonstrated a change in the symptom burden after administration of selexipag in addition to an ERA and PDE-5i.6 Recently, a randomized control study (TRITON study) is also under analysis which investigated the efficacy and safety of triple oral combination therapy with macitentan, tadalafil, and selexipag versus dual oral combination therapy with macitentan and tadalafil.18 The present study is the first to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag using real-world data.
Our results of improved hemodynamics are consistent with previous observational studies that investigated the effectiveness of triple combination therapy including prostacyclin infusion.7 Sitbon et al.7 reported that with intravenous administration of epoprostenol and oral administration of bosentan and sildenafil, the mean PAP, PVR, and cardiac index improved by 33%, 71%, and 119%, respectively. Another observational study involving a combination of ambrisentan, tadalafil, and subcutaneous treprostinil also demonstrated significant improvement of the mean PAP, PVR, and cardiac index by 30%, 66%, and 94%, respectively.8 There are similarities between the results of these previous studies and the results of the present study, suggesting that triple oral combination therapy with macitentan, riociguat, and selexipag can powerfully improve the hemodynamics in patients with PAH. In the TRITON study, triple oral combination therapy improved PVR by 54%, although it was almost the same degree as dual oral combination therapy.18 Improvement of hemodynamic in this study was greater than that of the TRITON study, partly because of the difference of the study design. Although findings from observational study, results in this study provided the possibility that triple oral combination therapy could also improve hemodynamics in the real-world population as well as the randomized controlled trial.
Our study also demonstrated a favorable long-term prognosis as well as improvement of the RVFAC, 6MWD, WHO-FC, and BNP concentration with triple oral combination therapy. In a past retrospective study of the dual combination of an ERA and PDE-5i, the 3-year overall survival rate was nearly 80%.19 In another French registry in which most patients were treated with monotherapy, the 3-year survival rate was <70%.20 The prognosis in the present study appears to be superior to that in previous reports. The low rate of mortality and hospitalization for heart failure was consistent with the TRITON study, in which the risk of first disease progression events was decreased about 41% in the triple oral therapy group.18 These results in this study could verify the efficacy of triple oral combination therapy in preventing disease progression of triple oral combination therapy found in the randomized controlled study.
In the present study, the treatment response in most of the low-/intermediate-risk patients was favorable with administration of the triple oral combination therapy, and around half of the high-risk patients did not need prostacyclin infusion. The current PAH guideline recommends initial oral therapy for low-/intermediate-risk patients, while high-risk patients are recommended to receive initial combination therapy including prostacyclin infusion.10 Patients in this study did not present decompensated heart failure and the urgent initiation of prostacyclin infusion was not necessary. Therefore, the triple oral combination therapy was initiated first and its efficacy was assessed within 6 months. Our data support recommendations in guidelines in low-/intermediate-risk patients and provide a novel possibility that around half of high-risk patients can be treated without prostacyclin infusion. Moreover, 66.7% of the patients who needed prostacyclin infusion had gene mutations, suggesting that the need for prostacyclin infusion can be largely affected by their genetic background. Therefore, we should be especially careful when we use triple oral combination therapy to treat patients with specific etiologies of PAH such as gene mutations.
With respect to safety, a past study investigating the combination of tadalafil as a PDE-5i and ambrisentan as an ERA showed that the discontinuation rate of dual combination therapy because of adverse events was 12% within 2 years of the mean duration of drug use.1 In the subgroup analysis of the GRIPHON study, which investigated the effectiveness of selexipag for the patients of PAH, a triple oral combination therapy with selexipag, ERA, and PDE-5i was discontinued in 19.0% of patients due to adverse events.6 The rate of 15% in the present study was lower than that of the GRIPHON study, suggesting good tolerability in real world data. With regard to the maximum tolerated dose, a past subgroup analysis that investigated the change in the symptom burden after taking selexipag in addition to an ERA and PDE-5i showed that only 27.9% of patients who received selexipag reached the maximum dose of selexipag.6 Another study of the combination of riociguat and macitentan showed that about 70% of patients reached the maximum maintenance dose of riociguat. In the present study, 76.9% and 92.3% of patients could be up-titrated to the maximum dose with selexipag and riociguat, respectively. Thus, this study demonstrated that it is quite possible to up-titrate each drug to the maximum dose, even in patients treated with triple oral combination therapy.
The subgroup analysis showed that the hemodynamics, right ventricular function, and clinical function powerfully improved, and the degree of improvement was similar to those in the overall patient analysis. Moreover, no patients died or were hospitalized for heart failure during the observation period. These results suggest that triple oral combination therapy with macitentan, riociguat, and selexipag can be a promising treatment strategy in treatment-naïve patients.
This study has some limitations. This was a small, single-center, retrospective study that included various types of PAH and some patients were not treatment naïve at baseline. Each etiology of PAH might have affected the results of the study differently. Prostacyclin infusion was initiated within 7 months, and no patients underwent prostacyclin infusion after 7 months, which is towards a bias of an initial high-risk population of patients in which initial triple oral combination treatment was chosen. The drug regimens were decided by the physicians. Furthermore, indirect Fick method was adopted as the measurement of CO. This was not recommended in the European Society of Cardiology/European Respiratory Society Guidelines 2015, but was admitted for use in the practical situation in the Japanese PAH guideline.11 As the results could be affected by the measurement methods of CO, further validation would be warranted.
Conclusion
This study demonstrated the effectiveness of triple oral combination therapy with macitentan, riociguat, and selexipag in patients with PAH. Our data suggest that this triple oral combination therapy is associated with improvement of hemodynamics, right ventricular function, and clinical function with good tolerability. In particular, this triple oral combination therapy can be a promising therapeutic strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further investigation is required to validate these findings.
Supplemental Material
sj-pdf-1-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-1-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-2-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-2-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-3-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-3-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-4-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-4-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-5-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-pdf-7-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
Click here for additional data file.
Supplemental material, sj-pdf-7-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
sj-tif-6-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
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Supplemental material, sj-tif-6-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
We thank all the doctors, nurses, and supporting medical staff members who were involved in the care of the patients enrolled in this study. We also thank Angela Morben, DVM, ELS, from Edanz Group (https://en-author-services.edanzgroup.com/ac), for editing a draft of this manuscript.
Author contribution(s): Mizuki Momoi: Data curation; Formal analysis; Investigation; Writing-original draft.
Takahiro Hiraide: Conceptualization; Methodology; Writing-review & editing.
Yoshiki Shinya: Conceptualization; Validation; Writing-review & editing.
Hiromi Momota: Data curation; Validation; Methodology; Writing-review & editing.
Shogo Fukui: Data curation; Validation; Formal analysis; Writing-review & editing.
Michiyuki Kawakami: Data curation; Validation; Formal analysis; Writing-review & editing.
Yuji Itabashi: Methodology; Data curation; Resources, Writing-review & editing.
Keiichi Fukuda: Supervision; Investigation; Writing-review & editing.
Masaharu Kataoka: Conceptualization; Project administration; Writing-review & editing.
Conflict of interest statement: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Masaharu Kataoka https://orcid.org/0000-0001-8034-1005
Supplemental material: Supplemental material for this article is available online. | Recovering | ReactionOutcome | CC BY-NC | 33627044 | 19,134,415 | 2021 |
What was the outcome of reaction 'Nausea'? | Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension.
The evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.
Among consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan-Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.
Twenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12-47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.
Triple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings.The reviews of this paper are available via the supplemental material section.
Introduction
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by elevated pulmonary arterial pressure (PAP) due to remodeling of the pulmonary arterial bed and right sided-heart failure. Three types of PAH-specific vasodilators targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway have been developed. Combination therapy targeting these different pathways has recently been shown to improve hemodynamics, clinical functions, and even hard endpoints including survival or worsening of PAH in several recent randomized controlled trials and metanalyses.1–5 The effectiveness of triple combination therapy targeting all three of these pathways has also been reported.6–8 However, two such studies analyzed patients who were treated with two types of oral vasodilators and prostacyclin infusion,7,8 and another study was a subgroup analysis of a randomized controlled trial demonstrating a change in the symptom burden by the addition of selexipag, a prostacyclin receptor agonist, to background double combination therapy targeting other pathways.6 Therefore, evidence of the efficacy and safety of triple oral combination therapy remains scarce.
The most recently approved PAH-specific vasodilators targeting each of the three types of pathways are macitentan, which is an endothelin receptor antagonist (ERA); riociguat, which is a soluble guanylate cyclase stimulator targeting the nitric oxide pathway; and selexipag, which is an oral non-prostanoid prostacyclin receptor agonist. All three of these are orally available drugs. The effectiveness of these vasodilators for PAH has recently been proven;2,3,9 however, no clinical trials have been performed to investigate the effectiveness of the combination of these three vasodilators. Furthermore, although the current guideline recommends initial oral therapy for patients with low or intermediate risk,10 how many patients with low or intermediate risk can actually be treated with only oral combination therapy remains poorly documented to date.
Therefore, the purposes of this study were to clarify the clinical effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag and to assess which risk groups can be adequately treated with this combination therapy.
Methods
Study design
This retrospective study was performed in Keio University Hospital in Japan. This study was approved by the Ethics Committee of Keio University Hospital, and written informed consent was obtained from all patients when they received genetic tests or were hospitalized. Patients with PAH who had received triple oral combination therapy with macitentan, riociguat, and selexipag were evaluated among all consecutive patients who were referred to Keio University Hospital from 2009 to 2020.
The diagnosis of PAH was made according to the current guideline.11 Patients who were lost to follow-up or underwent maintenance hemodialysis were excluded. Baseline data were measured at the time of referral to our hospital. If patients were treatment-naïve upon referral to our hospital, the combination of macitentan, riociguat, and selexipag was initiated after diagnosis. The method of up-titration and prioritization of the vasodilators as well as the selection of sequential therapy or upfront therapy was determined at the discretion of the specialized physicians. The doses of the vasodilators were titrated to the maximal tolerated doses. For patients who had already received other PAH-specific vasodilators at the time of enrollment, these drugs targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway were switched to macitentan, riociguat, and selexipag, respectively, with the intention of further improvement of hemodynamics.
Patients received genetic counseling, and genetic tests were performed with informed consent. The methods of the genetic tests, including whole-exome sequencing, are described in our previous reports.12,13
Parameters and outcomes
Dedicated cardiologists performed right-heart catheterization (RHC) without sedation at baseline and follow-up. The right arterial pressure, mean PAP, and pulmonary arterial wedge pressure were measured by RHC. The zero pressure point was set at the level of the midthorax. Cardiac output (CO) was calculated by the Fick technique using oxygen consumption estimated by 125 times the body surface area according to a previous report.14 Pulmonary vascular resistance (PVR) was calculated as the difference between the mean PAP and pulmonary arterial wedge pressure divided by the CO.
The 6-minute walk distance (6MWD), blood concentration of B-type natriuretic peptide (BNP), and World Health Organization functional class (WHO-FC) were measured at the time of hospitalization for RHC.
Standard two-dimensional, M-mode, and Doppler images, including the tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic excursion velocity (RVS’), were obtained by echocardiographers in accordance with the current echocardiography guideline.15 Dedicated cardiologists analyzed the data and measured the right atrial area (RAA), right ventricular end-diastolic area (RVEDA), right ventricular end-systolic area, and right ventricular fractional area change (RVFAC).
Hemodynamic changes measured by RHC, echocardiographic changes, and changes in the 6MWD, BNP concentration, and WHO-FC were assessed from baseline to follow-up.
The events of all-cause death, hospitalization for heart failure, initiation of prostacyclin infusion, and discontinuation of any of the three vasodilators (macitentan, riociguat, and selexipag) because of adverse events since administration of all three vasodilators were collected. The observation period was terminated when patients died, underwent prostacyclin infusion, or stopped taking macitentan, riociguat, or selexipag for any reason.
All patients enrolled in this study were divided into two groups by risk assessment using the three-category REVEAL 2.0 risk score,16 and the prostacyclin infusion-free rate was analyzed in each group. If the value was unmeasured, the value of zero was assigned. According to the three-category REVEAL 2.0 risk score, the high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), and the low-/intermediate-risk group was defined as patients with a predicted 1-year survival rate of ⩾90% (REVEAL 2.0 risk score ⩽8).
Subgroup analysis
Patients who were treatment-naïve at baseline and treated with only macitentan, riociguat, and selexipag for PAH were also independently assessed by subgroup analysis. Their hemodynamics, echocardiography, and clinical function were measured and clinical events were collected similarly to the overall patient analysis.
Statistical analysis
Data are described as median and interquartile range unless otherwise indicated. Wilcoxon’s signed rank test was used to compare the parameters of hemodynamics, echocardiography, 6MWD, and BNP concentration from baseline to the latest follow-up. The cases which had a missing value either at baseline or follow-up were excluded from each analysis. Differences with a p-value of <0.05 were considered statistically significant. All p-values were two-tailed. Event-free rates were analyzed using the Kaplan–Meier method. All analyses were performed using R software (version 3.6.3), and figures were obtained using GraphPad Prism (version 8.0 for Mac; GraphPad Software, La Jolla, CA, USA).
Results
Patient characteristics
The patients’ baseline characteristics and medications are presented in Table 1 and Supplemental material Table 1 online. One patient who was lost to follow-up and one patient who had been undergoing maintenance hemodialysis were excluded; thus, 26 patients were enrolled in this study. The patients were predominantly female (73.1%) with a median age of 38 years. The major etiology of PAH was idiopathic PAH (38.5%) followed by connective tissue disease-associated PAH (26.9%), heritable PAH (19.2%), and congenital heart disease-associated PAH (15.4%). Most patients were treatment-naïve (65.4%), and others were taking some PAH medications at baseline.
Table 1. Demographics and characteristics at baseline.
Variable Triple oral combination therapy
N = 26
Female 19 (73.1)
Age, years 38 (23–48)
WHO-FC
I/II/III/IV 0/9/16/1 (0.0/34.6/61.5/3.8)
BNP, pg/mL 105.25 (36.7–285.5)
6MWD, m 397.5 (312.8–441.8)
PAH etiology
IPAH 10 (38.5)
HPAH 5 (19.2)
CTD-PAH 7 (26.9)
CHD-PAH 4 (15.4)
Medication
Treatment-naïve 17 (65.4)
Single 3 (11.5)
Double 2 (7.7)
Triple 4 (15.4)
Risk assessment*
High risk 12 (46.2)
Intermediate risk 4 (15.4)
Low risk 10 (38.5)
Genetic mutation**
BMPR2 5 (23.8)
ACVRL 1 (4.8)
RNF213 1 (4.8)
Data are expressed as number (%) or median (interquartile range).
* Risk assessment was calculated using the three-category REVEAL 2.0 risk score.16 The high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), the intermediate-risk group was defined as patients with a predicted 1-year survival rate of 90–<95% (REVEAL 2.0 risk score = 7 or 8), and the low-risk group was defined as patients with a predicted 1-year survival rate of ⩾95% (REVEAL 2.0 risk score ⩽6).
** Among 26 patients, 21 were genetically tested and 15 had no genetic mutations related to PAH.
6MWD, 6-minute walk distance; ACVRL1, activin A receptor-like kinase 1; BMPR2, bone morphogenetic protein receptor type 2; BNP, B-type natriuretic peptide; CHD, congenital heart disease; CTD, connective tissue disease; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; RNF213, ring finger protein 213; WHO-FC, World Health Organization functional class.
Ten patients with idiopathic PAH, five with heritable PAH, three with connective tissue disease-associated PAH, and three with congenital heart disease-associated PAH were genetically tested. All five patients with heritable PAH had mutations in known PAH-related genes such as bone morphogenetic protein receptor type 2 (BMPR2) and one patient with idiopathic PAH had a mutation in ring finger protein 213 (RNF213), which we recently reported as a novel PAH-related gene.13,17
Safety and tolerability
Discontinuation of macitentan, riociguat, or selexipag because of adverse events occurred in four of 26 patients (15%). Among these four patients, one had diarrhea with selexipag, one had suspected myelosuppression with macitentan, one had nausea with riociguat, and one had hypotension with riociguat. These patients changed their drug to another drug targeting the same pathway. No adverse events, including death, hospitalization for heart failure, or prostacyclin infusion, were observed after discontinuation of each drug.
The maximum tolerated doses of the vasodilators are summarized in Supplemental Table 2. In detail, 25 (96.2%), 24 (92.3%), and 20 (76.9%) patients were taking the maximum dose of macitentan, riociguat, and selexipag, respectively. Seventeen (65.4%) patients reached the maximum dose of all three vasodilators.
Changes and outcomes after treatment
Hemodynamic data were available for 18 patients. The detailed study flow chart is shown in Supplemental Figure 1. The hemodynamics, WHO-FC, BNP concentration, and 6MWD at baseline and follow-up are presented in Table 2. The median observation period was 441 (229–1103) days. Hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 65% decrease in the mean PVR. The CO significantly increased by 82% from baseline to follow-up. Although >70% of patients had a WHO-FC of III or IV at baseline, 89% of patients had a WHO-FC of I or II at follow-up. The 6MWD and BNP concentration were also significantly improved [Figure 1(a)].
Table 2. Changes in clinical parameters.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 6.5 (4.0–8.0) 4.0 (3.0–5.0) −2.5 (−38) 0.005
Mean PAP, mmHg 56.0 (46.3–65.5) 40.0 (30.0–47.0) −16.0 (−29) <0.001
PAWP, mmHg 7.5 (6.0–9.8) 9.0 (8.0–11.0) 1.5 (20) 0.68
CO, L/min 3.3 (2.4–4.5) 6.0 (5.1–6.7) 2.7 (82) <0.001
CI, L/min per m2 2.2 (1.7–2.7) 3.8 (3.3–4.5) 1.6 (73) <0.001
PVR, WU 13.5 (8.8–21.5) 4.7 (2.8–6.9) −8.8 (−65) <0.001
Echocardiography
TAPSE, cm 1.5 (1.3–1.8) 2.3 (1.9–2.6) 0.8 (53) 0.001
RVS’, cm 9.7 (7.8–11.8) 13.3 (12.4–14.4) 3.6 (37) 0.001
RAA, cm2 17.2 (14.9–21.3) 16.4 (14.1–21.0) −0.8 (−5) 0.49
RVEDA, cm2 26.9 (22.8–33.1) 24.1 (21.0–30.3) −2.8 (−10) 0.21
RVESA, cm2 20.4 (16.3–23.9) 16.4 (13.8–21.1) −4.0 (−20) 0.006
FAC, % 23.6 (16.2–26.9) 32.9 (29.1–35.8) 9.3 (39) <0.001
WHO-FC
I or II 4 (22) 16 (89) – –
III or IV 14 (78) 2 (11) – –
6MWD, m 405.0 (303.0–441.8) 472.0 (439.5–493.5) 67.0 (17) 0.046
BNP, pg/mL 187.8 (36.7–379.5) 17.5 (10.3–27.2) −170.3 (−91) <0.001
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Eighteen patients were analyzed in hemodynamics, and 20 patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 1. Hemodynamic and echocardiographic changes.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Echocardiographic data were available for 20 patients (Supplemental Figure 1). The echocardiographic data are presented in Table 2. The median follow-up period was 737 (256–1179) days. Right ventricular function based on the TAPSE, RVS’, and RVFAC was significantly improved from baseline to follow-up, although the RAA and RVEDA were not [Figure 1(b)].
The Kaplan–Meier curves since administration of all three vasodilators are shown in Figure 2. The 1- and 2-year survival rates were both 93.3%. One patient died of multiple organ failure after femoral neck fracture during the observation period. The overall survival rate was 92.3% with median follow-up period of 33 (24–43) months. No patients were hospitalized for heart failure during the observation period. Prostacyclin infusion was initiated in six patients (25.4%) within 1 year. Among these six patients, selexipag was switched to subcutaneous infusion of treprostinil in one patient, an intravenous infusion of epoprostenol was added to the triple oral combination therapy in another patient, and a subcutaneous infusion of treprostinil was added to the triple oral combination therapy in the remaining four patients. Selexipag was not discontinued in some patients to reduce maintenance dose of the prostacyclin for infusion. No other patients underwent prostacyclin infusion after 1 year. Among six patients who underwent prostacyclin infusion within 1 year, three patients had a BMPR2 mutation, one patient had an RNF213 mutation, and one patient had Eisenmenger syndrome due to an atrial septal defect. Composite events of all-cause death, hospitalization for heart failure, and initiation of prostacyclin infusion occurred in 16.6% of the patients within 6 months and 30.4% of the patients in 1 and 2 years.
Figure 2. Event-free rates in all patients with triple oral combination therapy.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy are shown (n = 26). The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Among 14 patients who were classified as low-/intermediate-risk by the three-category REVEAL 2.0 risk score,16 the prostacyclin-free rate was 92.9% at 3 years, while the rate was 55.0% at 2 years in 12 high-risk patients (Figure 3). The difference was not statistically significant (p = 0.058). Hemodynamic changes from baseline to follow-up in each low/intermediate and high-risk group are summarized in Supplemental Table 3. Among five patients who were classified as high-risk based on the three-category REVEAL 2.0 risk score and needed prostacyclin infusion, three patients had BMPR2 mutations and one patient had a RNF213 mutation.
Figure 3. Kaplan–Meier curve for prostacyclin-free rate in each risk category.
The prostacyclin infusion-free rates in each risk category are shown. The patients were divided into two risk categories by the REVEAL 2.0 risk score.16 The p-values were calculated by the log-rank test.
Subgroup analysis in treatment-naïve patients
Seventeen patients were treatment-naïve at baseline. Six patients were treatment naïve at baseline, but treated with other pulmonary vasodilators. In five out of these six patients, oral medication was switched from beraprost to selexipag, and in one patient, it was switched from ambrisentan and tadalafil to macitentan and riociguat. Thus, these six patients were excluded from the subgroup analysis. Among the remaining 11 patients for the subgroup analysis, the median time from initiation of the first PAH drug to the start of the third PAH drug was 24 (12–47) days. The way of up-titration in treatment naïve patients was as follows. Macitentan 10 mg was initiated at first and followed by riociguat 3.0 mg within 2 weeks. The dose of riociguat was up-titrated by 1.5 mg every 2 weeks with attention to adverse effects. In 36% of treatment naïve patients, selexipag was initiated after riociguat was up-titrated to maximum tolerated dose, whereas selexipag was started within 2 weeks from initiating macitentan in 64% of patients. Selexipag was increased by 0.4 mg every 2 weeks to maximum tolerated dose with attention to side effects. One patient (9.1%) discontinued macitentan because of suspected myelosuppression, and another patient (9.1%) discontinued riociguat because of nausea. RHC data in 10 patients and echocardiographic data in nine patients were available at baseline and at follow-up during the triple oral combination therapy. The patients’ hemodynamic and right ventricular function parameters are presented in Table 3 and Figure 4. The median follow-up period of the hemodynamic analysis was 293 (211–473) days. The hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 66% decrease in the PVR. The CO increased by 90% from baseline to follow-up. The median follow-up period of echocardiography was 385 (230–594) days. The TAPSE, RVS’, and RVFAC, indicating right ventricular function, increased significantly. The WHO-FC, 6MWD, and BNP concentration in this subgroup also improved significantly. In the Kaplan–Meier analysis, no patients died or were hospitalized for heart failure (Figure 5). Prostacyclin infusion was initiated in 31.8% of patients within 7 months, and no patients underwent prostacyclin infusion after 7 months.
Table 3. Changes in clinical parameters among treatment-naïve patients at baseline.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 7.5 (4.3–8.8) 4.0 (3.3–5.0) −3.5 (−47) 0.022
Mean PAP, mmHg 63.0 (55.0–75.8) 44.5 (37.0–51.5) −18.5 (−29) 0.006
PAWP, mmHg 7.5 (6.3–9.8) 8.0 (6.5–10.3) 0.5 (7) 0.61
CO, L/min 3.1 (2.4–4.3) 5.9 (5.1–7.2) 2.8 (90) 0.006
CI, L/min per m2 2.1 (1.7–2.5) 4.2 (3.5–4.6) 2.1 (100) 0.006
PVR, WU 17.5 (13.2–21.9) 5.9 (3.8–9.6) −11.6 (−66) 0.006
Echocardiography
TAPSE, cm 1.4 (1.3–1.5) 2.3 (2.1–2.7) 0.9 (64) 0.009
RVS’, cm 9.3 (7.9–10.8) 13.5 (13.0–14.3) 4.2 (45) 0.035
RAA, cm2 18.5 (15.0–21.1) 15.2 (13.5–16.7) −3.3 (−18) 0.076
RVEDA, cm2 27.0 (25.0–33.2) 23.6 (21.0–24.6) −3.4 (−13) 0.058
RVESA, cm2 22.9 (18.7–25.4) 14.8 (14.0–16.8) −8.1 (−35) 0.009
FAC, % 22.9 (15.9–25.2) 33.1 (29.5–35.0) 10.2 (45) 0.018
WHO-FC
I or II 1 (10) 8 (80)
III or IV 9 (90) 2 (20)
6MWD, m 400.0 (326.5–432.0) 471.5 (451.5–479.2) 71.5 (18) 0.030
BNP, pg/mL 200.8 (41.9–379.5) 20.2 (12.6–24.5) −180.6 (−90) 0.006
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Ten patients were analyzed in hemodynamics, and nine patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 4. Hemodynamic and echocardiographic changes in treatment-naïve patients.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Figure 5. Event-free rates in treatment-naïve patients.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy in treatment-naïve patients are shown. The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite endpoint of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Discussion
In the present study, triple oral combination therapy with macitentan, riociguat, and selexipag improved the hemodynamics, right ventricular function, and clinical function with good tolerability in patients with PAH. Most of the low-/intermediate-risk patients and around half of the high-risk patients could be treated sufficiently with this triple oral combination therapy although it is difficult to generalize these findings.
Two previous studies investigated the efficacy of the combination of prostacyclin infusion, an ERA, and a phosphodiesterase-5 inhibitor (PDE-5i) for PAH,7,8 but data regarding triple oral combination therapy are limited. One study related to triple oral combination therapy is the subgroup analysis of the GRIPHON study, which demonstrated a change in the symptom burden after administration of selexipag in addition to an ERA and PDE-5i.6 Recently, a randomized control study (TRITON study) is also under analysis which investigated the efficacy and safety of triple oral combination therapy with macitentan, tadalafil, and selexipag versus dual oral combination therapy with macitentan and tadalafil.18 The present study is the first to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag using real-world data.
Our results of improved hemodynamics are consistent with previous observational studies that investigated the effectiveness of triple combination therapy including prostacyclin infusion.7 Sitbon et al.7 reported that with intravenous administration of epoprostenol and oral administration of bosentan and sildenafil, the mean PAP, PVR, and cardiac index improved by 33%, 71%, and 119%, respectively. Another observational study involving a combination of ambrisentan, tadalafil, and subcutaneous treprostinil also demonstrated significant improvement of the mean PAP, PVR, and cardiac index by 30%, 66%, and 94%, respectively.8 There are similarities between the results of these previous studies and the results of the present study, suggesting that triple oral combination therapy with macitentan, riociguat, and selexipag can powerfully improve the hemodynamics in patients with PAH. In the TRITON study, triple oral combination therapy improved PVR by 54%, although it was almost the same degree as dual oral combination therapy.18 Improvement of hemodynamic in this study was greater than that of the TRITON study, partly because of the difference of the study design. Although findings from observational study, results in this study provided the possibility that triple oral combination therapy could also improve hemodynamics in the real-world population as well as the randomized controlled trial.
Our study also demonstrated a favorable long-term prognosis as well as improvement of the RVFAC, 6MWD, WHO-FC, and BNP concentration with triple oral combination therapy. In a past retrospective study of the dual combination of an ERA and PDE-5i, the 3-year overall survival rate was nearly 80%.19 In another French registry in which most patients were treated with monotherapy, the 3-year survival rate was <70%.20 The prognosis in the present study appears to be superior to that in previous reports. The low rate of mortality and hospitalization for heart failure was consistent with the TRITON study, in which the risk of first disease progression events was decreased about 41% in the triple oral therapy group.18 These results in this study could verify the efficacy of triple oral combination therapy in preventing disease progression of triple oral combination therapy found in the randomized controlled study.
In the present study, the treatment response in most of the low-/intermediate-risk patients was favorable with administration of the triple oral combination therapy, and around half of the high-risk patients did not need prostacyclin infusion. The current PAH guideline recommends initial oral therapy for low-/intermediate-risk patients, while high-risk patients are recommended to receive initial combination therapy including prostacyclin infusion.10 Patients in this study did not present decompensated heart failure and the urgent initiation of prostacyclin infusion was not necessary. Therefore, the triple oral combination therapy was initiated first and its efficacy was assessed within 6 months. Our data support recommendations in guidelines in low-/intermediate-risk patients and provide a novel possibility that around half of high-risk patients can be treated without prostacyclin infusion. Moreover, 66.7% of the patients who needed prostacyclin infusion had gene mutations, suggesting that the need for prostacyclin infusion can be largely affected by their genetic background. Therefore, we should be especially careful when we use triple oral combination therapy to treat patients with specific etiologies of PAH such as gene mutations.
With respect to safety, a past study investigating the combination of tadalafil as a PDE-5i and ambrisentan as an ERA showed that the discontinuation rate of dual combination therapy because of adverse events was 12% within 2 years of the mean duration of drug use.1 In the subgroup analysis of the GRIPHON study, which investigated the effectiveness of selexipag for the patients of PAH, a triple oral combination therapy with selexipag, ERA, and PDE-5i was discontinued in 19.0% of patients due to adverse events.6 The rate of 15% in the present study was lower than that of the GRIPHON study, suggesting good tolerability in real world data. With regard to the maximum tolerated dose, a past subgroup analysis that investigated the change in the symptom burden after taking selexipag in addition to an ERA and PDE-5i showed that only 27.9% of patients who received selexipag reached the maximum dose of selexipag.6 Another study of the combination of riociguat and macitentan showed that about 70% of patients reached the maximum maintenance dose of riociguat. In the present study, 76.9% and 92.3% of patients could be up-titrated to the maximum dose with selexipag and riociguat, respectively. Thus, this study demonstrated that it is quite possible to up-titrate each drug to the maximum dose, even in patients treated with triple oral combination therapy.
The subgroup analysis showed that the hemodynamics, right ventricular function, and clinical function powerfully improved, and the degree of improvement was similar to those in the overall patient analysis. Moreover, no patients died or were hospitalized for heart failure during the observation period. These results suggest that triple oral combination therapy with macitentan, riociguat, and selexipag can be a promising treatment strategy in treatment-naïve patients.
This study has some limitations. This was a small, single-center, retrospective study that included various types of PAH and some patients were not treatment naïve at baseline. Each etiology of PAH might have affected the results of the study differently. Prostacyclin infusion was initiated within 7 months, and no patients underwent prostacyclin infusion after 7 months, which is towards a bias of an initial high-risk population of patients in which initial triple oral combination treatment was chosen. The drug regimens were decided by the physicians. Furthermore, indirect Fick method was adopted as the measurement of CO. This was not recommended in the European Society of Cardiology/European Respiratory Society Guidelines 2015, but was admitted for use in the practical situation in the Japanese PAH guideline.11 As the results could be affected by the measurement methods of CO, further validation would be warranted.
Conclusion
This study demonstrated the effectiveness of triple oral combination therapy with macitentan, riociguat, and selexipag in patients with PAH. Our data suggest that this triple oral combination therapy is associated with improvement of hemodynamics, right ventricular function, and clinical function with good tolerability. In particular, this triple oral combination therapy can be a promising therapeutic strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further investigation is required to validate these findings.
Supplemental Material
sj-pdf-1-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
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Supplemental material, sj-pdf-1-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-2-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-3-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-4-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-5-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-pdf-7-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
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Supplemental material, sj-tif-6-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
We thank all the doctors, nurses, and supporting medical staff members who were involved in the care of the patients enrolled in this study. We also thank Angela Morben, DVM, ELS, from Edanz Group (https://en-author-services.edanzgroup.com/ac), for editing a draft of this manuscript.
Author contribution(s): Mizuki Momoi: Data curation; Formal analysis; Investigation; Writing-original draft.
Takahiro Hiraide: Conceptualization; Methodology; Writing-review & editing.
Yoshiki Shinya: Conceptualization; Validation; Writing-review & editing.
Hiromi Momota: Data curation; Validation; Methodology; Writing-review & editing.
Shogo Fukui: Data curation; Validation; Formal analysis; Writing-review & editing.
Michiyuki Kawakami: Data curation; Validation; Formal analysis; Writing-review & editing.
Yuji Itabashi: Methodology; Data curation; Resources, Writing-review & editing.
Keiichi Fukuda: Supervision; Investigation; Writing-review & editing.
Masaharu Kataoka: Conceptualization; Project administration; Writing-review & editing.
Conflict of interest statement: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Masaharu Kataoka https://orcid.org/0000-0001-8034-1005
Supplemental material: Supplemental material for this article is available online. | Recovering | ReactionOutcome | CC BY-NC | 33627044 | 19,134,415 | 2021 |
What was the outcome of reaction 'White blood cell count decreased'? | Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension.
The evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.
Among consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan-Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.
Twenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12-47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.
Triple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings.The reviews of this paper are available via the supplemental material section.
Introduction
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by elevated pulmonary arterial pressure (PAP) due to remodeling of the pulmonary arterial bed and right sided-heart failure. Three types of PAH-specific vasodilators targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway have been developed. Combination therapy targeting these different pathways has recently been shown to improve hemodynamics, clinical functions, and even hard endpoints including survival or worsening of PAH in several recent randomized controlled trials and metanalyses.1–5 The effectiveness of triple combination therapy targeting all three of these pathways has also been reported.6–8 However, two such studies analyzed patients who were treated with two types of oral vasodilators and prostacyclin infusion,7,8 and another study was a subgroup analysis of a randomized controlled trial demonstrating a change in the symptom burden by the addition of selexipag, a prostacyclin receptor agonist, to background double combination therapy targeting other pathways.6 Therefore, evidence of the efficacy and safety of triple oral combination therapy remains scarce.
The most recently approved PAH-specific vasodilators targeting each of the three types of pathways are macitentan, which is an endothelin receptor antagonist (ERA); riociguat, which is a soluble guanylate cyclase stimulator targeting the nitric oxide pathway; and selexipag, which is an oral non-prostanoid prostacyclin receptor agonist. All three of these are orally available drugs. The effectiveness of these vasodilators for PAH has recently been proven;2,3,9 however, no clinical trials have been performed to investigate the effectiveness of the combination of these three vasodilators. Furthermore, although the current guideline recommends initial oral therapy for patients with low or intermediate risk,10 how many patients with low or intermediate risk can actually be treated with only oral combination therapy remains poorly documented to date.
Therefore, the purposes of this study were to clarify the clinical effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag and to assess which risk groups can be adequately treated with this combination therapy.
Methods
Study design
This retrospective study was performed in Keio University Hospital in Japan. This study was approved by the Ethics Committee of Keio University Hospital, and written informed consent was obtained from all patients when they received genetic tests or were hospitalized. Patients with PAH who had received triple oral combination therapy with macitentan, riociguat, and selexipag were evaluated among all consecutive patients who were referred to Keio University Hospital from 2009 to 2020.
The diagnosis of PAH was made according to the current guideline.11 Patients who were lost to follow-up or underwent maintenance hemodialysis were excluded. Baseline data were measured at the time of referral to our hospital. If patients were treatment-naïve upon referral to our hospital, the combination of macitentan, riociguat, and selexipag was initiated after diagnosis. The method of up-titration and prioritization of the vasodilators as well as the selection of sequential therapy or upfront therapy was determined at the discretion of the specialized physicians. The doses of the vasodilators were titrated to the maximal tolerated doses. For patients who had already received other PAH-specific vasodilators at the time of enrollment, these drugs targeting the endothelin pathway, nitric oxide pathway, and prostacyclin pathway were switched to macitentan, riociguat, and selexipag, respectively, with the intention of further improvement of hemodynamics.
Patients received genetic counseling, and genetic tests were performed with informed consent. The methods of the genetic tests, including whole-exome sequencing, are described in our previous reports.12,13
Parameters and outcomes
Dedicated cardiologists performed right-heart catheterization (RHC) without sedation at baseline and follow-up. The right arterial pressure, mean PAP, and pulmonary arterial wedge pressure were measured by RHC. The zero pressure point was set at the level of the midthorax. Cardiac output (CO) was calculated by the Fick technique using oxygen consumption estimated by 125 times the body surface area according to a previous report.14 Pulmonary vascular resistance (PVR) was calculated as the difference between the mean PAP and pulmonary arterial wedge pressure divided by the CO.
The 6-minute walk distance (6MWD), blood concentration of B-type natriuretic peptide (BNP), and World Health Organization functional class (WHO-FC) were measured at the time of hospitalization for RHC.
Standard two-dimensional, M-mode, and Doppler images, including the tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic excursion velocity (RVS’), were obtained by echocardiographers in accordance with the current echocardiography guideline.15 Dedicated cardiologists analyzed the data and measured the right atrial area (RAA), right ventricular end-diastolic area (RVEDA), right ventricular end-systolic area, and right ventricular fractional area change (RVFAC).
Hemodynamic changes measured by RHC, echocardiographic changes, and changes in the 6MWD, BNP concentration, and WHO-FC were assessed from baseline to follow-up.
The events of all-cause death, hospitalization for heart failure, initiation of prostacyclin infusion, and discontinuation of any of the three vasodilators (macitentan, riociguat, and selexipag) because of adverse events since administration of all three vasodilators were collected. The observation period was terminated when patients died, underwent prostacyclin infusion, or stopped taking macitentan, riociguat, or selexipag for any reason.
All patients enrolled in this study were divided into two groups by risk assessment using the three-category REVEAL 2.0 risk score,16 and the prostacyclin infusion-free rate was analyzed in each group. If the value was unmeasured, the value of zero was assigned. According to the three-category REVEAL 2.0 risk score, the high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), and the low-/intermediate-risk group was defined as patients with a predicted 1-year survival rate of ⩾90% (REVEAL 2.0 risk score ⩽8).
Subgroup analysis
Patients who were treatment-naïve at baseline and treated with only macitentan, riociguat, and selexipag for PAH were also independently assessed by subgroup analysis. Their hemodynamics, echocardiography, and clinical function were measured and clinical events were collected similarly to the overall patient analysis.
Statistical analysis
Data are described as median and interquartile range unless otherwise indicated. Wilcoxon’s signed rank test was used to compare the parameters of hemodynamics, echocardiography, 6MWD, and BNP concentration from baseline to the latest follow-up. The cases which had a missing value either at baseline or follow-up were excluded from each analysis. Differences with a p-value of <0.05 were considered statistically significant. All p-values were two-tailed. Event-free rates were analyzed using the Kaplan–Meier method. All analyses were performed using R software (version 3.6.3), and figures were obtained using GraphPad Prism (version 8.0 for Mac; GraphPad Software, La Jolla, CA, USA).
Results
Patient characteristics
The patients’ baseline characteristics and medications are presented in Table 1 and Supplemental material Table 1 online. One patient who was lost to follow-up and one patient who had been undergoing maintenance hemodialysis were excluded; thus, 26 patients were enrolled in this study. The patients were predominantly female (73.1%) with a median age of 38 years. The major etiology of PAH was idiopathic PAH (38.5%) followed by connective tissue disease-associated PAH (26.9%), heritable PAH (19.2%), and congenital heart disease-associated PAH (15.4%). Most patients were treatment-naïve (65.4%), and others were taking some PAH medications at baseline.
Table 1. Demographics and characteristics at baseline.
Variable Triple oral combination therapy
N = 26
Female 19 (73.1)
Age, years 38 (23–48)
WHO-FC
I/II/III/IV 0/9/16/1 (0.0/34.6/61.5/3.8)
BNP, pg/mL 105.25 (36.7–285.5)
6MWD, m 397.5 (312.8–441.8)
PAH etiology
IPAH 10 (38.5)
HPAH 5 (19.2)
CTD-PAH 7 (26.9)
CHD-PAH 4 (15.4)
Medication
Treatment-naïve 17 (65.4)
Single 3 (11.5)
Double 2 (7.7)
Triple 4 (15.4)
Risk assessment*
High risk 12 (46.2)
Intermediate risk 4 (15.4)
Low risk 10 (38.5)
Genetic mutation**
BMPR2 5 (23.8)
ACVRL 1 (4.8)
RNF213 1 (4.8)
Data are expressed as number (%) or median (interquartile range).
* Risk assessment was calculated using the three-category REVEAL 2.0 risk score.16 The high-risk group was defined as patients with a predicted 1-year survival rate of <90% (REVEAL 2.0 risk score ⩾9), the intermediate-risk group was defined as patients with a predicted 1-year survival rate of 90–<95% (REVEAL 2.0 risk score = 7 or 8), and the low-risk group was defined as patients with a predicted 1-year survival rate of ⩾95% (REVEAL 2.0 risk score ⩽6).
** Among 26 patients, 21 were genetically tested and 15 had no genetic mutations related to PAH.
6MWD, 6-minute walk distance; ACVRL1, activin A receptor-like kinase 1; BMPR2, bone morphogenetic protein receptor type 2; BNP, B-type natriuretic peptide; CHD, congenital heart disease; CTD, connective tissue disease; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; RNF213, ring finger protein 213; WHO-FC, World Health Organization functional class.
Ten patients with idiopathic PAH, five with heritable PAH, three with connective tissue disease-associated PAH, and three with congenital heart disease-associated PAH were genetically tested. All five patients with heritable PAH had mutations in known PAH-related genes such as bone morphogenetic protein receptor type 2 (BMPR2) and one patient with idiopathic PAH had a mutation in ring finger protein 213 (RNF213), which we recently reported as a novel PAH-related gene.13,17
Safety and tolerability
Discontinuation of macitentan, riociguat, or selexipag because of adverse events occurred in four of 26 patients (15%). Among these four patients, one had diarrhea with selexipag, one had suspected myelosuppression with macitentan, one had nausea with riociguat, and one had hypotension with riociguat. These patients changed their drug to another drug targeting the same pathway. No adverse events, including death, hospitalization for heart failure, or prostacyclin infusion, were observed after discontinuation of each drug.
The maximum tolerated doses of the vasodilators are summarized in Supplemental Table 2. In detail, 25 (96.2%), 24 (92.3%), and 20 (76.9%) patients were taking the maximum dose of macitentan, riociguat, and selexipag, respectively. Seventeen (65.4%) patients reached the maximum dose of all three vasodilators.
Changes and outcomes after treatment
Hemodynamic data were available for 18 patients. The detailed study flow chart is shown in Supplemental Figure 1. The hemodynamics, WHO-FC, BNP concentration, and 6MWD at baseline and follow-up are presented in Table 2. The median observation period was 441 (229–1103) days. Hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 65% decrease in the mean PVR. The CO significantly increased by 82% from baseline to follow-up. Although >70% of patients had a WHO-FC of III or IV at baseline, 89% of patients had a WHO-FC of I or II at follow-up. The 6MWD and BNP concentration were also significantly improved [Figure 1(a)].
Table 2. Changes in clinical parameters.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 6.5 (4.0–8.0) 4.0 (3.0–5.0) −2.5 (−38) 0.005
Mean PAP, mmHg 56.0 (46.3–65.5) 40.0 (30.0–47.0) −16.0 (−29) <0.001
PAWP, mmHg 7.5 (6.0–9.8) 9.0 (8.0–11.0) 1.5 (20) 0.68
CO, L/min 3.3 (2.4–4.5) 6.0 (5.1–6.7) 2.7 (82) <0.001
CI, L/min per m2 2.2 (1.7–2.7) 3.8 (3.3–4.5) 1.6 (73) <0.001
PVR, WU 13.5 (8.8–21.5) 4.7 (2.8–6.9) −8.8 (−65) <0.001
Echocardiography
TAPSE, cm 1.5 (1.3–1.8) 2.3 (1.9–2.6) 0.8 (53) 0.001
RVS’, cm 9.7 (7.8–11.8) 13.3 (12.4–14.4) 3.6 (37) 0.001
RAA, cm2 17.2 (14.9–21.3) 16.4 (14.1–21.0) −0.8 (−5) 0.49
RVEDA, cm2 26.9 (22.8–33.1) 24.1 (21.0–30.3) −2.8 (−10) 0.21
RVESA, cm2 20.4 (16.3–23.9) 16.4 (13.8–21.1) −4.0 (−20) 0.006
FAC, % 23.6 (16.2–26.9) 32.9 (29.1–35.8) 9.3 (39) <0.001
WHO-FC
I or II 4 (22) 16 (89) – –
III or IV 14 (78) 2 (11) – –
6MWD, m 405.0 (303.0–441.8) 472.0 (439.5–493.5) 67.0 (17) 0.046
BNP, pg/mL 187.8 (36.7–379.5) 17.5 (10.3–27.2) −170.3 (−91) <0.001
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Eighteen patients were analyzed in hemodynamics, and 20 patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 1. Hemodynamic and echocardiographic changes.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Echocardiographic data were available for 20 patients (Supplemental Figure 1). The echocardiographic data are presented in Table 2. The median follow-up period was 737 (256–1179) days. Right ventricular function based on the TAPSE, RVS’, and RVFAC was significantly improved from baseline to follow-up, although the RAA and RVEDA were not [Figure 1(b)].
The Kaplan–Meier curves since administration of all three vasodilators are shown in Figure 2. The 1- and 2-year survival rates were both 93.3%. One patient died of multiple organ failure after femoral neck fracture during the observation period. The overall survival rate was 92.3% with median follow-up period of 33 (24–43) months. No patients were hospitalized for heart failure during the observation period. Prostacyclin infusion was initiated in six patients (25.4%) within 1 year. Among these six patients, selexipag was switched to subcutaneous infusion of treprostinil in one patient, an intravenous infusion of epoprostenol was added to the triple oral combination therapy in another patient, and a subcutaneous infusion of treprostinil was added to the triple oral combination therapy in the remaining four patients. Selexipag was not discontinued in some patients to reduce maintenance dose of the prostacyclin for infusion. No other patients underwent prostacyclin infusion after 1 year. Among six patients who underwent prostacyclin infusion within 1 year, three patients had a BMPR2 mutation, one patient had an RNF213 mutation, and one patient had Eisenmenger syndrome due to an atrial septal defect. Composite events of all-cause death, hospitalization for heart failure, and initiation of prostacyclin infusion occurred in 16.6% of the patients within 6 months and 30.4% of the patients in 1 and 2 years.
Figure 2. Event-free rates in all patients with triple oral combination therapy.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy are shown (n = 26). The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Among 14 patients who were classified as low-/intermediate-risk by the three-category REVEAL 2.0 risk score,16 the prostacyclin-free rate was 92.9% at 3 years, while the rate was 55.0% at 2 years in 12 high-risk patients (Figure 3). The difference was not statistically significant (p = 0.058). Hemodynamic changes from baseline to follow-up in each low/intermediate and high-risk group are summarized in Supplemental Table 3. Among five patients who were classified as high-risk based on the three-category REVEAL 2.0 risk score and needed prostacyclin infusion, three patients had BMPR2 mutations and one patient had a RNF213 mutation.
Figure 3. Kaplan–Meier curve for prostacyclin-free rate in each risk category.
The prostacyclin infusion-free rates in each risk category are shown. The patients were divided into two risk categories by the REVEAL 2.0 risk score.16 The p-values were calculated by the log-rank test.
Subgroup analysis in treatment-naïve patients
Seventeen patients were treatment-naïve at baseline. Six patients were treatment naïve at baseline, but treated with other pulmonary vasodilators. In five out of these six patients, oral medication was switched from beraprost to selexipag, and in one patient, it was switched from ambrisentan and tadalafil to macitentan and riociguat. Thus, these six patients were excluded from the subgroup analysis. Among the remaining 11 patients for the subgroup analysis, the median time from initiation of the first PAH drug to the start of the third PAH drug was 24 (12–47) days. The way of up-titration in treatment naïve patients was as follows. Macitentan 10 mg was initiated at first and followed by riociguat 3.0 mg within 2 weeks. The dose of riociguat was up-titrated by 1.5 mg every 2 weeks with attention to adverse effects. In 36% of treatment naïve patients, selexipag was initiated after riociguat was up-titrated to maximum tolerated dose, whereas selexipag was started within 2 weeks from initiating macitentan in 64% of patients. Selexipag was increased by 0.4 mg every 2 weeks to maximum tolerated dose with attention to side effects. One patient (9.1%) discontinued macitentan because of suspected myelosuppression, and another patient (9.1%) discontinued riociguat because of nausea. RHC data in 10 patients and echocardiographic data in nine patients were available at baseline and at follow-up during the triple oral combination therapy. The patients’ hemodynamic and right ventricular function parameters are presented in Table 3 and Figure 4. The median follow-up period of the hemodynamic analysis was 293 (211–473) days. The hemodynamic parameters were significantly improved with a 29% decrease in the mean PAP and 66% decrease in the PVR. The CO increased by 90% from baseline to follow-up. The median follow-up period of echocardiography was 385 (230–594) days. The TAPSE, RVS’, and RVFAC, indicating right ventricular function, increased significantly. The WHO-FC, 6MWD, and BNP concentration in this subgroup also improved significantly. In the Kaplan–Meier analysis, no patients died or were hospitalized for heart failure (Figure 5). Prostacyclin infusion was initiated in 31.8% of patients within 7 months, and no patients underwent prostacyclin infusion after 7 months.
Table 3. Changes in clinical parameters among treatment-naïve patients at baseline.
Variable Baseline Follow-up Change (%) p-value*
Hemodynamics
Mean RAP, mmHg 7.5 (4.3–8.8) 4.0 (3.3–5.0) −3.5 (−47) 0.022
Mean PAP, mmHg 63.0 (55.0–75.8) 44.5 (37.0–51.5) −18.5 (−29) 0.006
PAWP, mmHg 7.5 (6.3–9.8) 8.0 (6.5–10.3) 0.5 (7) 0.61
CO, L/min 3.1 (2.4–4.3) 5.9 (5.1–7.2) 2.8 (90) 0.006
CI, L/min per m2 2.1 (1.7–2.5) 4.2 (3.5–4.6) 2.1 (100) 0.006
PVR, WU 17.5 (13.2–21.9) 5.9 (3.8–9.6) −11.6 (−66) 0.006
Echocardiography
TAPSE, cm 1.4 (1.3–1.5) 2.3 (2.1–2.7) 0.9 (64) 0.009
RVS’, cm 9.3 (7.9–10.8) 13.5 (13.0–14.3) 4.2 (45) 0.035
RAA, cm2 18.5 (15.0–21.1) 15.2 (13.5–16.7) −3.3 (−18) 0.076
RVEDA, cm2 27.0 (25.0–33.2) 23.6 (21.0–24.6) −3.4 (−13) 0.058
RVESA, cm2 22.9 (18.7–25.4) 14.8 (14.0–16.8) −8.1 (−35) 0.009
FAC, % 22.9 (15.9–25.2) 33.1 (29.5–35.0) 10.2 (45) 0.018
WHO-FC
I or II 1 (10) 8 (80)
III or IV 9 (90) 2 (20)
6MWD, m 400.0 (326.5–432.0) 471.5 (451.5–479.2) 71.5 (18) 0.030
BNP, pg/mL 200.8 (41.9–379.5) 20.2 (12.6–24.5) −180.6 (−90) 0.006
Data are expressed as number (%) or median (interquartile range). The number of subjects at baseline and follow-up was the same equal number in each parameter. Ten patients were analyzed in hemodynamics, and nine patients in echocardiography.
* p-value was calculated using a Wilcoxon’s signed rank test for comparison of baseline and follow-up.
6MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; FAC, fractional area change; PAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, mean right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVS’, right ventricular systolic excursion velocity; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class; WU, Wood units.
Figure 4. Hemodynamic and echocardiographic changes in treatment-naïve patients.
The patients’ (a) hemodynamic parameters and (b) echocardiographic parameters at baseline and follow-up are compared.
*p < 0.05.
CO, cardiac output; FAC, fractional area change; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAA, right atrial area; RAP, right atrial pressure; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; WU, Wood units.
Figure 5. Event-free rates in treatment-naïve patients.
The Kaplan–Meier curves for event-free rates since initiation of triple combination therapy in treatment-naïve patients are shown. The events are defined as (a) all-cause death, (b) hospitalization for heart failure, (c) prostacyclin infusion, and (d) the composite endpoint of all-cause death, hospitalization, and heart failure.
HF, heart failure.
Discussion
In the present study, triple oral combination therapy with macitentan, riociguat, and selexipag improved the hemodynamics, right ventricular function, and clinical function with good tolerability in patients with PAH. Most of the low-/intermediate-risk patients and around half of the high-risk patients could be treated sufficiently with this triple oral combination therapy although it is difficult to generalize these findings.
Two previous studies investigated the efficacy of the combination of prostacyclin infusion, an ERA, and a phosphodiesterase-5 inhibitor (PDE-5i) for PAH,7,8 but data regarding triple oral combination therapy are limited. One study related to triple oral combination therapy is the subgroup analysis of the GRIPHON study, which demonstrated a change in the symptom burden after administration of selexipag in addition to an ERA and PDE-5i.6 Recently, a randomized control study (TRITON study) is also under analysis which investigated the efficacy and safety of triple oral combination therapy with macitentan, tadalafil, and selexipag versus dual oral combination therapy with macitentan and tadalafil.18 The present study is the first to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag using real-world data.
Our results of improved hemodynamics are consistent with previous observational studies that investigated the effectiveness of triple combination therapy including prostacyclin infusion.7 Sitbon et al.7 reported that with intravenous administration of epoprostenol and oral administration of bosentan and sildenafil, the mean PAP, PVR, and cardiac index improved by 33%, 71%, and 119%, respectively. Another observational study involving a combination of ambrisentan, tadalafil, and subcutaneous treprostinil also demonstrated significant improvement of the mean PAP, PVR, and cardiac index by 30%, 66%, and 94%, respectively.8 There are similarities between the results of these previous studies and the results of the present study, suggesting that triple oral combination therapy with macitentan, riociguat, and selexipag can powerfully improve the hemodynamics in patients with PAH. In the TRITON study, triple oral combination therapy improved PVR by 54%, although it was almost the same degree as dual oral combination therapy.18 Improvement of hemodynamic in this study was greater than that of the TRITON study, partly because of the difference of the study design. Although findings from observational study, results in this study provided the possibility that triple oral combination therapy could also improve hemodynamics in the real-world population as well as the randomized controlled trial.
Our study also demonstrated a favorable long-term prognosis as well as improvement of the RVFAC, 6MWD, WHO-FC, and BNP concentration with triple oral combination therapy. In a past retrospective study of the dual combination of an ERA and PDE-5i, the 3-year overall survival rate was nearly 80%.19 In another French registry in which most patients were treated with monotherapy, the 3-year survival rate was <70%.20 The prognosis in the present study appears to be superior to that in previous reports. The low rate of mortality and hospitalization for heart failure was consistent with the TRITON study, in which the risk of first disease progression events was decreased about 41% in the triple oral therapy group.18 These results in this study could verify the efficacy of triple oral combination therapy in preventing disease progression of triple oral combination therapy found in the randomized controlled study.
In the present study, the treatment response in most of the low-/intermediate-risk patients was favorable with administration of the triple oral combination therapy, and around half of the high-risk patients did not need prostacyclin infusion. The current PAH guideline recommends initial oral therapy for low-/intermediate-risk patients, while high-risk patients are recommended to receive initial combination therapy including prostacyclin infusion.10 Patients in this study did not present decompensated heart failure and the urgent initiation of prostacyclin infusion was not necessary. Therefore, the triple oral combination therapy was initiated first and its efficacy was assessed within 6 months. Our data support recommendations in guidelines in low-/intermediate-risk patients and provide a novel possibility that around half of high-risk patients can be treated without prostacyclin infusion. Moreover, 66.7% of the patients who needed prostacyclin infusion had gene mutations, suggesting that the need for prostacyclin infusion can be largely affected by their genetic background. Therefore, we should be especially careful when we use triple oral combination therapy to treat patients with specific etiologies of PAH such as gene mutations.
With respect to safety, a past study investigating the combination of tadalafil as a PDE-5i and ambrisentan as an ERA showed that the discontinuation rate of dual combination therapy because of adverse events was 12% within 2 years of the mean duration of drug use.1 In the subgroup analysis of the GRIPHON study, which investigated the effectiveness of selexipag for the patients of PAH, a triple oral combination therapy with selexipag, ERA, and PDE-5i was discontinued in 19.0% of patients due to adverse events.6 The rate of 15% in the present study was lower than that of the GRIPHON study, suggesting good tolerability in real world data. With regard to the maximum tolerated dose, a past subgroup analysis that investigated the change in the symptom burden after taking selexipag in addition to an ERA and PDE-5i showed that only 27.9% of patients who received selexipag reached the maximum dose of selexipag.6 Another study of the combination of riociguat and macitentan showed that about 70% of patients reached the maximum maintenance dose of riociguat. In the present study, 76.9% and 92.3% of patients could be up-titrated to the maximum dose with selexipag and riociguat, respectively. Thus, this study demonstrated that it is quite possible to up-titrate each drug to the maximum dose, even in patients treated with triple oral combination therapy.
The subgroup analysis showed that the hemodynamics, right ventricular function, and clinical function powerfully improved, and the degree of improvement was similar to those in the overall patient analysis. Moreover, no patients died or were hospitalized for heart failure during the observation period. These results suggest that triple oral combination therapy with macitentan, riociguat, and selexipag can be a promising treatment strategy in treatment-naïve patients.
This study has some limitations. This was a small, single-center, retrospective study that included various types of PAH and some patients were not treatment naïve at baseline. Each etiology of PAH might have affected the results of the study differently. Prostacyclin infusion was initiated within 7 months, and no patients underwent prostacyclin infusion after 7 months, which is towards a bias of an initial high-risk population of patients in which initial triple oral combination treatment was chosen. The drug regimens were decided by the physicians. Furthermore, indirect Fick method was adopted as the measurement of CO. This was not recommended in the European Society of Cardiology/European Respiratory Society Guidelines 2015, but was admitted for use in the practical situation in the Japanese PAH guideline.11 As the results could be affected by the measurement methods of CO, further validation would be warranted.
Conclusion
This study demonstrated the effectiveness of triple oral combination therapy with macitentan, riociguat, and selexipag in patients with PAH. Our data suggest that this triple oral combination therapy is associated with improvement of hemodynamics, right ventricular function, and clinical function with good tolerability. In particular, this triple oral combination therapy can be a promising therapeutic strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further investigation is required to validate these findings.
Supplemental Material
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sj-tif-6-tar-10.1177_1753466621995048 – Supplemental material for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension
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Supplemental material, sj-tif-6-tar-10.1177_1753466621995048 for Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension by Mizuki Momoi, Takahiro Hiraide, Yoshiki Shinya, Hiromi Momota, Shogo Fukui, Michiyuki Kawakami, Yuji Itabashi, Keiichi Fukuda and Masaharu Kataoka in Therapeutic Advances in Respiratory Disease
We thank all the doctors, nurses, and supporting medical staff members who were involved in the care of the patients enrolled in this study. We also thank Angela Morben, DVM, ELS, from Edanz Group (https://en-author-services.edanzgroup.com/ac), for editing a draft of this manuscript.
Author contribution(s): Mizuki Momoi: Data curation; Formal analysis; Investigation; Writing-original draft.
Takahiro Hiraide: Conceptualization; Methodology; Writing-review & editing.
Yoshiki Shinya: Conceptualization; Validation; Writing-review & editing.
Hiromi Momota: Data curation; Validation; Methodology; Writing-review & editing.
Shogo Fukui: Data curation; Validation; Formal analysis; Writing-review & editing.
Michiyuki Kawakami: Data curation; Validation; Formal analysis; Writing-review & editing.
Yuji Itabashi: Methodology; Data curation; Resources, Writing-review & editing.
Keiichi Fukuda: Supervision; Investigation; Writing-review & editing.
Masaharu Kataoka: Conceptualization; Project administration; Writing-review & editing.
Conflict of interest statement: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Masaharu Kataoka https://orcid.org/0000-0001-8034-1005
Supplemental material: Supplemental material for this article is available online. | Not recovered | ReactionOutcome | CC BY-NC | 33627044 | 19,134,415 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Exposure during pregnancy'. | A case of recurrence of adult-onset Still's disease in the third trimester: a case report and literature review.
BACKGROUND
Adult-onset Still's disease (AOSD) is a self-inflammatory disease showing macrophage and neutrophil activation by inflammatory cytokines such as TNF-α, IL-6, and IL-18. Although some cases with the flare of AOSD during pregnancy have been reported, most had flares in the first or second trimester and few had flares in the third trimester. In this report, we present the case of a patient with recurrent flare of AOSD in the third trimester and discuss the management of AOSD in the third trimester with the review of previous literatures.
METHODS
A 38-year-old woman in complete AOSD remission without medication presented with impaired liver function, low platelet count, mild fever, abdominal pain, splenomegaly, and elevated ferritin and IL-18 levels at 30 gestational weeks. Although the laboratory data and physical examination finding suggested HELLP syndrome or acute fatty liver of pregnancy and we considered the termination of her pregnancy, her fetus was in a reactive status. Considering her fetal status, some specific findings of AOSD, and her AOSD history, we and rheumatologists diagnosed her with AOSD recurrence and started systemic steroid therapy. In her clinical course, three flares of AOSD occurred, twice in the third trimester and once in postpartum; twice systemic steroid pulse therapies were then needed. Ultimately, a healthy infant was delivered transvaginally at 36 gestational weeks spontaneously.
CONCLUSIONS
Specific findings of the flare of AOSD such as fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for differentiation from HELLP syndrome and AFLP in the third trimester. With the careful management supported by rheumatologists, patients complicated with the flare of AOSD may continue their pregnancy longer than we expected.
Background
Adult-onset Still’s disease (AOSD) is a self-inflammatory disease exhibiting macrophage and neutrophil activation by inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-18 (IL-18). Its incidence is 1.6–4.0 in 1,000,000 people per year [1]. AOSD more likely occurs in women, affecting 50 to 70%, than in men [1]. It mostly affects young adults (median age at diagnosis: 36 years) [1], indicating the reproductive ages in women. The Yamaguchi criteria [2] are commonly used to diagnose AOSD because they suggest major symptoms and laboratory findings of AOSD; common manifestations are remittent fever over 39 °C lasting more than a week, arthralgia or arthritis, typical rash, high white blood cell count, elevated liver enzymes, and splenomegaly (Table 1). In addition, some AOSD cases manifest abdominal pain and nausea [1]. If findings such as elevated liver enzyme and abdominal pain happen during pregnancy, AOSD may be misinterpreted as hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome and acute fatty liver of pregnancy (AFLP). Currently, although the association between the disease onset of AOSD and pregnancy has already been widely investigated [3, 4], such relationship remains unclear. Moreover, reported cases of AOSD flares at third trimester are few, and the management and features of AOSD, which has similar features to HELLP syndrome and AFLP, at the third trimester have not been reported yet. Herein, we report a rare case of a pregnant woman with AOSD recurrence at her 30 gestational weeks and reviewed the previous reports on the flares of AOSD related to pregnancy. Written informed consent for the publication of this report was obtained from the patient.
Table 1 Yamaguchi criteria for the diagnosis of adult-onset Still’s disease [2]
Major criteria Fever ≥39 °C lasting ≥1 week
Arthralgia or arthritis lasting ≥2 weeks
Typical nonpruritic salmon-colored rash
Leukocytosis ≥10,000/μl with granulocytes ≥80%
Minor criteria Sore throat
Lymphadenopathy
Splenomegaly
Abnormal liver function tests
Negative tests for antinuclear antibody and rheumatoid factor
Exclusion criteria Infection
Malignancy
Other rheumatic disease (vasculitis)
Diagnosis of adult-onset Still’s disease if ≥5 criteria are present with ≥2 being major criteria and no exclusion criteria
Case presentation
A 38-year-old primigravida with well-controlled gestational diabetes mellitus (GDM) was introduced from her home doctor to our hospital, presenting with mild fever, liver dysfunction, elevated ferritin, low platelet count, and proteinuria at 30 weeks and 5 days of gestation. She was diagnosed with AOSD 6 years ago in our hospital based on typical symptoms, including fever, malaise, cervical lymphadenopathy, rash, liver disfunction, and high serum ferritin levels. Although the rheumatologists performed biopsies of her bone marrow and lymph node, the results of these examination were normal and the possibility of other hematologic diseases was denied. After the combination treatment with systemic steroid and tocilizumab administration, she was in complete clinical remission without medication at conception. Upon arrival, her body temperature, blood pressure, and heart rate were 37.7 °C, 101/63 mmHg, and 103 beats/min. In systemic physical examinations, no abnormalities were found. The laboratory findings at arrival are presented in Table 2; The results indicated liver dysfunction, low platelet, and elevated IL-18 and aldolase levels. No apparent coagulopathy findings were observed. Basic infectious disease tests including Epstein–Barr virus and cytomegalovirus were all negative. Nonstress test and fetal sonography revealed perfect biophysical profile scoring of her fetus, mild polyhydramnios (maximum vertical pocket of amnion: 8.3 cm), and an estimated fetal body weight (EFBW) of 1663 g (+ 0.8 standard deviation [SD]). However, splenomegaly was detected by additional abdominal sonography. Although HELLP syndrome or AFLP was suspected upon admission according to liver dysfunction and low platelet count at third trimester and termination of pregnancy could be possible, her clinical course and examination results did not match well to Sibai’s criteria for HELLP syndrome [5] and Swansea’s criteria for AFLP [6]. Moreover, her general condition and fetal status did not require urgent intervention. Considering the findings such as mild fever, elevated ferritin level, high level of IL-18, splenomegaly, and good fetal status, she was ultimately diagnosed with recurrence flare of AOSD by us and some rheumatologists. Thus, systemic steroid pulse therapy (first dose: 250 mg of methylprednisolone [mPSL] for 3 days) was initiated and switched to oral prednisolone (PSL) thereafter. Additionally, the patient was carefully followed up by frequent laboratory tests and transabdominal fetal sonography. Figure 1 illustrates her clinical course after hospitalization at 30 gestational weeks. Clinical AOSD findings such as fever, liver dysfunction, and high ferritin level were well controlled for 3 weeks after the initiation of systemic steroid therapy; hence, the oral PSL dosage was gradually reduced. However, another steroid pulse therapy was needed for the second flare of AOSD that happened at her 33 gestational weeks with elevated liver enzymes and rash on her trunk. In her clinical course, although with maintained uneventful fetal status, the growth of the fetus had been gradually restricted, resulting in intrauterine growth restriction (IUGR). At 36 weeks and 0 days of gestation, she had irregular uterine contractions without apparent infectious findings, and preterm premature rupture of membrane (pPROM). Finally, she spontaneously delivered a female infant transvaginally at 36 weeks and 3 days of gestation. Her infant had a low birth weight (2440 g) but was very healthy; the Apgar score was 9/10, and pH of the umbilical artery was 7.312. Moreover, no abnormal findings of the amniotic fluid at delivery and no pathological features in her placenta and umbilical cord were found. At 12 days postpartum, she had elevated ferritin levels and extremely low platelet count, indicating the third AOSD flare by a rheumatologist; thus, the dosage of oral PSL was increased and maintained for months. During her follow-up checkup as an outpatient by rheumatologists at 1 year postpartum, her C-reactive protein (CRP) and ferritin levels were within the reference range, and her platelet count gradually increased, indicating a well-controlled AOSD.
Table 2 Laboratory findings
Value Reference intervals, unit
T-Bil 0.7 0.4–1.5, mg/dl
AST 491 13–30, U/L
ALT 438 7–23, U/L
LDH 653 124–222, U/L
γ-GTP 10 9–32, U/L
BUN 6.4 8.0–20.0, mg/dl
Cre 0.58 0.46–0.79, mg/dl
BS 84 80–110, mg/dl
UA 3.3 2.6–7.0, mg/dl
CRP 1.81 0.00–0.14, mg/dl
TG 163 30–149, mg/dl
Ferritin 281 5–157, ng/ml
WBC 2980 3300–8600, /μl
RBC 3.93 3.86–4.92, × 106/μl
Hb 10.7 11.6–14.8, g/dl
Ht 32.5 35.1–44.4, %
Plt 108 158–348, × 103 /μl
PT-INR 0.89 0.90–1.10
APTT 33 25–35, seconds
Fib 407 200–400, mg/dl
AT III 96 80–130, %
Urinary protein 0.33 0.02–0.12, g/day
IL-18 175,116 0–211, pg/ml
Aldolase 30.6 2.5–7.5, U/L
Fig. 1 Clinical course, laboratory data, and treatment of the patient. Initial mPSL pulse therapy was provided for 3 days after 30 weeks and 5 days of gestation and then switched to oral PSL therapy. At 33 weeks and 0 days of gestation, another pulse therapy was provided for the second flare. EFBW was restricted gradually from − 0.6 SD to − 1.5 SD. At 36 weeks and 0 days of gestation, this patient started irregular uterine contractions and finally delivered a healthy infant spontaneously at 36 weeks and 3 days of gestation. At 12 days postpartum, she experienced the third flare, and oral PSL therapy was maintained
Discussion and conclusions
The flare of AOSD in pregnancy was first reported in 1980 by Stein et al. [7]. Currently, nearly 30 reports about AOSD associated with pregnancy have been published [3, 4, 7–32]. Hence, we reviewed the cases of AOSD complications during pregnancy [3, 4, 7–32]. A total of 53 flares in 47 pregnant women, including our case, have been recorded. The clinical course of AOSD during pregnancy consists of three types: first-onset type, which refers to the first onset of AOSD related to pregnancy [3, 4, 7, 8, 11, 12, 14, 17–25, 28–30, 32], recurrent-flare type, which refers to a recurrent flare related to pregnancy with previous AOSD diagnosis [4, 7, 9, 13, 14, 16, 25, 31], and no-flare type, which is only a complication with no flare related to pregnancy [4, 9, 10, 14, 15, 17, 26, 27]. In the literature review, the cases were divided into these three types shown in Table 3 and our case belongs to the recurrent-flare type.
Table 3 Review of pregnancy cases with adult onset Still’s disease classified into three types
Total: 47 pregnant women and 53 pregnancies
First onset (Number = 26) Recurrent flare (Number = 13) No flare (Number = 14)
Age at pregnancy (year), Median [IQR] 29 [25–33] (1 unknown case) 31 [29–34] 27 [26–30] (1 unknown case)
Parity, %
Primigravida 50 (8/16) 80 (8/10) 69.2 (9/13)
Multigravida 50 (8/16) 20 (2/10) 30.8 (4/13)
Unknown, number 10 3 1
Timing of flare, %
1st trimester 24 (6/25) 23.1 (3/13) –
2nd trimester 52 (13/25) 38.5 (5/13) –
3rd trimester 8 (2/25) 7.7 (1/13) –
Postpartum 16 (4/25) 30.8 (4/13) –
Unknown, number 1 0 –
Major symptoms and complications, %
Fever 95.7 (22/23) 70 (7/10) –
Arthralgia, Arthritis 91.3 (21/23) 60 (6/10) –
Erythema, Rash 78.3 (18/23) 50 (5/10) –
Sore throat 65.2 (15/23) 30 (3/10) –
Lymphadenopathy 60.9 (14/23) 10 (1/10) –
Hepatomegaly, Liver dysfunction 34.8 (8/23) 30 (3/10) –
Splenomegaly 34.8 (8/23) 10 (1/10) –
HLH 8.7 (2/23) 10 (1/10) –
Unknown, number 3 3 –
Major treatment, %
Corticosteroid 82.6 (19/23) 69.2 (9/13) 28.6 (4/14)
Anakinra 13.0 (3/23) 7.7 (1/13) 28.6 (4/14)
IVIg 17.4 (4/23) 7.7 (1/13) 7.1 (1/14)
NSAIDs 21.7 (5/23) 7.7 (1/13) 14.3 (2/14)
HCQ 4.3 (1/23) 15.4 (2/13) 7.1 (1/14)
No medication – – 57.1 (8/14)
Unknown, number 3 0 0
Delivery, %
Transvaginal 66.7 (12/18) 50 (4/8) 62.5 (5/8)
Cesarean section 22.2 (4/18) 50 (4/8) 25 (2/8)
Abortion 11.1 (2/18) 0 (0/8) 12.5 (1/8)
Unknown, number 8 5 6
Major obstetrical and perinatal complications, %
Preterm birth 32 (8/25) 33.3 (4/12) 16.7 (2/12)
IUGR 8 (2/25) 41.7 (5/12) 8.3 (1/12)
pPROM 12 (3/25) 8.3 (1/12) 8.3 (1/12)
No major complication 48 (12/25) 41.7 (5/12) 50 (6/12)
Others, number 2 for OHD, 1 for neonatal HLH, 1 for preeclampsia, and 1 for neonatal death for IRDS 1 for GDM, and 1 for OHD 1 for neonatal HLH, 1 for GDM, and 1 for HDP
Unknown, number 1 1 2
The median age of patients at pregnancy was almost 30 years (median [interquartile range (IQR)]: 29 [25–33], 31 [29–34], and 27 [26–30] for the first-onset, recurrent-flare, and no-flare types, respectively), indicating that women with AOSD during pregnancy were younger than the general population at first diagnosis [1]. Regarding parity, AOSD flare mainly happens among primigravida patients, with the recurrent-flare type obtaining the highest rate (83.3%), although all patients in this type are in clinical remission at conception [4, 7, 9, 13, 14, 16, 25, 31]. Our case was also in clinical remission and did not require any medication at conception.
Most likely, the AOSD flare occurred until second trimester and at postpartum, with limited reports of flare at third trimester; the first-onset type was found only in two cases [21, 24] and the recurrent-flare type in one case, which is our case. Although AOSD flare occurring at third trimester is extremely rare, the clinical symptoms of AOSD are similar to those of HELLP syndrome and AFLP, suggesting that close attention to perinatal management is crucial. Generally, the Yamaguchi criteria [2] is adopted for the diagnosing AOSD (Table 1). However, we needed to assess AOSD recurrence in a comprehensive way by considering the clinical features and laboratory findings because no criteria for the diagnosis of AOSD recurrence are currently available. In fact, the review showed that most of the major symptoms of AOSD detected in the recurrent-flare type are relatively fewer than in the first-onset type. In addition, the major symptoms and findings of AOSD are elevated liver enzyme, leukocytosis, and sometimes abdominal pain or nausea, which are difficult to distinguish from HELLP syndrome or AFLP, particularly in cases with flare occurring at third trimester. Elevated ferritin [2] and IL-18 [33], which are reportedly biomarkers of AOSD activity, are considered better diagnostic markers than any other markers. Specific AOSD features such as fever, splenomegaly, and typical rash can support the possibility of AOSD. Izuka et al. recently reported that elevated serum aldolase can be a useful biomarker of AOSD [34]. In our case, the serum aldolase level was high (30.6 U/L), which supported the diagnosis of recurrent AOSD flare. Finally, we and some rheumatologists comprehensively diagnosed the patient with AOSD recurrence flare in consideration of the AOSD findings such as elevated ferritin, IL-18, and aldolase levels, splenomegaly, and uneventful fetal status.
AOSD treatments generally include PSL/mPSL, nonsteroidal anti-inflammatory agents (NSAIDs) and in more severe cases, methotrexate, anakinra (interleukin-1 [IL-1] inhibitor), intravenous immune globulin (IVIg), cyclosporine, or tacrolimus. However, selecting the appropriate medication for pregnant patients entails some limitations. Jamilloux Y et al. recommended corticosteroids as the first treatment choice, and IVIg and IL-1 inhibitor as the second treatment choice for AOSD [35]. Our review also showed that corticosteroid was mainly used, followed by IL-1 inhibitor and IVIg. In Japan, where most of the IL-1 antagonists have not yet been approved, tacrolimus may be a reasonable second choice for severe AOSD flare in pregnancy, and some successful management cases reported to have used this medication during pregnancy [11, 23]. In our case, twice mPSL pulse therapy followed by oral PSL was chosen; consequently, pregnancy was maintained until 36 gestational weeks.
In almost one-third of cases in both the first-onset and recurrent-flare types, the main obstetrical complication was preterm birth. Some reports showed that other autoimmune diseases or autoinflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis, occurring during pregnancy are risk factors for preterm birth, and maternal disease activity contributes to the increased risk of preterm delivery [36–38]. Furthermore, long-term steroidal use is another risk factor for preterm birth [37, 38]. Our review results showed that the incidence of preterm delivery in both the first-onset and recurrent-flare types of AOSD was almost twice higher than that in the no-flare type. Therefore, the high disease activity of AOSD and long-term use of systemic steroids may be possible reasons for the high incidence of preterm delivery in patients with AOSD. Our case also delivered prematurely, with high disease activity and long-term systemic steroid use including twice steroid pulse therapies. Hemophagocytic lymphohistiocytosis (HLH) is also a severe and crucial complication of AOSD. HLH was diagnosed in some cases having the first-onset and recurrent-flare types and in neonatal cases delivered from mothers with AOSD, even in clinical remission. Meanwhile, we believe that in general, the overall severity of AOSD during pregnancy may be better than the HELLP syndrome and AFLP. In fact, lethal complication was only found in one case wherein a premature fetus died at 28 weeks old because of infantile respiratory distress syndrome (IRDS) in the first-onset type, as reported by Green et al. in 1982 [8]. Therefore, with the cooperation of rheumatologists and pediatricians, pregnant patients with AOSD can maintain their pregnancy by paying special attention to prematurity, fetal growth, and HLH, even if the case is in clinical remission.
The relationship of pathogenesis between AOSD and pregnancy remains unclear. Ida A et al. reported that serum IL-18 levels were significantly elevated in pregnant women from the first trimester until the onset of labor than in nonpregnant women [39]. They noticed further increment of serum IL-18 levels after labor, lasting until at least the third day of postpartum. This result parallels the clinical feature of AOSD in pregnancy, that is, AOSD flares are likely to happen in the first/second trimester and postpartum. Considering that our case had also prominently high IL-18 levels, IL-18 elevation may cause the flare of AOSD during pregnancy, suggesting that pregnancy may be a risk factor of AOSD. Therefore, the serum IL-18 levels as a follow-up during pregnancy may be a useful predictive and diagnostic marker of AOSD flare; however, further investigations are required.
From the abovementioned consideration, patients with AOSD can be pregnant and continue pregnancy safely while under treatment, considering that the prognosis of pregnant women with AOSD and their fetuses is favorable in previous cases. Furthermore, for a safer pregnancy in patients complicated with AOSD, we, as obstetricians, need tight cooperation with rheumatologists and pediatricians for the sufficient control of AOSD activity and perinatal care and should provide enough explanation to patients on the risks of flares during pregnancy. Moreover, we conduct frequent laboratory tests and careful follow-up in preparation for flares, premature birth, and HLH. If the flare happens at third trimester, as in our case, we need to differentiate AOSD from HELLP syndrome and AFLP because of the similarity of laboratory data and physical findings. Fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for the differentiation from HELLP syndrome and AFLP.
To our knowledge, this report is the first to present the recurrent flare of AOSD during pregnancy at third trimester. However, we need to further investigate on the proper management of pregnant women with AOSD.
Abbreviations
AOSDAdult-onset Still’s disease
TNF-αTumor necrosis factor-α
IL-6Interleukin-6
IL-18Interleukin-18
HELLPHemolysis, elevated liver enzymes and low platelet count
AFLPAcute fatty liver of pregnancy
GDMGestational diabetes mellitus
EFBWEstimated fetal body weight
SDStandard deviation
mPSLMethylprednisolone
PSLPrednisolone
IUGRIntrauterine growth restriction
pPROMPreterm premature rupture of membrane
CRPC-reactive protein
IQRInterquartile range
NSAIDsNonsteroidal anti-inflammatory agents
IL-1Interleukin-1
IVIgIntravenous immune globulin
HLHHemophagocytic lymphohistiocytosis
IRDSInfantile respiratory distress syndrome
NVDNormal vaginal delivery
T-BilTotal bilirubin
ASTAspartate aminotransferase
ALTAlanine aminotransferase
LDHLactate dehydrogenase
γ-GTPγ-glutamyl transpeptidase
BUNBlood urea nitrogen
CreCreatinine
BSBlood sugar
TGTriglyceride
WBCWhite blood cell
RBCRed blood cell
HbHemoglobin
HtHematocrit
PltPlatelet
PT-INRProthrombin-time international normalized ratio
APTTActivated partial thromboplastin time
FibFibrinogen
AT IIIAntithrombin III
HCQHydroxychloroquine
OHDOligohydramnios
HDPHypertensive disorders of pregnancy
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Acknowledgements
The authors would like to thank Enago (www.enago.jp) for the English language review.
Authors’ contributions
SH collected and interpreted the patient’s data, collected previous reports and wrote the first draft of this paper. MS and HO also interpreted the data and revised the first draft. SI and HY also revised the first draft and support the data collection. All authors approved the final manuscript.
Authors’ information
SH was a junior resident of the Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan at the time of this work. Now, SH belongs to the Department of Obstetrics and Gynecology, the Jikei University School of Medicine.
Funding
All authors had no funding support related to this report.
Availability of data and materials
The datasets that support the findings about this case are available from the corresponding author, SH, on reasonable request.
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 of this journal.
Competing interests
The authors declare that they have no competing interests. | METHYLPREDNISOLONE, PREDNISOLONE | DrugsGivenReaction | CC BY | 33627085 | 19,473,663 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Foetal exposure during pregnancy'. | A case of recurrence of adult-onset Still's disease in the third trimester: a case report and literature review.
BACKGROUND
Adult-onset Still's disease (AOSD) is a self-inflammatory disease showing macrophage and neutrophil activation by inflammatory cytokines such as TNF-α, IL-6, and IL-18. Although some cases with the flare of AOSD during pregnancy have been reported, most had flares in the first or second trimester and few had flares in the third trimester. In this report, we present the case of a patient with recurrent flare of AOSD in the third trimester and discuss the management of AOSD in the third trimester with the review of previous literatures.
METHODS
A 38-year-old woman in complete AOSD remission without medication presented with impaired liver function, low platelet count, mild fever, abdominal pain, splenomegaly, and elevated ferritin and IL-18 levels at 30 gestational weeks. Although the laboratory data and physical examination finding suggested HELLP syndrome or acute fatty liver of pregnancy and we considered the termination of her pregnancy, her fetus was in a reactive status. Considering her fetal status, some specific findings of AOSD, and her AOSD history, we and rheumatologists diagnosed her with AOSD recurrence and started systemic steroid therapy. In her clinical course, three flares of AOSD occurred, twice in the third trimester and once in postpartum; twice systemic steroid pulse therapies were then needed. Ultimately, a healthy infant was delivered transvaginally at 36 gestational weeks spontaneously.
CONCLUSIONS
Specific findings of the flare of AOSD such as fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for differentiation from HELLP syndrome and AFLP in the third trimester. With the careful management supported by rheumatologists, patients complicated with the flare of AOSD may continue their pregnancy longer than we expected.
Background
Adult-onset Still’s disease (AOSD) is a self-inflammatory disease exhibiting macrophage and neutrophil activation by inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-18 (IL-18). Its incidence is 1.6–4.0 in 1,000,000 people per year [1]. AOSD more likely occurs in women, affecting 50 to 70%, than in men [1]. It mostly affects young adults (median age at diagnosis: 36 years) [1], indicating the reproductive ages in women. The Yamaguchi criteria [2] are commonly used to diagnose AOSD because they suggest major symptoms and laboratory findings of AOSD; common manifestations are remittent fever over 39 °C lasting more than a week, arthralgia or arthritis, typical rash, high white blood cell count, elevated liver enzymes, and splenomegaly (Table 1). In addition, some AOSD cases manifest abdominal pain and nausea [1]. If findings such as elevated liver enzyme and abdominal pain happen during pregnancy, AOSD may be misinterpreted as hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome and acute fatty liver of pregnancy (AFLP). Currently, although the association between the disease onset of AOSD and pregnancy has already been widely investigated [3, 4], such relationship remains unclear. Moreover, reported cases of AOSD flares at third trimester are few, and the management and features of AOSD, which has similar features to HELLP syndrome and AFLP, at the third trimester have not been reported yet. Herein, we report a rare case of a pregnant woman with AOSD recurrence at her 30 gestational weeks and reviewed the previous reports on the flares of AOSD related to pregnancy. Written informed consent for the publication of this report was obtained from the patient.
Table 1 Yamaguchi criteria for the diagnosis of adult-onset Still’s disease [2]
Major criteria Fever ≥39 °C lasting ≥1 week
Arthralgia or arthritis lasting ≥2 weeks
Typical nonpruritic salmon-colored rash
Leukocytosis ≥10,000/μl with granulocytes ≥80%
Minor criteria Sore throat
Lymphadenopathy
Splenomegaly
Abnormal liver function tests
Negative tests for antinuclear antibody and rheumatoid factor
Exclusion criteria Infection
Malignancy
Other rheumatic disease (vasculitis)
Diagnosis of adult-onset Still’s disease if ≥5 criteria are present with ≥2 being major criteria and no exclusion criteria
Case presentation
A 38-year-old primigravida with well-controlled gestational diabetes mellitus (GDM) was introduced from her home doctor to our hospital, presenting with mild fever, liver dysfunction, elevated ferritin, low platelet count, and proteinuria at 30 weeks and 5 days of gestation. She was diagnosed with AOSD 6 years ago in our hospital based on typical symptoms, including fever, malaise, cervical lymphadenopathy, rash, liver disfunction, and high serum ferritin levels. Although the rheumatologists performed biopsies of her bone marrow and lymph node, the results of these examination were normal and the possibility of other hematologic diseases was denied. After the combination treatment with systemic steroid and tocilizumab administration, she was in complete clinical remission without medication at conception. Upon arrival, her body temperature, blood pressure, and heart rate were 37.7 °C, 101/63 mmHg, and 103 beats/min. In systemic physical examinations, no abnormalities were found. The laboratory findings at arrival are presented in Table 2; The results indicated liver dysfunction, low platelet, and elevated IL-18 and aldolase levels. No apparent coagulopathy findings were observed. Basic infectious disease tests including Epstein–Barr virus and cytomegalovirus were all negative. Nonstress test and fetal sonography revealed perfect biophysical profile scoring of her fetus, mild polyhydramnios (maximum vertical pocket of amnion: 8.3 cm), and an estimated fetal body weight (EFBW) of 1663 g (+ 0.8 standard deviation [SD]). However, splenomegaly was detected by additional abdominal sonography. Although HELLP syndrome or AFLP was suspected upon admission according to liver dysfunction and low platelet count at third trimester and termination of pregnancy could be possible, her clinical course and examination results did not match well to Sibai’s criteria for HELLP syndrome [5] and Swansea’s criteria for AFLP [6]. Moreover, her general condition and fetal status did not require urgent intervention. Considering the findings such as mild fever, elevated ferritin level, high level of IL-18, splenomegaly, and good fetal status, she was ultimately diagnosed with recurrence flare of AOSD by us and some rheumatologists. Thus, systemic steroid pulse therapy (first dose: 250 mg of methylprednisolone [mPSL] for 3 days) was initiated and switched to oral prednisolone (PSL) thereafter. Additionally, the patient was carefully followed up by frequent laboratory tests and transabdominal fetal sonography. Figure 1 illustrates her clinical course after hospitalization at 30 gestational weeks. Clinical AOSD findings such as fever, liver dysfunction, and high ferritin level were well controlled for 3 weeks after the initiation of systemic steroid therapy; hence, the oral PSL dosage was gradually reduced. However, another steroid pulse therapy was needed for the second flare of AOSD that happened at her 33 gestational weeks with elevated liver enzymes and rash on her trunk. In her clinical course, although with maintained uneventful fetal status, the growth of the fetus had been gradually restricted, resulting in intrauterine growth restriction (IUGR). At 36 weeks and 0 days of gestation, she had irregular uterine contractions without apparent infectious findings, and preterm premature rupture of membrane (pPROM). Finally, she spontaneously delivered a female infant transvaginally at 36 weeks and 3 days of gestation. Her infant had a low birth weight (2440 g) but was very healthy; the Apgar score was 9/10, and pH of the umbilical artery was 7.312. Moreover, no abnormal findings of the amniotic fluid at delivery and no pathological features in her placenta and umbilical cord were found. At 12 days postpartum, she had elevated ferritin levels and extremely low platelet count, indicating the third AOSD flare by a rheumatologist; thus, the dosage of oral PSL was increased and maintained for months. During her follow-up checkup as an outpatient by rheumatologists at 1 year postpartum, her C-reactive protein (CRP) and ferritin levels were within the reference range, and her platelet count gradually increased, indicating a well-controlled AOSD.
Table 2 Laboratory findings
Value Reference intervals, unit
T-Bil 0.7 0.4–1.5, mg/dl
AST 491 13–30, U/L
ALT 438 7–23, U/L
LDH 653 124–222, U/L
γ-GTP 10 9–32, U/L
BUN 6.4 8.0–20.0, mg/dl
Cre 0.58 0.46–0.79, mg/dl
BS 84 80–110, mg/dl
UA 3.3 2.6–7.0, mg/dl
CRP 1.81 0.00–0.14, mg/dl
TG 163 30–149, mg/dl
Ferritin 281 5–157, ng/ml
WBC 2980 3300–8600, /μl
RBC 3.93 3.86–4.92, × 106/μl
Hb 10.7 11.6–14.8, g/dl
Ht 32.5 35.1–44.4, %
Plt 108 158–348, × 103 /μl
PT-INR 0.89 0.90–1.10
APTT 33 25–35, seconds
Fib 407 200–400, mg/dl
AT III 96 80–130, %
Urinary protein 0.33 0.02–0.12, g/day
IL-18 175,116 0–211, pg/ml
Aldolase 30.6 2.5–7.5, U/L
Fig. 1 Clinical course, laboratory data, and treatment of the patient. Initial mPSL pulse therapy was provided for 3 days after 30 weeks and 5 days of gestation and then switched to oral PSL therapy. At 33 weeks and 0 days of gestation, another pulse therapy was provided for the second flare. EFBW was restricted gradually from − 0.6 SD to − 1.5 SD. At 36 weeks and 0 days of gestation, this patient started irregular uterine contractions and finally delivered a healthy infant spontaneously at 36 weeks and 3 days of gestation. At 12 days postpartum, she experienced the third flare, and oral PSL therapy was maintained
Discussion and conclusions
The flare of AOSD in pregnancy was first reported in 1980 by Stein et al. [7]. Currently, nearly 30 reports about AOSD associated with pregnancy have been published [3, 4, 7–32]. Hence, we reviewed the cases of AOSD complications during pregnancy [3, 4, 7–32]. A total of 53 flares in 47 pregnant women, including our case, have been recorded. The clinical course of AOSD during pregnancy consists of three types: first-onset type, which refers to the first onset of AOSD related to pregnancy [3, 4, 7, 8, 11, 12, 14, 17–25, 28–30, 32], recurrent-flare type, which refers to a recurrent flare related to pregnancy with previous AOSD diagnosis [4, 7, 9, 13, 14, 16, 25, 31], and no-flare type, which is only a complication with no flare related to pregnancy [4, 9, 10, 14, 15, 17, 26, 27]. In the literature review, the cases were divided into these three types shown in Table 3 and our case belongs to the recurrent-flare type.
Table 3 Review of pregnancy cases with adult onset Still’s disease classified into three types
Total: 47 pregnant women and 53 pregnancies
First onset (Number = 26) Recurrent flare (Number = 13) No flare (Number = 14)
Age at pregnancy (year), Median [IQR] 29 [25–33] (1 unknown case) 31 [29–34] 27 [26–30] (1 unknown case)
Parity, %
Primigravida 50 (8/16) 80 (8/10) 69.2 (9/13)
Multigravida 50 (8/16) 20 (2/10) 30.8 (4/13)
Unknown, number 10 3 1
Timing of flare, %
1st trimester 24 (6/25) 23.1 (3/13) –
2nd trimester 52 (13/25) 38.5 (5/13) –
3rd trimester 8 (2/25) 7.7 (1/13) –
Postpartum 16 (4/25) 30.8 (4/13) –
Unknown, number 1 0 –
Major symptoms and complications, %
Fever 95.7 (22/23) 70 (7/10) –
Arthralgia, Arthritis 91.3 (21/23) 60 (6/10) –
Erythema, Rash 78.3 (18/23) 50 (5/10) –
Sore throat 65.2 (15/23) 30 (3/10) –
Lymphadenopathy 60.9 (14/23) 10 (1/10) –
Hepatomegaly, Liver dysfunction 34.8 (8/23) 30 (3/10) –
Splenomegaly 34.8 (8/23) 10 (1/10) –
HLH 8.7 (2/23) 10 (1/10) –
Unknown, number 3 3 –
Major treatment, %
Corticosteroid 82.6 (19/23) 69.2 (9/13) 28.6 (4/14)
Anakinra 13.0 (3/23) 7.7 (1/13) 28.6 (4/14)
IVIg 17.4 (4/23) 7.7 (1/13) 7.1 (1/14)
NSAIDs 21.7 (5/23) 7.7 (1/13) 14.3 (2/14)
HCQ 4.3 (1/23) 15.4 (2/13) 7.1 (1/14)
No medication – – 57.1 (8/14)
Unknown, number 3 0 0
Delivery, %
Transvaginal 66.7 (12/18) 50 (4/8) 62.5 (5/8)
Cesarean section 22.2 (4/18) 50 (4/8) 25 (2/8)
Abortion 11.1 (2/18) 0 (0/8) 12.5 (1/8)
Unknown, number 8 5 6
Major obstetrical and perinatal complications, %
Preterm birth 32 (8/25) 33.3 (4/12) 16.7 (2/12)
IUGR 8 (2/25) 41.7 (5/12) 8.3 (1/12)
pPROM 12 (3/25) 8.3 (1/12) 8.3 (1/12)
No major complication 48 (12/25) 41.7 (5/12) 50 (6/12)
Others, number 2 for OHD, 1 for neonatal HLH, 1 for preeclampsia, and 1 for neonatal death for IRDS 1 for GDM, and 1 for OHD 1 for neonatal HLH, 1 for GDM, and 1 for HDP
Unknown, number 1 1 2
The median age of patients at pregnancy was almost 30 years (median [interquartile range (IQR)]: 29 [25–33], 31 [29–34], and 27 [26–30] for the first-onset, recurrent-flare, and no-flare types, respectively), indicating that women with AOSD during pregnancy were younger than the general population at first diagnosis [1]. Regarding parity, AOSD flare mainly happens among primigravida patients, with the recurrent-flare type obtaining the highest rate (83.3%), although all patients in this type are in clinical remission at conception [4, 7, 9, 13, 14, 16, 25, 31]. Our case was also in clinical remission and did not require any medication at conception.
Most likely, the AOSD flare occurred until second trimester and at postpartum, with limited reports of flare at third trimester; the first-onset type was found only in two cases [21, 24] and the recurrent-flare type in one case, which is our case. Although AOSD flare occurring at third trimester is extremely rare, the clinical symptoms of AOSD are similar to those of HELLP syndrome and AFLP, suggesting that close attention to perinatal management is crucial. Generally, the Yamaguchi criteria [2] is adopted for the diagnosing AOSD (Table 1). However, we needed to assess AOSD recurrence in a comprehensive way by considering the clinical features and laboratory findings because no criteria for the diagnosis of AOSD recurrence are currently available. In fact, the review showed that most of the major symptoms of AOSD detected in the recurrent-flare type are relatively fewer than in the first-onset type. In addition, the major symptoms and findings of AOSD are elevated liver enzyme, leukocytosis, and sometimes abdominal pain or nausea, which are difficult to distinguish from HELLP syndrome or AFLP, particularly in cases with flare occurring at third trimester. Elevated ferritin [2] and IL-18 [33], which are reportedly biomarkers of AOSD activity, are considered better diagnostic markers than any other markers. Specific AOSD features such as fever, splenomegaly, and typical rash can support the possibility of AOSD. Izuka et al. recently reported that elevated serum aldolase can be a useful biomarker of AOSD [34]. In our case, the serum aldolase level was high (30.6 U/L), which supported the diagnosis of recurrent AOSD flare. Finally, we and some rheumatologists comprehensively diagnosed the patient with AOSD recurrence flare in consideration of the AOSD findings such as elevated ferritin, IL-18, and aldolase levels, splenomegaly, and uneventful fetal status.
AOSD treatments generally include PSL/mPSL, nonsteroidal anti-inflammatory agents (NSAIDs) and in more severe cases, methotrexate, anakinra (interleukin-1 [IL-1] inhibitor), intravenous immune globulin (IVIg), cyclosporine, or tacrolimus. However, selecting the appropriate medication for pregnant patients entails some limitations. Jamilloux Y et al. recommended corticosteroids as the first treatment choice, and IVIg and IL-1 inhibitor as the second treatment choice for AOSD [35]. Our review also showed that corticosteroid was mainly used, followed by IL-1 inhibitor and IVIg. In Japan, where most of the IL-1 antagonists have not yet been approved, tacrolimus may be a reasonable second choice for severe AOSD flare in pregnancy, and some successful management cases reported to have used this medication during pregnancy [11, 23]. In our case, twice mPSL pulse therapy followed by oral PSL was chosen; consequently, pregnancy was maintained until 36 gestational weeks.
In almost one-third of cases in both the first-onset and recurrent-flare types, the main obstetrical complication was preterm birth. Some reports showed that other autoimmune diseases or autoinflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis, occurring during pregnancy are risk factors for preterm birth, and maternal disease activity contributes to the increased risk of preterm delivery [36–38]. Furthermore, long-term steroidal use is another risk factor for preterm birth [37, 38]. Our review results showed that the incidence of preterm delivery in both the first-onset and recurrent-flare types of AOSD was almost twice higher than that in the no-flare type. Therefore, the high disease activity of AOSD and long-term use of systemic steroids may be possible reasons for the high incidence of preterm delivery in patients with AOSD. Our case also delivered prematurely, with high disease activity and long-term systemic steroid use including twice steroid pulse therapies. Hemophagocytic lymphohistiocytosis (HLH) is also a severe and crucial complication of AOSD. HLH was diagnosed in some cases having the first-onset and recurrent-flare types and in neonatal cases delivered from mothers with AOSD, even in clinical remission. Meanwhile, we believe that in general, the overall severity of AOSD during pregnancy may be better than the HELLP syndrome and AFLP. In fact, lethal complication was only found in one case wherein a premature fetus died at 28 weeks old because of infantile respiratory distress syndrome (IRDS) in the first-onset type, as reported by Green et al. in 1982 [8]. Therefore, with the cooperation of rheumatologists and pediatricians, pregnant patients with AOSD can maintain their pregnancy by paying special attention to prematurity, fetal growth, and HLH, even if the case is in clinical remission.
The relationship of pathogenesis between AOSD and pregnancy remains unclear. Ida A et al. reported that serum IL-18 levels were significantly elevated in pregnant women from the first trimester until the onset of labor than in nonpregnant women [39]. They noticed further increment of serum IL-18 levels after labor, lasting until at least the third day of postpartum. This result parallels the clinical feature of AOSD in pregnancy, that is, AOSD flares are likely to happen in the first/second trimester and postpartum. Considering that our case had also prominently high IL-18 levels, IL-18 elevation may cause the flare of AOSD during pregnancy, suggesting that pregnancy may be a risk factor of AOSD. Therefore, the serum IL-18 levels as a follow-up during pregnancy may be a useful predictive and diagnostic marker of AOSD flare; however, further investigations are required.
From the abovementioned consideration, patients with AOSD can be pregnant and continue pregnancy safely while under treatment, considering that the prognosis of pregnant women with AOSD and their fetuses is favorable in previous cases. Furthermore, for a safer pregnancy in patients complicated with AOSD, we, as obstetricians, need tight cooperation with rheumatologists and pediatricians for the sufficient control of AOSD activity and perinatal care and should provide enough explanation to patients on the risks of flares during pregnancy. Moreover, we conduct frequent laboratory tests and careful follow-up in preparation for flares, premature birth, and HLH. If the flare happens at third trimester, as in our case, we need to differentiate AOSD from HELLP syndrome and AFLP because of the similarity of laboratory data and physical findings. Fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for the differentiation from HELLP syndrome and AFLP.
To our knowledge, this report is the first to present the recurrent flare of AOSD during pregnancy at third trimester. However, we need to further investigate on the proper management of pregnant women with AOSD.
Abbreviations
AOSDAdult-onset Still’s disease
TNF-αTumor necrosis factor-α
IL-6Interleukin-6
IL-18Interleukin-18
HELLPHemolysis, elevated liver enzymes and low platelet count
AFLPAcute fatty liver of pregnancy
GDMGestational diabetes mellitus
EFBWEstimated fetal body weight
SDStandard deviation
mPSLMethylprednisolone
PSLPrednisolone
IUGRIntrauterine growth restriction
pPROMPreterm premature rupture of membrane
CRPC-reactive protein
IQRInterquartile range
NSAIDsNonsteroidal anti-inflammatory agents
IL-1Interleukin-1
IVIgIntravenous immune globulin
HLHHemophagocytic lymphohistiocytosis
IRDSInfantile respiratory distress syndrome
NVDNormal vaginal delivery
T-BilTotal bilirubin
ASTAspartate aminotransferase
ALTAlanine aminotransferase
LDHLactate dehydrogenase
γ-GTPγ-glutamyl transpeptidase
BUNBlood urea nitrogen
CreCreatinine
BSBlood sugar
TGTriglyceride
WBCWhite blood cell
RBCRed blood cell
HbHemoglobin
HtHematocrit
PltPlatelet
PT-INRProthrombin-time international normalized ratio
APTTActivated partial thromboplastin time
FibFibrinogen
AT IIIAntithrombin III
HCQHydroxychloroquine
OHDOligohydramnios
HDPHypertensive disorders of pregnancy
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Acknowledgements
The authors would like to thank Enago (www.enago.jp) for the English language review.
Authors’ contributions
SH collected and interpreted the patient’s data, collected previous reports and wrote the first draft of this paper. MS and HO also interpreted the data and revised the first draft. SI and HY also revised the first draft and support the data collection. All authors approved the final manuscript.
Authors’ information
SH was a junior resident of the Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan at the time of this work. Now, SH belongs to the Department of Obstetrics and Gynecology, the Jikei University School of Medicine.
Funding
All authors had no funding support related to this report.
Availability of data and materials
The datasets that support the findings about this case are available from the corresponding author, SH, on reasonable request.
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 of this journal.
Competing interests
The authors declare that they have no competing interests. | METHYLPREDNISOLONE, PREDNISOLONE | DrugsGivenReaction | CC BY | 33627085 | 19,473,834 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Foetal growth restriction'. | A case of recurrence of adult-onset Still's disease in the third trimester: a case report and literature review.
BACKGROUND
Adult-onset Still's disease (AOSD) is a self-inflammatory disease showing macrophage and neutrophil activation by inflammatory cytokines such as TNF-α, IL-6, and IL-18. Although some cases with the flare of AOSD during pregnancy have been reported, most had flares in the first or second trimester and few had flares in the third trimester. In this report, we present the case of a patient with recurrent flare of AOSD in the third trimester and discuss the management of AOSD in the third trimester with the review of previous literatures.
METHODS
A 38-year-old woman in complete AOSD remission without medication presented with impaired liver function, low platelet count, mild fever, abdominal pain, splenomegaly, and elevated ferritin and IL-18 levels at 30 gestational weeks. Although the laboratory data and physical examination finding suggested HELLP syndrome or acute fatty liver of pregnancy and we considered the termination of her pregnancy, her fetus was in a reactive status. Considering her fetal status, some specific findings of AOSD, and her AOSD history, we and rheumatologists diagnosed her with AOSD recurrence and started systemic steroid therapy. In her clinical course, three flares of AOSD occurred, twice in the third trimester and once in postpartum; twice systemic steroid pulse therapies were then needed. Ultimately, a healthy infant was delivered transvaginally at 36 gestational weeks spontaneously.
CONCLUSIONS
Specific findings of the flare of AOSD such as fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for differentiation from HELLP syndrome and AFLP in the third trimester. With the careful management supported by rheumatologists, patients complicated with the flare of AOSD may continue their pregnancy longer than we expected.
Background
Adult-onset Still’s disease (AOSD) is a self-inflammatory disease exhibiting macrophage and neutrophil activation by inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-18 (IL-18). Its incidence is 1.6–4.0 in 1,000,000 people per year [1]. AOSD more likely occurs in women, affecting 50 to 70%, than in men [1]. It mostly affects young adults (median age at diagnosis: 36 years) [1], indicating the reproductive ages in women. The Yamaguchi criteria [2] are commonly used to diagnose AOSD because they suggest major symptoms and laboratory findings of AOSD; common manifestations are remittent fever over 39 °C lasting more than a week, arthralgia or arthritis, typical rash, high white blood cell count, elevated liver enzymes, and splenomegaly (Table 1). In addition, some AOSD cases manifest abdominal pain and nausea [1]. If findings such as elevated liver enzyme and abdominal pain happen during pregnancy, AOSD may be misinterpreted as hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome and acute fatty liver of pregnancy (AFLP). Currently, although the association between the disease onset of AOSD and pregnancy has already been widely investigated [3, 4], such relationship remains unclear. Moreover, reported cases of AOSD flares at third trimester are few, and the management and features of AOSD, which has similar features to HELLP syndrome and AFLP, at the third trimester have not been reported yet. Herein, we report a rare case of a pregnant woman with AOSD recurrence at her 30 gestational weeks and reviewed the previous reports on the flares of AOSD related to pregnancy. Written informed consent for the publication of this report was obtained from the patient.
Table 1 Yamaguchi criteria for the diagnosis of adult-onset Still’s disease [2]
Major criteria Fever ≥39 °C lasting ≥1 week
Arthralgia or arthritis lasting ≥2 weeks
Typical nonpruritic salmon-colored rash
Leukocytosis ≥10,000/μl with granulocytes ≥80%
Minor criteria Sore throat
Lymphadenopathy
Splenomegaly
Abnormal liver function tests
Negative tests for antinuclear antibody and rheumatoid factor
Exclusion criteria Infection
Malignancy
Other rheumatic disease (vasculitis)
Diagnosis of adult-onset Still’s disease if ≥5 criteria are present with ≥2 being major criteria and no exclusion criteria
Case presentation
A 38-year-old primigravida with well-controlled gestational diabetes mellitus (GDM) was introduced from her home doctor to our hospital, presenting with mild fever, liver dysfunction, elevated ferritin, low platelet count, and proteinuria at 30 weeks and 5 days of gestation. She was diagnosed with AOSD 6 years ago in our hospital based on typical symptoms, including fever, malaise, cervical lymphadenopathy, rash, liver disfunction, and high serum ferritin levels. Although the rheumatologists performed biopsies of her bone marrow and lymph node, the results of these examination were normal and the possibility of other hematologic diseases was denied. After the combination treatment with systemic steroid and tocilizumab administration, she was in complete clinical remission without medication at conception. Upon arrival, her body temperature, blood pressure, and heart rate were 37.7 °C, 101/63 mmHg, and 103 beats/min. In systemic physical examinations, no abnormalities were found. The laboratory findings at arrival are presented in Table 2; The results indicated liver dysfunction, low platelet, and elevated IL-18 and aldolase levels. No apparent coagulopathy findings were observed. Basic infectious disease tests including Epstein–Barr virus and cytomegalovirus were all negative. Nonstress test and fetal sonography revealed perfect biophysical profile scoring of her fetus, mild polyhydramnios (maximum vertical pocket of amnion: 8.3 cm), and an estimated fetal body weight (EFBW) of 1663 g (+ 0.8 standard deviation [SD]). However, splenomegaly was detected by additional abdominal sonography. Although HELLP syndrome or AFLP was suspected upon admission according to liver dysfunction and low platelet count at third trimester and termination of pregnancy could be possible, her clinical course and examination results did not match well to Sibai’s criteria for HELLP syndrome [5] and Swansea’s criteria for AFLP [6]. Moreover, her general condition and fetal status did not require urgent intervention. Considering the findings such as mild fever, elevated ferritin level, high level of IL-18, splenomegaly, and good fetal status, she was ultimately diagnosed with recurrence flare of AOSD by us and some rheumatologists. Thus, systemic steroid pulse therapy (first dose: 250 mg of methylprednisolone [mPSL] for 3 days) was initiated and switched to oral prednisolone (PSL) thereafter. Additionally, the patient was carefully followed up by frequent laboratory tests and transabdominal fetal sonography. Figure 1 illustrates her clinical course after hospitalization at 30 gestational weeks. Clinical AOSD findings such as fever, liver dysfunction, and high ferritin level were well controlled for 3 weeks after the initiation of systemic steroid therapy; hence, the oral PSL dosage was gradually reduced. However, another steroid pulse therapy was needed for the second flare of AOSD that happened at her 33 gestational weeks with elevated liver enzymes and rash on her trunk. In her clinical course, although with maintained uneventful fetal status, the growth of the fetus had been gradually restricted, resulting in intrauterine growth restriction (IUGR). At 36 weeks and 0 days of gestation, she had irregular uterine contractions without apparent infectious findings, and preterm premature rupture of membrane (pPROM). Finally, she spontaneously delivered a female infant transvaginally at 36 weeks and 3 days of gestation. Her infant had a low birth weight (2440 g) but was very healthy; the Apgar score was 9/10, and pH of the umbilical artery was 7.312. Moreover, no abnormal findings of the amniotic fluid at delivery and no pathological features in her placenta and umbilical cord were found. At 12 days postpartum, she had elevated ferritin levels and extremely low platelet count, indicating the third AOSD flare by a rheumatologist; thus, the dosage of oral PSL was increased and maintained for months. During her follow-up checkup as an outpatient by rheumatologists at 1 year postpartum, her C-reactive protein (CRP) and ferritin levels were within the reference range, and her platelet count gradually increased, indicating a well-controlled AOSD.
Table 2 Laboratory findings
Value Reference intervals, unit
T-Bil 0.7 0.4–1.5, mg/dl
AST 491 13–30, U/L
ALT 438 7–23, U/L
LDH 653 124–222, U/L
γ-GTP 10 9–32, U/L
BUN 6.4 8.0–20.0, mg/dl
Cre 0.58 0.46–0.79, mg/dl
BS 84 80–110, mg/dl
UA 3.3 2.6–7.0, mg/dl
CRP 1.81 0.00–0.14, mg/dl
TG 163 30–149, mg/dl
Ferritin 281 5–157, ng/ml
WBC 2980 3300–8600, /μl
RBC 3.93 3.86–4.92, × 106/μl
Hb 10.7 11.6–14.8, g/dl
Ht 32.5 35.1–44.4, %
Plt 108 158–348, × 103 /μl
PT-INR 0.89 0.90–1.10
APTT 33 25–35, seconds
Fib 407 200–400, mg/dl
AT III 96 80–130, %
Urinary protein 0.33 0.02–0.12, g/day
IL-18 175,116 0–211, pg/ml
Aldolase 30.6 2.5–7.5, U/L
Fig. 1 Clinical course, laboratory data, and treatment of the patient. Initial mPSL pulse therapy was provided for 3 days after 30 weeks and 5 days of gestation and then switched to oral PSL therapy. At 33 weeks and 0 days of gestation, another pulse therapy was provided for the second flare. EFBW was restricted gradually from − 0.6 SD to − 1.5 SD. At 36 weeks and 0 days of gestation, this patient started irregular uterine contractions and finally delivered a healthy infant spontaneously at 36 weeks and 3 days of gestation. At 12 days postpartum, she experienced the third flare, and oral PSL therapy was maintained
Discussion and conclusions
The flare of AOSD in pregnancy was first reported in 1980 by Stein et al. [7]. Currently, nearly 30 reports about AOSD associated with pregnancy have been published [3, 4, 7–32]. Hence, we reviewed the cases of AOSD complications during pregnancy [3, 4, 7–32]. A total of 53 flares in 47 pregnant women, including our case, have been recorded. The clinical course of AOSD during pregnancy consists of three types: first-onset type, which refers to the first onset of AOSD related to pregnancy [3, 4, 7, 8, 11, 12, 14, 17–25, 28–30, 32], recurrent-flare type, which refers to a recurrent flare related to pregnancy with previous AOSD diagnosis [4, 7, 9, 13, 14, 16, 25, 31], and no-flare type, which is only a complication with no flare related to pregnancy [4, 9, 10, 14, 15, 17, 26, 27]. In the literature review, the cases were divided into these three types shown in Table 3 and our case belongs to the recurrent-flare type.
Table 3 Review of pregnancy cases with adult onset Still’s disease classified into three types
Total: 47 pregnant women and 53 pregnancies
First onset (Number = 26) Recurrent flare (Number = 13) No flare (Number = 14)
Age at pregnancy (year), Median [IQR] 29 [25–33] (1 unknown case) 31 [29–34] 27 [26–30] (1 unknown case)
Parity, %
Primigravida 50 (8/16) 80 (8/10) 69.2 (9/13)
Multigravida 50 (8/16) 20 (2/10) 30.8 (4/13)
Unknown, number 10 3 1
Timing of flare, %
1st trimester 24 (6/25) 23.1 (3/13) –
2nd trimester 52 (13/25) 38.5 (5/13) –
3rd trimester 8 (2/25) 7.7 (1/13) –
Postpartum 16 (4/25) 30.8 (4/13) –
Unknown, number 1 0 –
Major symptoms and complications, %
Fever 95.7 (22/23) 70 (7/10) –
Arthralgia, Arthritis 91.3 (21/23) 60 (6/10) –
Erythema, Rash 78.3 (18/23) 50 (5/10) –
Sore throat 65.2 (15/23) 30 (3/10) –
Lymphadenopathy 60.9 (14/23) 10 (1/10) –
Hepatomegaly, Liver dysfunction 34.8 (8/23) 30 (3/10) –
Splenomegaly 34.8 (8/23) 10 (1/10) –
HLH 8.7 (2/23) 10 (1/10) –
Unknown, number 3 3 –
Major treatment, %
Corticosteroid 82.6 (19/23) 69.2 (9/13) 28.6 (4/14)
Anakinra 13.0 (3/23) 7.7 (1/13) 28.6 (4/14)
IVIg 17.4 (4/23) 7.7 (1/13) 7.1 (1/14)
NSAIDs 21.7 (5/23) 7.7 (1/13) 14.3 (2/14)
HCQ 4.3 (1/23) 15.4 (2/13) 7.1 (1/14)
No medication – – 57.1 (8/14)
Unknown, number 3 0 0
Delivery, %
Transvaginal 66.7 (12/18) 50 (4/8) 62.5 (5/8)
Cesarean section 22.2 (4/18) 50 (4/8) 25 (2/8)
Abortion 11.1 (2/18) 0 (0/8) 12.5 (1/8)
Unknown, number 8 5 6
Major obstetrical and perinatal complications, %
Preterm birth 32 (8/25) 33.3 (4/12) 16.7 (2/12)
IUGR 8 (2/25) 41.7 (5/12) 8.3 (1/12)
pPROM 12 (3/25) 8.3 (1/12) 8.3 (1/12)
No major complication 48 (12/25) 41.7 (5/12) 50 (6/12)
Others, number 2 for OHD, 1 for neonatal HLH, 1 for preeclampsia, and 1 for neonatal death for IRDS 1 for GDM, and 1 for OHD 1 for neonatal HLH, 1 for GDM, and 1 for HDP
Unknown, number 1 1 2
The median age of patients at pregnancy was almost 30 years (median [interquartile range (IQR)]: 29 [25–33], 31 [29–34], and 27 [26–30] for the first-onset, recurrent-flare, and no-flare types, respectively), indicating that women with AOSD during pregnancy were younger than the general population at first diagnosis [1]. Regarding parity, AOSD flare mainly happens among primigravida patients, with the recurrent-flare type obtaining the highest rate (83.3%), although all patients in this type are in clinical remission at conception [4, 7, 9, 13, 14, 16, 25, 31]. Our case was also in clinical remission and did not require any medication at conception.
Most likely, the AOSD flare occurred until second trimester and at postpartum, with limited reports of flare at third trimester; the first-onset type was found only in two cases [21, 24] and the recurrent-flare type in one case, which is our case. Although AOSD flare occurring at third trimester is extremely rare, the clinical symptoms of AOSD are similar to those of HELLP syndrome and AFLP, suggesting that close attention to perinatal management is crucial. Generally, the Yamaguchi criteria [2] is adopted for the diagnosing AOSD (Table 1). However, we needed to assess AOSD recurrence in a comprehensive way by considering the clinical features and laboratory findings because no criteria for the diagnosis of AOSD recurrence are currently available. In fact, the review showed that most of the major symptoms of AOSD detected in the recurrent-flare type are relatively fewer than in the first-onset type. In addition, the major symptoms and findings of AOSD are elevated liver enzyme, leukocytosis, and sometimes abdominal pain or nausea, which are difficult to distinguish from HELLP syndrome or AFLP, particularly in cases with flare occurring at third trimester. Elevated ferritin [2] and IL-18 [33], which are reportedly biomarkers of AOSD activity, are considered better diagnostic markers than any other markers. Specific AOSD features such as fever, splenomegaly, and typical rash can support the possibility of AOSD. Izuka et al. recently reported that elevated serum aldolase can be a useful biomarker of AOSD [34]. In our case, the serum aldolase level was high (30.6 U/L), which supported the diagnosis of recurrent AOSD flare. Finally, we and some rheumatologists comprehensively diagnosed the patient with AOSD recurrence flare in consideration of the AOSD findings such as elevated ferritin, IL-18, and aldolase levels, splenomegaly, and uneventful fetal status.
AOSD treatments generally include PSL/mPSL, nonsteroidal anti-inflammatory agents (NSAIDs) and in more severe cases, methotrexate, anakinra (interleukin-1 [IL-1] inhibitor), intravenous immune globulin (IVIg), cyclosporine, or tacrolimus. However, selecting the appropriate medication for pregnant patients entails some limitations. Jamilloux Y et al. recommended corticosteroids as the first treatment choice, and IVIg and IL-1 inhibitor as the second treatment choice for AOSD [35]. Our review also showed that corticosteroid was mainly used, followed by IL-1 inhibitor and IVIg. In Japan, where most of the IL-1 antagonists have not yet been approved, tacrolimus may be a reasonable second choice for severe AOSD flare in pregnancy, and some successful management cases reported to have used this medication during pregnancy [11, 23]. In our case, twice mPSL pulse therapy followed by oral PSL was chosen; consequently, pregnancy was maintained until 36 gestational weeks.
In almost one-third of cases in both the first-onset and recurrent-flare types, the main obstetrical complication was preterm birth. Some reports showed that other autoimmune diseases or autoinflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis, occurring during pregnancy are risk factors for preterm birth, and maternal disease activity contributes to the increased risk of preterm delivery [36–38]. Furthermore, long-term steroidal use is another risk factor for preterm birth [37, 38]. Our review results showed that the incidence of preterm delivery in both the first-onset and recurrent-flare types of AOSD was almost twice higher than that in the no-flare type. Therefore, the high disease activity of AOSD and long-term use of systemic steroids may be possible reasons for the high incidence of preterm delivery in patients with AOSD. Our case also delivered prematurely, with high disease activity and long-term systemic steroid use including twice steroid pulse therapies. Hemophagocytic lymphohistiocytosis (HLH) is also a severe and crucial complication of AOSD. HLH was diagnosed in some cases having the first-onset and recurrent-flare types and in neonatal cases delivered from mothers with AOSD, even in clinical remission. Meanwhile, we believe that in general, the overall severity of AOSD during pregnancy may be better than the HELLP syndrome and AFLP. In fact, lethal complication was only found in one case wherein a premature fetus died at 28 weeks old because of infantile respiratory distress syndrome (IRDS) in the first-onset type, as reported by Green et al. in 1982 [8]. Therefore, with the cooperation of rheumatologists and pediatricians, pregnant patients with AOSD can maintain their pregnancy by paying special attention to prematurity, fetal growth, and HLH, even if the case is in clinical remission.
The relationship of pathogenesis between AOSD and pregnancy remains unclear. Ida A et al. reported that serum IL-18 levels were significantly elevated in pregnant women from the first trimester until the onset of labor than in nonpregnant women [39]. They noticed further increment of serum IL-18 levels after labor, lasting until at least the third day of postpartum. This result parallels the clinical feature of AOSD in pregnancy, that is, AOSD flares are likely to happen in the first/second trimester and postpartum. Considering that our case had also prominently high IL-18 levels, IL-18 elevation may cause the flare of AOSD during pregnancy, suggesting that pregnancy may be a risk factor of AOSD. Therefore, the serum IL-18 levels as a follow-up during pregnancy may be a useful predictive and diagnostic marker of AOSD flare; however, further investigations are required.
From the abovementioned consideration, patients with AOSD can be pregnant and continue pregnancy safely while under treatment, considering that the prognosis of pregnant women with AOSD and their fetuses is favorable in previous cases. Furthermore, for a safer pregnancy in patients complicated with AOSD, we, as obstetricians, need tight cooperation with rheumatologists and pediatricians for the sufficient control of AOSD activity and perinatal care and should provide enough explanation to patients on the risks of flares during pregnancy. Moreover, we conduct frequent laboratory tests and careful follow-up in preparation for flares, premature birth, and HLH. If the flare happens at third trimester, as in our case, we need to differentiate AOSD from HELLP syndrome and AFLP because of the similarity of laboratory data and physical findings. Fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for the differentiation from HELLP syndrome and AFLP.
To our knowledge, this report is the first to present the recurrent flare of AOSD during pregnancy at third trimester. However, we need to further investigate on the proper management of pregnant women with AOSD.
Abbreviations
AOSDAdult-onset Still’s disease
TNF-αTumor necrosis factor-α
IL-6Interleukin-6
IL-18Interleukin-18
HELLPHemolysis, elevated liver enzymes and low platelet count
AFLPAcute fatty liver of pregnancy
GDMGestational diabetes mellitus
EFBWEstimated fetal body weight
SDStandard deviation
mPSLMethylprednisolone
PSLPrednisolone
IUGRIntrauterine growth restriction
pPROMPreterm premature rupture of membrane
CRPC-reactive protein
IQRInterquartile range
NSAIDsNonsteroidal anti-inflammatory agents
IL-1Interleukin-1
IVIgIntravenous immune globulin
HLHHemophagocytic lymphohistiocytosis
IRDSInfantile respiratory distress syndrome
NVDNormal vaginal delivery
T-BilTotal bilirubin
ASTAspartate aminotransferase
ALTAlanine aminotransferase
LDHLactate dehydrogenase
γ-GTPγ-glutamyl transpeptidase
BUNBlood urea nitrogen
CreCreatinine
BSBlood sugar
TGTriglyceride
WBCWhite blood cell
RBCRed blood cell
HbHemoglobin
HtHematocrit
PltPlatelet
PT-INRProthrombin-time international normalized ratio
APTTActivated partial thromboplastin time
FibFibrinogen
AT IIIAntithrombin III
HCQHydroxychloroquine
OHDOligohydramnios
HDPHypertensive disorders of pregnancy
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors would like to thank Enago (www.enago.jp) for the English language review.
Authors’ contributions
SH collected and interpreted the patient’s data, collected previous reports and wrote the first draft of this paper. MS and HO also interpreted the data and revised the first draft. SI and HY also revised the first draft and support the data collection. All authors approved the final manuscript.
Authors’ information
SH was a junior resident of the Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan at the time of this work. Now, SH belongs to the Department of Obstetrics and Gynecology, the Jikei University School of Medicine.
Funding
All authors had no funding support related to this report.
Availability of data and materials
The datasets that support the findings about this case are available from the corresponding author, SH, on reasonable request.
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 of this journal.
Competing interests
The authors declare that they have no competing interests. | METHYLPREDNISOLONE, PREDNISOLONE | DrugsGivenReaction | CC BY | 33627085 | 19,473,834 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Maternal exposure during pregnancy'. | A case of recurrence of adult-onset Still's disease in the third trimester: a case report and literature review.
BACKGROUND
Adult-onset Still's disease (AOSD) is a self-inflammatory disease showing macrophage and neutrophil activation by inflammatory cytokines such as TNF-α, IL-6, and IL-18. Although some cases with the flare of AOSD during pregnancy have been reported, most had flares in the first or second trimester and few had flares in the third trimester. In this report, we present the case of a patient with recurrent flare of AOSD in the third trimester and discuss the management of AOSD in the third trimester with the review of previous literatures.
METHODS
A 38-year-old woman in complete AOSD remission without medication presented with impaired liver function, low platelet count, mild fever, abdominal pain, splenomegaly, and elevated ferritin and IL-18 levels at 30 gestational weeks. Although the laboratory data and physical examination finding suggested HELLP syndrome or acute fatty liver of pregnancy and we considered the termination of her pregnancy, her fetus was in a reactive status. Considering her fetal status, some specific findings of AOSD, and her AOSD history, we and rheumatologists diagnosed her with AOSD recurrence and started systemic steroid therapy. In her clinical course, three flares of AOSD occurred, twice in the third trimester and once in postpartum; twice systemic steroid pulse therapies were then needed. Ultimately, a healthy infant was delivered transvaginally at 36 gestational weeks spontaneously.
CONCLUSIONS
Specific findings of the flare of AOSD such as fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for differentiation from HELLP syndrome and AFLP in the third trimester. With the careful management supported by rheumatologists, patients complicated with the flare of AOSD may continue their pregnancy longer than we expected.
Background
Adult-onset Still’s disease (AOSD) is a self-inflammatory disease exhibiting macrophage and neutrophil activation by inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-18 (IL-18). Its incidence is 1.6–4.0 in 1,000,000 people per year [1]. AOSD more likely occurs in women, affecting 50 to 70%, than in men [1]. It mostly affects young adults (median age at diagnosis: 36 years) [1], indicating the reproductive ages in women. The Yamaguchi criteria [2] are commonly used to diagnose AOSD because they suggest major symptoms and laboratory findings of AOSD; common manifestations are remittent fever over 39 °C lasting more than a week, arthralgia or arthritis, typical rash, high white blood cell count, elevated liver enzymes, and splenomegaly (Table 1). In addition, some AOSD cases manifest abdominal pain and nausea [1]. If findings such as elevated liver enzyme and abdominal pain happen during pregnancy, AOSD may be misinterpreted as hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome and acute fatty liver of pregnancy (AFLP). Currently, although the association between the disease onset of AOSD and pregnancy has already been widely investigated [3, 4], such relationship remains unclear. Moreover, reported cases of AOSD flares at third trimester are few, and the management and features of AOSD, which has similar features to HELLP syndrome and AFLP, at the third trimester have not been reported yet. Herein, we report a rare case of a pregnant woman with AOSD recurrence at her 30 gestational weeks and reviewed the previous reports on the flares of AOSD related to pregnancy. Written informed consent for the publication of this report was obtained from the patient.
Table 1 Yamaguchi criteria for the diagnosis of adult-onset Still’s disease [2]
Major criteria Fever ≥39 °C lasting ≥1 week
Arthralgia or arthritis lasting ≥2 weeks
Typical nonpruritic salmon-colored rash
Leukocytosis ≥10,000/μl with granulocytes ≥80%
Minor criteria Sore throat
Lymphadenopathy
Splenomegaly
Abnormal liver function tests
Negative tests for antinuclear antibody and rheumatoid factor
Exclusion criteria Infection
Malignancy
Other rheumatic disease (vasculitis)
Diagnosis of adult-onset Still’s disease if ≥5 criteria are present with ≥2 being major criteria and no exclusion criteria
Case presentation
A 38-year-old primigravida with well-controlled gestational diabetes mellitus (GDM) was introduced from her home doctor to our hospital, presenting with mild fever, liver dysfunction, elevated ferritin, low platelet count, and proteinuria at 30 weeks and 5 days of gestation. She was diagnosed with AOSD 6 years ago in our hospital based on typical symptoms, including fever, malaise, cervical lymphadenopathy, rash, liver disfunction, and high serum ferritin levels. Although the rheumatologists performed biopsies of her bone marrow and lymph node, the results of these examination were normal and the possibility of other hematologic diseases was denied. After the combination treatment with systemic steroid and tocilizumab administration, she was in complete clinical remission without medication at conception. Upon arrival, her body temperature, blood pressure, and heart rate were 37.7 °C, 101/63 mmHg, and 103 beats/min. In systemic physical examinations, no abnormalities were found. The laboratory findings at arrival are presented in Table 2; The results indicated liver dysfunction, low platelet, and elevated IL-18 and aldolase levels. No apparent coagulopathy findings were observed. Basic infectious disease tests including Epstein–Barr virus and cytomegalovirus were all negative. Nonstress test and fetal sonography revealed perfect biophysical profile scoring of her fetus, mild polyhydramnios (maximum vertical pocket of amnion: 8.3 cm), and an estimated fetal body weight (EFBW) of 1663 g (+ 0.8 standard deviation [SD]). However, splenomegaly was detected by additional abdominal sonography. Although HELLP syndrome or AFLP was suspected upon admission according to liver dysfunction and low platelet count at third trimester and termination of pregnancy could be possible, her clinical course and examination results did not match well to Sibai’s criteria for HELLP syndrome [5] and Swansea’s criteria for AFLP [6]. Moreover, her general condition and fetal status did not require urgent intervention. Considering the findings such as mild fever, elevated ferritin level, high level of IL-18, splenomegaly, and good fetal status, she was ultimately diagnosed with recurrence flare of AOSD by us and some rheumatologists. Thus, systemic steroid pulse therapy (first dose: 250 mg of methylprednisolone [mPSL] for 3 days) was initiated and switched to oral prednisolone (PSL) thereafter. Additionally, the patient was carefully followed up by frequent laboratory tests and transabdominal fetal sonography. Figure 1 illustrates her clinical course after hospitalization at 30 gestational weeks. Clinical AOSD findings such as fever, liver dysfunction, and high ferritin level were well controlled for 3 weeks after the initiation of systemic steroid therapy; hence, the oral PSL dosage was gradually reduced. However, another steroid pulse therapy was needed for the second flare of AOSD that happened at her 33 gestational weeks with elevated liver enzymes and rash on her trunk. In her clinical course, although with maintained uneventful fetal status, the growth of the fetus had been gradually restricted, resulting in intrauterine growth restriction (IUGR). At 36 weeks and 0 days of gestation, she had irregular uterine contractions without apparent infectious findings, and preterm premature rupture of membrane (pPROM). Finally, she spontaneously delivered a female infant transvaginally at 36 weeks and 3 days of gestation. Her infant had a low birth weight (2440 g) but was very healthy; the Apgar score was 9/10, and pH of the umbilical artery was 7.312. Moreover, no abnormal findings of the amniotic fluid at delivery and no pathological features in her placenta and umbilical cord were found. At 12 days postpartum, she had elevated ferritin levels and extremely low platelet count, indicating the third AOSD flare by a rheumatologist; thus, the dosage of oral PSL was increased and maintained for months. During her follow-up checkup as an outpatient by rheumatologists at 1 year postpartum, her C-reactive protein (CRP) and ferritin levels were within the reference range, and her platelet count gradually increased, indicating a well-controlled AOSD.
Table 2 Laboratory findings
Value Reference intervals, unit
T-Bil 0.7 0.4–1.5, mg/dl
AST 491 13–30, U/L
ALT 438 7–23, U/L
LDH 653 124–222, U/L
γ-GTP 10 9–32, U/L
BUN 6.4 8.0–20.0, mg/dl
Cre 0.58 0.46–0.79, mg/dl
BS 84 80–110, mg/dl
UA 3.3 2.6–7.0, mg/dl
CRP 1.81 0.00–0.14, mg/dl
TG 163 30–149, mg/dl
Ferritin 281 5–157, ng/ml
WBC 2980 3300–8600, /μl
RBC 3.93 3.86–4.92, × 106/μl
Hb 10.7 11.6–14.8, g/dl
Ht 32.5 35.1–44.4, %
Plt 108 158–348, × 103 /μl
PT-INR 0.89 0.90–1.10
APTT 33 25–35, seconds
Fib 407 200–400, mg/dl
AT III 96 80–130, %
Urinary protein 0.33 0.02–0.12, g/day
IL-18 175,116 0–211, pg/ml
Aldolase 30.6 2.5–7.5, U/L
Fig. 1 Clinical course, laboratory data, and treatment of the patient. Initial mPSL pulse therapy was provided for 3 days after 30 weeks and 5 days of gestation and then switched to oral PSL therapy. At 33 weeks and 0 days of gestation, another pulse therapy was provided for the second flare. EFBW was restricted gradually from − 0.6 SD to − 1.5 SD. At 36 weeks and 0 days of gestation, this patient started irregular uterine contractions and finally delivered a healthy infant spontaneously at 36 weeks and 3 days of gestation. At 12 days postpartum, she experienced the third flare, and oral PSL therapy was maintained
Discussion and conclusions
The flare of AOSD in pregnancy was first reported in 1980 by Stein et al. [7]. Currently, nearly 30 reports about AOSD associated with pregnancy have been published [3, 4, 7–32]. Hence, we reviewed the cases of AOSD complications during pregnancy [3, 4, 7–32]. A total of 53 flares in 47 pregnant women, including our case, have been recorded. The clinical course of AOSD during pregnancy consists of three types: first-onset type, which refers to the first onset of AOSD related to pregnancy [3, 4, 7, 8, 11, 12, 14, 17–25, 28–30, 32], recurrent-flare type, which refers to a recurrent flare related to pregnancy with previous AOSD diagnosis [4, 7, 9, 13, 14, 16, 25, 31], and no-flare type, which is only a complication with no flare related to pregnancy [4, 9, 10, 14, 15, 17, 26, 27]. In the literature review, the cases were divided into these three types shown in Table 3 and our case belongs to the recurrent-flare type.
Table 3 Review of pregnancy cases with adult onset Still’s disease classified into three types
Total: 47 pregnant women and 53 pregnancies
First onset (Number = 26) Recurrent flare (Number = 13) No flare (Number = 14)
Age at pregnancy (year), Median [IQR] 29 [25–33] (1 unknown case) 31 [29–34] 27 [26–30] (1 unknown case)
Parity, %
Primigravida 50 (8/16) 80 (8/10) 69.2 (9/13)
Multigravida 50 (8/16) 20 (2/10) 30.8 (4/13)
Unknown, number 10 3 1
Timing of flare, %
1st trimester 24 (6/25) 23.1 (3/13) –
2nd trimester 52 (13/25) 38.5 (5/13) –
3rd trimester 8 (2/25) 7.7 (1/13) –
Postpartum 16 (4/25) 30.8 (4/13) –
Unknown, number 1 0 –
Major symptoms and complications, %
Fever 95.7 (22/23) 70 (7/10) –
Arthralgia, Arthritis 91.3 (21/23) 60 (6/10) –
Erythema, Rash 78.3 (18/23) 50 (5/10) –
Sore throat 65.2 (15/23) 30 (3/10) –
Lymphadenopathy 60.9 (14/23) 10 (1/10) –
Hepatomegaly, Liver dysfunction 34.8 (8/23) 30 (3/10) –
Splenomegaly 34.8 (8/23) 10 (1/10) –
HLH 8.7 (2/23) 10 (1/10) –
Unknown, number 3 3 –
Major treatment, %
Corticosteroid 82.6 (19/23) 69.2 (9/13) 28.6 (4/14)
Anakinra 13.0 (3/23) 7.7 (1/13) 28.6 (4/14)
IVIg 17.4 (4/23) 7.7 (1/13) 7.1 (1/14)
NSAIDs 21.7 (5/23) 7.7 (1/13) 14.3 (2/14)
HCQ 4.3 (1/23) 15.4 (2/13) 7.1 (1/14)
No medication – – 57.1 (8/14)
Unknown, number 3 0 0
Delivery, %
Transvaginal 66.7 (12/18) 50 (4/8) 62.5 (5/8)
Cesarean section 22.2 (4/18) 50 (4/8) 25 (2/8)
Abortion 11.1 (2/18) 0 (0/8) 12.5 (1/8)
Unknown, number 8 5 6
Major obstetrical and perinatal complications, %
Preterm birth 32 (8/25) 33.3 (4/12) 16.7 (2/12)
IUGR 8 (2/25) 41.7 (5/12) 8.3 (1/12)
pPROM 12 (3/25) 8.3 (1/12) 8.3 (1/12)
No major complication 48 (12/25) 41.7 (5/12) 50 (6/12)
Others, number 2 for OHD, 1 for neonatal HLH, 1 for preeclampsia, and 1 for neonatal death for IRDS 1 for GDM, and 1 for OHD 1 for neonatal HLH, 1 for GDM, and 1 for HDP
Unknown, number 1 1 2
The median age of patients at pregnancy was almost 30 years (median [interquartile range (IQR)]: 29 [25–33], 31 [29–34], and 27 [26–30] for the first-onset, recurrent-flare, and no-flare types, respectively), indicating that women with AOSD during pregnancy were younger than the general population at first diagnosis [1]. Regarding parity, AOSD flare mainly happens among primigravida patients, with the recurrent-flare type obtaining the highest rate (83.3%), although all patients in this type are in clinical remission at conception [4, 7, 9, 13, 14, 16, 25, 31]. Our case was also in clinical remission and did not require any medication at conception.
Most likely, the AOSD flare occurred until second trimester and at postpartum, with limited reports of flare at third trimester; the first-onset type was found only in two cases [21, 24] and the recurrent-flare type in one case, which is our case. Although AOSD flare occurring at third trimester is extremely rare, the clinical symptoms of AOSD are similar to those of HELLP syndrome and AFLP, suggesting that close attention to perinatal management is crucial. Generally, the Yamaguchi criteria [2] is adopted for the diagnosing AOSD (Table 1). However, we needed to assess AOSD recurrence in a comprehensive way by considering the clinical features and laboratory findings because no criteria for the diagnosis of AOSD recurrence are currently available. In fact, the review showed that most of the major symptoms of AOSD detected in the recurrent-flare type are relatively fewer than in the first-onset type. In addition, the major symptoms and findings of AOSD are elevated liver enzyme, leukocytosis, and sometimes abdominal pain or nausea, which are difficult to distinguish from HELLP syndrome or AFLP, particularly in cases with flare occurring at third trimester. Elevated ferritin [2] and IL-18 [33], which are reportedly biomarkers of AOSD activity, are considered better diagnostic markers than any other markers. Specific AOSD features such as fever, splenomegaly, and typical rash can support the possibility of AOSD. Izuka et al. recently reported that elevated serum aldolase can be a useful biomarker of AOSD [34]. In our case, the serum aldolase level was high (30.6 U/L), which supported the diagnosis of recurrent AOSD flare. Finally, we and some rheumatologists comprehensively diagnosed the patient with AOSD recurrence flare in consideration of the AOSD findings such as elevated ferritin, IL-18, and aldolase levels, splenomegaly, and uneventful fetal status.
AOSD treatments generally include PSL/mPSL, nonsteroidal anti-inflammatory agents (NSAIDs) and in more severe cases, methotrexate, anakinra (interleukin-1 [IL-1] inhibitor), intravenous immune globulin (IVIg), cyclosporine, or tacrolimus. However, selecting the appropriate medication for pregnant patients entails some limitations. Jamilloux Y et al. recommended corticosteroids as the first treatment choice, and IVIg and IL-1 inhibitor as the second treatment choice for AOSD [35]. Our review also showed that corticosteroid was mainly used, followed by IL-1 inhibitor and IVIg. In Japan, where most of the IL-1 antagonists have not yet been approved, tacrolimus may be a reasonable second choice for severe AOSD flare in pregnancy, and some successful management cases reported to have used this medication during pregnancy [11, 23]. In our case, twice mPSL pulse therapy followed by oral PSL was chosen; consequently, pregnancy was maintained until 36 gestational weeks.
In almost one-third of cases in both the first-onset and recurrent-flare types, the main obstetrical complication was preterm birth. Some reports showed that other autoimmune diseases or autoinflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis, occurring during pregnancy are risk factors for preterm birth, and maternal disease activity contributes to the increased risk of preterm delivery [36–38]. Furthermore, long-term steroidal use is another risk factor for preterm birth [37, 38]. Our review results showed that the incidence of preterm delivery in both the first-onset and recurrent-flare types of AOSD was almost twice higher than that in the no-flare type. Therefore, the high disease activity of AOSD and long-term use of systemic steroids may be possible reasons for the high incidence of preterm delivery in patients with AOSD. Our case also delivered prematurely, with high disease activity and long-term systemic steroid use including twice steroid pulse therapies. Hemophagocytic lymphohistiocytosis (HLH) is also a severe and crucial complication of AOSD. HLH was diagnosed in some cases having the first-onset and recurrent-flare types and in neonatal cases delivered from mothers with AOSD, even in clinical remission. Meanwhile, we believe that in general, the overall severity of AOSD during pregnancy may be better than the HELLP syndrome and AFLP. In fact, lethal complication was only found in one case wherein a premature fetus died at 28 weeks old because of infantile respiratory distress syndrome (IRDS) in the first-onset type, as reported by Green et al. in 1982 [8]. Therefore, with the cooperation of rheumatologists and pediatricians, pregnant patients with AOSD can maintain their pregnancy by paying special attention to prematurity, fetal growth, and HLH, even if the case is in clinical remission.
The relationship of pathogenesis between AOSD and pregnancy remains unclear. Ida A et al. reported that serum IL-18 levels were significantly elevated in pregnant women from the first trimester until the onset of labor than in nonpregnant women [39]. They noticed further increment of serum IL-18 levels after labor, lasting until at least the third day of postpartum. This result parallels the clinical feature of AOSD in pregnancy, that is, AOSD flares are likely to happen in the first/second trimester and postpartum. Considering that our case had also prominently high IL-18 levels, IL-18 elevation may cause the flare of AOSD during pregnancy, suggesting that pregnancy may be a risk factor of AOSD. Therefore, the serum IL-18 levels as a follow-up during pregnancy may be a useful predictive and diagnostic marker of AOSD flare; however, further investigations are required.
From the abovementioned consideration, patients with AOSD can be pregnant and continue pregnancy safely while under treatment, considering that the prognosis of pregnant women with AOSD and their fetuses is favorable in previous cases. Furthermore, for a safer pregnancy in patients complicated with AOSD, we, as obstetricians, need tight cooperation with rheumatologists and pediatricians for the sufficient control of AOSD activity and perinatal care and should provide enough explanation to patients on the risks of flares during pregnancy. Moreover, we conduct frequent laboratory tests and careful follow-up in preparation for flares, premature birth, and HLH. If the flare happens at third trimester, as in our case, we need to differentiate AOSD from HELLP syndrome and AFLP because of the similarity of laboratory data and physical findings. Fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for the differentiation from HELLP syndrome and AFLP.
To our knowledge, this report is the first to present the recurrent flare of AOSD during pregnancy at third trimester. However, we need to further investigate on the proper management of pregnant women with AOSD.
Abbreviations
AOSDAdult-onset Still’s disease
TNF-αTumor necrosis factor-α
IL-6Interleukin-6
IL-18Interleukin-18
HELLPHemolysis, elevated liver enzymes and low platelet count
AFLPAcute fatty liver of pregnancy
GDMGestational diabetes mellitus
EFBWEstimated fetal body weight
SDStandard deviation
mPSLMethylprednisolone
PSLPrednisolone
IUGRIntrauterine growth restriction
pPROMPreterm premature rupture of membrane
CRPC-reactive protein
IQRInterquartile range
NSAIDsNonsteroidal anti-inflammatory agents
IL-1Interleukin-1
IVIgIntravenous immune globulin
HLHHemophagocytic lymphohistiocytosis
IRDSInfantile respiratory distress syndrome
NVDNormal vaginal delivery
T-BilTotal bilirubin
ASTAspartate aminotransferase
ALTAlanine aminotransferase
LDHLactate dehydrogenase
γ-GTPγ-glutamyl transpeptidase
BUNBlood urea nitrogen
CreCreatinine
BSBlood sugar
TGTriglyceride
WBCWhite blood cell
RBCRed blood cell
HbHemoglobin
HtHematocrit
PltPlatelet
PT-INRProthrombin-time international normalized ratio
APTTActivated partial thromboplastin time
FibFibrinogen
AT IIIAntithrombin III
HCQHydroxychloroquine
OHDOligohydramnios
HDPHypertensive disorders of pregnancy
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors would like to thank Enago (www.enago.jp) for the English language review.
Authors’ contributions
SH collected and interpreted the patient’s data, collected previous reports and wrote the first draft of this paper. MS and HO also interpreted the data and revised the first draft. SI and HY also revised the first draft and support the data collection. All authors approved the final manuscript.
Authors’ information
SH was a junior resident of the Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan at the time of this work. Now, SH belongs to the Department of Obstetrics and Gynecology, the Jikei University School of Medicine.
Funding
All authors had no funding support related to this report.
Availability of data and materials
The datasets that support the findings about this case are available from the corresponding author, SH, on reasonable request.
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 of this journal.
Competing interests
The authors declare that they have no competing interests. | METHYLPREDNISOLONE, PREDNISOLONE | DrugsGivenReaction | CC BY | 33627085 | 19,525,796 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Normal newborn'. | A case of recurrence of adult-onset Still's disease in the third trimester: a case report and literature review.
BACKGROUND
Adult-onset Still's disease (AOSD) is a self-inflammatory disease showing macrophage and neutrophil activation by inflammatory cytokines such as TNF-α, IL-6, and IL-18. Although some cases with the flare of AOSD during pregnancy have been reported, most had flares in the first or second trimester and few had flares in the third trimester. In this report, we present the case of a patient with recurrent flare of AOSD in the third trimester and discuss the management of AOSD in the third trimester with the review of previous literatures.
METHODS
A 38-year-old woman in complete AOSD remission without medication presented with impaired liver function, low platelet count, mild fever, abdominal pain, splenomegaly, and elevated ferritin and IL-18 levels at 30 gestational weeks. Although the laboratory data and physical examination finding suggested HELLP syndrome or acute fatty liver of pregnancy and we considered the termination of her pregnancy, her fetus was in a reactive status. Considering her fetal status, some specific findings of AOSD, and her AOSD history, we and rheumatologists diagnosed her with AOSD recurrence and started systemic steroid therapy. In her clinical course, three flares of AOSD occurred, twice in the third trimester and once in postpartum; twice systemic steroid pulse therapies were then needed. Ultimately, a healthy infant was delivered transvaginally at 36 gestational weeks spontaneously.
CONCLUSIONS
Specific findings of the flare of AOSD such as fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for differentiation from HELLP syndrome and AFLP in the third trimester. With the careful management supported by rheumatologists, patients complicated with the flare of AOSD may continue their pregnancy longer than we expected.
Background
Adult-onset Still’s disease (AOSD) is a self-inflammatory disease exhibiting macrophage and neutrophil activation by inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-18 (IL-18). Its incidence is 1.6–4.0 in 1,000,000 people per year [1]. AOSD more likely occurs in women, affecting 50 to 70%, than in men [1]. It mostly affects young adults (median age at diagnosis: 36 years) [1], indicating the reproductive ages in women. The Yamaguchi criteria [2] are commonly used to diagnose AOSD because they suggest major symptoms and laboratory findings of AOSD; common manifestations are remittent fever over 39 °C lasting more than a week, arthralgia or arthritis, typical rash, high white blood cell count, elevated liver enzymes, and splenomegaly (Table 1). In addition, some AOSD cases manifest abdominal pain and nausea [1]. If findings such as elevated liver enzyme and abdominal pain happen during pregnancy, AOSD may be misinterpreted as hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome and acute fatty liver of pregnancy (AFLP). Currently, although the association between the disease onset of AOSD and pregnancy has already been widely investigated [3, 4], such relationship remains unclear. Moreover, reported cases of AOSD flares at third trimester are few, and the management and features of AOSD, which has similar features to HELLP syndrome and AFLP, at the third trimester have not been reported yet. Herein, we report a rare case of a pregnant woman with AOSD recurrence at her 30 gestational weeks and reviewed the previous reports on the flares of AOSD related to pregnancy. Written informed consent for the publication of this report was obtained from the patient.
Table 1 Yamaguchi criteria for the diagnosis of adult-onset Still’s disease [2]
Major criteria Fever ≥39 °C lasting ≥1 week
Arthralgia or arthritis lasting ≥2 weeks
Typical nonpruritic salmon-colored rash
Leukocytosis ≥10,000/μl with granulocytes ≥80%
Minor criteria Sore throat
Lymphadenopathy
Splenomegaly
Abnormal liver function tests
Negative tests for antinuclear antibody and rheumatoid factor
Exclusion criteria Infection
Malignancy
Other rheumatic disease (vasculitis)
Diagnosis of adult-onset Still’s disease if ≥5 criteria are present with ≥2 being major criteria and no exclusion criteria
Case presentation
A 38-year-old primigravida with well-controlled gestational diabetes mellitus (GDM) was introduced from her home doctor to our hospital, presenting with mild fever, liver dysfunction, elevated ferritin, low platelet count, and proteinuria at 30 weeks and 5 days of gestation. She was diagnosed with AOSD 6 years ago in our hospital based on typical symptoms, including fever, malaise, cervical lymphadenopathy, rash, liver disfunction, and high serum ferritin levels. Although the rheumatologists performed biopsies of her bone marrow and lymph node, the results of these examination were normal and the possibility of other hematologic diseases was denied. After the combination treatment with systemic steroid and tocilizumab administration, she was in complete clinical remission without medication at conception. Upon arrival, her body temperature, blood pressure, and heart rate were 37.7 °C, 101/63 mmHg, and 103 beats/min. In systemic physical examinations, no abnormalities were found. The laboratory findings at arrival are presented in Table 2; The results indicated liver dysfunction, low platelet, and elevated IL-18 and aldolase levels. No apparent coagulopathy findings were observed. Basic infectious disease tests including Epstein–Barr virus and cytomegalovirus were all negative. Nonstress test and fetal sonography revealed perfect biophysical profile scoring of her fetus, mild polyhydramnios (maximum vertical pocket of amnion: 8.3 cm), and an estimated fetal body weight (EFBW) of 1663 g (+ 0.8 standard deviation [SD]). However, splenomegaly was detected by additional abdominal sonography. Although HELLP syndrome or AFLP was suspected upon admission according to liver dysfunction and low platelet count at third trimester and termination of pregnancy could be possible, her clinical course and examination results did not match well to Sibai’s criteria for HELLP syndrome [5] and Swansea’s criteria for AFLP [6]. Moreover, her general condition and fetal status did not require urgent intervention. Considering the findings such as mild fever, elevated ferritin level, high level of IL-18, splenomegaly, and good fetal status, she was ultimately diagnosed with recurrence flare of AOSD by us and some rheumatologists. Thus, systemic steroid pulse therapy (first dose: 250 mg of methylprednisolone [mPSL] for 3 days) was initiated and switched to oral prednisolone (PSL) thereafter. Additionally, the patient was carefully followed up by frequent laboratory tests and transabdominal fetal sonography. Figure 1 illustrates her clinical course after hospitalization at 30 gestational weeks. Clinical AOSD findings such as fever, liver dysfunction, and high ferritin level were well controlled for 3 weeks after the initiation of systemic steroid therapy; hence, the oral PSL dosage was gradually reduced. However, another steroid pulse therapy was needed for the second flare of AOSD that happened at her 33 gestational weeks with elevated liver enzymes and rash on her trunk. In her clinical course, although with maintained uneventful fetal status, the growth of the fetus had been gradually restricted, resulting in intrauterine growth restriction (IUGR). At 36 weeks and 0 days of gestation, she had irregular uterine contractions without apparent infectious findings, and preterm premature rupture of membrane (pPROM). Finally, she spontaneously delivered a female infant transvaginally at 36 weeks and 3 days of gestation. Her infant had a low birth weight (2440 g) but was very healthy; the Apgar score was 9/10, and pH of the umbilical artery was 7.312. Moreover, no abnormal findings of the amniotic fluid at delivery and no pathological features in her placenta and umbilical cord were found. At 12 days postpartum, she had elevated ferritin levels and extremely low platelet count, indicating the third AOSD flare by a rheumatologist; thus, the dosage of oral PSL was increased and maintained for months. During her follow-up checkup as an outpatient by rheumatologists at 1 year postpartum, her C-reactive protein (CRP) and ferritin levels were within the reference range, and her platelet count gradually increased, indicating a well-controlled AOSD.
Table 2 Laboratory findings
Value Reference intervals, unit
T-Bil 0.7 0.4–1.5, mg/dl
AST 491 13–30, U/L
ALT 438 7–23, U/L
LDH 653 124–222, U/L
γ-GTP 10 9–32, U/L
BUN 6.4 8.0–20.0, mg/dl
Cre 0.58 0.46–0.79, mg/dl
BS 84 80–110, mg/dl
UA 3.3 2.6–7.0, mg/dl
CRP 1.81 0.00–0.14, mg/dl
TG 163 30–149, mg/dl
Ferritin 281 5–157, ng/ml
WBC 2980 3300–8600, /μl
RBC 3.93 3.86–4.92, × 106/μl
Hb 10.7 11.6–14.8, g/dl
Ht 32.5 35.1–44.4, %
Plt 108 158–348, × 103 /μl
PT-INR 0.89 0.90–1.10
APTT 33 25–35, seconds
Fib 407 200–400, mg/dl
AT III 96 80–130, %
Urinary protein 0.33 0.02–0.12, g/day
IL-18 175,116 0–211, pg/ml
Aldolase 30.6 2.5–7.5, U/L
Fig. 1 Clinical course, laboratory data, and treatment of the patient. Initial mPSL pulse therapy was provided for 3 days after 30 weeks and 5 days of gestation and then switched to oral PSL therapy. At 33 weeks and 0 days of gestation, another pulse therapy was provided for the second flare. EFBW was restricted gradually from − 0.6 SD to − 1.5 SD. At 36 weeks and 0 days of gestation, this patient started irregular uterine contractions and finally delivered a healthy infant spontaneously at 36 weeks and 3 days of gestation. At 12 days postpartum, she experienced the third flare, and oral PSL therapy was maintained
Discussion and conclusions
The flare of AOSD in pregnancy was first reported in 1980 by Stein et al. [7]. Currently, nearly 30 reports about AOSD associated with pregnancy have been published [3, 4, 7–32]. Hence, we reviewed the cases of AOSD complications during pregnancy [3, 4, 7–32]. A total of 53 flares in 47 pregnant women, including our case, have been recorded. The clinical course of AOSD during pregnancy consists of three types: first-onset type, which refers to the first onset of AOSD related to pregnancy [3, 4, 7, 8, 11, 12, 14, 17–25, 28–30, 32], recurrent-flare type, which refers to a recurrent flare related to pregnancy with previous AOSD diagnosis [4, 7, 9, 13, 14, 16, 25, 31], and no-flare type, which is only a complication with no flare related to pregnancy [4, 9, 10, 14, 15, 17, 26, 27]. In the literature review, the cases were divided into these three types shown in Table 3 and our case belongs to the recurrent-flare type.
Table 3 Review of pregnancy cases with adult onset Still’s disease classified into three types
Total: 47 pregnant women and 53 pregnancies
First onset (Number = 26) Recurrent flare (Number = 13) No flare (Number = 14)
Age at pregnancy (year), Median [IQR] 29 [25–33] (1 unknown case) 31 [29–34] 27 [26–30] (1 unknown case)
Parity, %
Primigravida 50 (8/16) 80 (8/10) 69.2 (9/13)
Multigravida 50 (8/16) 20 (2/10) 30.8 (4/13)
Unknown, number 10 3 1
Timing of flare, %
1st trimester 24 (6/25) 23.1 (3/13) –
2nd trimester 52 (13/25) 38.5 (5/13) –
3rd trimester 8 (2/25) 7.7 (1/13) –
Postpartum 16 (4/25) 30.8 (4/13) –
Unknown, number 1 0 –
Major symptoms and complications, %
Fever 95.7 (22/23) 70 (7/10) –
Arthralgia, Arthritis 91.3 (21/23) 60 (6/10) –
Erythema, Rash 78.3 (18/23) 50 (5/10) –
Sore throat 65.2 (15/23) 30 (3/10) –
Lymphadenopathy 60.9 (14/23) 10 (1/10) –
Hepatomegaly, Liver dysfunction 34.8 (8/23) 30 (3/10) –
Splenomegaly 34.8 (8/23) 10 (1/10) –
HLH 8.7 (2/23) 10 (1/10) –
Unknown, number 3 3 –
Major treatment, %
Corticosteroid 82.6 (19/23) 69.2 (9/13) 28.6 (4/14)
Anakinra 13.0 (3/23) 7.7 (1/13) 28.6 (4/14)
IVIg 17.4 (4/23) 7.7 (1/13) 7.1 (1/14)
NSAIDs 21.7 (5/23) 7.7 (1/13) 14.3 (2/14)
HCQ 4.3 (1/23) 15.4 (2/13) 7.1 (1/14)
No medication – – 57.1 (8/14)
Unknown, number 3 0 0
Delivery, %
Transvaginal 66.7 (12/18) 50 (4/8) 62.5 (5/8)
Cesarean section 22.2 (4/18) 50 (4/8) 25 (2/8)
Abortion 11.1 (2/18) 0 (0/8) 12.5 (1/8)
Unknown, number 8 5 6
Major obstetrical and perinatal complications, %
Preterm birth 32 (8/25) 33.3 (4/12) 16.7 (2/12)
IUGR 8 (2/25) 41.7 (5/12) 8.3 (1/12)
pPROM 12 (3/25) 8.3 (1/12) 8.3 (1/12)
No major complication 48 (12/25) 41.7 (5/12) 50 (6/12)
Others, number 2 for OHD, 1 for neonatal HLH, 1 for preeclampsia, and 1 for neonatal death for IRDS 1 for GDM, and 1 for OHD 1 for neonatal HLH, 1 for GDM, and 1 for HDP
Unknown, number 1 1 2
The median age of patients at pregnancy was almost 30 years (median [interquartile range (IQR)]: 29 [25–33], 31 [29–34], and 27 [26–30] for the first-onset, recurrent-flare, and no-flare types, respectively), indicating that women with AOSD during pregnancy were younger than the general population at first diagnosis [1]. Regarding parity, AOSD flare mainly happens among primigravida patients, with the recurrent-flare type obtaining the highest rate (83.3%), although all patients in this type are in clinical remission at conception [4, 7, 9, 13, 14, 16, 25, 31]. Our case was also in clinical remission and did not require any medication at conception.
Most likely, the AOSD flare occurred until second trimester and at postpartum, with limited reports of flare at third trimester; the first-onset type was found only in two cases [21, 24] and the recurrent-flare type in one case, which is our case. Although AOSD flare occurring at third trimester is extremely rare, the clinical symptoms of AOSD are similar to those of HELLP syndrome and AFLP, suggesting that close attention to perinatal management is crucial. Generally, the Yamaguchi criteria [2] is adopted for the diagnosing AOSD (Table 1). However, we needed to assess AOSD recurrence in a comprehensive way by considering the clinical features and laboratory findings because no criteria for the diagnosis of AOSD recurrence are currently available. In fact, the review showed that most of the major symptoms of AOSD detected in the recurrent-flare type are relatively fewer than in the first-onset type. In addition, the major symptoms and findings of AOSD are elevated liver enzyme, leukocytosis, and sometimes abdominal pain or nausea, which are difficult to distinguish from HELLP syndrome or AFLP, particularly in cases with flare occurring at third trimester. Elevated ferritin [2] and IL-18 [33], which are reportedly biomarkers of AOSD activity, are considered better diagnostic markers than any other markers. Specific AOSD features such as fever, splenomegaly, and typical rash can support the possibility of AOSD. Izuka et al. recently reported that elevated serum aldolase can be a useful biomarker of AOSD [34]. In our case, the serum aldolase level was high (30.6 U/L), which supported the diagnosis of recurrent AOSD flare. Finally, we and some rheumatologists comprehensively diagnosed the patient with AOSD recurrence flare in consideration of the AOSD findings such as elevated ferritin, IL-18, and aldolase levels, splenomegaly, and uneventful fetal status.
AOSD treatments generally include PSL/mPSL, nonsteroidal anti-inflammatory agents (NSAIDs) and in more severe cases, methotrexate, anakinra (interleukin-1 [IL-1] inhibitor), intravenous immune globulin (IVIg), cyclosporine, or tacrolimus. However, selecting the appropriate medication for pregnant patients entails some limitations. Jamilloux Y et al. recommended corticosteroids as the first treatment choice, and IVIg and IL-1 inhibitor as the second treatment choice for AOSD [35]. Our review also showed that corticosteroid was mainly used, followed by IL-1 inhibitor and IVIg. In Japan, where most of the IL-1 antagonists have not yet been approved, tacrolimus may be a reasonable second choice for severe AOSD flare in pregnancy, and some successful management cases reported to have used this medication during pregnancy [11, 23]. In our case, twice mPSL pulse therapy followed by oral PSL was chosen; consequently, pregnancy was maintained until 36 gestational weeks.
In almost one-third of cases in both the first-onset and recurrent-flare types, the main obstetrical complication was preterm birth. Some reports showed that other autoimmune diseases or autoinflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis, occurring during pregnancy are risk factors for preterm birth, and maternal disease activity contributes to the increased risk of preterm delivery [36–38]. Furthermore, long-term steroidal use is another risk factor for preterm birth [37, 38]. Our review results showed that the incidence of preterm delivery in both the first-onset and recurrent-flare types of AOSD was almost twice higher than that in the no-flare type. Therefore, the high disease activity of AOSD and long-term use of systemic steroids may be possible reasons for the high incidence of preterm delivery in patients with AOSD. Our case also delivered prematurely, with high disease activity and long-term systemic steroid use including twice steroid pulse therapies. Hemophagocytic lymphohistiocytosis (HLH) is also a severe and crucial complication of AOSD. HLH was diagnosed in some cases having the first-onset and recurrent-flare types and in neonatal cases delivered from mothers with AOSD, even in clinical remission. Meanwhile, we believe that in general, the overall severity of AOSD during pregnancy may be better than the HELLP syndrome and AFLP. In fact, lethal complication was only found in one case wherein a premature fetus died at 28 weeks old because of infantile respiratory distress syndrome (IRDS) in the first-onset type, as reported by Green et al. in 1982 [8]. Therefore, with the cooperation of rheumatologists and pediatricians, pregnant patients with AOSD can maintain their pregnancy by paying special attention to prematurity, fetal growth, and HLH, even if the case is in clinical remission.
The relationship of pathogenesis between AOSD and pregnancy remains unclear. Ida A et al. reported that serum IL-18 levels were significantly elevated in pregnant women from the first trimester until the onset of labor than in nonpregnant women [39]. They noticed further increment of serum IL-18 levels after labor, lasting until at least the third day of postpartum. This result parallels the clinical feature of AOSD in pregnancy, that is, AOSD flares are likely to happen in the first/second trimester and postpartum. Considering that our case had also prominently high IL-18 levels, IL-18 elevation may cause the flare of AOSD during pregnancy, suggesting that pregnancy may be a risk factor of AOSD. Therefore, the serum IL-18 levels as a follow-up during pregnancy may be a useful predictive and diagnostic marker of AOSD flare; however, further investigations are required.
From the abovementioned consideration, patients with AOSD can be pregnant and continue pregnancy safely while under treatment, considering that the prognosis of pregnant women with AOSD and their fetuses is favorable in previous cases. Furthermore, for a safer pregnancy in patients complicated with AOSD, we, as obstetricians, need tight cooperation with rheumatologists and pediatricians for the sufficient control of AOSD activity and perinatal care and should provide enough explanation to patients on the risks of flares during pregnancy. Moreover, we conduct frequent laboratory tests and careful follow-up in preparation for flares, premature birth, and HLH. If the flare happens at third trimester, as in our case, we need to differentiate AOSD from HELLP syndrome and AFLP because of the similarity of laboratory data and physical findings. Fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for the differentiation from HELLP syndrome and AFLP.
To our knowledge, this report is the first to present the recurrent flare of AOSD during pregnancy at third trimester. However, we need to further investigate on the proper management of pregnant women with AOSD.
Abbreviations
AOSDAdult-onset Still’s disease
TNF-αTumor necrosis factor-α
IL-6Interleukin-6
IL-18Interleukin-18
HELLPHemolysis, elevated liver enzymes and low platelet count
AFLPAcute fatty liver of pregnancy
GDMGestational diabetes mellitus
EFBWEstimated fetal body weight
SDStandard deviation
mPSLMethylprednisolone
PSLPrednisolone
IUGRIntrauterine growth restriction
pPROMPreterm premature rupture of membrane
CRPC-reactive protein
IQRInterquartile range
NSAIDsNonsteroidal anti-inflammatory agents
IL-1Interleukin-1
IVIgIntravenous immune globulin
HLHHemophagocytic lymphohistiocytosis
IRDSInfantile respiratory distress syndrome
NVDNormal vaginal delivery
T-BilTotal bilirubin
ASTAspartate aminotransferase
ALTAlanine aminotransferase
LDHLactate dehydrogenase
γ-GTPγ-glutamyl transpeptidase
BUNBlood urea nitrogen
CreCreatinine
BSBlood sugar
TGTriglyceride
WBCWhite blood cell
RBCRed blood cell
HbHemoglobin
HtHematocrit
PltPlatelet
PT-INRProthrombin-time international normalized ratio
APTTActivated partial thromboplastin time
FibFibrinogen
AT IIIAntithrombin III
HCQHydroxychloroquine
OHDOligohydramnios
HDPHypertensive disorders of pregnancy
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Acknowledgements
The authors would like to thank Enago (www.enago.jp) for the English language review.
Authors’ contributions
SH collected and interpreted the patient’s data, collected previous reports and wrote the first draft of this paper. MS and HO also interpreted the data and revised the first draft. SI and HY also revised the first draft and support the data collection. All authors approved the final manuscript.
Authors’ information
SH was a junior resident of the Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan at the time of this work. Now, SH belongs to the Department of Obstetrics and Gynecology, the Jikei University School of Medicine.
Funding
All authors had no funding support related to this report.
Availability of data and materials
The datasets that support the findings about this case are available from the corresponding author, SH, on reasonable request.
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 of this journal.
Competing interests
The authors declare that they have no competing interests. | METHYLPREDNISOLONE, PREDNISOLONE | DrugsGivenReaction | CC BY | 33627085 | 19,525,796 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Premature delivery'. | A case of recurrence of adult-onset Still's disease in the third trimester: a case report and literature review.
BACKGROUND
Adult-onset Still's disease (AOSD) is a self-inflammatory disease showing macrophage and neutrophil activation by inflammatory cytokines such as TNF-α, IL-6, and IL-18. Although some cases with the flare of AOSD during pregnancy have been reported, most had flares in the first or second trimester and few had flares in the third trimester. In this report, we present the case of a patient with recurrent flare of AOSD in the third trimester and discuss the management of AOSD in the third trimester with the review of previous literatures.
METHODS
A 38-year-old woman in complete AOSD remission without medication presented with impaired liver function, low platelet count, mild fever, abdominal pain, splenomegaly, and elevated ferritin and IL-18 levels at 30 gestational weeks. Although the laboratory data and physical examination finding suggested HELLP syndrome or acute fatty liver of pregnancy and we considered the termination of her pregnancy, her fetus was in a reactive status. Considering her fetal status, some specific findings of AOSD, and her AOSD history, we and rheumatologists diagnosed her with AOSD recurrence and started systemic steroid therapy. In her clinical course, three flares of AOSD occurred, twice in the third trimester and once in postpartum; twice systemic steroid pulse therapies were then needed. Ultimately, a healthy infant was delivered transvaginally at 36 gestational weeks spontaneously.
CONCLUSIONS
Specific findings of the flare of AOSD such as fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for differentiation from HELLP syndrome and AFLP in the third trimester. With the careful management supported by rheumatologists, patients complicated with the flare of AOSD may continue their pregnancy longer than we expected.
Background
Adult-onset Still’s disease (AOSD) is a self-inflammatory disease exhibiting macrophage and neutrophil activation by inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-18 (IL-18). Its incidence is 1.6–4.0 in 1,000,000 people per year [1]. AOSD more likely occurs in women, affecting 50 to 70%, than in men [1]. It mostly affects young adults (median age at diagnosis: 36 years) [1], indicating the reproductive ages in women. The Yamaguchi criteria [2] are commonly used to diagnose AOSD because they suggest major symptoms and laboratory findings of AOSD; common manifestations are remittent fever over 39 °C lasting more than a week, arthralgia or arthritis, typical rash, high white blood cell count, elevated liver enzymes, and splenomegaly (Table 1). In addition, some AOSD cases manifest abdominal pain and nausea [1]. If findings such as elevated liver enzyme and abdominal pain happen during pregnancy, AOSD may be misinterpreted as hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome and acute fatty liver of pregnancy (AFLP). Currently, although the association between the disease onset of AOSD and pregnancy has already been widely investigated [3, 4], such relationship remains unclear. Moreover, reported cases of AOSD flares at third trimester are few, and the management and features of AOSD, which has similar features to HELLP syndrome and AFLP, at the third trimester have not been reported yet. Herein, we report a rare case of a pregnant woman with AOSD recurrence at her 30 gestational weeks and reviewed the previous reports on the flares of AOSD related to pregnancy. Written informed consent for the publication of this report was obtained from the patient.
Table 1 Yamaguchi criteria for the diagnosis of adult-onset Still’s disease [2]
Major criteria Fever ≥39 °C lasting ≥1 week
Arthralgia or arthritis lasting ≥2 weeks
Typical nonpruritic salmon-colored rash
Leukocytosis ≥10,000/μl with granulocytes ≥80%
Minor criteria Sore throat
Lymphadenopathy
Splenomegaly
Abnormal liver function tests
Negative tests for antinuclear antibody and rheumatoid factor
Exclusion criteria Infection
Malignancy
Other rheumatic disease (vasculitis)
Diagnosis of adult-onset Still’s disease if ≥5 criteria are present with ≥2 being major criteria and no exclusion criteria
Case presentation
A 38-year-old primigravida with well-controlled gestational diabetes mellitus (GDM) was introduced from her home doctor to our hospital, presenting with mild fever, liver dysfunction, elevated ferritin, low platelet count, and proteinuria at 30 weeks and 5 days of gestation. She was diagnosed with AOSD 6 years ago in our hospital based on typical symptoms, including fever, malaise, cervical lymphadenopathy, rash, liver disfunction, and high serum ferritin levels. Although the rheumatologists performed biopsies of her bone marrow and lymph node, the results of these examination were normal and the possibility of other hematologic diseases was denied. After the combination treatment with systemic steroid and tocilizumab administration, she was in complete clinical remission without medication at conception. Upon arrival, her body temperature, blood pressure, and heart rate were 37.7 °C, 101/63 mmHg, and 103 beats/min. In systemic physical examinations, no abnormalities were found. The laboratory findings at arrival are presented in Table 2; The results indicated liver dysfunction, low platelet, and elevated IL-18 and aldolase levels. No apparent coagulopathy findings were observed. Basic infectious disease tests including Epstein–Barr virus and cytomegalovirus were all negative. Nonstress test and fetal sonography revealed perfect biophysical profile scoring of her fetus, mild polyhydramnios (maximum vertical pocket of amnion: 8.3 cm), and an estimated fetal body weight (EFBW) of 1663 g (+ 0.8 standard deviation [SD]). However, splenomegaly was detected by additional abdominal sonography. Although HELLP syndrome or AFLP was suspected upon admission according to liver dysfunction and low platelet count at third trimester and termination of pregnancy could be possible, her clinical course and examination results did not match well to Sibai’s criteria for HELLP syndrome [5] and Swansea’s criteria for AFLP [6]. Moreover, her general condition and fetal status did not require urgent intervention. Considering the findings such as mild fever, elevated ferritin level, high level of IL-18, splenomegaly, and good fetal status, she was ultimately diagnosed with recurrence flare of AOSD by us and some rheumatologists. Thus, systemic steroid pulse therapy (first dose: 250 mg of methylprednisolone [mPSL] for 3 days) was initiated and switched to oral prednisolone (PSL) thereafter. Additionally, the patient was carefully followed up by frequent laboratory tests and transabdominal fetal sonography. Figure 1 illustrates her clinical course after hospitalization at 30 gestational weeks. Clinical AOSD findings such as fever, liver dysfunction, and high ferritin level were well controlled for 3 weeks after the initiation of systemic steroid therapy; hence, the oral PSL dosage was gradually reduced. However, another steroid pulse therapy was needed for the second flare of AOSD that happened at her 33 gestational weeks with elevated liver enzymes and rash on her trunk. In her clinical course, although with maintained uneventful fetal status, the growth of the fetus had been gradually restricted, resulting in intrauterine growth restriction (IUGR). At 36 weeks and 0 days of gestation, she had irregular uterine contractions without apparent infectious findings, and preterm premature rupture of membrane (pPROM). Finally, she spontaneously delivered a female infant transvaginally at 36 weeks and 3 days of gestation. Her infant had a low birth weight (2440 g) but was very healthy; the Apgar score was 9/10, and pH of the umbilical artery was 7.312. Moreover, no abnormal findings of the amniotic fluid at delivery and no pathological features in her placenta and umbilical cord were found. At 12 days postpartum, she had elevated ferritin levels and extremely low platelet count, indicating the third AOSD flare by a rheumatologist; thus, the dosage of oral PSL was increased and maintained for months. During her follow-up checkup as an outpatient by rheumatologists at 1 year postpartum, her C-reactive protein (CRP) and ferritin levels were within the reference range, and her platelet count gradually increased, indicating a well-controlled AOSD.
Table 2 Laboratory findings
Value Reference intervals, unit
T-Bil 0.7 0.4–1.5, mg/dl
AST 491 13–30, U/L
ALT 438 7–23, U/L
LDH 653 124–222, U/L
γ-GTP 10 9–32, U/L
BUN 6.4 8.0–20.0, mg/dl
Cre 0.58 0.46–0.79, mg/dl
BS 84 80–110, mg/dl
UA 3.3 2.6–7.0, mg/dl
CRP 1.81 0.00–0.14, mg/dl
TG 163 30–149, mg/dl
Ferritin 281 5–157, ng/ml
WBC 2980 3300–8600, /μl
RBC 3.93 3.86–4.92, × 106/μl
Hb 10.7 11.6–14.8, g/dl
Ht 32.5 35.1–44.4, %
Plt 108 158–348, × 103 /μl
PT-INR 0.89 0.90–1.10
APTT 33 25–35, seconds
Fib 407 200–400, mg/dl
AT III 96 80–130, %
Urinary protein 0.33 0.02–0.12, g/day
IL-18 175,116 0–211, pg/ml
Aldolase 30.6 2.5–7.5, U/L
Fig. 1 Clinical course, laboratory data, and treatment of the patient. Initial mPSL pulse therapy was provided for 3 days after 30 weeks and 5 days of gestation and then switched to oral PSL therapy. At 33 weeks and 0 days of gestation, another pulse therapy was provided for the second flare. EFBW was restricted gradually from − 0.6 SD to − 1.5 SD. At 36 weeks and 0 days of gestation, this patient started irregular uterine contractions and finally delivered a healthy infant spontaneously at 36 weeks and 3 days of gestation. At 12 days postpartum, she experienced the third flare, and oral PSL therapy was maintained
Discussion and conclusions
The flare of AOSD in pregnancy was first reported in 1980 by Stein et al. [7]. Currently, nearly 30 reports about AOSD associated with pregnancy have been published [3, 4, 7–32]. Hence, we reviewed the cases of AOSD complications during pregnancy [3, 4, 7–32]. A total of 53 flares in 47 pregnant women, including our case, have been recorded. The clinical course of AOSD during pregnancy consists of three types: first-onset type, which refers to the first onset of AOSD related to pregnancy [3, 4, 7, 8, 11, 12, 14, 17–25, 28–30, 32], recurrent-flare type, which refers to a recurrent flare related to pregnancy with previous AOSD diagnosis [4, 7, 9, 13, 14, 16, 25, 31], and no-flare type, which is only a complication with no flare related to pregnancy [4, 9, 10, 14, 15, 17, 26, 27]. In the literature review, the cases were divided into these three types shown in Table 3 and our case belongs to the recurrent-flare type.
Table 3 Review of pregnancy cases with adult onset Still’s disease classified into three types
Total: 47 pregnant women and 53 pregnancies
First onset (Number = 26) Recurrent flare (Number = 13) No flare (Number = 14)
Age at pregnancy (year), Median [IQR] 29 [25–33] (1 unknown case) 31 [29–34] 27 [26–30] (1 unknown case)
Parity, %
Primigravida 50 (8/16) 80 (8/10) 69.2 (9/13)
Multigravida 50 (8/16) 20 (2/10) 30.8 (4/13)
Unknown, number 10 3 1
Timing of flare, %
1st trimester 24 (6/25) 23.1 (3/13) –
2nd trimester 52 (13/25) 38.5 (5/13) –
3rd trimester 8 (2/25) 7.7 (1/13) –
Postpartum 16 (4/25) 30.8 (4/13) –
Unknown, number 1 0 –
Major symptoms and complications, %
Fever 95.7 (22/23) 70 (7/10) –
Arthralgia, Arthritis 91.3 (21/23) 60 (6/10) –
Erythema, Rash 78.3 (18/23) 50 (5/10) –
Sore throat 65.2 (15/23) 30 (3/10) –
Lymphadenopathy 60.9 (14/23) 10 (1/10) –
Hepatomegaly, Liver dysfunction 34.8 (8/23) 30 (3/10) –
Splenomegaly 34.8 (8/23) 10 (1/10) –
HLH 8.7 (2/23) 10 (1/10) –
Unknown, number 3 3 –
Major treatment, %
Corticosteroid 82.6 (19/23) 69.2 (9/13) 28.6 (4/14)
Anakinra 13.0 (3/23) 7.7 (1/13) 28.6 (4/14)
IVIg 17.4 (4/23) 7.7 (1/13) 7.1 (1/14)
NSAIDs 21.7 (5/23) 7.7 (1/13) 14.3 (2/14)
HCQ 4.3 (1/23) 15.4 (2/13) 7.1 (1/14)
No medication – – 57.1 (8/14)
Unknown, number 3 0 0
Delivery, %
Transvaginal 66.7 (12/18) 50 (4/8) 62.5 (5/8)
Cesarean section 22.2 (4/18) 50 (4/8) 25 (2/8)
Abortion 11.1 (2/18) 0 (0/8) 12.5 (1/8)
Unknown, number 8 5 6
Major obstetrical and perinatal complications, %
Preterm birth 32 (8/25) 33.3 (4/12) 16.7 (2/12)
IUGR 8 (2/25) 41.7 (5/12) 8.3 (1/12)
pPROM 12 (3/25) 8.3 (1/12) 8.3 (1/12)
No major complication 48 (12/25) 41.7 (5/12) 50 (6/12)
Others, number 2 for OHD, 1 for neonatal HLH, 1 for preeclampsia, and 1 for neonatal death for IRDS 1 for GDM, and 1 for OHD 1 for neonatal HLH, 1 for GDM, and 1 for HDP
Unknown, number 1 1 2
The median age of patients at pregnancy was almost 30 years (median [interquartile range (IQR)]: 29 [25–33], 31 [29–34], and 27 [26–30] for the first-onset, recurrent-flare, and no-flare types, respectively), indicating that women with AOSD during pregnancy were younger than the general population at first diagnosis [1]. Regarding parity, AOSD flare mainly happens among primigravida patients, with the recurrent-flare type obtaining the highest rate (83.3%), although all patients in this type are in clinical remission at conception [4, 7, 9, 13, 14, 16, 25, 31]. Our case was also in clinical remission and did not require any medication at conception.
Most likely, the AOSD flare occurred until second trimester and at postpartum, with limited reports of flare at third trimester; the first-onset type was found only in two cases [21, 24] and the recurrent-flare type in one case, which is our case. Although AOSD flare occurring at third trimester is extremely rare, the clinical symptoms of AOSD are similar to those of HELLP syndrome and AFLP, suggesting that close attention to perinatal management is crucial. Generally, the Yamaguchi criteria [2] is adopted for the diagnosing AOSD (Table 1). However, we needed to assess AOSD recurrence in a comprehensive way by considering the clinical features and laboratory findings because no criteria for the diagnosis of AOSD recurrence are currently available. In fact, the review showed that most of the major symptoms of AOSD detected in the recurrent-flare type are relatively fewer than in the first-onset type. In addition, the major symptoms and findings of AOSD are elevated liver enzyme, leukocytosis, and sometimes abdominal pain or nausea, which are difficult to distinguish from HELLP syndrome or AFLP, particularly in cases with flare occurring at third trimester. Elevated ferritin [2] and IL-18 [33], which are reportedly biomarkers of AOSD activity, are considered better diagnostic markers than any other markers. Specific AOSD features such as fever, splenomegaly, and typical rash can support the possibility of AOSD. Izuka et al. recently reported that elevated serum aldolase can be a useful biomarker of AOSD [34]. In our case, the serum aldolase level was high (30.6 U/L), which supported the diagnosis of recurrent AOSD flare. Finally, we and some rheumatologists comprehensively diagnosed the patient with AOSD recurrence flare in consideration of the AOSD findings such as elevated ferritin, IL-18, and aldolase levels, splenomegaly, and uneventful fetal status.
AOSD treatments generally include PSL/mPSL, nonsteroidal anti-inflammatory agents (NSAIDs) and in more severe cases, methotrexate, anakinra (interleukin-1 [IL-1] inhibitor), intravenous immune globulin (IVIg), cyclosporine, or tacrolimus. However, selecting the appropriate medication for pregnant patients entails some limitations. Jamilloux Y et al. recommended corticosteroids as the first treatment choice, and IVIg and IL-1 inhibitor as the second treatment choice for AOSD [35]. Our review also showed that corticosteroid was mainly used, followed by IL-1 inhibitor and IVIg. In Japan, where most of the IL-1 antagonists have not yet been approved, tacrolimus may be a reasonable second choice for severe AOSD flare in pregnancy, and some successful management cases reported to have used this medication during pregnancy [11, 23]. In our case, twice mPSL pulse therapy followed by oral PSL was chosen; consequently, pregnancy was maintained until 36 gestational weeks.
In almost one-third of cases in both the first-onset and recurrent-flare types, the main obstetrical complication was preterm birth. Some reports showed that other autoimmune diseases or autoinflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis, occurring during pregnancy are risk factors for preterm birth, and maternal disease activity contributes to the increased risk of preterm delivery [36–38]. Furthermore, long-term steroidal use is another risk factor for preterm birth [37, 38]. Our review results showed that the incidence of preterm delivery in both the first-onset and recurrent-flare types of AOSD was almost twice higher than that in the no-flare type. Therefore, the high disease activity of AOSD and long-term use of systemic steroids may be possible reasons for the high incidence of preterm delivery in patients with AOSD. Our case also delivered prematurely, with high disease activity and long-term systemic steroid use including twice steroid pulse therapies. Hemophagocytic lymphohistiocytosis (HLH) is also a severe and crucial complication of AOSD. HLH was diagnosed in some cases having the first-onset and recurrent-flare types and in neonatal cases delivered from mothers with AOSD, even in clinical remission. Meanwhile, we believe that in general, the overall severity of AOSD during pregnancy may be better than the HELLP syndrome and AFLP. In fact, lethal complication was only found in one case wherein a premature fetus died at 28 weeks old because of infantile respiratory distress syndrome (IRDS) in the first-onset type, as reported by Green et al. in 1982 [8]. Therefore, with the cooperation of rheumatologists and pediatricians, pregnant patients with AOSD can maintain their pregnancy by paying special attention to prematurity, fetal growth, and HLH, even if the case is in clinical remission.
The relationship of pathogenesis between AOSD and pregnancy remains unclear. Ida A et al. reported that serum IL-18 levels were significantly elevated in pregnant women from the first trimester until the onset of labor than in nonpregnant women [39]. They noticed further increment of serum IL-18 levels after labor, lasting until at least the third day of postpartum. This result parallels the clinical feature of AOSD in pregnancy, that is, AOSD flares are likely to happen in the first/second trimester and postpartum. Considering that our case had also prominently high IL-18 levels, IL-18 elevation may cause the flare of AOSD during pregnancy, suggesting that pregnancy may be a risk factor of AOSD. Therefore, the serum IL-18 levels as a follow-up during pregnancy may be a useful predictive and diagnostic marker of AOSD flare; however, further investigations are required.
From the abovementioned consideration, patients with AOSD can be pregnant and continue pregnancy safely while under treatment, considering that the prognosis of pregnant women with AOSD and their fetuses is favorable in previous cases. Furthermore, for a safer pregnancy in patients complicated with AOSD, we, as obstetricians, need tight cooperation with rheumatologists and pediatricians for the sufficient control of AOSD activity and perinatal care and should provide enough explanation to patients on the risks of flares during pregnancy. Moreover, we conduct frequent laboratory tests and careful follow-up in preparation for flares, premature birth, and HLH. If the flare happens at third trimester, as in our case, we need to differentiate AOSD from HELLP syndrome and AFLP because of the similarity of laboratory data and physical findings. Fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for the differentiation from HELLP syndrome and AFLP.
To our knowledge, this report is the first to present the recurrent flare of AOSD during pregnancy at third trimester. However, we need to further investigate on the proper management of pregnant women with AOSD.
Abbreviations
AOSDAdult-onset Still’s disease
TNF-αTumor necrosis factor-α
IL-6Interleukin-6
IL-18Interleukin-18
HELLPHemolysis, elevated liver enzymes and low platelet count
AFLPAcute fatty liver of pregnancy
GDMGestational diabetes mellitus
EFBWEstimated fetal body weight
SDStandard deviation
mPSLMethylprednisolone
PSLPrednisolone
IUGRIntrauterine growth restriction
pPROMPreterm premature rupture of membrane
CRPC-reactive protein
IQRInterquartile range
NSAIDsNonsteroidal anti-inflammatory agents
IL-1Interleukin-1
IVIgIntravenous immune globulin
HLHHemophagocytic lymphohistiocytosis
IRDSInfantile respiratory distress syndrome
NVDNormal vaginal delivery
T-BilTotal bilirubin
ASTAspartate aminotransferase
ALTAlanine aminotransferase
LDHLactate dehydrogenase
γ-GTPγ-glutamyl transpeptidase
BUNBlood urea nitrogen
CreCreatinine
BSBlood sugar
TGTriglyceride
WBCWhite blood cell
RBCRed blood cell
HbHemoglobin
HtHematocrit
PltPlatelet
PT-INRProthrombin-time international normalized ratio
APTTActivated partial thromboplastin time
FibFibrinogen
AT IIIAntithrombin III
HCQHydroxychloroquine
OHDOligohydramnios
HDPHypertensive disorders of pregnancy
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Acknowledgements
The authors would like to thank Enago (www.enago.jp) for the English language review.
Authors’ contributions
SH collected and interpreted the patient’s data, collected previous reports and wrote the first draft of this paper. MS and HO also interpreted the data and revised the first draft. SI and HY also revised the first draft and support the data collection. All authors approved the final manuscript.
Authors’ information
SH was a junior resident of the Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan at the time of this work. Now, SH belongs to the Department of Obstetrics and Gynecology, the Jikei University School of Medicine.
Funding
All authors had no funding support related to this report.
Availability of data and materials
The datasets that support the findings about this case are available from the corresponding author, SH, on reasonable request.
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 of this journal.
Competing interests
The authors declare that they have no competing interests. | METHYLPREDNISOLONE, PREDNISOLONE | DrugsGivenReaction | CC BY | 33627085 | 19,525,796 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Preterm premature rupture of membranes'. | A case of recurrence of adult-onset Still's disease in the third trimester: a case report and literature review.
BACKGROUND
Adult-onset Still's disease (AOSD) is a self-inflammatory disease showing macrophage and neutrophil activation by inflammatory cytokines such as TNF-α, IL-6, and IL-18. Although some cases with the flare of AOSD during pregnancy have been reported, most had flares in the first or second trimester and few had flares in the third trimester. In this report, we present the case of a patient with recurrent flare of AOSD in the third trimester and discuss the management of AOSD in the third trimester with the review of previous literatures.
METHODS
A 38-year-old woman in complete AOSD remission without medication presented with impaired liver function, low platelet count, mild fever, abdominal pain, splenomegaly, and elevated ferritin and IL-18 levels at 30 gestational weeks. Although the laboratory data and physical examination finding suggested HELLP syndrome or acute fatty liver of pregnancy and we considered the termination of her pregnancy, her fetus was in a reactive status. Considering her fetal status, some specific findings of AOSD, and her AOSD history, we and rheumatologists diagnosed her with AOSD recurrence and started systemic steroid therapy. In her clinical course, three flares of AOSD occurred, twice in the third trimester and once in postpartum; twice systemic steroid pulse therapies were then needed. Ultimately, a healthy infant was delivered transvaginally at 36 gestational weeks spontaneously.
CONCLUSIONS
Specific findings of the flare of AOSD such as fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for differentiation from HELLP syndrome and AFLP in the third trimester. With the careful management supported by rheumatologists, patients complicated with the flare of AOSD may continue their pregnancy longer than we expected.
Background
Adult-onset Still’s disease (AOSD) is a self-inflammatory disease exhibiting macrophage and neutrophil activation by inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-18 (IL-18). Its incidence is 1.6–4.0 in 1,000,000 people per year [1]. AOSD more likely occurs in women, affecting 50 to 70%, than in men [1]. It mostly affects young adults (median age at diagnosis: 36 years) [1], indicating the reproductive ages in women. The Yamaguchi criteria [2] are commonly used to diagnose AOSD because they suggest major symptoms and laboratory findings of AOSD; common manifestations are remittent fever over 39 °C lasting more than a week, arthralgia or arthritis, typical rash, high white blood cell count, elevated liver enzymes, and splenomegaly (Table 1). In addition, some AOSD cases manifest abdominal pain and nausea [1]. If findings such as elevated liver enzyme and abdominal pain happen during pregnancy, AOSD may be misinterpreted as hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome and acute fatty liver of pregnancy (AFLP). Currently, although the association between the disease onset of AOSD and pregnancy has already been widely investigated [3, 4], such relationship remains unclear. Moreover, reported cases of AOSD flares at third trimester are few, and the management and features of AOSD, which has similar features to HELLP syndrome and AFLP, at the third trimester have not been reported yet. Herein, we report a rare case of a pregnant woman with AOSD recurrence at her 30 gestational weeks and reviewed the previous reports on the flares of AOSD related to pregnancy. Written informed consent for the publication of this report was obtained from the patient.
Table 1 Yamaguchi criteria for the diagnosis of adult-onset Still’s disease [2]
Major criteria Fever ≥39 °C lasting ≥1 week
Arthralgia or arthritis lasting ≥2 weeks
Typical nonpruritic salmon-colored rash
Leukocytosis ≥10,000/μl with granulocytes ≥80%
Minor criteria Sore throat
Lymphadenopathy
Splenomegaly
Abnormal liver function tests
Negative tests for antinuclear antibody and rheumatoid factor
Exclusion criteria Infection
Malignancy
Other rheumatic disease (vasculitis)
Diagnosis of adult-onset Still’s disease if ≥5 criteria are present with ≥2 being major criteria and no exclusion criteria
Case presentation
A 38-year-old primigravida with well-controlled gestational diabetes mellitus (GDM) was introduced from her home doctor to our hospital, presenting with mild fever, liver dysfunction, elevated ferritin, low platelet count, and proteinuria at 30 weeks and 5 days of gestation. She was diagnosed with AOSD 6 years ago in our hospital based on typical symptoms, including fever, malaise, cervical lymphadenopathy, rash, liver disfunction, and high serum ferritin levels. Although the rheumatologists performed biopsies of her bone marrow and lymph node, the results of these examination were normal and the possibility of other hematologic diseases was denied. After the combination treatment with systemic steroid and tocilizumab administration, she was in complete clinical remission without medication at conception. Upon arrival, her body temperature, blood pressure, and heart rate were 37.7 °C, 101/63 mmHg, and 103 beats/min. In systemic physical examinations, no abnormalities were found. The laboratory findings at arrival are presented in Table 2; The results indicated liver dysfunction, low platelet, and elevated IL-18 and aldolase levels. No apparent coagulopathy findings were observed. Basic infectious disease tests including Epstein–Barr virus and cytomegalovirus were all negative. Nonstress test and fetal sonography revealed perfect biophysical profile scoring of her fetus, mild polyhydramnios (maximum vertical pocket of amnion: 8.3 cm), and an estimated fetal body weight (EFBW) of 1663 g (+ 0.8 standard deviation [SD]). However, splenomegaly was detected by additional abdominal sonography. Although HELLP syndrome or AFLP was suspected upon admission according to liver dysfunction and low platelet count at third trimester and termination of pregnancy could be possible, her clinical course and examination results did not match well to Sibai’s criteria for HELLP syndrome [5] and Swansea’s criteria for AFLP [6]. Moreover, her general condition and fetal status did not require urgent intervention. Considering the findings such as mild fever, elevated ferritin level, high level of IL-18, splenomegaly, and good fetal status, she was ultimately diagnosed with recurrence flare of AOSD by us and some rheumatologists. Thus, systemic steroid pulse therapy (first dose: 250 mg of methylprednisolone [mPSL] for 3 days) was initiated and switched to oral prednisolone (PSL) thereafter. Additionally, the patient was carefully followed up by frequent laboratory tests and transabdominal fetal sonography. Figure 1 illustrates her clinical course after hospitalization at 30 gestational weeks. Clinical AOSD findings such as fever, liver dysfunction, and high ferritin level were well controlled for 3 weeks after the initiation of systemic steroid therapy; hence, the oral PSL dosage was gradually reduced. However, another steroid pulse therapy was needed for the second flare of AOSD that happened at her 33 gestational weeks with elevated liver enzymes and rash on her trunk. In her clinical course, although with maintained uneventful fetal status, the growth of the fetus had been gradually restricted, resulting in intrauterine growth restriction (IUGR). At 36 weeks and 0 days of gestation, she had irregular uterine contractions without apparent infectious findings, and preterm premature rupture of membrane (pPROM). Finally, she spontaneously delivered a female infant transvaginally at 36 weeks and 3 days of gestation. Her infant had a low birth weight (2440 g) but was very healthy; the Apgar score was 9/10, and pH of the umbilical artery was 7.312. Moreover, no abnormal findings of the amniotic fluid at delivery and no pathological features in her placenta and umbilical cord were found. At 12 days postpartum, she had elevated ferritin levels and extremely low platelet count, indicating the third AOSD flare by a rheumatologist; thus, the dosage of oral PSL was increased and maintained for months. During her follow-up checkup as an outpatient by rheumatologists at 1 year postpartum, her C-reactive protein (CRP) and ferritin levels were within the reference range, and her platelet count gradually increased, indicating a well-controlled AOSD.
Table 2 Laboratory findings
Value Reference intervals, unit
T-Bil 0.7 0.4–1.5, mg/dl
AST 491 13–30, U/L
ALT 438 7–23, U/L
LDH 653 124–222, U/L
γ-GTP 10 9–32, U/L
BUN 6.4 8.0–20.0, mg/dl
Cre 0.58 0.46–0.79, mg/dl
BS 84 80–110, mg/dl
UA 3.3 2.6–7.0, mg/dl
CRP 1.81 0.00–0.14, mg/dl
TG 163 30–149, mg/dl
Ferritin 281 5–157, ng/ml
WBC 2980 3300–8600, /μl
RBC 3.93 3.86–4.92, × 106/μl
Hb 10.7 11.6–14.8, g/dl
Ht 32.5 35.1–44.4, %
Plt 108 158–348, × 103 /μl
PT-INR 0.89 0.90–1.10
APTT 33 25–35, seconds
Fib 407 200–400, mg/dl
AT III 96 80–130, %
Urinary protein 0.33 0.02–0.12, g/day
IL-18 175,116 0–211, pg/ml
Aldolase 30.6 2.5–7.5, U/L
Fig. 1 Clinical course, laboratory data, and treatment of the patient. Initial mPSL pulse therapy was provided for 3 days after 30 weeks and 5 days of gestation and then switched to oral PSL therapy. At 33 weeks and 0 days of gestation, another pulse therapy was provided for the second flare. EFBW was restricted gradually from − 0.6 SD to − 1.5 SD. At 36 weeks and 0 days of gestation, this patient started irregular uterine contractions and finally delivered a healthy infant spontaneously at 36 weeks and 3 days of gestation. At 12 days postpartum, she experienced the third flare, and oral PSL therapy was maintained
Discussion and conclusions
The flare of AOSD in pregnancy was first reported in 1980 by Stein et al. [7]. Currently, nearly 30 reports about AOSD associated with pregnancy have been published [3, 4, 7–32]. Hence, we reviewed the cases of AOSD complications during pregnancy [3, 4, 7–32]. A total of 53 flares in 47 pregnant women, including our case, have been recorded. The clinical course of AOSD during pregnancy consists of three types: first-onset type, which refers to the first onset of AOSD related to pregnancy [3, 4, 7, 8, 11, 12, 14, 17–25, 28–30, 32], recurrent-flare type, which refers to a recurrent flare related to pregnancy with previous AOSD diagnosis [4, 7, 9, 13, 14, 16, 25, 31], and no-flare type, which is only a complication with no flare related to pregnancy [4, 9, 10, 14, 15, 17, 26, 27]. In the literature review, the cases were divided into these three types shown in Table 3 and our case belongs to the recurrent-flare type.
Table 3 Review of pregnancy cases with adult onset Still’s disease classified into three types
Total: 47 pregnant women and 53 pregnancies
First onset (Number = 26) Recurrent flare (Number = 13) No flare (Number = 14)
Age at pregnancy (year), Median [IQR] 29 [25–33] (1 unknown case) 31 [29–34] 27 [26–30] (1 unknown case)
Parity, %
Primigravida 50 (8/16) 80 (8/10) 69.2 (9/13)
Multigravida 50 (8/16) 20 (2/10) 30.8 (4/13)
Unknown, number 10 3 1
Timing of flare, %
1st trimester 24 (6/25) 23.1 (3/13) –
2nd trimester 52 (13/25) 38.5 (5/13) –
3rd trimester 8 (2/25) 7.7 (1/13) –
Postpartum 16 (4/25) 30.8 (4/13) –
Unknown, number 1 0 –
Major symptoms and complications, %
Fever 95.7 (22/23) 70 (7/10) –
Arthralgia, Arthritis 91.3 (21/23) 60 (6/10) –
Erythema, Rash 78.3 (18/23) 50 (5/10) –
Sore throat 65.2 (15/23) 30 (3/10) –
Lymphadenopathy 60.9 (14/23) 10 (1/10) –
Hepatomegaly, Liver dysfunction 34.8 (8/23) 30 (3/10) –
Splenomegaly 34.8 (8/23) 10 (1/10) –
HLH 8.7 (2/23) 10 (1/10) –
Unknown, number 3 3 –
Major treatment, %
Corticosteroid 82.6 (19/23) 69.2 (9/13) 28.6 (4/14)
Anakinra 13.0 (3/23) 7.7 (1/13) 28.6 (4/14)
IVIg 17.4 (4/23) 7.7 (1/13) 7.1 (1/14)
NSAIDs 21.7 (5/23) 7.7 (1/13) 14.3 (2/14)
HCQ 4.3 (1/23) 15.4 (2/13) 7.1 (1/14)
No medication – – 57.1 (8/14)
Unknown, number 3 0 0
Delivery, %
Transvaginal 66.7 (12/18) 50 (4/8) 62.5 (5/8)
Cesarean section 22.2 (4/18) 50 (4/8) 25 (2/8)
Abortion 11.1 (2/18) 0 (0/8) 12.5 (1/8)
Unknown, number 8 5 6
Major obstetrical and perinatal complications, %
Preterm birth 32 (8/25) 33.3 (4/12) 16.7 (2/12)
IUGR 8 (2/25) 41.7 (5/12) 8.3 (1/12)
pPROM 12 (3/25) 8.3 (1/12) 8.3 (1/12)
No major complication 48 (12/25) 41.7 (5/12) 50 (6/12)
Others, number 2 for OHD, 1 for neonatal HLH, 1 for preeclampsia, and 1 for neonatal death for IRDS 1 for GDM, and 1 for OHD 1 for neonatal HLH, 1 for GDM, and 1 for HDP
Unknown, number 1 1 2
The median age of patients at pregnancy was almost 30 years (median [interquartile range (IQR)]: 29 [25–33], 31 [29–34], and 27 [26–30] for the first-onset, recurrent-flare, and no-flare types, respectively), indicating that women with AOSD during pregnancy were younger than the general population at first diagnosis [1]. Regarding parity, AOSD flare mainly happens among primigravida patients, with the recurrent-flare type obtaining the highest rate (83.3%), although all patients in this type are in clinical remission at conception [4, 7, 9, 13, 14, 16, 25, 31]. Our case was also in clinical remission and did not require any medication at conception.
Most likely, the AOSD flare occurred until second trimester and at postpartum, with limited reports of flare at third trimester; the first-onset type was found only in two cases [21, 24] and the recurrent-flare type in one case, which is our case. Although AOSD flare occurring at third trimester is extremely rare, the clinical symptoms of AOSD are similar to those of HELLP syndrome and AFLP, suggesting that close attention to perinatal management is crucial. Generally, the Yamaguchi criteria [2] is adopted for the diagnosing AOSD (Table 1). However, we needed to assess AOSD recurrence in a comprehensive way by considering the clinical features and laboratory findings because no criteria for the diagnosis of AOSD recurrence are currently available. In fact, the review showed that most of the major symptoms of AOSD detected in the recurrent-flare type are relatively fewer than in the first-onset type. In addition, the major symptoms and findings of AOSD are elevated liver enzyme, leukocytosis, and sometimes abdominal pain or nausea, which are difficult to distinguish from HELLP syndrome or AFLP, particularly in cases with flare occurring at third trimester. Elevated ferritin [2] and IL-18 [33], which are reportedly biomarkers of AOSD activity, are considered better diagnostic markers than any other markers. Specific AOSD features such as fever, splenomegaly, and typical rash can support the possibility of AOSD. Izuka et al. recently reported that elevated serum aldolase can be a useful biomarker of AOSD [34]. In our case, the serum aldolase level was high (30.6 U/L), which supported the diagnosis of recurrent AOSD flare. Finally, we and some rheumatologists comprehensively diagnosed the patient with AOSD recurrence flare in consideration of the AOSD findings such as elevated ferritin, IL-18, and aldolase levels, splenomegaly, and uneventful fetal status.
AOSD treatments generally include PSL/mPSL, nonsteroidal anti-inflammatory agents (NSAIDs) and in more severe cases, methotrexate, anakinra (interleukin-1 [IL-1] inhibitor), intravenous immune globulin (IVIg), cyclosporine, or tacrolimus. However, selecting the appropriate medication for pregnant patients entails some limitations. Jamilloux Y et al. recommended corticosteroids as the first treatment choice, and IVIg and IL-1 inhibitor as the second treatment choice for AOSD [35]. Our review also showed that corticosteroid was mainly used, followed by IL-1 inhibitor and IVIg. In Japan, where most of the IL-1 antagonists have not yet been approved, tacrolimus may be a reasonable second choice for severe AOSD flare in pregnancy, and some successful management cases reported to have used this medication during pregnancy [11, 23]. In our case, twice mPSL pulse therapy followed by oral PSL was chosen; consequently, pregnancy was maintained until 36 gestational weeks.
In almost one-third of cases in both the first-onset and recurrent-flare types, the main obstetrical complication was preterm birth. Some reports showed that other autoimmune diseases or autoinflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis, occurring during pregnancy are risk factors for preterm birth, and maternal disease activity contributes to the increased risk of preterm delivery [36–38]. Furthermore, long-term steroidal use is another risk factor for preterm birth [37, 38]. Our review results showed that the incidence of preterm delivery in both the first-onset and recurrent-flare types of AOSD was almost twice higher than that in the no-flare type. Therefore, the high disease activity of AOSD and long-term use of systemic steroids may be possible reasons for the high incidence of preterm delivery in patients with AOSD. Our case also delivered prematurely, with high disease activity and long-term systemic steroid use including twice steroid pulse therapies. Hemophagocytic lymphohistiocytosis (HLH) is also a severe and crucial complication of AOSD. HLH was diagnosed in some cases having the first-onset and recurrent-flare types and in neonatal cases delivered from mothers with AOSD, even in clinical remission. Meanwhile, we believe that in general, the overall severity of AOSD during pregnancy may be better than the HELLP syndrome and AFLP. In fact, lethal complication was only found in one case wherein a premature fetus died at 28 weeks old because of infantile respiratory distress syndrome (IRDS) in the first-onset type, as reported by Green et al. in 1982 [8]. Therefore, with the cooperation of rheumatologists and pediatricians, pregnant patients with AOSD can maintain their pregnancy by paying special attention to prematurity, fetal growth, and HLH, even if the case is in clinical remission.
The relationship of pathogenesis between AOSD and pregnancy remains unclear. Ida A et al. reported that serum IL-18 levels were significantly elevated in pregnant women from the first trimester until the onset of labor than in nonpregnant women [39]. They noticed further increment of serum IL-18 levels after labor, lasting until at least the third day of postpartum. This result parallels the clinical feature of AOSD in pregnancy, that is, AOSD flares are likely to happen in the first/second trimester and postpartum. Considering that our case had also prominently high IL-18 levels, IL-18 elevation may cause the flare of AOSD during pregnancy, suggesting that pregnancy may be a risk factor of AOSD. Therefore, the serum IL-18 levels as a follow-up during pregnancy may be a useful predictive and diagnostic marker of AOSD flare; however, further investigations are required.
From the abovementioned consideration, patients with AOSD can be pregnant and continue pregnancy safely while under treatment, considering that the prognosis of pregnant women with AOSD and their fetuses is favorable in previous cases. Furthermore, for a safer pregnancy in patients complicated with AOSD, we, as obstetricians, need tight cooperation with rheumatologists and pediatricians for the sufficient control of AOSD activity and perinatal care and should provide enough explanation to patients on the risks of flares during pregnancy. Moreover, we conduct frequent laboratory tests and careful follow-up in preparation for flares, premature birth, and HLH. If the flare happens at third trimester, as in our case, we need to differentiate AOSD from HELLP syndrome and AFLP because of the similarity of laboratory data and physical findings. Fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for the differentiation from HELLP syndrome and AFLP.
To our knowledge, this report is the first to present the recurrent flare of AOSD during pregnancy at third trimester. However, we need to further investigate on the proper management of pregnant women with AOSD.
Abbreviations
AOSDAdult-onset Still’s disease
TNF-αTumor necrosis factor-α
IL-6Interleukin-6
IL-18Interleukin-18
HELLPHemolysis, elevated liver enzymes and low platelet count
AFLPAcute fatty liver of pregnancy
GDMGestational diabetes mellitus
EFBWEstimated fetal body weight
SDStandard deviation
mPSLMethylprednisolone
PSLPrednisolone
IUGRIntrauterine growth restriction
pPROMPreterm premature rupture of membrane
CRPC-reactive protein
IQRInterquartile range
NSAIDsNonsteroidal anti-inflammatory agents
IL-1Interleukin-1
IVIgIntravenous immune globulin
HLHHemophagocytic lymphohistiocytosis
IRDSInfantile respiratory distress syndrome
NVDNormal vaginal delivery
T-BilTotal bilirubin
ASTAspartate aminotransferase
ALTAlanine aminotransferase
LDHLactate dehydrogenase
γ-GTPγ-glutamyl transpeptidase
BUNBlood urea nitrogen
CreCreatinine
BSBlood sugar
TGTriglyceride
WBCWhite blood cell
RBCRed blood cell
HbHemoglobin
HtHematocrit
PltPlatelet
PT-INRProthrombin-time international normalized ratio
APTTActivated partial thromboplastin time
FibFibrinogen
AT IIIAntithrombin III
HCQHydroxychloroquine
OHDOligohydramnios
HDPHypertensive disorders of pregnancy
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors would like to thank Enago (www.enago.jp) for the English language review.
Authors’ contributions
SH collected and interpreted the patient’s data, collected previous reports and wrote the first draft of this paper. MS and HO also interpreted the data and revised the first draft. SI and HY also revised the first draft and support the data collection. All authors approved the final manuscript.
Authors’ information
SH was a junior resident of the Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan at the time of this work. Now, SH belongs to the Department of Obstetrics and Gynecology, the Jikei University School of Medicine.
Funding
All authors had no funding support related to this report.
Availability of data and materials
The datasets that support the findings about this case are available from the corresponding author, SH, on reasonable request.
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 of this journal.
Competing interests
The authors declare that they have no competing interests. | METHYLPREDNISOLONE, PREDNISOLONE | DrugsGivenReaction | CC BY | 33627085 | 19,473,663 | 2021-02-24 |
What was the administration route of drug 'METHYLPREDNISOLONE'? | A case of recurrence of adult-onset Still's disease in the third trimester: a case report and literature review.
BACKGROUND
Adult-onset Still's disease (AOSD) is a self-inflammatory disease showing macrophage and neutrophil activation by inflammatory cytokines such as TNF-α, IL-6, and IL-18. Although some cases with the flare of AOSD during pregnancy have been reported, most had flares in the first or second trimester and few had flares in the third trimester. In this report, we present the case of a patient with recurrent flare of AOSD in the third trimester and discuss the management of AOSD in the third trimester with the review of previous literatures.
METHODS
A 38-year-old woman in complete AOSD remission without medication presented with impaired liver function, low platelet count, mild fever, abdominal pain, splenomegaly, and elevated ferritin and IL-18 levels at 30 gestational weeks. Although the laboratory data and physical examination finding suggested HELLP syndrome or acute fatty liver of pregnancy and we considered the termination of her pregnancy, her fetus was in a reactive status. Considering her fetal status, some specific findings of AOSD, and her AOSD history, we and rheumatologists diagnosed her with AOSD recurrence and started systemic steroid therapy. In her clinical course, three flares of AOSD occurred, twice in the third trimester and once in postpartum; twice systemic steroid pulse therapies were then needed. Ultimately, a healthy infant was delivered transvaginally at 36 gestational weeks spontaneously.
CONCLUSIONS
Specific findings of the flare of AOSD such as fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for differentiation from HELLP syndrome and AFLP in the third trimester. With the careful management supported by rheumatologists, patients complicated with the flare of AOSD may continue their pregnancy longer than we expected.
Background
Adult-onset Still’s disease (AOSD) is a self-inflammatory disease exhibiting macrophage and neutrophil activation by inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-18 (IL-18). Its incidence is 1.6–4.0 in 1,000,000 people per year [1]. AOSD more likely occurs in women, affecting 50 to 70%, than in men [1]. It mostly affects young adults (median age at diagnosis: 36 years) [1], indicating the reproductive ages in women. The Yamaguchi criteria [2] are commonly used to diagnose AOSD because they suggest major symptoms and laboratory findings of AOSD; common manifestations are remittent fever over 39 °C lasting more than a week, arthralgia or arthritis, typical rash, high white blood cell count, elevated liver enzymes, and splenomegaly (Table 1). In addition, some AOSD cases manifest abdominal pain and nausea [1]. If findings such as elevated liver enzyme and abdominal pain happen during pregnancy, AOSD may be misinterpreted as hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome and acute fatty liver of pregnancy (AFLP). Currently, although the association between the disease onset of AOSD and pregnancy has already been widely investigated [3, 4], such relationship remains unclear. Moreover, reported cases of AOSD flares at third trimester are few, and the management and features of AOSD, which has similar features to HELLP syndrome and AFLP, at the third trimester have not been reported yet. Herein, we report a rare case of a pregnant woman with AOSD recurrence at her 30 gestational weeks and reviewed the previous reports on the flares of AOSD related to pregnancy. Written informed consent for the publication of this report was obtained from the patient.
Table 1 Yamaguchi criteria for the diagnosis of adult-onset Still’s disease [2]
Major criteria Fever ≥39 °C lasting ≥1 week
Arthralgia or arthritis lasting ≥2 weeks
Typical nonpruritic salmon-colored rash
Leukocytosis ≥10,000/μl with granulocytes ≥80%
Minor criteria Sore throat
Lymphadenopathy
Splenomegaly
Abnormal liver function tests
Negative tests for antinuclear antibody and rheumatoid factor
Exclusion criteria Infection
Malignancy
Other rheumatic disease (vasculitis)
Diagnosis of adult-onset Still’s disease if ≥5 criteria are present with ≥2 being major criteria and no exclusion criteria
Case presentation
A 38-year-old primigravida with well-controlled gestational diabetes mellitus (GDM) was introduced from her home doctor to our hospital, presenting with mild fever, liver dysfunction, elevated ferritin, low platelet count, and proteinuria at 30 weeks and 5 days of gestation. She was diagnosed with AOSD 6 years ago in our hospital based on typical symptoms, including fever, malaise, cervical lymphadenopathy, rash, liver disfunction, and high serum ferritin levels. Although the rheumatologists performed biopsies of her bone marrow and lymph node, the results of these examination were normal and the possibility of other hematologic diseases was denied. After the combination treatment with systemic steroid and tocilizumab administration, she was in complete clinical remission without medication at conception. Upon arrival, her body temperature, blood pressure, and heart rate were 37.7 °C, 101/63 mmHg, and 103 beats/min. In systemic physical examinations, no abnormalities were found. The laboratory findings at arrival are presented in Table 2; The results indicated liver dysfunction, low platelet, and elevated IL-18 and aldolase levels. No apparent coagulopathy findings were observed. Basic infectious disease tests including Epstein–Barr virus and cytomegalovirus were all negative. Nonstress test and fetal sonography revealed perfect biophysical profile scoring of her fetus, mild polyhydramnios (maximum vertical pocket of amnion: 8.3 cm), and an estimated fetal body weight (EFBW) of 1663 g (+ 0.8 standard deviation [SD]). However, splenomegaly was detected by additional abdominal sonography. Although HELLP syndrome or AFLP was suspected upon admission according to liver dysfunction and low platelet count at third trimester and termination of pregnancy could be possible, her clinical course and examination results did not match well to Sibai’s criteria for HELLP syndrome [5] and Swansea’s criteria for AFLP [6]. Moreover, her general condition and fetal status did not require urgent intervention. Considering the findings such as mild fever, elevated ferritin level, high level of IL-18, splenomegaly, and good fetal status, she was ultimately diagnosed with recurrence flare of AOSD by us and some rheumatologists. Thus, systemic steroid pulse therapy (first dose: 250 mg of methylprednisolone [mPSL] for 3 days) was initiated and switched to oral prednisolone (PSL) thereafter. Additionally, the patient was carefully followed up by frequent laboratory tests and transabdominal fetal sonography. Figure 1 illustrates her clinical course after hospitalization at 30 gestational weeks. Clinical AOSD findings such as fever, liver dysfunction, and high ferritin level were well controlled for 3 weeks after the initiation of systemic steroid therapy; hence, the oral PSL dosage was gradually reduced. However, another steroid pulse therapy was needed for the second flare of AOSD that happened at her 33 gestational weeks with elevated liver enzymes and rash on her trunk. In her clinical course, although with maintained uneventful fetal status, the growth of the fetus had been gradually restricted, resulting in intrauterine growth restriction (IUGR). At 36 weeks and 0 days of gestation, she had irregular uterine contractions without apparent infectious findings, and preterm premature rupture of membrane (pPROM). Finally, she spontaneously delivered a female infant transvaginally at 36 weeks and 3 days of gestation. Her infant had a low birth weight (2440 g) but was very healthy; the Apgar score was 9/10, and pH of the umbilical artery was 7.312. Moreover, no abnormal findings of the amniotic fluid at delivery and no pathological features in her placenta and umbilical cord were found. At 12 days postpartum, she had elevated ferritin levels and extremely low platelet count, indicating the third AOSD flare by a rheumatologist; thus, the dosage of oral PSL was increased and maintained for months. During her follow-up checkup as an outpatient by rheumatologists at 1 year postpartum, her C-reactive protein (CRP) and ferritin levels were within the reference range, and her platelet count gradually increased, indicating a well-controlled AOSD.
Table 2 Laboratory findings
Value Reference intervals, unit
T-Bil 0.7 0.4–1.5, mg/dl
AST 491 13–30, U/L
ALT 438 7–23, U/L
LDH 653 124–222, U/L
γ-GTP 10 9–32, U/L
BUN 6.4 8.0–20.0, mg/dl
Cre 0.58 0.46–0.79, mg/dl
BS 84 80–110, mg/dl
UA 3.3 2.6–7.0, mg/dl
CRP 1.81 0.00–0.14, mg/dl
TG 163 30–149, mg/dl
Ferritin 281 5–157, ng/ml
WBC 2980 3300–8600, /μl
RBC 3.93 3.86–4.92, × 106/μl
Hb 10.7 11.6–14.8, g/dl
Ht 32.5 35.1–44.4, %
Plt 108 158–348, × 103 /μl
PT-INR 0.89 0.90–1.10
APTT 33 25–35, seconds
Fib 407 200–400, mg/dl
AT III 96 80–130, %
Urinary protein 0.33 0.02–0.12, g/day
IL-18 175,116 0–211, pg/ml
Aldolase 30.6 2.5–7.5, U/L
Fig. 1 Clinical course, laboratory data, and treatment of the patient. Initial mPSL pulse therapy was provided for 3 days after 30 weeks and 5 days of gestation and then switched to oral PSL therapy. At 33 weeks and 0 days of gestation, another pulse therapy was provided for the second flare. EFBW was restricted gradually from − 0.6 SD to − 1.5 SD. At 36 weeks and 0 days of gestation, this patient started irregular uterine contractions and finally delivered a healthy infant spontaneously at 36 weeks and 3 days of gestation. At 12 days postpartum, she experienced the third flare, and oral PSL therapy was maintained
Discussion and conclusions
The flare of AOSD in pregnancy was first reported in 1980 by Stein et al. [7]. Currently, nearly 30 reports about AOSD associated with pregnancy have been published [3, 4, 7–32]. Hence, we reviewed the cases of AOSD complications during pregnancy [3, 4, 7–32]. A total of 53 flares in 47 pregnant women, including our case, have been recorded. The clinical course of AOSD during pregnancy consists of three types: first-onset type, which refers to the first onset of AOSD related to pregnancy [3, 4, 7, 8, 11, 12, 14, 17–25, 28–30, 32], recurrent-flare type, which refers to a recurrent flare related to pregnancy with previous AOSD diagnosis [4, 7, 9, 13, 14, 16, 25, 31], and no-flare type, which is only a complication with no flare related to pregnancy [4, 9, 10, 14, 15, 17, 26, 27]. In the literature review, the cases were divided into these three types shown in Table 3 and our case belongs to the recurrent-flare type.
Table 3 Review of pregnancy cases with adult onset Still’s disease classified into three types
Total: 47 pregnant women and 53 pregnancies
First onset (Number = 26) Recurrent flare (Number = 13) No flare (Number = 14)
Age at pregnancy (year), Median [IQR] 29 [25–33] (1 unknown case) 31 [29–34] 27 [26–30] (1 unknown case)
Parity, %
Primigravida 50 (8/16) 80 (8/10) 69.2 (9/13)
Multigravida 50 (8/16) 20 (2/10) 30.8 (4/13)
Unknown, number 10 3 1
Timing of flare, %
1st trimester 24 (6/25) 23.1 (3/13) –
2nd trimester 52 (13/25) 38.5 (5/13) –
3rd trimester 8 (2/25) 7.7 (1/13) –
Postpartum 16 (4/25) 30.8 (4/13) –
Unknown, number 1 0 –
Major symptoms and complications, %
Fever 95.7 (22/23) 70 (7/10) –
Arthralgia, Arthritis 91.3 (21/23) 60 (6/10) –
Erythema, Rash 78.3 (18/23) 50 (5/10) –
Sore throat 65.2 (15/23) 30 (3/10) –
Lymphadenopathy 60.9 (14/23) 10 (1/10) –
Hepatomegaly, Liver dysfunction 34.8 (8/23) 30 (3/10) –
Splenomegaly 34.8 (8/23) 10 (1/10) –
HLH 8.7 (2/23) 10 (1/10) –
Unknown, number 3 3 –
Major treatment, %
Corticosteroid 82.6 (19/23) 69.2 (9/13) 28.6 (4/14)
Anakinra 13.0 (3/23) 7.7 (1/13) 28.6 (4/14)
IVIg 17.4 (4/23) 7.7 (1/13) 7.1 (1/14)
NSAIDs 21.7 (5/23) 7.7 (1/13) 14.3 (2/14)
HCQ 4.3 (1/23) 15.4 (2/13) 7.1 (1/14)
No medication – – 57.1 (8/14)
Unknown, number 3 0 0
Delivery, %
Transvaginal 66.7 (12/18) 50 (4/8) 62.5 (5/8)
Cesarean section 22.2 (4/18) 50 (4/8) 25 (2/8)
Abortion 11.1 (2/18) 0 (0/8) 12.5 (1/8)
Unknown, number 8 5 6
Major obstetrical and perinatal complications, %
Preterm birth 32 (8/25) 33.3 (4/12) 16.7 (2/12)
IUGR 8 (2/25) 41.7 (5/12) 8.3 (1/12)
pPROM 12 (3/25) 8.3 (1/12) 8.3 (1/12)
No major complication 48 (12/25) 41.7 (5/12) 50 (6/12)
Others, number 2 for OHD, 1 for neonatal HLH, 1 for preeclampsia, and 1 for neonatal death for IRDS 1 for GDM, and 1 for OHD 1 for neonatal HLH, 1 for GDM, and 1 for HDP
Unknown, number 1 1 2
The median age of patients at pregnancy was almost 30 years (median [interquartile range (IQR)]: 29 [25–33], 31 [29–34], and 27 [26–30] for the first-onset, recurrent-flare, and no-flare types, respectively), indicating that women with AOSD during pregnancy were younger than the general population at first diagnosis [1]. Regarding parity, AOSD flare mainly happens among primigravida patients, with the recurrent-flare type obtaining the highest rate (83.3%), although all patients in this type are in clinical remission at conception [4, 7, 9, 13, 14, 16, 25, 31]. Our case was also in clinical remission and did not require any medication at conception.
Most likely, the AOSD flare occurred until second trimester and at postpartum, with limited reports of flare at third trimester; the first-onset type was found only in two cases [21, 24] and the recurrent-flare type in one case, which is our case. Although AOSD flare occurring at third trimester is extremely rare, the clinical symptoms of AOSD are similar to those of HELLP syndrome and AFLP, suggesting that close attention to perinatal management is crucial. Generally, the Yamaguchi criteria [2] is adopted for the diagnosing AOSD (Table 1). However, we needed to assess AOSD recurrence in a comprehensive way by considering the clinical features and laboratory findings because no criteria for the diagnosis of AOSD recurrence are currently available. In fact, the review showed that most of the major symptoms of AOSD detected in the recurrent-flare type are relatively fewer than in the first-onset type. In addition, the major symptoms and findings of AOSD are elevated liver enzyme, leukocytosis, and sometimes abdominal pain or nausea, which are difficult to distinguish from HELLP syndrome or AFLP, particularly in cases with flare occurring at third trimester. Elevated ferritin [2] and IL-18 [33], which are reportedly biomarkers of AOSD activity, are considered better diagnostic markers than any other markers. Specific AOSD features such as fever, splenomegaly, and typical rash can support the possibility of AOSD. Izuka et al. recently reported that elevated serum aldolase can be a useful biomarker of AOSD [34]. In our case, the serum aldolase level was high (30.6 U/L), which supported the diagnosis of recurrent AOSD flare. Finally, we and some rheumatologists comprehensively diagnosed the patient with AOSD recurrence flare in consideration of the AOSD findings such as elevated ferritin, IL-18, and aldolase levels, splenomegaly, and uneventful fetal status.
AOSD treatments generally include PSL/mPSL, nonsteroidal anti-inflammatory agents (NSAIDs) and in more severe cases, methotrexate, anakinra (interleukin-1 [IL-1] inhibitor), intravenous immune globulin (IVIg), cyclosporine, or tacrolimus. However, selecting the appropriate medication for pregnant patients entails some limitations. Jamilloux Y et al. recommended corticosteroids as the first treatment choice, and IVIg and IL-1 inhibitor as the second treatment choice for AOSD [35]. Our review also showed that corticosteroid was mainly used, followed by IL-1 inhibitor and IVIg. In Japan, where most of the IL-1 antagonists have not yet been approved, tacrolimus may be a reasonable second choice for severe AOSD flare in pregnancy, and some successful management cases reported to have used this medication during pregnancy [11, 23]. In our case, twice mPSL pulse therapy followed by oral PSL was chosen; consequently, pregnancy was maintained until 36 gestational weeks.
In almost one-third of cases in both the first-onset and recurrent-flare types, the main obstetrical complication was preterm birth. Some reports showed that other autoimmune diseases or autoinflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis, occurring during pregnancy are risk factors for preterm birth, and maternal disease activity contributes to the increased risk of preterm delivery [36–38]. Furthermore, long-term steroidal use is another risk factor for preterm birth [37, 38]. Our review results showed that the incidence of preterm delivery in both the first-onset and recurrent-flare types of AOSD was almost twice higher than that in the no-flare type. Therefore, the high disease activity of AOSD and long-term use of systemic steroids may be possible reasons for the high incidence of preterm delivery in patients with AOSD. Our case also delivered prematurely, with high disease activity and long-term systemic steroid use including twice steroid pulse therapies. Hemophagocytic lymphohistiocytosis (HLH) is also a severe and crucial complication of AOSD. HLH was diagnosed in some cases having the first-onset and recurrent-flare types and in neonatal cases delivered from mothers with AOSD, even in clinical remission. Meanwhile, we believe that in general, the overall severity of AOSD during pregnancy may be better than the HELLP syndrome and AFLP. In fact, lethal complication was only found in one case wherein a premature fetus died at 28 weeks old because of infantile respiratory distress syndrome (IRDS) in the first-onset type, as reported by Green et al. in 1982 [8]. Therefore, with the cooperation of rheumatologists and pediatricians, pregnant patients with AOSD can maintain their pregnancy by paying special attention to prematurity, fetal growth, and HLH, even if the case is in clinical remission.
The relationship of pathogenesis between AOSD and pregnancy remains unclear. Ida A et al. reported that serum IL-18 levels were significantly elevated in pregnant women from the first trimester until the onset of labor than in nonpregnant women [39]. They noticed further increment of serum IL-18 levels after labor, lasting until at least the third day of postpartum. This result parallels the clinical feature of AOSD in pregnancy, that is, AOSD flares are likely to happen in the first/second trimester and postpartum. Considering that our case had also prominently high IL-18 levels, IL-18 elevation may cause the flare of AOSD during pregnancy, suggesting that pregnancy may be a risk factor of AOSD. Therefore, the serum IL-18 levels as a follow-up during pregnancy may be a useful predictive and diagnostic marker of AOSD flare; however, further investigations are required.
From the abovementioned consideration, patients with AOSD can be pregnant and continue pregnancy safely while under treatment, considering that the prognosis of pregnant women with AOSD and their fetuses is favorable in previous cases. Furthermore, for a safer pregnancy in patients complicated with AOSD, we, as obstetricians, need tight cooperation with rheumatologists and pediatricians for the sufficient control of AOSD activity and perinatal care and should provide enough explanation to patients on the risks of flares during pregnancy. Moreover, we conduct frequent laboratory tests and careful follow-up in preparation for flares, premature birth, and HLH. If the flare happens at third trimester, as in our case, we need to differentiate AOSD from HELLP syndrome and AFLP because of the similarity of laboratory data and physical findings. Fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for the differentiation from HELLP syndrome and AFLP.
To our knowledge, this report is the first to present the recurrent flare of AOSD during pregnancy at third trimester. However, we need to further investigate on the proper management of pregnant women with AOSD.
Abbreviations
AOSDAdult-onset Still’s disease
TNF-αTumor necrosis factor-α
IL-6Interleukin-6
IL-18Interleukin-18
HELLPHemolysis, elevated liver enzymes and low platelet count
AFLPAcute fatty liver of pregnancy
GDMGestational diabetes mellitus
EFBWEstimated fetal body weight
SDStandard deviation
mPSLMethylprednisolone
PSLPrednisolone
IUGRIntrauterine growth restriction
pPROMPreterm premature rupture of membrane
CRPC-reactive protein
IQRInterquartile range
NSAIDsNonsteroidal anti-inflammatory agents
IL-1Interleukin-1
IVIgIntravenous immune globulin
HLHHemophagocytic lymphohistiocytosis
IRDSInfantile respiratory distress syndrome
NVDNormal vaginal delivery
T-BilTotal bilirubin
ASTAspartate aminotransferase
ALTAlanine aminotransferase
LDHLactate dehydrogenase
γ-GTPγ-glutamyl transpeptidase
BUNBlood urea nitrogen
CreCreatinine
BSBlood sugar
TGTriglyceride
WBCWhite blood cell
RBCRed blood cell
HbHemoglobin
HtHematocrit
PltPlatelet
PT-INRProthrombin-time international normalized ratio
APTTActivated partial thromboplastin time
FibFibrinogen
AT IIIAntithrombin III
HCQHydroxychloroquine
OHDOligohydramnios
HDPHypertensive disorders of pregnancy
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors would like to thank Enago (www.enago.jp) for the English language review.
Authors’ contributions
SH collected and interpreted the patient’s data, collected previous reports and wrote the first draft of this paper. MS and HO also interpreted the data and revised the first draft. SI and HY also revised the first draft and support the data collection. All authors approved the final manuscript.
Authors’ information
SH was a junior resident of the Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan at the time of this work. Now, SH belongs to the Department of Obstetrics and Gynecology, the Jikei University School of Medicine.
Funding
All authors had no funding support related to this report.
Availability of data and materials
The datasets that support the findings about this case are available from the corresponding author, SH, on reasonable request.
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 of this journal.
Competing interests
The authors declare that they have no competing interests. | Transplacental | DrugAdministrationRoute | CC BY | 33627085 | 19,473,834 | 2021-02-24 |
What was the outcome of reaction 'Exposure during pregnancy'? | A case of recurrence of adult-onset Still's disease in the third trimester: a case report and literature review.
BACKGROUND
Adult-onset Still's disease (AOSD) is a self-inflammatory disease showing macrophage and neutrophil activation by inflammatory cytokines such as TNF-α, IL-6, and IL-18. Although some cases with the flare of AOSD during pregnancy have been reported, most had flares in the first or second trimester and few had flares in the third trimester. In this report, we present the case of a patient with recurrent flare of AOSD in the third trimester and discuss the management of AOSD in the third trimester with the review of previous literatures.
METHODS
A 38-year-old woman in complete AOSD remission without medication presented with impaired liver function, low platelet count, mild fever, abdominal pain, splenomegaly, and elevated ferritin and IL-18 levels at 30 gestational weeks. Although the laboratory data and physical examination finding suggested HELLP syndrome or acute fatty liver of pregnancy and we considered the termination of her pregnancy, her fetus was in a reactive status. Considering her fetal status, some specific findings of AOSD, and her AOSD history, we and rheumatologists diagnosed her with AOSD recurrence and started systemic steroid therapy. In her clinical course, three flares of AOSD occurred, twice in the third trimester and once in postpartum; twice systemic steroid pulse therapies were then needed. Ultimately, a healthy infant was delivered transvaginally at 36 gestational weeks spontaneously.
CONCLUSIONS
Specific findings of the flare of AOSD such as fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for differentiation from HELLP syndrome and AFLP in the third trimester. With the careful management supported by rheumatologists, patients complicated with the flare of AOSD may continue their pregnancy longer than we expected.
Background
Adult-onset Still’s disease (AOSD) is a self-inflammatory disease exhibiting macrophage and neutrophil activation by inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-18 (IL-18). Its incidence is 1.6–4.0 in 1,000,000 people per year [1]. AOSD more likely occurs in women, affecting 50 to 70%, than in men [1]. It mostly affects young adults (median age at diagnosis: 36 years) [1], indicating the reproductive ages in women. The Yamaguchi criteria [2] are commonly used to diagnose AOSD because they suggest major symptoms and laboratory findings of AOSD; common manifestations are remittent fever over 39 °C lasting more than a week, arthralgia or arthritis, typical rash, high white blood cell count, elevated liver enzymes, and splenomegaly (Table 1). In addition, some AOSD cases manifest abdominal pain and nausea [1]. If findings such as elevated liver enzyme and abdominal pain happen during pregnancy, AOSD may be misinterpreted as hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome and acute fatty liver of pregnancy (AFLP). Currently, although the association between the disease onset of AOSD and pregnancy has already been widely investigated [3, 4], such relationship remains unclear. Moreover, reported cases of AOSD flares at third trimester are few, and the management and features of AOSD, which has similar features to HELLP syndrome and AFLP, at the third trimester have not been reported yet. Herein, we report a rare case of a pregnant woman with AOSD recurrence at her 30 gestational weeks and reviewed the previous reports on the flares of AOSD related to pregnancy. Written informed consent for the publication of this report was obtained from the patient.
Table 1 Yamaguchi criteria for the diagnosis of adult-onset Still’s disease [2]
Major criteria Fever ≥39 °C lasting ≥1 week
Arthralgia or arthritis lasting ≥2 weeks
Typical nonpruritic salmon-colored rash
Leukocytosis ≥10,000/μl with granulocytes ≥80%
Minor criteria Sore throat
Lymphadenopathy
Splenomegaly
Abnormal liver function tests
Negative tests for antinuclear antibody and rheumatoid factor
Exclusion criteria Infection
Malignancy
Other rheumatic disease (vasculitis)
Diagnosis of adult-onset Still’s disease if ≥5 criteria are present with ≥2 being major criteria and no exclusion criteria
Case presentation
A 38-year-old primigravida with well-controlled gestational diabetes mellitus (GDM) was introduced from her home doctor to our hospital, presenting with mild fever, liver dysfunction, elevated ferritin, low platelet count, and proteinuria at 30 weeks and 5 days of gestation. She was diagnosed with AOSD 6 years ago in our hospital based on typical symptoms, including fever, malaise, cervical lymphadenopathy, rash, liver disfunction, and high serum ferritin levels. Although the rheumatologists performed biopsies of her bone marrow and lymph node, the results of these examination were normal and the possibility of other hematologic diseases was denied. After the combination treatment with systemic steroid and tocilizumab administration, she was in complete clinical remission without medication at conception. Upon arrival, her body temperature, blood pressure, and heart rate were 37.7 °C, 101/63 mmHg, and 103 beats/min. In systemic physical examinations, no abnormalities were found. The laboratory findings at arrival are presented in Table 2; The results indicated liver dysfunction, low platelet, and elevated IL-18 and aldolase levels. No apparent coagulopathy findings were observed. Basic infectious disease tests including Epstein–Barr virus and cytomegalovirus were all negative. Nonstress test and fetal sonography revealed perfect biophysical profile scoring of her fetus, mild polyhydramnios (maximum vertical pocket of amnion: 8.3 cm), and an estimated fetal body weight (EFBW) of 1663 g (+ 0.8 standard deviation [SD]). However, splenomegaly was detected by additional abdominal sonography. Although HELLP syndrome or AFLP was suspected upon admission according to liver dysfunction and low platelet count at third trimester and termination of pregnancy could be possible, her clinical course and examination results did not match well to Sibai’s criteria for HELLP syndrome [5] and Swansea’s criteria for AFLP [6]. Moreover, her general condition and fetal status did not require urgent intervention. Considering the findings such as mild fever, elevated ferritin level, high level of IL-18, splenomegaly, and good fetal status, she was ultimately diagnosed with recurrence flare of AOSD by us and some rheumatologists. Thus, systemic steroid pulse therapy (first dose: 250 mg of methylprednisolone [mPSL] for 3 days) was initiated and switched to oral prednisolone (PSL) thereafter. Additionally, the patient was carefully followed up by frequent laboratory tests and transabdominal fetal sonography. Figure 1 illustrates her clinical course after hospitalization at 30 gestational weeks. Clinical AOSD findings such as fever, liver dysfunction, and high ferritin level were well controlled for 3 weeks after the initiation of systemic steroid therapy; hence, the oral PSL dosage was gradually reduced. However, another steroid pulse therapy was needed for the second flare of AOSD that happened at her 33 gestational weeks with elevated liver enzymes and rash on her trunk. In her clinical course, although with maintained uneventful fetal status, the growth of the fetus had been gradually restricted, resulting in intrauterine growth restriction (IUGR). At 36 weeks and 0 days of gestation, she had irregular uterine contractions without apparent infectious findings, and preterm premature rupture of membrane (pPROM). Finally, she spontaneously delivered a female infant transvaginally at 36 weeks and 3 days of gestation. Her infant had a low birth weight (2440 g) but was very healthy; the Apgar score was 9/10, and pH of the umbilical artery was 7.312. Moreover, no abnormal findings of the amniotic fluid at delivery and no pathological features in her placenta and umbilical cord were found. At 12 days postpartum, she had elevated ferritin levels and extremely low platelet count, indicating the third AOSD flare by a rheumatologist; thus, the dosage of oral PSL was increased and maintained for months. During her follow-up checkup as an outpatient by rheumatologists at 1 year postpartum, her C-reactive protein (CRP) and ferritin levels were within the reference range, and her platelet count gradually increased, indicating a well-controlled AOSD.
Table 2 Laboratory findings
Value Reference intervals, unit
T-Bil 0.7 0.4–1.5, mg/dl
AST 491 13–30, U/L
ALT 438 7–23, U/L
LDH 653 124–222, U/L
γ-GTP 10 9–32, U/L
BUN 6.4 8.0–20.0, mg/dl
Cre 0.58 0.46–0.79, mg/dl
BS 84 80–110, mg/dl
UA 3.3 2.6–7.0, mg/dl
CRP 1.81 0.00–0.14, mg/dl
TG 163 30–149, mg/dl
Ferritin 281 5–157, ng/ml
WBC 2980 3300–8600, /μl
RBC 3.93 3.86–4.92, × 106/μl
Hb 10.7 11.6–14.8, g/dl
Ht 32.5 35.1–44.4, %
Plt 108 158–348, × 103 /μl
PT-INR 0.89 0.90–1.10
APTT 33 25–35, seconds
Fib 407 200–400, mg/dl
AT III 96 80–130, %
Urinary protein 0.33 0.02–0.12, g/day
IL-18 175,116 0–211, pg/ml
Aldolase 30.6 2.5–7.5, U/L
Fig. 1 Clinical course, laboratory data, and treatment of the patient. Initial mPSL pulse therapy was provided for 3 days after 30 weeks and 5 days of gestation and then switched to oral PSL therapy. At 33 weeks and 0 days of gestation, another pulse therapy was provided for the second flare. EFBW was restricted gradually from − 0.6 SD to − 1.5 SD. At 36 weeks and 0 days of gestation, this patient started irregular uterine contractions and finally delivered a healthy infant spontaneously at 36 weeks and 3 days of gestation. At 12 days postpartum, she experienced the third flare, and oral PSL therapy was maintained
Discussion and conclusions
The flare of AOSD in pregnancy was first reported in 1980 by Stein et al. [7]. Currently, nearly 30 reports about AOSD associated with pregnancy have been published [3, 4, 7–32]. Hence, we reviewed the cases of AOSD complications during pregnancy [3, 4, 7–32]. A total of 53 flares in 47 pregnant women, including our case, have been recorded. The clinical course of AOSD during pregnancy consists of three types: first-onset type, which refers to the first onset of AOSD related to pregnancy [3, 4, 7, 8, 11, 12, 14, 17–25, 28–30, 32], recurrent-flare type, which refers to a recurrent flare related to pregnancy with previous AOSD diagnosis [4, 7, 9, 13, 14, 16, 25, 31], and no-flare type, which is only a complication with no flare related to pregnancy [4, 9, 10, 14, 15, 17, 26, 27]. In the literature review, the cases were divided into these three types shown in Table 3 and our case belongs to the recurrent-flare type.
Table 3 Review of pregnancy cases with adult onset Still’s disease classified into three types
Total: 47 pregnant women and 53 pregnancies
First onset (Number = 26) Recurrent flare (Number = 13) No flare (Number = 14)
Age at pregnancy (year), Median [IQR] 29 [25–33] (1 unknown case) 31 [29–34] 27 [26–30] (1 unknown case)
Parity, %
Primigravida 50 (8/16) 80 (8/10) 69.2 (9/13)
Multigravida 50 (8/16) 20 (2/10) 30.8 (4/13)
Unknown, number 10 3 1
Timing of flare, %
1st trimester 24 (6/25) 23.1 (3/13) –
2nd trimester 52 (13/25) 38.5 (5/13) –
3rd trimester 8 (2/25) 7.7 (1/13) –
Postpartum 16 (4/25) 30.8 (4/13) –
Unknown, number 1 0 –
Major symptoms and complications, %
Fever 95.7 (22/23) 70 (7/10) –
Arthralgia, Arthritis 91.3 (21/23) 60 (6/10) –
Erythema, Rash 78.3 (18/23) 50 (5/10) –
Sore throat 65.2 (15/23) 30 (3/10) –
Lymphadenopathy 60.9 (14/23) 10 (1/10) –
Hepatomegaly, Liver dysfunction 34.8 (8/23) 30 (3/10) –
Splenomegaly 34.8 (8/23) 10 (1/10) –
HLH 8.7 (2/23) 10 (1/10) –
Unknown, number 3 3 –
Major treatment, %
Corticosteroid 82.6 (19/23) 69.2 (9/13) 28.6 (4/14)
Anakinra 13.0 (3/23) 7.7 (1/13) 28.6 (4/14)
IVIg 17.4 (4/23) 7.7 (1/13) 7.1 (1/14)
NSAIDs 21.7 (5/23) 7.7 (1/13) 14.3 (2/14)
HCQ 4.3 (1/23) 15.4 (2/13) 7.1 (1/14)
No medication – – 57.1 (8/14)
Unknown, number 3 0 0
Delivery, %
Transvaginal 66.7 (12/18) 50 (4/8) 62.5 (5/8)
Cesarean section 22.2 (4/18) 50 (4/8) 25 (2/8)
Abortion 11.1 (2/18) 0 (0/8) 12.5 (1/8)
Unknown, number 8 5 6
Major obstetrical and perinatal complications, %
Preterm birth 32 (8/25) 33.3 (4/12) 16.7 (2/12)
IUGR 8 (2/25) 41.7 (5/12) 8.3 (1/12)
pPROM 12 (3/25) 8.3 (1/12) 8.3 (1/12)
No major complication 48 (12/25) 41.7 (5/12) 50 (6/12)
Others, number 2 for OHD, 1 for neonatal HLH, 1 for preeclampsia, and 1 for neonatal death for IRDS 1 for GDM, and 1 for OHD 1 for neonatal HLH, 1 for GDM, and 1 for HDP
Unknown, number 1 1 2
The median age of patients at pregnancy was almost 30 years (median [interquartile range (IQR)]: 29 [25–33], 31 [29–34], and 27 [26–30] for the first-onset, recurrent-flare, and no-flare types, respectively), indicating that women with AOSD during pregnancy were younger than the general population at first diagnosis [1]. Regarding parity, AOSD flare mainly happens among primigravida patients, with the recurrent-flare type obtaining the highest rate (83.3%), although all patients in this type are in clinical remission at conception [4, 7, 9, 13, 14, 16, 25, 31]. Our case was also in clinical remission and did not require any medication at conception.
Most likely, the AOSD flare occurred until second trimester and at postpartum, with limited reports of flare at third trimester; the first-onset type was found only in two cases [21, 24] and the recurrent-flare type in one case, which is our case. Although AOSD flare occurring at third trimester is extremely rare, the clinical symptoms of AOSD are similar to those of HELLP syndrome and AFLP, suggesting that close attention to perinatal management is crucial. Generally, the Yamaguchi criteria [2] is adopted for the diagnosing AOSD (Table 1). However, we needed to assess AOSD recurrence in a comprehensive way by considering the clinical features and laboratory findings because no criteria for the diagnosis of AOSD recurrence are currently available. In fact, the review showed that most of the major symptoms of AOSD detected in the recurrent-flare type are relatively fewer than in the first-onset type. In addition, the major symptoms and findings of AOSD are elevated liver enzyme, leukocytosis, and sometimes abdominal pain or nausea, which are difficult to distinguish from HELLP syndrome or AFLP, particularly in cases with flare occurring at third trimester. Elevated ferritin [2] and IL-18 [33], which are reportedly biomarkers of AOSD activity, are considered better diagnostic markers than any other markers. Specific AOSD features such as fever, splenomegaly, and typical rash can support the possibility of AOSD. Izuka et al. recently reported that elevated serum aldolase can be a useful biomarker of AOSD [34]. In our case, the serum aldolase level was high (30.6 U/L), which supported the diagnosis of recurrent AOSD flare. Finally, we and some rheumatologists comprehensively diagnosed the patient with AOSD recurrence flare in consideration of the AOSD findings such as elevated ferritin, IL-18, and aldolase levels, splenomegaly, and uneventful fetal status.
AOSD treatments generally include PSL/mPSL, nonsteroidal anti-inflammatory agents (NSAIDs) and in more severe cases, methotrexate, anakinra (interleukin-1 [IL-1] inhibitor), intravenous immune globulin (IVIg), cyclosporine, or tacrolimus. However, selecting the appropriate medication for pregnant patients entails some limitations. Jamilloux Y et al. recommended corticosteroids as the first treatment choice, and IVIg and IL-1 inhibitor as the second treatment choice for AOSD [35]. Our review also showed that corticosteroid was mainly used, followed by IL-1 inhibitor and IVIg. In Japan, where most of the IL-1 antagonists have not yet been approved, tacrolimus may be a reasonable second choice for severe AOSD flare in pregnancy, and some successful management cases reported to have used this medication during pregnancy [11, 23]. In our case, twice mPSL pulse therapy followed by oral PSL was chosen; consequently, pregnancy was maintained until 36 gestational weeks.
In almost one-third of cases in both the first-onset and recurrent-flare types, the main obstetrical complication was preterm birth. Some reports showed that other autoimmune diseases or autoinflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis, occurring during pregnancy are risk factors for preterm birth, and maternal disease activity contributes to the increased risk of preterm delivery [36–38]. Furthermore, long-term steroidal use is another risk factor for preterm birth [37, 38]. Our review results showed that the incidence of preterm delivery in both the first-onset and recurrent-flare types of AOSD was almost twice higher than that in the no-flare type. Therefore, the high disease activity of AOSD and long-term use of systemic steroids may be possible reasons for the high incidence of preterm delivery in patients with AOSD. Our case also delivered prematurely, with high disease activity and long-term systemic steroid use including twice steroid pulse therapies. Hemophagocytic lymphohistiocytosis (HLH) is also a severe and crucial complication of AOSD. HLH was diagnosed in some cases having the first-onset and recurrent-flare types and in neonatal cases delivered from mothers with AOSD, even in clinical remission. Meanwhile, we believe that in general, the overall severity of AOSD during pregnancy may be better than the HELLP syndrome and AFLP. In fact, lethal complication was only found in one case wherein a premature fetus died at 28 weeks old because of infantile respiratory distress syndrome (IRDS) in the first-onset type, as reported by Green et al. in 1982 [8]. Therefore, with the cooperation of rheumatologists and pediatricians, pregnant patients with AOSD can maintain their pregnancy by paying special attention to prematurity, fetal growth, and HLH, even if the case is in clinical remission.
The relationship of pathogenesis between AOSD and pregnancy remains unclear. Ida A et al. reported that serum IL-18 levels were significantly elevated in pregnant women from the first trimester until the onset of labor than in nonpregnant women [39]. They noticed further increment of serum IL-18 levels after labor, lasting until at least the third day of postpartum. This result parallels the clinical feature of AOSD in pregnancy, that is, AOSD flares are likely to happen in the first/second trimester and postpartum. Considering that our case had also prominently high IL-18 levels, IL-18 elevation may cause the flare of AOSD during pregnancy, suggesting that pregnancy may be a risk factor of AOSD. Therefore, the serum IL-18 levels as a follow-up during pregnancy may be a useful predictive and diagnostic marker of AOSD flare; however, further investigations are required.
From the abovementioned consideration, patients with AOSD can be pregnant and continue pregnancy safely while under treatment, considering that the prognosis of pregnant women with AOSD and their fetuses is favorable in previous cases. Furthermore, for a safer pregnancy in patients complicated with AOSD, we, as obstetricians, need tight cooperation with rheumatologists and pediatricians for the sufficient control of AOSD activity and perinatal care and should provide enough explanation to patients on the risks of flares during pregnancy. Moreover, we conduct frequent laboratory tests and careful follow-up in preparation for flares, premature birth, and HLH. If the flare happens at third trimester, as in our case, we need to differentiate AOSD from HELLP syndrome and AFLP because of the similarity of laboratory data and physical findings. Fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for the differentiation from HELLP syndrome and AFLP.
To our knowledge, this report is the first to present the recurrent flare of AOSD during pregnancy at third trimester. However, we need to further investigate on the proper management of pregnant women with AOSD.
Abbreviations
AOSDAdult-onset Still’s disease
TNF-αTumor necrosis factor-α
IL-6Interleukin-6
IL-18Interleukin-18
HELLPHemolysis, elevated liver enzymes and low platelet count
AFLPAcute fatty liver of pregnancy
GDMGestational diabetes mellitus
EFBWEstimated fetal body weight
SDStandard deviation
mPSLMethylprednisolone
PSLPrednisolone
IUGRIntrauterine growth restriction
pPROMPreterm premature rupture of membrane
CRPC-reactive protein
IQRInterquartile range
NSAIDsNonsteroidal anti-inflammatory agents
IL-1Interleukin-1
IVIgIntravenous immune globulin
HLHHemophagocytic lymphohistiocytosis
IRDSInfantile respiratory distress syndrome
NVDNormal vaginal delivery
T-BilTotal bilirubin
ASTAspartate aminotransferase
ALTAlanine aminotransferase
LDHLactate dehydrogenase
γ-GTPγ-glutamyl transpeptidase
BUNBlood urea nitrogen
CreCreatinine
BSBlood sugar
TGTriglyceride
WBCWhite blood cell
RBCRed blood cell
HbHemoglobin
HtHematocrit
PltPlatelet
PT-INRProthrombin-time international normalized ratio
APTTActivated partial thromboplastin time
FibFibrinogen
AT IIIAntithrombin III
HCQHydroxychloroquine
OHDOligohydramnios
HDPHypertensive disorders of pregnancy
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Acknowledgements
The authors would like to thank Enago (www.enago.jp) for the English language review.
Authors’ contributions
SH collected and interpreted the patient’s data, collected previous reports and wrote the first draft of this paper. MS and HO also interpreted the data and revised the first draft. SI and HY also revised the first draft and support the data collection. All authors approved the final manuscript.
Authors’ information
SH was a junior resident of the Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan at the time of this work. Now, SH belongs to the Department of Obstetrics and Gynecology, the Jikei University School of Medicine.
Funding
All authors had no funding support related to this report.
Availability of data and materials
The datasets that support the findings about this case are available from the corresponding author, SH, on reasonable request.
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 of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33627085 | 19,473,663 | 2021-02-24 |
What was the outcome of reaction 'Foetal exposure during pregnancy'? | A case of recurrence of adult-onset Still's disease in the third trimester: a case report and literature review.
BACKGROUND
Adult-onset Still's disease (AOSD) is a self-inflammatory disease showing macrophage and neutrophil activation by inflammatory cytokines such as TNF-α, IL-6, and IL-18. Although some cases with the flare of AOSD during pregnancy have been reported, most had flares in the first or second trimester and few had flares in the third trimester. In this report, we present the case of a patient with recurrent flare of AOSD in the third trimester and discuss the management of AOSD in the third trimester with the review of previous literatures.
METHODS
A 38-year-old woman in complete AOSD remission without medication presented with impaired liver function, low platelet count, mild fever, abdominal pain, splenomegaly, and elevated ferritin and IL-18 levels at 30 gestational weeks. Although the laboratory data and physical examination finding suggested HELLP syndrome or acute fatty liver of pregnancy and we considered the termination of her pregnancy, her fetus was in a reactive status. Considering her fetal status, some specific findings of AOSD, and her AOSD history, we and rheumatologists diagnosed her with AOSD recurrence and started systemic steroid therapy. In her clinical course, three flares of AOSD occurred, twice in the third trimester and once in postpartum; twice systemic steroid pulse therapies were then needed. Ultimately, a healthy infant was delivered transvaginally at 36 gestational weeks spontaneously.
CONCLUSIONS
Specific findings of the flare of AOSD such as fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for differentiation from HELLP syndrome and AFLP in the third trimester. With the careful management supported by rheumatologists, patients complicated with the flare of AOSD may continue their pregnancy longer than we expected.
Background
Adult-onset Still’s disease (AOSD) is a self-inflammatory disease exhibiting macrophage and neutrophil activation by inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-18 (IL-18). Its incidence is 1.6–4.0 in 1,000,000 people per year [1]. AOSD more likely occurs in women, affecting 50 to 70%, than in men [1]. It mostly affects young adults (median age at diagnosis: 36 years) [1], indicating the reproductive ages in women. The Yamaguchi criteria [2] are commonly used to diagnose AOSD because they suggest major symptoms and laboratory findings of AOSD; common manifestations are remittent fever over 39 °C lasting more than a week, arthralgia or arthritis, typical rash, high white blood cell count, elevated liver enzymes, and splenomegaly (Table 1). In addition, some AOSD cases manifest abdominal pain and nausea [1]. If findings such as elevated liver enzyme and abdominal pain happen during pregnancy, AOSD may be misinterpreted as hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome and acute fatty liver of pregnancy (AFLP). Currently, although the association between the disease onset of AOSD and pregnancy has already been widely investigated [3, 4], such relationship remains unclear. Moreover, reported cases of AOSD flares at third trimester are few, and the management and features of AOSD, which has similar features to HELLP syndrome and AFLP, at the third trimester have not been reported yet. Herein, we report a rare case of a pregnant woman with AOSD recurrence at her 30 gestational weeks and reviewed the previous reports on the flares of AOSD related to pregnancy. Written informed consent for the publication of this report was obtained from the patient.
Table 1 Yamaguchi criteria for the diagnosis of adult-onset Still’s disease [2]
Major criteria Fever ≥39 °C lasting ≥1 week
Arthralgia or arthritis lasting ≥2 weeks
Typical nonpruritic salmon-colored rash
Leukocytosis ≥10,000/μl with granulocytes ≥80%
Minor criteria Sore throat
Lymphadenopathy
Splenomegaly
Abnormal liver function tests
Negative tests for antinuclear antibody and rheumatoid factor
Exclusion criteria Infection
Malignancy
Other rheumatic disease (vasculitis)
Diagnosis of adult-onset Still’s disease if ≥5 criteria are present with ≥2 being major criteria and no exclusion criteria
Case presentation
A 38-year-old primigravida with well-controlled gestational diabetes mellitus (GDM) was introduced from her home doctor to our hospital, presenting with mild fever, liver dysfunction, elevated ferritin, low platelet count, and proteinuria at 30 weeks and 5 days of gestation. She was diagnosed with AOSD 6 years ago in our hospital based on typical symptoms, including fever, malaise, cervical lymphadenopathy, rash, liver disfunction, and high serum ferritin levels. Although the rheumatologists performed biopsies of her bone marrow and lymph node, the results of these examination were normal and the possibility of other hematologic diseases was denied. After the combination treatment with systemic steroid and tocilizumab administration, she was in complete clinical remission without medication at conception. Upon arrival, her body temperature, blood pressure, and heart rate were 37.7 °C, 101/63 mmHg, and 103 beats/min. In systemic physical examinations, no abnormalities were found. The laboratory findings at arrival are presented in Table 2; The results indicated liver dysfunction, low platelet, and elevated IL-18 and aldolase levels. No apparent coagulopathy findings were observed. Basic infectious disease tests including Epstein–Barr virus and cytomegalovirus were all negative. Nonstress test and fetal sonography revealed perfect biophysical profile scoring of her fetus, mild polyhydramnios (maximum vertical pocket of amnion: 8.3 cm), and an estimated fetal body weight (EFBW) of 1663 g (+ 0.8 standard deviation [SD]). However, splenomegaly was detected by additional abdominal sonography. Although HELLP syndrome or AFLP was suspected upon admission according to liver dysfunction and low platelet count at third trimester and termination of pregnancy could be possible, her clinical course and examination results did not match well to Sibai’s criteria for HELLP syndrome [5] and Swansea’s criteria for AFLP [6]. Moreover, her general condition and fetal status did not require urgent intervention. Considering the findings such as mild fever, elevated ferritin level, high level of IL-18, splenomegaly, and good fetal status, she was ultimately diagnosed with recurrence flare of AOSD by us and some rheumatologists. Thus, systemic steroid pulse therapy (first dose: 250 mg of methylprednisolone [mPSL] for 3 days) was initiated and switched to oral prednisolone (PSL) thereafter. Additionally, the patient was carefully followed up by frequent laboratory tests and transabdominal fetal sonography. Figure 1 illustrates her clinical course after hospitalization at 30 gestational weeks. Clinical AOSD findings such as fever, liver dysfunction, and high ferritin level were well controlled for 3 weeks after the initiation of systemic steroid therapy; hence, the oral PSL dosage was gradually reduced. However, another steroid pulse therapy was needed for the second flare of AOSD that happened at her 33 gestational weeks with elevated liver enzymes and rash on her trunk. In her clinical course, although with maintained uneventful fetal status, the growth of the fetus had been gradually restricted, resulting in intrauterine growth restriction (IUGR). At 36 weeks and 0 days of gestation, she had irregular uterine contractions without apparent infectious findings, and preterm premature rupture of membrane (pPROM). Finally, she spontaneously delivered a female infant transvaginally at 36 weeks and 3 days of gestation. Her infant had a low birth weight (2440 g) but was very healthy; the Apgar score was 9/10, and pH of the umbilical artery was 7.312. Moreover, no abnormal findings of the amniotic fluid at delivery and no pathological features in her placenta and umbilical cord were found. At 12 days postpartum, she had elevated ferritin levels and extremely low platelet count, indicating the third AOSD flare by a rheumatologist; thus, the dosage of oral PSL was increased and maintained for months. During her follow-up checkup as an outpatient by rheumatologists at 1 year postpartum, her C-reactive protein (CRP) and ferritin levels were within the reference range, and her platelet count gradually increased, indicating a well-controlled AOSD.
Table 2 Laboratory findings
Value Reference intervals, unit
T-Bil 0.7 0.4–1.5, mg/dl
AST 491 13–30, U/L
ALT 438 7–23, U/L
LDH 653 124–222, U/L
γ-GTP 10 9–32, U/L
BUN 6.4 8.0–20.0, mg/dl
Cre 0.58 0.46–0.79, mg/dl
BS 84 80–110, mg/dl
UA 3.3 2.6–7.0, mg/dl
CRP 1.81 0.00–0.14, mg/dl
TG 163 30–149, mg/dl
Ferritin 281 5–157, ng/ml
WBC 2980 3300–8600, /μl
RBC 3.93 3.86–4.92, × 106/μl
Hb 10.7 11.6–14.8, g/dl
Ht 32.5 35.1–44.4, %
Plt 108 158–348, × 103 /μl
PT-INR 0.89 0.90–1.10
APTT 33 25–35, seconds
Fib 407 200–400, mg/dl
AT III 96 80–130, %
Urinary protein 0.33 0.02–0.12, g/day
IL-18 175,116 0–211, pg/ml
Aldolase 30.6 2.5–7.5, U/L
Fig. 1 Clinical course, laboratory data, and treatment of the patient. Initial mPSL pulse therapy was provided for 3 days after 30 weeks and 5 days of gestation and then switched to oral PSL therapy. At 33 weeks and 0 days of gestation, another pulse therapy was provided for the second flare. EFBW was restricted gradually from − 0.6 SD to − 1.5 SD. At 36 weeks and 0 days of gestation, this patient started irregular uterine contractions and finally delivered a healthy infant spontaneously at 36 weeks and 3 days of gestation. At 12 days postpartum, she experienced the third flare, and oral PSL therapy was maintained
Discussion and conclusions
The flare of AOSD in pregnancy was first reported in 1980 by Stein et al. [7]. Currently, nearly 30 reports about AOSD associated with pregnancy have been published [3, 4, 7–32]. Hence, we reviewed the cases of AOSD complications during pregnancy [3, 4, 7–32]. A total of 53 flares in 47 pregnant women, including our case, have been recorded. The clinical course of AOSD during pregnancy consists of three types: first-onset type, which refers to the first onset of AOSD related to pregnancy [3, 4, 7, 8, 11, 12, 14, 17–25, 28–30, 32], recurrent-flare type, which refers to a recurrent flare related to pregnancy with previous AOSD diagnosis [4, 7, 9, 13, 14, 16, 25, 31], and no-flare type, which is only a complication with no flare related to pregnancy [4, 9, 10, 14, 15, 17, 26, 27]. In the literature review, the cases were divided into these three types shown in Table 3 and our case belongs to the recurrent-flare type.
Table 3 Review of pregnancy cases with adult onset Still’s disease classified into three types
Total: 47 pregnant women and 53 pregnancies
First onset (Number = 26) Recurrent flare (Number = 13) No flare (Number = 14)
Age at pregnancy (year), Median [IQR] 29 [25–33] (1 unknown case) 31 [29–34] 27 [26–30] (1 unknown case)
Parity, %
Primigravida 50 (8/16) 80 (8/10) 69.2 (9/13)
Multigravida 50 (8/16) 20 (2/10) 30.8 (4/13)
Unknown, number 10 3 1
Timing of flare, %
1st trimester 24 (6/25) 23.1 (3/13) –
2nd trimester 52 (13/25) 38.5 (5/13) –
3rd trimester 8 (2/25) 7.7 (1/13) –
Postpartum 16 (4/25) 30.8 (4/13) –
Unknown, number 1 0 –
Major symptoms and complications, %
Fever 95.7 (22/23) 70 (7/10) –
Arthralgia, Arthritis 91.3 (21/23) 60 (6/10) –
Erythema, Rash 78.3 (18/23) 50 (5/10) –
Sore throat 65.2 (15/23) 30 (3/10) –
Lymphadenopathy 60.9 (14/23) 10 (1/10) –
Hepatomegaly, Liver dysfunction 34.8 (8/23) 30 (3/10) –
Splenomegaly 34.8 (8/23) 10 (1/10) –
HLH 8.7 (2/23) 10 (1/10) –
Unknown, number 3 3 –
Major treatment, %
Corticosteroid 82.6 (19/23) 69.2 (9/13) 28.6 (4/14)
Anakinra 13.0 (3/23) 7.7 (1/13) 28.6 (4/14)
IVIg 17.4 (4/23) 7.7 (1/13) 7.1 (1/14)
NSAIDs 21.7 (5/23) 7.7 (1/13) 14.3 (2/14)
HCQ 4.3 (1/23) 15.4 (2/13) 7.1 (1/14)
No medication – – 57.1 (8/14)
Unknown, number 3 0 0
Delivery, %
Transvaginal 66.7 (12/18) 50 (4/8) 62.5 (5/8)
Cesarean section 22.2 (4/18) 50 (4/8) 25 (2/8)
Abortion 11.1 (2/18) 0 (0/8) 12.5 (1/8)
Unknown, number 8 5 6
Major obstetrical and perinatal complications, %
Preterm birth 32 (8/25) 33.3 (4/12) 16.7 (2/12)
IUGR 8 (2/25) 41.7 (5/12) 8.3 (1/12)
pPROM 12 (3/25) 8.3 (1/12) 8.3 (1/12)
No major complication 48 (12/25) 41.7 (5/12) 50 (6/12)
Others, number 2 for OHD, 1 for neonatal HLH, 1 for preeclampsia, and 1 for neonatal death for IRDS 1 for GDM, and 1 for OHD 1 for neonatal HLH, 1 for GDM, and 1 for HDP
Unknown, number 1 1 2
The median age of patients at pregnancy was almost 30 years (median [interquartile range (IQR)]: 29 [25–33], 31 [29–34], and 27 [26–30] for the first-onset, recurrent-flare, and no-flare types, respectively), indicating that women with AOSD during pregnancy were younger than the general population at first diagnosis [1]. Regarding parity, AOSD flare mainly happens among primigravida patients, with the recurrent-flare type obtaining the highest rate (83.3%), although all patients in this type are in clinical remission at conception [4, 7, 9, 13, 14, 16, 25, 31]. Our case was also in clinical remission and did not require any medication at conception.
Most likely, the AOSD flare occurred until second trimester and at postpartum, with limited reports of flare at third trimester; the first-onset type was found only in two cases [21, 24] and the recurrent-flare type in one case, which is our case. Although AOSD flare occurring at third trimester is extremely rare, the clinical symptoms of AOSD are similar to those of HELLP syndrome and AFLP, suggesting that close attention to perinatal management is crucial. Generally, the Yamaguchi criteria [2] is adopted for the diagnosing AOSD (Table 1). However, we needed to assess AOSD recurrence in a comprehensive way by considering the clinical features and laboratory findings because no criteria for the diagnosis of AOSD recurrence are currently available. In fact, the review showed that most of the major symptoms of AOSD detected in the recurrent-flare type are relatively fewer than in the first-onset type. In addition, the major symptoms and findings of AOSD are elevated liver enzyme, leukocytosis, and sometimes abdominal pain or nausea, which are difficult to distinguish from HELLP syndrome or AFLP, particularly in cases with flare occurring at third trimester. Elevated ferritin [2] and IL-18 [33], which are reportedly biomarkers of AOSD activity, are considered better diagnostic markers than any other markers. Specific AOSD features such as fever, splenomegaly, and typical rash can support the possibility of AOSD. Izuka et al. recently reported that elevated serum aldolase can be a useful biomarker of AOSD [34]. In our case, the serum aldolase level was high (30.6 U/L), which supported the diagnosis of recurrent AOSD flare. Finally, we and some rheumatologists comprehensively diagnosed the patient with AOSD recurrence flare in consideration of the AOSD findings such as elevated ferritin, IL-18, and aldolase levels, splenomegaly, and uneventful fetal status.
AOSD treatments generally include PSL/mPSL, nonsteroidal anti-inflammatory agents (NSAIDs) and in more severe cases, methotrexate, anakinra (interleukin-1 [IL-1] inhibitor), intravenous immune globulin (IVIg), cyclosporine, or tacrolimus. However, selecting the appropriate medication for pregnant patients entails some limitations. Jamilloux Y et al. recommended corticosteroids as the first treatment choice, and IVIg and IL-1 inhibitor as the second treatment choice for AOSD [35]. Our review also showed that corticosteroid was mainly used, followed by IL-1 inhibitor and IVIg. In Japan, where most of the IL-1 antagonists have not yet been approved, tacrolimus may be a reasonable second choice for severe AOSD flare in pregnancy, and some successful management cases reported to have used this medication during pregnancy [11, 23]. In our case, twice mPSL pulse therapy followed by oral PSL was chosen; consequently, pregnancy was maintained until 36 gestational weeks.
In almost one-third of cases in both the first-onset and recurrent-flare types, the main obstetrical complication was preterm birth. Some reports showed that other autoimmune diseases or autoinflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis, occurring during pregnancy are risk factors for preterm birth, and maternal disease activity contributes to the increased risk of preterm delivery [36–38]. Furthermore, long-term steroidal use is another risk factor for preterm birth [37, 38]. Our review results showed that the incidence of preterm delivery in both the first-onset and recurrent-flare types of AOSD was almost twice higher than that in the no-flare type. Therefore, the high disease activity of AOSD and long-term use of systemic steroids may be possible reasons for the high incidence of preterm delivery in patients with AOSD. Our case also delivered prematurely, with high disease activity and long-term systemic steroid use including twice steroid pulse therapies. Hemophagocytic lymphohistiocytosis (HLH) is also a severe and crucial complication of AOSD. HLH was diagnosed in some cases having the first-onset and recurrent-flare types and in neonatal cases delivered from mothers with AOSD, even in clinical remission. Meanwhile, we believe that in general, the overall severity of AOSD during pregnancy may be better than the HELLP syndrome and AFLP. In fact, lethal complication was only found in one case wherein a premature fetus died at 28 weeks old because of infantile respiratory distress syndrome (IRDS) in the first-onset type, as reported by Green et al. in 1982 [8]. Therefore, with the cooperation of rheumatologists and pediatricians, pregnant patients with AOSD can maintain their pregnancy by paying special attention to prematurity, fetal growth, and HLH, even if the case is in clinical remission.
The relationship of pathogenesis between AOSD and pregnancy remains unclear. Ida A et al. reported that serum IL-18 levels were significantly elevated in pregnant women from the first trimester until the onset of labor than in nonpregnant women [39]. They noticed further increment of serum IL-18 levels after labor, lasting until at least the third day of postpartum. This result parallels the clinical feature of AOSD in pregnancy, that is, AOSD flares are likely to happen in the first/second trimester and postpartum. Considering that our case had also prominently high IL-18 levels, IL-18 elevation may cause the flare of AOSD during pregnancy, suggesting that pregnancy may be a risk factor of AOSD. Therefore, the serum IL-18 levels as a follow-up during pregnancy may be a useful predictive and diagnostic marker of AOSD flare; however, further investigations are required.
From the abovementioned consideration, patients with AOSD can be pregnant and continue pregnancy safely while under treatment, considering that the prognosis of pregnant women with AOSD and their fetuses is favorable in previous cases. Furthermore, for a safer pregnancy in patients complicated with AOSD, we, as obstetricians, need tight cooperation with rheumatologists and pediatricians for the sufficient control of AOSD activity and perinatal care and should provide enough explanation to patients on the risks of flares during pregnancy. Moreover, we conduct frequent laboratory tests and careful follow-up in preparation for flares, premature birth, and HLH. If the flare happens at third trimester, as in our case, we need to differentiate AOSD from HELLP syndrome and AFLP because of the similarity of laboratory data and physical findings. Fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for the differentiation from HELLP syndrome and AFLP.
To our knowledge, this report is the first to present the recurrent flare of AOSD during pregnancy at third trimester. However, we need to further investigate on the proper management of pregnant women with AOSD.
Abbreviations
AOSDAdult-onset Still’s disease
TNF-αTumor necrosis factor-α
IL-6Interleukin-6
IL-18Interleukin-18
HELLPHemolysis, elevated liver enzymes and low platelet count
AFLPAcute fatty liver of pregnancy
GDMGestational diabetes mellitus
EFBWEstimated fetal body weight
SDStandard deviation
mPSLMethylprednisolone
PSLPrednisolone
IUGRIntrauterine growth restriction
pPROMPreterm premature rupture of membrane
CRPC-reactive protein
IQRInterquartile range
NSAIDsNonsteroidal anti-inflammatory agents
IL-1Interleukin-1
IVIgIntravenous immune globulin
HLHHemophagocytic lymphohistiocytosis
IRDSInfantile respiratory distress syndrome
NVDNormal vaginal delivery
T-BilTotal bilirubin
ASTAspartate aminotransferase
ALTAlanine aminotransferase
LDHLactate dehydrogenase
γ-GTPγ-glutamyl transpeptidase
BUNBlood urea nitrogen
CreCreatinine
BSBlood sugar
TGTriglyceride
WBCWhite blood cell
RBCRed blood cell
HbHemoglobin
HtHematocrit
PltPlatelet
PT-INRProthrombin-time international normalized ratio
APTTActivated partial thromboplastin time
FibFibrinogen
AT IIIAntithrombin III
HCQHydroxychloroquine
OHDOligohydramnios
HDPHypertensive disorders of pregnancy
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Acknowledgements
The authors would like to thank Enago (www.enago.jp) for the English language review.
Authors’ contributions
SH collected and interpreted the patient’s data, collected previous reports and wrote the first draft of this paper. MS and HO also interpreted the data and revised the first draft. SI and HY also revised the first draft and support the data collection. All authors approved the final manuscript.
Authors’ information
SH was a junior resident of the Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan at the time of this work. Now, SH belongs to the Department of Obstetrics and Gynecology, the Jikei University School of Medicine.
Funding
All authors had no funding support related to this report.
Availability of data and materials
The datasets that support the findings about this case are available from the corresponding author, SH, on reasonable request.
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 of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33627085 | 19,473,834 | 2021-02-24 |
What was the outcome of reaction 'Foetal growth restriction'? | A case of recurrence of adult-onset Still's disease in the third trimester: a case report and literature review.
BACKGROUND
Adult-onset Still's disease (AOSD) is a self-inflammatory disease showing macrophage and neutrophil activation by inflammatory cytokines such as TNF-α, IL-6, and IL-18. Although some cases with the flare of AOSD during pregnancy have been reported, most had flares in the first or second trimester and few had flares in the third trimester. In this report, we present the case of a patient with recurrent flare of AOSD in the third trimester and discuss the management of AOSD in the third trimester with the review of previous literatures.
METHODS
A 38-year-old woman in complete AOSD remission without medication presented with impaired liver function, low platelet count, mild fever, abdominal pain, splenomegaly, and elevated ferritin and IL-18 levels at 30 gestational weeks. Although the laboratory data and physical examination finding suggested HELLP syndrome or acute fatty liver of pregnancy and we considered the termination of her pregnancy, her fetus was in a reactive status. Considering her fetal status, some specific findings of AOSD, and her AOSD history, we and rheumatologists diagnosed her with AOSD recurrence and started systemic steroid therapy. In her clinical course, three flares of AOSD occurred, twice in the third trimester and once in postpartum; twice systemic steroid pulse therapies were then needed. Ultimately, a healthy infant was delivered transvaginally at 36 gestational weeks spontaneously.
CONCLUSIONS
Specific findings of the flare of AOSD such as fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for differentiation from HELLP syndrome and AFLP in the third trimester. With the careful management supported by rheumatologists, patients complicated with the flare of AOSD may continue their pregnancy longer than we expected.
Background
Adult-onset Still’s disease (AOSD) is a self-inflammatory disease exhibiting macrophage and neutrophil activation by inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-18 (IL-18). Its incidence is 1.6–4.0 in 1,000,000 people per year [1]. AOSD more likely occurs in women, affecting 50 to 70%, than in men [1]. It mostly affects young adults (median age at diagnosis: 36 years) [1], indicating the reproductive ages in women. The Yamaguchi criteria [2] are commonly used to diagnose AOSD because they suggest major symptoms and laboratory findings of AOSD; common manifestations are remittent fever over 39 °C lasting more than a week, arthralgia or arthritis, typical rash, high white blood cell count, elevated liver enzymes, and splenomegaly (Table 1). In addition, some AOSD cases manifest abdominal pain and nausea [1]. If findings such as elevated liver enzyme and abdominal pain happen during pregnancy, AOSD may be misinterpreted as hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome and acute fatty liver of pregnancy (AFLP). Currently, although the association between the disease onset of AOSD and pregnancy has already been widely investigated [3, 4], such relationship remains unclear. Moreover, reported cases of AOSD flares at third trimester are few, and the management and features of AOSD, which has similar features to HELLP syndrome and AFLP, at the third trimester have not been reported yet. Herein, we report a rare case of a pregnant woman with AOSD recurrence at her 30 gestational weeks and reviewed the previous reports on the flares of AOSD related to pregnancy. Written informed consent for the publication of this report was obtained from the patient.
Table 1 Yamaguchi criteria for the diagnosis of adult-onset Still’s disease [2]
Major criteria Fever ≥39 °C lasting ≥1 week
Arthralgia or arthritis lasting ≥2 weeks
Typical nonpruritic salmon-colored rash
Leukocytosis ≥10,000/μl with granulocytes ≥80%
Minor criteria Sore throat
Lymphadenopathy
Splenomegaly
Abnormal liver function tests
Negative tests for antinuclear antibody and rheumatoid factor
Exclusion criteria Infection
Malignancy
Other rheumatic disease (vasculitis)
Diagnosis of adult-onset Still’s disease if ≥5 criteria are present with ≥2 being major criteria and no exclusion criteria
Case presentation
A 38-year-old primigravida with well-controlled gestational diabetes mellitus (GDM) was introduced from her home doctor to our hospital, presenting with mild fever, liver dysfunction, elevated ferritin, low platelet count, and proteinuria at 30 weeks and 5 days of gestation. She was diagnosed with AOSD 6 years ago in our hospital based on typical symptoms, including fever, malaise, cervical lymphadenopathy, rash, liver disfunction, and high serum ferritin levels. Although the rheumatologists performed biopsies of her bone marrow and lymph node, the results of these examination were normal and the possibility of other hematologic diseases was denied. After the combination treatment with systemic steroid and tocilizumab administration, she was in complete clinical remission without medication at conception. Upon arrival, her body temperature, blood pressure, and heart rate were 37.7 °C, 101/63 mmHg, and 103 beats/min. In systemic physical examinations, no abnormalities were found. The laboratory findings at arrival are presented in Table 2; The results indicated liver dysfunction, low platelet, and elevated IL-18 and aldolase levels. No apparent coagulopathy findings were observed. Basic infectious disease tests including Epstein–Barr virus and cytomegalovirus were all negative. Nonstress test and fetal sonography revealed perfect biophysical profile scoring of her fetus, mild polyhydramnios (maximum vertical pocket of amnion: 8.3 cm), and an estimated fetal body weight (EFBW) of 1663 g (+ 0.8 standard deviation [SD]). However, splenomegaly was detected by additional abdominal sonography. Although HELLP syndrome or AFLP was suspected upon admission according to liver dysfunction and low platelet count at third trimester and termination of pregnancy could be possible, her clinical course and examination results did not match well to Sibai’s criteria for HELLP syndrome [5] and Swansea’s criteria for AFLP [6]. Moreover, her general condition and fetal status did not require urgent intervention. Considering the findings such as mild fever, elevated ferritin level, high level of IL-18, splenomegaly, and good fetal status, she was ultimately diagnosed with recurrence flare of AOSD by us and some rheumatologists. Thus, systemic steroid pulse therapy (first dose: 250 mg of methylprednisolone [mPSL] for 3 days) was initiated and switched to oral prednisolone (PSL) thereafter. Additionally, the patient was carefully followed up by frequent laboratory tests and transabdominal fetal sonography. Figure 1 illustrates her clinical course after hospitalization at 30 gestational weeks. Clinical AOSD findings such as fever, liver dysfunction, and high ferritin level were well controlled for 3 weeks after the initiation of systemic steroid therapy; hence, the oral PSL dosage was gradually reduced. However, another steroid pulse therapy was needed for the second flare of AOSD that happened at her 33 gestational weeks with elevated liver enzymes and rash on her trunk. In her clinical course, although with maintained uneventful fetal status, the growth of the fetus had been gradually restricted, resulting in intrauterine growth restriction (IUGR). At 36 weeks and 0 days of gestation, she had irregular uterine contractions without apparent infectious findings, and preterm premature rupture of membrane (pPROM). Finally, she spontaneously delivered a female infant transvaginally at 36 weeks and 3 days of gestation. Her infant had a low birth weight (2440 g) but was very healthy; the Apgar score was 9/10, and pH of the umbilical artery was 7.312. Moreover, no abnormal findings of the amniotic fluid at delivery and no pathological features in her placenta and umbilical cord were found. At 12 days postpartum, she had elevated ferritin levels and extremely low platelet count, indicating the third AOSD flare by a rheumatologist; thus, the dosage of oral PSL was increased and maintained for months. During her follow-up checkup as an outpatient by rheumatologists at 1 year postpartum, her C-reactive protein (CRP) and ferritin levels were within the reference range, and her platelet count gradually increased, indicating a well-controlled AOSD.
Table 2 Laboratory findings
Value Reference intervals, unit
T-Bil 0.7 0.4–1.5, mg/dl
AST 491 13–30, U/L
ALT 438 7–23, U/L
LDH 653 124–222, U/L
γ-GTP 10 9–32, U/L
BUN 6.4 8.0–20.0, mg/dl
Cre 0.58 0.46–0.79, mg/dl
BS 84 80–110, mg/dl
UA 3.3 2.6–7.0, mg/dl
CRP 1.81 0.00–0.14, mg/dl
TG 163 30–149, mg/dl
Ferritin 281 5–157, ng/ml
WBC 2980 3300–8600, /μl
RBC 3.93 3.86–4.92, × 106/μl
Hb 10.7 11.6–14.8, g/dl
Ht 32.5 35.1–44.4, %
Plt 108 158–348, × 103 /μl
PT-INR 0.89 0.90–1.10
APTT 33 25–35, seconds
Fib 407 200–400, mg/dl
AT III 96 80–130, %
Urinary protein 0.33 0.02–0.12, g/day
IL-18 175,116 0–211, pg/ml
Aldolase 30.6 2.5–7.5, U/L
Fig. 1 Clinical course, laboratory data, and treatment of the patient. Initial mPSL pulse therapy was provided for 3 days after 30 weeks and 5 days of gestation and then switched to oral PSL therapy. At 33 weeks and 0 days of gestation, another pulse therapy was provided for the second flare. EFBW was restricted gradually from − 0.6 SD to − 1.5 SD. At 36 weeks and 0 days of gestation, this patient started irregular uterine contractions and finally delivered a healthy infant spontaneously at 36 weeks and 3 days of gestation. At 12 days postpartum, she experienced the third flare, and oral PSL therapy was maintained
Discussion and conclusions
The flare of AOSD in pregnancy was first reported in 1980 by Stein et al. [7]. Currently, nearly 30 reports about AOSD associated with pregnancy have been published [3, 4, 7–32]. Hence, we reviewed the cases of AOSD complications during pregnancy [3, 4, 7–32]. A total of 53 flares in 47 pregnant women, including our case, have been recorded. The clinical course of AOSD during pregnancy consists of three types: first-onset type, which refers to the first onset of AOSD related to pregnancy [3, 4, 7, 8, 11, 12, 14, 17–25, 28–30, 32], recurrent-flare type, which refers to a recurrent flare related to pregnancy with previous AOSD diagnosis [4, 7, 9, 13, 14, 16, 25, 31], and no-flare type, which is only a complication with no flare related to pregnancy [4, 9, 10, 14, 15, 17, 26, 27]. In the literature review, the cases were divided into these three types shown in Table 3 and our case belongs to the recurrent-flare type.
Table 3 Review of pregnancy cases with adult onset Still’s disease classified into three types
Total: 47 pregnant women and 53 pregnancies
First onset (Number = 26) Recurrent flare (Number = 13) No flare (Number = 14)
Age at pregnancy (year), Median [IQR] 29 [25–33] (1 unknown case) 31 [29–34] 27 [26–30] (1 unknown case)
Parity, %
Primigravida 50 (8/16) 80 (8/10) 69.2 (9/13)
Multigravida 50 (8/16) 20 (2/10) 30.8 (4/13)
Unknown, number 10 3 1
Timing of flare, %
1st trimester 24 (6/25) 23.1 (3/13) –
2nd trimester 52 (13/25) 38.5 (5/13) –
3rd trimester 8 (2/25) 7.7 (1/13) –
Postpartum 16 (4/25) 30.8 (4/13) –
Unknown, number 1 0 –
Major symptoms and complications, %
Fever 95.7 (22/23) 70 (7/10) –
Arthralgia, Arthritis 91.3 (21/23) 60 (6/10) –
Erythema, Rash 78.3 (18/23) 50 (5/10) –
Sore throat 65.2 (15/23) 30 (3/10) –
Lymphadenopathy 60.9 (14/23) 10 (1/10) –
Hepatomegaly, Liver dysfunction 34.8 (8/23) 30 (3/10) –
Splenomegaly 34.8 (8/23) 10 (1/10) –
HLH 8.7 (2/23) 10 (1/10) –
Unknown, number 3 3 –
Major treatment, %
Corticosteroid 82.6 (19/23) 69.2 (9/13) 28.6 (4/14)
Anakinra 13.0 (3/23) 7.7 (1/13) 28.6 (4/14)
IVIg 17.4 (4/23) 7.7 (1/13) 7.1 (1/14)
NSAIDs 21.7 (5/23) 7.7 (1/13) 14.3 (2/14)
HCQ 4.3 (1/23) 15.4 (2/13) 7.1 (1/14)
No medication – – 57.1 (8/14)
Unknown, number 3 0 0
Delivery, %
Transvaginal 66.7 (12/18) 50 (4/8) 62.5 (5/8)
Cesarean section 22.2 (4/18) 50 (4/8) 25 (2/8)
Abortion 11.1 (2/18) 0 (0/8) 12.5 (1/8)
Unknown, number 8 5 6
Major obstetrical and perinatal complications, %
Preterm birth 32 (8/25) 33.3 (4/12) 16.7 (2/12)
IUGR 8 (2/25) 41.7 (5/12) 8.3 (1/12)
pPROM 12 (3/25) 8.3 (1/12) 8.3 (1/12)
No major complication 48 (12/25) 41.7 (5/12) 50 (6/12)
Others, number 2 for OHD, 1 for neonatal HLH, 1 for preeclampsia, and 1 for neonatal death for IRDS 1 for GDM, and 1 for OHD 1 for neonatal HLH, 1 for GDM, and 1 for HDP
Unknown, number 1 1 2
The median age of patients at pregnancy was almost 30 years (median [interquartile range (IQR)]: 29 [25–33], 31 [29–34], and 27 [26–30] for the first-onset, recurrent-flare, and no-flare types, respectively), indicating that women with AOSD during pregnancy were younger than the general population at first diagnosis [1]. Regarding parity, AOSD flare mainly happens among primigravida patients, with the recurrent-flare type obtaining the highest rate (83.3%), although all patients in this type are in clinical remission at conception [4, 7, 9, 13, 14, 16, 25, 31]. Our case was also in clinical remission and did not require any medication at conception.
Most likely, the AOSD flare occurred until second trimester and at postpartum, with limited reports of flare at third trimester; the first-onset type was found only in two cases [21, 24] and the recurrent-flare type in one case, which is our case. Although AOSD flare occurring at third trimester is extremely rare, the clinical symptoms of AOSD are similar to those of HELLP syndrome and AFLP, suggesting that close attention to perinatal management is crucial. Generally, the Yamaguchi criteria [2] is adopted for the diagnosing AOSD (Table 1). However, we needed to assess AOSD recurrence in a comprehensive way by considering the clinical features and laboratory findings because no criteria for the diagnosis of AOSD recurrence are currently available. In fact, the review showed that most of the major symptoms of AOSD detected in the recurrent-flare type are relatively fewer than in the first-onset type. In addition, the major symptoms and findings of AOSD are elevated liver enzyme, leukocytosis, and sometimes abdominal pain or nausea, which are difficult to distinguish from HELLP syndrome or AFLP, particularly in cases with flare occurring at third trimester. Elevated ferritin [2] and IL-18 [33], which are reportedly biomarkers of AOSD activity, are considered better diagnostic markers than any other markers. Specific AOSD features such as fever, splenomegaly, and typical rash can support the possibility of AOSD. Izuka et al. recently reported that elevated serum aldolase can be a useful biomarker of AOSD [34]. In our case, the serum aldolase level was high (30.6 U/L), which supported the diagnosis of recurrent AOSD flare. Finally, we and some rheumatologists comprehensively diagnosed the patient with AOSD recurrence flare in consideration of the AOSD findings such as elevated ferritin, IL-18, and aldolase levels, splenomegaly, and uneventful fetal status.
AOSD treatments generally include PSL/mPSL, nonsteroidal anti-inflammatory agents (NSAIDs) and in more severe cases, methotrexate, anakinra (interleukin-1 [IL-1] inhibitor), intravenous immune globulin (IVIg), cyclosporine, or tacrolimus. However, selecting the appropriate medication for pregnant patients entails some limitations. Jamilloux Y et al. recommended corticosteroids as the first treatment choice, and IVIg and IL-1 inhibitor as the second treatment choice for AOSD [35]. Our review also showed that corticosteroid was mainly used, followed by IL-1 inhibitor and IVIg. In Japan, where most of the IL-1 antagonists have not yet been approved, tacrolimus may be a reasonable second choice for severe AOSD flare in pregnancy, and some successful management cases reported to have used this medication during pregnancy [11, 23]. In our case, twice mPSL pulse therapy followed by oral PSL was chosen; consequently, pregnancy was maintained until 36 gestational weeks.
In almost one-third of cases in both the first-onset and recurrent-flare types, the main obstetrical complication was preterm birth. Some reports showed that other autoimmune diseases or autoinflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis, occurring during pregnancy are risk factors for preterm birth, and maternal disease activity contributes to the increased risk of preterm delivery [36–38]. Furthermore, long-term steroidal use is another risk factor for preterm birth [37, 38]. Our review results showed that the incidence of preterm delivery in both the first-onset and recurrent-flare types of AOSD was almost twice higher than that in the no-flare type. Therefore, the high disease activity of AOSD and long-term use of systemic steroids may be possible reasons for the high incidence of preterm delivery in patients with AOSD. Our case also delivered prematurely, with high disease activity and long-term systemic steroid use including twice steroid pulse therapies. Hemophagocytic lymphohistiocytosis (HLH) is also a severe and crucial complication of AOSD. HLH was diagnosed in some cases having the first-onset and recurrent-flare types and in neonatal cases delivered from mothers with AOSD, even in clinical remission. Meanwhile, we believe that in general, the overall severity of AOSD during pregnancy may be better than the HELLP syndrome and AFLP. In fact, lethal complication was only found in one case wherein a premature fetus died at 28 weeks old because of infantile respiratory distress syndrome (IRDS) in the first-onset type, as reported by Green et al. in 1982 [8]. Therefore, with the cooperation of rheumatologists and pediatricians, pregnant patients with AOSD can maintain their pregnancy by paying special attention to prematurity, fetal growth, and HLH, even if the case is in clinical remission.
The relationship of pathogenesis between AOSD and pregnancy remains unclear. Ida A et al. reported that serum IL-18 levels were significantly elevated in pregnant women from the first trimester until the onset of labor than in nonpregnant women [39]. They noticed further increment of serum IL-18 levels after labor, lasting until at least the third day of postpartum. This result parallels the clinical feature of AOSD in pregnancy, that is, AOSD flares are likely to happen in the first/second trimester and postpartum. Considering that our case had also prominently high IL-18 levels, IL-18 elevation may cause the flare of AOSD during pregnancy, suggesting that pregnancy may be a risk factor of AOSD. Therefore, the serum IL-18 levels as a follow-up during pregnancy may be a useful predictive and diagnostic marker of AOSD flare; however, further investigations are required.
From the abovementioned consideration, patients with AOSD can be pregnant and continue pregnancy safely while under treatment, considering that the prognosis of pregnant women with AOSD and their fetuses is favorable in previous cases. Furthermore, for a safer pregnancy in patients complicated with AOSD, we, as obstetricians, need tight cooperation with rheumatologists and pediatricians for the sufficient control of AOSD activity and perinatal care and should provide enough explanation to patients on the risks of flares during pregnancy. Moreover, we conduct frequent laboratory tests and careful follow-up in preparation for flares, premature birth, and HLH. If the flare happens at third trimester, as in our case, we need to differentiate AOSD from HELLP syndrome and AFLP because of the similarity of laboratory data and physical findings. Fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for the differentiation from HELLP syndrome and AFLP.
To our knowledge, this report is the first to present the recurrent flare of AOSD during pregnancy at third trimester. However, we need to further investigate on the proper management of pregnant women with AOSD.
Abbreviations
AOSDAdult-onset Still’s disease
TNF-αTumor necrosis factor-α
IL-6Interleukin-6
IL-18Interleukin-18
HELLPHemolysis, elevated liver enzymes and low platelet count
AFLPAcute fatty liver of pregnancy
GDMGestational diabetes mellitus
EFBWEstimated fetal body weight
SDStandard deviation
mPSLMethylprednisolone
PSLPrednisolone
IUGRIntrauterine growth restriction
pPROMPreterm premature rupture of membrane
CRPC-reactive protein
IQRInterquartile range
NSAIDsNonsteroidal anti-inflammatory agents
IL-1Interleukin-1
IVIgIntravenous immune globulin
HLHHemophagocytic lymphohistiocytosis
IRDSInfantile respiratory distress syndrome
NVDNormal vaginal delivery
T-BilTotal bilirubin
ASTAspartate aminotransferase
ALTAlanine aminotransferase
LDHLactate dehydrogenase
γ-GTPγ-glutamyl transpeptidase
BUNBlood urea nitrogen
CreCreatinine
BSBlood sugar
TGTriglyceride
WBCWhite blood cell
RBCRed blood cell
HbHemoglobin
HtHematocrit
PltPlatelet
PT-INRProthrombin-time international normalized ratio
APTTActivated partial thromboplastin time
FibFibrinogen
AT IIIAntithrombin III
HCQHydroxychloroquine
OHDOligohydramnios
HDPHypertensive disorders of pregnancy
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors would like to thank Enago (www.enago.jp) for the English language review.
Authors’ contributions
SH collected and interpreted the patient’s data, collected previous reports and wrote the first draft of this paper. MS and HO also interpreted the data and revised the first draft. SI and HY also revised the first draft and support the data collection. All authors approved the final manuscript.
Authors’ information
SH was a junior resident of the Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan at the time of this work. Now, SH belongs to the Department of Obstetrics and Gynecology, the Jikei University School of Medicine.
Funding
All authors had no funding support related to this report.
Availability of data and materials
The datasets that support the findings about this case are available from the corresponding author, SH, on reasonable request.
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 of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33627085 | 19,473,834 | 2021-02-24 |
What was the outcome of reaction 'Maternal exposure during pregnancy'? | A case of recurrence of adult-onset Still's disease in the third trimester: a case report and literature review.
BACKGROUND
Adult-onset Still's disease (AOSD) is a self-inflammatory disease showing macrophage and neutrophil activation by inflammatory cytokines such as TNF-α, IL-6, and IL-18. Although some cases with the flare of AOSD during pregnancy have been reported, most had flares in the first or second trimester and few had flares in the third trimester. In this report, we present the case of a patient with recurrent flare of AOSD in the third trimester and discuss the management of AOSD in the third trimester with the review of previous literatures.
METHODS
A 38-year-old woman in complete AOSD remission without medication presented with impaired liver function, low platelet count, mild fever, abdominal pain, splenomegaly, and elevated ferritin and IL-18 levels at 30 gestational weeks. Although the laboratory data and physical examination finding suggested HELLP syndrome or acute fatty liver of pregnancy and we considered the termination of her pregnancy, her fetus was in a reactive status. Considering her fetal status, some specific findings of AOSD, and her AOSD history, we and rheumatologists diagnosed her with AOSD recurrence and started systemic steroid therapy. In her clinical course, three flares of AOSD occurred, twice in the third trimester and once in postpartum; twice systemic steroid pulse therapies were then needed. Ultimately, a healthy infant was delivered transvaginally at 36 gestational weeks spontaneously.
CONCLUSIONS
Specific findings of the flare of AOSD such as fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for differentiation from HELLP syndrome and AFLP in the third trimester. With the careful management supported by rheumatologists, patients complicated with the flare of AOSD may continue their pregnancy longer than we expected.
Background
Adult-onset Still’s disease (AOSD) is a self-inflammatory disease exhibiting macrophage and neutrophil activation by inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-18 (IL-18). Its incidence is 1.6–4.0 in 1,000,000 people per year [1]. AOSD more likely occurs in women, affecting 50 to 70%, than in men [1]. It mostly affects young adults (median age at diagnosis: 36 years) [1], indicating the reproductive ages in women. The Yamaguchi criteria [2] are commonly used to diagnose AOSD because they suggest major symptoms and laboratory findings of AOSD; common manifestations are remittent fever over 39 °C lasting more than a week, arthralgia or arthritis, typical rash, high white blood cell count, elevated liver enzymes, and splenomegaly (Table 1). In addition, some AOSD cases manifest abdominal pain and nausea [1]. If findings such as elevated liver enzyme and abdominal pain happen during pregnancy, AOSD may be misinterpreted as hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome and acute fatty liver of pregnancy (AFLP). Currently, although the association between the disease onset of AOSD and pregnancy has already been widely investigated [3, 4], such relationship remains unclear. Moreover, reported cases of AOSD flares at third trimester are few, and the management and features of AOSD, which has similar features to HELLP syndrome and AFLP, at the third trimester have not been reported yet. Herein, we report a rare case of a pregnant woman with AOSD recurrence at her 30 gestational weeks and reviewed the previous reports on the flares of AOSD related to pregnancy. Written informed consent for the publication of this report was obtained from the patient.
Table 1 Yamaguchi criteria for the diagnosis of adult-onset Still’s disease [2]
Major criteria Fever ≥39 °C lasting ≥1 week
Arthralgia or arthritis lasting ≥2 weeks
Typical nonpruritic salmon-colored rash
Leukocytosis ≥10,000/μl with granulocytes ≥80%
Minor criteria Sore throat
Lymphadenopathy
Splenomegaly
Abnormal liver function tests
Negative tests for antinuclear antibody and rheumatoid factor
Exclusion criteria Infection
Malignancy
Other rheumatic disease (vasculitis)
Diagnosis of adult-onset Still’s disease if ≥5 criteria are present with ≥2 being major criteria and no exclusion criteria
Case presentation
A 38-year-old primigravida with well-controlled gestational diabetes mellitus (GDM) was introduced from her home doctor to our hospital, presenting with mild fever, liver dysfunction, elevated ferritin, low platelet count, and proteinuria at 30 weeks and 5 days of gestation. She was diagnosed with AOSD 6 years ago in our hospital based on typical symptoms, including fever, malaise, cervical lymphadenopathy, rash, liver disfunction, and high serum ferritin levels. Although the rheumatologists performed biopsies of her bone marrow and lymph node, the results of these examination were normal and the possibility of other hematologic diseases was denied. After the combination treatment with systemic steroid and tocilizumab administration, she was in complete clinical remission without medication at conception. Upon arrival, her body temperature, blood pressure, and heart rate were 37.7 °C, 101/63 mmHg, and 103 beats/min. In systemic physical examinations, no abnormalities were found. The laboratory findings at arrival are presented in Table 2; The results indicated liver dysfunction, low platelet, and elevated IL-18 and aldolase levels. No apparent coagulopathy findings were observed. Basic infectious disease tests including Epstein–Barr virus and cytomegalovirus were all negative. Nonstress test and fetal sonography revealed perfect biophysical profile scoring of her fetus, mild polyhydramnios (maximum vertical pocket of amnion: 8.3 cm), and an estimated fetal body weight (EFBW) of 1663 g (+ 0.8 standard deviation [SD]). However, splenomegaly was detected by additional abdominal sonography. Although HELLP syndrome or AFLP was suspected upon admission according to liver dysfunction and low platelet count at third trimester and termination of pregnancy could be possible, her clinical course and examination results did not match well to Sibai’s criteria for HELLP syndrome [5] and Swansea’s criteria for AFLP [6]. Moreover, her general condition and fetal status did not require urgent intervention. Considering the findings such as mild fever, elevated ferritin level, high level of IL-18, splenomegaly, and good fetal status, she was ultimately diagnosed with recurrence flare of AOSD by us and some rheumatologists. Thus, systemic steroid pulse therapy (first dose: 250 mg of methylprednisolone [mPSL] for 3 days) was initiated and switched to oral prednisolone (PSL) thereafter. Additionally, the patient was carefully followed up by frequent laboratory tests and transabdominal fetal sonography. Figure 1 illustrates her clinical course after hospitalization at 30 gestational weeks. Clinical AOSD findings such as fever, liver dysfunction, and high ferritin level were well controlled for 3 weeks after the initiation of systemic steroid therapy; hence, the oral PSL dosage was gradually reduced. However, another steroid pulse therapy was needed for the second flare of AOSD that happened at her 33 gestational weeks with elevated liver enzymes and rash on her trunk. In her clinical course, although with maintained uneventful fetal status, the growth of the fetus had been gradually restricted, resulting in intrauterine growth restriction (IUGR). At 36 weeks and 0 days of gestation, she had irregular uterine contractions without apparent infectious findings, and preterm premature rupture of membrane (pPROM). Finally, she spontaneously delivered a female infant transvaginally at 36 weeks and 3 days of gestation. Her infant had a low birth weight (2440 g) but was very healthy; the Apgar score was 9/10, and pH of the umbilical artery was 7.312. Moreover, no abnormal findings of the amniotic fluid at delivery and no pathological features in her placenta and umbilical cord were found. At 12 days postpartum, she had elevated ferritin levels and extremely low platelet count, indicating the third AOSD flare by a rheumatologist; thus, the dosage of oral PSL was increased and maintained for months. During her follow-up checkup as an outpatient by rheumatologists at 1 year postpartum, her C-reactive protein (CRP) and ferritin levels were within the reference range, and her platelet count gradually increased, indicating a well-controlled AOSD.
Table 2 Laboratory findings
Value Reference intervals, unit
T-Bil 0.7 0.4–1.5, mg/dl
AST 491 13–30, U/L
ALT 438 7–23, U/L
LDH 653 124–222, U/L
γ-GTP 10 9–32, U/L
BUN 6.4 8.0–20.0, mg/dl
Cre 0.58 0.46–0.79, mg/dl
BS 84 80–110, mg/dl
UA 3.3 2.6–7.0, mg/dl
CRP 1.81 0.00–0.14, mg/dl
TG 163 30–149, mg/dl
Ferritin 281 5–157, ng/ml
WBC 2980 3300–8600, /μl
RBC 3.93 3.86–4.92, × 106/μl
Hb 10.7 11.6–14.8, g/dl
Ht 32.5 35.1–44.4, %
Plt 108 158–348, × 103 /μl
PT-INR 0.89 0.90–1.10
APTT 33 25–35, seconds
Fib 407 200–400, mg/dl
AT III 96 80–130, %
Urinary protein 0.33 0.02–0.12, g/day
IL-18 175,116 0–211, pg/ml
Aldolase 30.6 2.5–7.5, U/L
Fig. 1 Clinical course, laboratory data, and treatment of the patient. Initial mPSL pulse therapy was provided for 3 days after 30 weeks and 5 days of gestation and then switched to oral PSL therapy. At 33 weeks and 0 days of gestation, another pulse therapy was provided for the second flare. EFBW was restricted gradually from − 0.6 SD to − 1.5 SD. At 36 weeks and 0 days of gestation, this patient started irregular uterine contractions and finally delivered a healthy infant spontaneously at 36 weeks and 3 days of gestation. At 12 days postpartum, she experienced the third flare, and oral PSL therapy was maintained
Discussion and conclusions
The flare of AOSD in pregnancy was first reported in 1980 by Stein et al. [7]. Currently, nearly 30 reports about AOSD associated with pregnancy have been published [3, 4, 7–32]. Hence, we reviewed the cases of AOSD complications during pregnancy [3, 4, 7–32]. A total of 53 flares in 47 pregnant women, including our case, have been recorded. The clinical course of AOSD during pregnancy consists of three types: first-onset type, which refers to the first onset of AOSD related to pregnancy [3, 4, 7, 8, 11, 12, 14, 17–25, 28–30, 32], recurrent-flare type, which refers to a recurrent flare related to pregnancy with previous AOSD diagnosis [4, 7, 9, 13, 14, 16, 25, 31], and no-flare type, which is only a complication with no flare related to pregnancy [4, 9, 10, 14, 15, 17, 26, 27]. In the literature review, the cases were divided into these three types shown in Table 3 and our case belongs to the recurrent-flare type.
Table 3 Review of pregnancy cases with adult onset Still’s disease classified into three types
Total: 47 pregnant women and 53 pregnancies
First onset (Number = 26) Recurrent flare (Number = 13) No flare (Number = 14)
Age at pregnancy (year), Median [IQR] 29 [25–33] (1 unknown case) 31 [29–34] 27 [26–30] (1 unknown case)
Parity, %
Primigravida 50 (8/16) 80 (8/10) 69.2 (9/13)
Multigravida 50 (8/16) 20 (2/10) 30.8 (4/13)
Unknown, number 10 3 1
Timing of flare, %
1st trimester 24 (6/25) 23.1 (3/13) –
2nd trimester 52 (13/25) 38.5 (5/13) –
3rd trimester 8 (2/25) 7.7 (1/13) –
Postpartum 16 (4/25) 30.8 (4/13) –
Unknown, number 1 0 –
Major symptoms and complications, %
Fever 95.7 (22/23) 70 (7/10) –
Arthralgia, Arthritis 91.3 (21/23) 60 (6/10) –
Erythema, Rash 78.3 (18/23) 50 (5/10) –
Sore throat 65.2 (15/23) 30 (3/10) –
Lymphadenopathy 60.9 (14/23) 10 (1/10) –
Hepatomegaly, Liver dysfunction 34.8 (8/23) 30 (3/10) –
Splenomegaly 34.8 (8/23) 10 (1/10) –
HLH 8.7 (2/23) 10 (1/10) –
Unknown, number 3 3 –
Major treatment, %
Corticosteroid 82.6 (19/23) 69.2 (9/13) 28.6 (4/14)
Anakinra 13.0 (3/23) 7.7 (1/13) 28.6 (4/14)
IVIg 17.4 (4/23) 7.7 (1/13) 7.1 (1/14)
NSAIDs 21.7 (5/23) 7.7 (1/13) 14.3 (2/14)
HCQ 4.3 (1/23) 15.4 (2/13) 7.1 (1/14)
No medication – – 57.1 (8/14)
Unknown, number 3 0 0
Delivery, %
Transvaginal 66.7 (12/18) 50 (4/8) 62.5 (5/8)
Cesarean section 22.2 (4/18) 50 (4/8) 25 (2/8)
Abortion 11.1 (2/18) 0 (0/8) 12.5 (1/8)
Unknown, number 8 5 6
Major obstetrical and perinatal complications, %
Preterm birth 32 (8/25) 33.3 (4/12) 16.7 (2/12)
IUGR 8 (2/25) 41.7 (5/12) 8.3 (1/12)
pPROM 12 (3/25) 8.3 (1/12) 8.3 (1/12)
No major complication 48 (12/25) 41.7 (5/12) 50 (6/12)
Others, number 2 for OHD, 1 for neonatal HLH, 1 for preeclampsia, and 1 for neonatal death for IRDS 1 for GDM, and 1 for OHD 1 for neonatal HLH, 1 for GDM, and 1 for HDP
Unknown, number 1 1 2
The median age of patients at pregnancy was almost 30 years (median [interquartile range (IQR)]: 29 [25–33], 31 [29–34], and 27 [26–30] for the first-onset, recurrent-flare, and no-flare types, respectively), indicating that women with AOSD during pregnancy were younger than the general population at first diagnosis [1]. Regarding parity, AOSD flare mainly happens among primigravida patients, with the recurrent-flare type obtaining the highest rate (83.3%), although all patients in this type are in clinical remission at conception [4, 7, 9, 13, 14, 16, 25, 31]. Our case was also in clinical remission and did not require any medication at conception.
Most likely, the AOSD flare occurred until second trimester and at postpartum, with limited reports of flare at third trimester; the first-onset type was found only in two cases [21, 24] and the recurrent-flare type in one case, which is our case. Although AOSD flare occurring at third trimester is extremely rare, the clinical symptoms of AOSD are similar to those of HELLP syndrome and AFLP, suggesting that close attention to perinatal management is crucial. Generally, the Yamaguchi criteria [2] is adopted for the diagnosing AOSD (Table 1). However, we needed to assess AOSD recurrence in a comprehensive way by considering the clinical features and laboratory findings because no criteria for the diagnosis of AOSD recurrence are currently available. In fact, the review showed that most of the major symptoms of AOSD detected in the recurrent-flare type are relatively fewer than in the first-onset type. In addition, the major symptoms and findings of AOSD are elevated liver enzyme, leukocytosis, and sometimes abdominal pain or nausea, which are difficult to distinguish from HELLP syndrome or AFLP, particularly in cases with flare occurring at third trimester. Elevated ferritin [2] and IL-18 [33], which are reportedly biomarkers of AOSD activity, are considered better diagnostic markers than any other markers. Specific AOSD features such as fever, splenomegaly, and typical rash can support the possibility of AOSD. Izuka et al. recently reported that elevated serum aldolase can be a useful biomarker of AOSD [34]. In our case, the serum aldolase level was high (30.6 U/L), which supported the diagnosis of recurrent AOSD flare. Finally, we and some rheumatologists comprehensively diagnosed the patient with AOSD recurrence flare in consideration of the AOSD findings such as elevated ferritin, IL-18, and aldolase levels, splenomegaly, and uneventful fetal status.
AOSD treatments generally include PSL/mPSL, nonsteroidal anti-inflammatory agents (NSAIDs) and in more severe cases, methotrexate, anakinra (interleukin-1 [IL-1] inhibitor), intravenous immune globulin (IVIg), cyclosporine, or tacrolimus. However, selecting the appropriate medication for pregnant patients entails some limitations. Jamilloux Y et al. recommended corticosteroids as the first treatment choice, and IVIg and IL-1 inhibitor as the second treatment choice for AOSD [35]. Our review also showed that corticosteroid was mainly used, followed by IL-1 inhibitor and IVIg. In Japan, where most of the IL-1 antagonists have not yet been approved, tacrolimus may be a reasonable second choice for severe AOSD flare in pregnancy, and some successful management cases reported to have used this medication during pregnancy [11, 23]. In our case, twice mPSL pulse therapy followed by oral PSL was chosen; consequently, pregnancy was maintained until 36 gestational weeks.
In almost one-third of cases in both the first-onset and recurrent-flare types, the main obstetrical complication was preterm birth. Some reports showed that other autoimmune diseases or autoinflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis, occurring during pregnancy are risk factors for preterm birth, and maternal disease activity contributes to the increased risk of preterm delivery [36–38]. Furthermore, long-term steroidal use is another risk factor for preterm birth [37, 38]. Our review results showed that the incidence of preterm delivery in both the first-onset and recurrent-flare types of AOSD was almost twice higher than that in the no-flare type. Therefore, the high disease activity of AOSD and long-term use of systemic steroids may be possible reasons for the high incidence of preterm delivery in patients with AOSD. Our case also delivered prematurely, with high disease activity and long-term systemic steroid use including twice steroid pulse therapies. Hemophagocytic lymphohistiocytosis (HLH) is also a severe and crucial complication of AOSD. HLH was diagnosed in some cases having the first-onset and recurrent-flare types and in neonatal cases delivered from mothers with AOSD, even in clinical remission. Meanwhile, we believe that in general, the overall severity of AOSD during pregnancy may be better than the HELLP syndrome and AFLP. In fact, lethal complication was only found in one case wherein a premature fetus died at 28 weeks old because of infantile respiratory distress syndrome (IRDS) in the first-onset type, as reported by Green et al. in 1982 [8]. Therefore, with the cooperation of rheumatologists and pediatricians, pregnant patients with AOSD can maintain their pregnancy by paying special attention to prematurity, fetal growth, and HLH, even if the case is in clinical remission.
The relationship of pathogenesis between AOSD and pregnancy remains unclear. Ida A et al. reported that serum IL-18 levels were significantly elevated in pregnant women from the first trimester until the onset of labor than in nonpregnant women [39]. They noticed further increment of serum IL-18 levels after labor, lasting until at least the third day of postpartum. This result parallels the clinical feature of AOSD in pregnancy, that is, AOSD flares are likely to happen in the first/second trimester and postpartum. Considering that our case had also prominently high IL-18 levels, IL-18 elevation may cause the flare of AOSD during pregnancy, suggesting that pregnancy may be a risk factor of AOSD. Therefore, the serum IL-18 levels as a follow-up during pregnancy may be a useful predictive and diagnostic marker of AOSD flare; however, further investigations are required.
From the abovementioned consideration, patients with AOSD can be pregnant and continue pregnancy safely while under treatment, considering that the prognosis of pregnant women with AOSD and their fetuses is favorable in previous cases. Furthermore, for a safer pregnancy in patients complicated with AOSD, we, as obstetricians, need tight cooperation with rheumatologists and pediatricians for the sufficient control of AOSD activity and perinatal care and should provide enough explanation to patients on the risks of flares during pregnancy. Moreover, we conduct frequent laboratory tests and careful follow-up in preparation for flares, premature birth, and HLH. If the flare happens at third trimester, as in our case, we need to differentiate AOSD from HELLP syndrome and AFLP because of the similarity of laboratory data and physical findings. Fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for the differentiation from HELLP syndrome and AFLP.
To our knowledge, this report is the first to present the recurrent flare of AOSD during pregnancy at third trimester. However, we need to further investigate on the proper management of pregnant women with AOSD.
Abbreviations
AOSDAdult-onset Still’s disease
TNF-αTumor necrosis factor-α
IL-6Interleukin-6
IL-18Interleukin-18
HELLPHemolysis, elevated liver enzymes and low platelet count
AFLPAcute fatty liver of pregnancy
GDMGestational diabetes mellitus
EFBWEstimated fetal body weight
SDStandard deviation
mPSLMethylprednisolone
PSLPrednisolone
IUGRIntrauterine growth restriction
pPROMPreterm premature rupture of membrane
CRPC-reactive protein
IQRInterquartile range
NSAIDsNonsteroidal anti-inflammatory agents
IL-1Interleukin-1
IVIgIntravenous immune globulin
HLHHemophagocytic lymphohistiocytosis
IRDSInfantile respiratory distress syndrome
NVDNormal vaginal delivery
T-BilTotal bilirubin
ASTAspartate aminotransferase
ALTAlanine aminotransferase
LDHLactate dehydrogenase
γ-GTPγ-glutamyl transpeptidase
BUNBlood urea nitrogen
CreCreatinine
BSBlood sugar
TGTriglyceride
WBCWhite blood cell
RBCRed blood cell
HbHemoglobin
HtHematocrit
PltPlatelet
PT-INRProthrombin-time international normalized ratio
APTTActivated partial thromboplastin time
FibFibrinogen
AT IIIAntithrombin III
HCQHydroxychloroquine
OHDOligohydramnios
HDPHypertensive disorders of pregnancy
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors would like to thank Enago (www.enago.jp) for the English language review.
Authors’ contributions
SH collected and interpreted the patient’s data, collected previous reports and wrote the first draft of this paper. MS and HO also interpreted the data and revised the first draft. SI and HY also revised the first draft and support the data collection. All authors approved the final manuscript.
Authors’ information
SH was a junior resident of the Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan at the time of this work. Now, SH belongs to the Department of Obstetrics and Gynecology, the Jikei University School of Medicine.
Funding
All authors had no funding support related to this report.
Availability of data and materials
The datasets that support the findings about this case are available from the corresponding author, SH, on reasonable request.
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 of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33627085 | 19,487,180 | 2021-02-24 |
What was the outcome of reaction 'Premature delivery'? | A case of recurrence of adult-onset Still's disease in the third trimester: a case report and literature review.
BACKGROUND
Adult-onset Still's disease (AOSD) is a self-inflammatory disease showing macrophage and neutrophil activation by inflammatory cytokines such as TNF-α, IL-6, and IL-18. Although some cases with the flare of AOSD during pregnancy have been reported, most had flares in the first or second trimester and few had flares in the third trimester. In this report, we present the case of a patient with recurrent flare of AOSD in the third trimester and discuss the management of AOSD in the third trimester with the review of previous literatures.
METHODS
A 38-year-old woman in complete AOSD remission without medication presented with impaired liver function, low platelet count, mild fever, abdominal pain, splenomegaly, and elevated ferritin and IL-18 levels at 30 gestational weeks. Although the laboratory data and physical examination finding suggested HELLP syndrome or acute fatty liver of pregnancy and we considered the termination of her pregnancy, her fetus was in a reactive status. Considering her fetal status, some specific findings of AOSD, and her AOSD history, we and rheumatologists diagnosed her with AOSD recurrence and started systemic steroid therapy. In her clinical course, three flares of AOSD occurred, twice in the third trimester and once in postpartum; twice systemic steroid pulse therapies were then needed. Ultimately, a healthy infant was delivered transvaginally at 36 gestational weeks spontaneously.
CONCLUSIONS
Specific findings of the flare of AOSD such as fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for differentiation from HELLP syndrome and AFLP in the third trimester. With the careful management supported by rheumatologists, patients complicated with the flare of AOSD may continue their pregnancy longer than we expected.
Background
Adult-onset Still’s disease (AOSD) is a self-inflammatory disease exhibiting macrophage and neutrophil activation by inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-18 (IL-18). Its incidence is 1.6–4.0 in 1,000,000 people per year [1]. AOSD more likely occurs in women, affecting 50 to 70%, than in men [1]. It mostly affects young adults (median age at diagnosis: 36 years) [1], indicating the reproductive ages in women. The Yamaguchi criteria [2] are commonly used to diagnose AOSD because they suggest major symptoms and laboratory findings of AOSD; common manifestations are remittent fever over 39 °C lasting more than a week, arthralgia or arthritis, typical rash, high white blood cell count, elevated liver enzymes, and splenomegaly (Table 1). In addition, some AOSD cases manifest abdominal pain and nausea [1]. If findings such as elevated liver enzyme and abdominal pain happen during pregnancy, AOSD may be misinterpreted as hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome and acute fatty liver of pregnancy (AFLP). Currently, although the association between the disease onset of AOSD and pregnancy has already been widely investigated [3, 4], such relationship remains unclear. Moreover, reported cases of AOSD flares at third trimester are few, and the management and features of AOSD, which has similar features to HELLP syndrome and AFLP, at the third trimester have not been reported yet. Herein, we report a rare case of a pregnant woman with AOSD recurrence at her 30 gestational weeks and reviewed the previous reports on the flares of AOSD related to pregnancy. Written informed consent for the publication of this report was obtained from the patient.
Table 1 Yamaguchi criteria for the diagnosis of adult-onset Still’s disease [2]
Major criteria Fever ≥39 °C lasting ≥1 week
Arthralgia or arthritis lasting ≥2 weeks
Typical nonpruritic salmon-colored rash
Leukocytosis ≥10,000/μl with granulocytes ≥80%
Minor criteria Sore throat
Lymphadenopathy
Splenomegaly
Abnormal liver function tests
Negative tests for antinuclear antibody and rheumatoid factor
Exclusion criteria Infection
Malignancy
Other rheumatic disease (vasculitis)
Diagnosis of adult-onset Still’s disease if ≥5 criteria are present with ≥2 being major criteria and no exclusion criteria
Case presentation
A 38-year-old primigravida with well-controlled gestational diabetes mellitus (GDM) was introduced from her home doctor to our hospital, presenting with mild fever, liver dysfunction, elevated ferritin, low platelet count, and proteinuria at 30 weeks and 5 days of gestation. She was diagnosed with AOSD 6 years ago in our hospital based on typical symptoms, including fever, malaise, cervical lymphadenopathy, rash, liver disfunction, and high serum ferritin levels. Although the rheumatologists performed biopsies of her bone marrow and lymph node, the results of these examination were normal and the possibility of other hematologic diseases was denied. After the combination treatment with systemic steroid and tocilizumab administration, she was in complete clinical remission without medication at conception. Upon arrival, her body temperature, blood pressure, and heart rate were 37.7 °C, 101/63 mmHg, and 103 beats/min. In systemic physical examinations, no abnormalities were found. The laboratory findings at arrival are presented in Table 2; The results indicated liver dysfunction, low platelet, and elevated IL-18 and aldolase levels. No apparent coagulopathy findings were observed. Basic infectious disease tests including Epstein–Barr virus and cytomegalovirus were all negative. Nonstress test and fetal sonography revealed perfect biophysical profile scoring of her fetus, mild polyhydramnios (maximum vertical pocket of amnion: 8.3 cm), and an estimated fetal body weight (EFBW) of 1663 g (+ 0.8 standard deviation [SD]). However, splenomegaly was detected by additional abdominal sonography. Although HELLP syndrome or AFLP was suspected upon admission according to liver dysfunction and low platelet count at third trimester and termination of pregnancy could be possible, her clinical course and examination results did not match well to Sibai’s criteria for HELLP syndrome [5] and Swansea’s criteria for AFLP [6]. Moreover, her general condition and fetal status did not require urgent intervention. Considering the findings such as mild fever, elevated ferritin level, high level of IL-18, splenomegaly, and good fetal status, she was ultimately diagnosed with recurrence flare of AOSD by us and some rheumatologists. Thus, systemic steroid pulse therapy (first dose: 250 mg of methylprednisolone [mPSL] for 3 days) was initiated and switched to oral prednisolone (PSL) thereafter. Additionally, the patient was carefully followed up by frequent laboratory tests and transabdominal fetal sonography. Figure 1 illustrates her clinical course after hospitalization at 30 gestational weeks. Clinical AOSD findings such as fever, liver dysfunction, and high ferritin level were well controlled for 3 weeks after the initiation of systemic steroid therapy; hence, the oral PSL dosage was gradually reduced. However, another steroid pulse therapy was needed for the second flare of AOSD that happened at her 33 gestational weeks with elevated liver enzymes and rash on her trunk. In her clinical course, although with maintained uneventful fetal status, the growth of the fetus had been gradually restricted, resulting in intrauterine growth restriction (IUGR). At 36 weeks and 0 days of gestation, she had irregular uterine contractions without apparent infectious findings, and preterm premature rupture of membrane (pPROM). Finally, she spontaneously delivered a female infant transvaginally at 36 weeks and 3 days of gestation. Her infant had a low birth weight (2440 g) but was very healthy; the Apgar score was 9/10, and pH of the umbilical artery was 7.312. Moreover, no abnormal findings of the amniotic fluid at delivery and no pathological features in her placenta and umbilical cord were found. At 12 days postpartum, she had elevated ferritin levels and extremely low platelet count, indicating the third AOSD flare by a rheumatologist; thus, the dosage of oral PSL was increased and maintained for months. During her follow-up checkup as an outpatient by rheumatologists at 1 year postpartum, her C-reactive protein (CRP) and ferritin levels were within the reference range, and her platelet count gradually increased, indicating a well-controlled AOSD.
Table 2 Laboratory findings
Value Reference intervals, unit
T-Bil 0.7 0.4–1.5, mg/dl
AST 491 13–30, U/L
ALT 438 7–23, U/L
LDH 653 124–222, U/L
γ-GTP 10 9–32, U/L
BUN 6.4 8.0–20.0, mg/dl
Cre 0.58 0.46–0.79, mg/dl
BS 84 80–110, mg/dl
UA 3.3 2.6–7.0, mg/dl
CRP 1.81 0.00–0.14, mg/dl
TG 163 30–149, mg/dl
Ferritin 281 5–157, ng/ml
WBC 2980 3300–8600, /μl
RBC 3.93 3.86–4.92, × 106/μl
Hb 10.7 11.6–14.8, g/dl
Ht 32.5 35.1–44.4, %
Plt 108 158–348, × 103 /μl
PT-INR 0.89 0.90–1.10
APTT 33 25–35, seconds
Fib 407 200–400, mg/dl
AT III 96 80–130, %
Urinary protein 0.33 0.02–0.12, g/day
IL-18 175,116 0–211, pg/ml
Aldolase 30.6 2.5–7.5, U/L
Fig. 1 Clinical course, laboratory data, and treatment of the patient. Initial mPSL pulse therapy was provided for 3 days after 30 weeks and 5 days of gestation and then switched to oral PSL therapy. At 33 weeks and 0 days of gestation, another pulse therapy was provided for the second flare. EFBW was restricted gradually from − 0.6 SD to − 1.5 SD. At 36 weeks and 0 days of gestation, this patient started irregular uterine contractions and finally delivered a healthy infant spontaneously at 36 weeks and 3 days of gestation. At 12 days postpartum, she experienced the third flare, and oral PSL therapy was maintained
Discussion and conclusions
The flare of AOSD in pregnancy was first reported in 1980 by Stein et al. [7]. Currently, nearly 30 reports about AOSD associated with pregnancy have been published [3, 4, 7–32]. Hence, we reviewed the cases of AOSD complications during pregnancy [3, 4, 7–32]. A total of 53 flares in 47 pregnant women, including our case, have been recorded. The clinical course of AOSD during pregnancy consists of three types: first-onset type, which refers to the first onset of AOSD related to pregnancy [3, 4, 7, 8, 11, 12, 14, 17–25, 28–30, 32], recurrent-flare type, which refers to a recurrent flare related to pregnancy with previous AOSD diagnosis [4, 7, 9, 13, 14, 16, 25, 31], and no-flare type, which is only a complication with no flare related to pregnancy [4, 9, 10, 14, 15, 17, 26, 27]. In the literature review, the cases were divided into these three types shown in Table 3 and our case belongs to the recurrent-flare type.
Table 3 Review of pregnancy cases with adult onset Still’s disease classified into three types
Total: 47 pregnant women and 53 pregnancies
First onset (Number = 26) Recurrent flare (Number = 13) No flare (Number = 14)
Age at pregnancy (year), Median [IQR] 29 [25–33] (1 unknown case) 31 [29–34] 27 [26–30] (1 unknown case)
Parity, %
Primigravida 50 (8/16) 80 (8/10) 69.2 (9/13)
Multigravida 50 (8/16) 20 (2/10) 30.8 (4/13)
Unknown, number 10 3 1
Timing of flare, %
1st trimester 24 (6/25) 23.1 (3/13) –
2nd trimester 52 (13/25) 38.5 (5/13) –
3rd trimester 8 (2/25) 7.7 (1/13) –
Postpartum 16 (4/25) 30.8 (4/13) –
Unknown, number 1 0 –
Major symptoms and complications, %
Fever 95.7 (22/23) 70 (7/10) –
Arthralgia, Arthritis 91.3 (21/23) 60 (6/10) –
Erythema, Rash 78.3 (18/23) 50 (5/10) –
Sore throat 65.2 (15/23) 30 (3/10) –
Lymphadenopathy 60.9 (14/23) 10 (1/10) –
Hepatomegaly, Liver dysfunction 34.8 (8/23) 30 (3/10) –
Splenomegaly 34.8 (8/23) 10 (1/10) –
HLH 8.7 (2/23) 10 (1/10) –
Unknown, number 3 3 –
Major treatment, %
Corticosteroid 82.6 (19/23) 69.2 (9/13) 28.6 (4/14)
Anakinra 13.0 (3/23) 7.7 (1/13) 28.6 (4/14)
IVIg 17.4 (4/23) 7.7 (1/13) 7.1 (1/14)
NSAIDs 21.7 (5/23) 7.7 (1/13) 14.3 (2/14)
HCQ 4.3 (1/23) 15.4 (2/13) 7.1 (1/14)
No medication – – 57.1 (8/14)
Unknown, number 3 0 0
Delivery, %
Transvaginal 66.7 (12/18) 50 (4/8) 62.5 (5/8)
Cesarean section 22.2 (4/18) 50 (4/8) 25 (2/8)
Abortion 11.1 (2/18) 0 (0/8) 12.5 (1/8)
Unknown, number 8 5 6
Major obstetrical and perinatal complications, %
Preterm birth 32 (8/25) 33.3 (4/12) 16.7 (2/12)
IUGR 8 (2/25) 41.7 (5/12) 8.3 (1/12)
pPROM 12 (3/25) 8.3 (1/12) 8.3 (1/12)
No major complication 48 (12/25) 41.7 (5/12) 50 (6/12)
Others, number 2 for OHD, 1 for neonatal HLH, 1 for preeclampsia, and 1 for neonatal death for IRDS 1 for GDM, and 1 for OHD 1 for neonatal HLH, 1 for GDM, and 1 for HDP
Unknown, number 1 1 2
The median age of patients at pregnancy was almost 30 years (median [interquartile range (IQR)]: 29 [25–33], 31 [29–34], and 27 [26–30] for the first-onset, recurrent-flare, and no-flare types, respectively), indicating that women with AOSD during pregnancy were younger than the general population at first diagnosis [1]. Regarding parity, AOSD flare mainly happens among primigravida patients, with the recurrent-flare type obtaining the highest rate (83.3%), although all patients in this type are in clinical remission at conception [4, 7, 9, 13, 14, 16, 25, 31]. Our case was also in clinical remission and did not require any medication at conception.
Most likely, the AOSD flare occurred until second trimester and at postpartum, with limited reports of flare at third trimester; the first-onset type was found only in two cases [21, 24] and the recurrent-flare type in one case, which is our case. Although AOSD flare occurring at third trimester is extremely rare, the clinical symptoms of AOSD are similar to those of HELLP syndrome and AFLP, suggesting that close attention to perinatal management is crucial. Generally, the Yamaguchi criteria [2] is adopted for the diagnosing AOSD (Table 1). However, we needed to assess AOSD recurrence in a comprehensive way by considering the clinical features and laboratory findings because no criteria for the diagnosis of AOSD recurrence are currently available. In fact, the review showed that most of the major symptoms of AOSD detected in the recurrent-flare type are relatively fewer than in the first-onset type. In addition, the major symptoms and findings of AOSD are elevated liver enzyme, leukocytosis, and sometimes abdominal pain or nausea, which are difficult to distinguish from HELLP syndrome or AFLP, particularly in cases with flare occurring at third trimester. Elevated ferritin [2] and IL-18 [33], which are reportedly biomarkers of AOSD activity, are considered better diagnostic markers than any other markers. Specific AOSD features such as fever, splenomegaly, and typical rash can support the possibility of AOSD. Izuka et al. recently reported that elevated serum aldolase can be a useful biomarker of AOSD [34]. In our case, the serum aldolase level was high (30.6 U/L), which supported the diagnosis of recurrent AOSD flare. Finally, we and some rheumatologists comprehensively diagnosed the patient with AOSD recurrence flare in consideration of the AOSD findings such as elevated ferritin, IL-18, and aldolase levels, splenomegaly, and uneventful fetal status.
AOSD treatments generally include PSL/mPSL, nonsteroidal anti-inflammatory agents (NSAIDs) and in more severe cases, methotrexate, anakinra (interleukin-1 [IL-1] inhibitor), intravenous immune globulin (IVIg), cyclosporine, or tacrolimus. However, selecting the appropriate medication for pregnant patients entails some limitations. Jamilloux Y et al. recommended corticosteroids as the first treatment choice, and IVIg and IL-1 inhibitor as the second treatment choice for AOSD [35]. Our review also showed that corticosteroid was mainly used, followed by IL-1 inhibitor and IVIg. In Japan, where most of the IL-1 antagonists have not yet been approved, tacrolimus may be a reasonable second choice for severe AOSD flare in pregnancy, and some successful management cases reported to have used this medication during pregnancy [11, 23]. In our case, twice mPSL pulse therapy followed by oral PSL was chosen; consequently, pregnancy was maintained until 36 gestational weeks.
In almost one-third of cases in both the first-onset and recurrent-flare types, the main obstetrical complication was preterm birth. Some reports showed that other autoimmune diseases or autoinflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis, occurring during pregnancy are risk factors for preterm birth, and maternal disease activity contributes to the increased risk of preterm delivery [36–38]. Furthermore, long-term steroidal use is another risk factor for preterm birth [37, 38]. Our review results showed that the incidence of preterm delivery in both the first-onset and recurrent-flare types of AOSD was almost twice higher than that in the no-flare type. Therefore, the high disease activity of AOSD and long-term use of systemic steroids may be possible reasons for the high incidence of preterm delivery in patients with AOSD. Our case also delivered prematurely, with high disease activity and long-term systemic steroid use including twice steroid pulse therapies. Hemophagocytic lymphohistiocytosis (HLH) is also a severe and crucial complication of AOSD. HLH was diagnosed in some cases having the first-onset and recurrent-flare types and in neonatal cases delivered from mothers with AOSD, even in clinical remission. Meanwhile, we believe that in general, the overall severity of AOSD during pregnancy may be better than the HELLP syndrome and AFLP. In fact, lethal complication was only found in one case wherein a premature fetus died at 28 weeks old because of infantile respiratory distress syndrome (IRDS) in the first-onset type, as reported by Green et al. in 1982 [8]. Therefore, with the cooperation of rheumatologists and pediatricians, pregnant patients with AOSD can maintain their pregnancy by paying special attention to prematurity, fetal growth, and HLH, even if the case is in clinical remission.
The relationship of pathogenesis between AOSD and pregnancy remains unclear. Ida A et al. reported that serum IL-18 levels were significantly elevated in pregnant women from the first trimester until the onset of labor than in nonpregnant women [39]. They noticed further increment of serum IL-18 levels after labor, lasting until at least the third day of postpartum. This result parallels the clinical feature of AOSD in pregnancy, that is, AOSD flares are likely to happen in the first/second trimester and postpartum. Considering that our case had also prominently high IL-18 levels, IL-18 elevation may cause the flare of AOSD during pregnancy, suggesting that pregnancy may be a risk factor of AOSD. Therefore, the serum IL-18 levels as a follow-up during pregnancy may be a useful predictive and diagnostic marker of AOSD flare; however, further investigations are required.
From the abovementioned consideration, patients with AOSD can be pregnant and continue pregnancy safely while under treatment, considering that the prognosis of pregnant women with AOSD and their fetuses is favorable in previous cases. Furthermore, for a safer pregnancy in patients complicated with AOSD, we, as obstetricians, need tight cooperation with rheumatologists and pediatricians for the sufficient control of AOSD activity and perinatal care and should provide enough explanation to patients on the risks of flares during pregnancy. Moreover, we conduct frequent laboratory tests and careful follow-up in preparation for flares, premature birth, and HLH. If the flare happens at third trimester, as in our case, we need to differentiate AOSD from HELLP syndrome and AFLP because of the similarity of laboratory data and physical findings. Fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for the differentiation from HELLP syndrome and AFLP.
To our knowledge, this report is the first to present the recurrent flare of AOSD during pregnancy at third trimester. However, we need to further investigate on the proper management of pregnant women with AOSD.
Abbreviations
AOSDAdult-onset Still’s disease
TNF-αTumor necrosis factor-α
IL-6Interleukin-6
IL-18Interleukin-18
HELLPHemolysis, elevated liver enzymes and low platelet count
AFLPAcute fatty liver of pregnancy
GDMGestational diabetes mellitus
EFBWEstimated fetal body weight
SDStandard deviation
mPSLMethylprednisolone
PSLPrednisolone
IUGRIntrauterine growth restriction
pPROMPreterm premature rupture of membrane
CRPC-reactive protein
IQRInterquartile range
NSAIDsNonsteroidal anti-inflammatory agents
IL-1Interleukin-1
IVIgIntravenous immune globulin
HLHHemophagocytic lymphohistiocytosis
IRDSInfantile respiratory distress syndrome
NVDNormal vaginal delivery
T-BilTotal bilirubin
ASTAspartate aminotransferase
ALTAlanine aminotransferase
LDHLactate dehydrogenase
γ-GTPγ-glutamyl transpeptidase
BUNBlood urea nitrogen
CreCreatinine
BSBlood sugar
TGTriglyceride
WBCWhite blood cell
RBCRed blood cell
HbHemoglobin
HtHematocrit
PltPlatelet
PT-INRProthrombin-time international normalized ratio
APTTActivated partial thromboplastin time
FibFibrinogen
AT IIIAntithrombin III
HCQHydroxychloroquine
OHDOligohydramnios
HDPHypertensive disorders of pregnancy
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Acknowledgements
The authors would like to thank Enago (www.enago.jp) for the English language review.
Authors’ contributions
SH collected and interpreted the patient’s data, collected previous reports and wrote the first draft of this paper. MS and HO also interpreted the data and revised the first draft. SI and HY also revised the first draft and support the data collection. All authors approved the final manuscript.
Authors’ information
SH was a junior resident of the Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan at the time of this work. Now, SH belongs to the Department of Obstetrics and Gynecology, the Jikei University School of Medicine.
Funding
All authors had no funding support related to this report.
Availability of data and materials
The datasets that support the findings about this case are available from the corresponding author, SH, on reasonable request.
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 of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33627085 | 19,487,180 | 2021-02-24 |
What was the outcome of reaction 'Preterm premature rupture of membranes'? | A case of recurrence of adult-onset Still's disease in the third trimester: a case report and literature review.
BACKGROUND
Adult-onset Still's disease (AOSD) is a self-inflammatory disease showing macrophage and neutrophil activation by inflammatory cytokines such as TNF-α, IL-6, and IL-18. Although some cases with the flare of AOSD during pregnancy have been reported, most had flares in the first or second trimester and few had flares in the third trimester. In this report, we present the case of a patient with recurrent flare of AOSD in the third trimester and discuss the management of AOSD in the third trimester with the review of previous literatures.
METHODS
A 38-year-old woman in complete AOSD remission without medication presented with impaired liver function, low platelet count, mild fever, abdominal pain, splenomegaly, and elevated ferritin and IL-18 levels at 30 gestational weeks. Although the laboratory data and physical examination finding suggested HELLP syndrome or acute fatty liver of pregnancy and we considered the termination of her pregnancy, her fetus was in a reactive status. Considering her fetal status, some specific findings of AOSD, and her AOSD history, we and rheumatologists diagnosed her with AOSD recurrence and started systemic steroid therapy. In her clinical course, three flares of AOSD occurred, twice in the third trimester and once in postpartum; twice systemic steroid pulse therapies were then needed. Ultimately, a healthy infant was delivered transvaginally at 36 gestational weeks spontaneously.
CONCLUSIONS
Specific findings of the flare of AOSD such as fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for differentiation from HELLP syndrome and AFLP in the third trimester. With the careful management supported by rheumatologists, patients complicated with the flare of AOSD may continue their pregnancy longer than we expected.
Background
Adult-onset Still’s disease (AOSD) is a self-inflammatory disease exhibiting macrophage and neutrophil activation by inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-18 (IL-18). Its incidence is 1.6–4.0 in 1,000,000 people per year [1]. AOSD more likely occurs in women, affecting 50 to 70%, than in men [1]. It mostly affects young adults (median age at diagnosis: 36 years) [1], indicating the reproductive ages in women. The Yamaguchi criteria [2] are commonly used to diagnose AOSD because they suggest major symptoms and laboratory findings of AOSD; common manifestations are remittent fever over 39 °C lasting more than a week, arthralgia or arthritis, typical rash, high white blood cell count, elevated liver enzymes, and splenomegaly (Table 1). In addition, some AOSD cases manifest abdominal pain and nausea [1]. If findings such as elevated liver enzyme and abdominal pain happen during pregnancy, AOSD may be misinterpreted as hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome and acute fatty liver of pregnancy (AFLP). Currently, although the association between the disease onset of AOSD and pregnancy has already been widely investigated [3, 4], such relationship remains unclear. Moreover, reported cases of AOSD flares at third trimester are few, and the management and features of AOSD, which has similar features to HELLP syndrome and AFLP, at the third trimester have not been reported yet. Herein, we report a rare case of a pregnant woman with AOSD recurrence at her 30 gestational weeks and reviewed the previous reports on the flares of AOSD related to pregnancy. Written informed consent for the publication of this report was obtained from the patient.
Table 1 Yamaguchi criteria for the diagnosis of adult-onset Still’s disease [2]
Major criteria Fever ≥39 °C lasting ≥1 week
Arthralgia or arthritis lasting ≥2 weeks
Typical nonpruritic salmon-colored rash
Leukocytosis ≥10,000/μl with granulocytes ≥80%
Minor criteria Sore throat
Lymphadenopathy
Splenomegaly
Abnormal liver function tests
Negative tests for antinuclear antibody and rheumatoid factor
Exclusion criteria Infection
Malignancy
Other rheumatic disease (vasculitis)
Diagnosis of adult-onset Still’s disease if ≥5 criteria are present with ≥2 being major criteria and no exclusion criteria
Case presentation
A 38-year-old primigravida with well-controlled gestational diabetes mellitus (GDM) was introduced from her home doctor to our hospital, presenting with mild fever, liver dysfunction, elevated ferritin, low platelet count, and proteinuria at 30 weeks and 5 days of gestation. She was diagnosed with AOSD 6 years ago in our hospital based on typical symptoms, including fever, malaise, cervical lymphadenopathy, rash, liver disfunction, and high serum ferritin levels. Although the rheumatologists performed biopsies of her bone marrow and lymph node, the results of these examination were normal and the possibility of other hematologic diseases was denied. After the combination treatment with systemic steroid and tocilizumab administration, she was in complete clinical remission without medication at conception. Upon arrival, her body temperature, blood pressure, and heart rate were 37.7 °C, 101/63 mmHg, and 103 beats/min. In systemic physical examinations, no abnormalities were found. The laboratory findings at arrival are presented in Table 2; The results indicated liver dysfunction, low platelet, and elevated IL-18 and aldolase levels. No apparent coagulopathy findings were observed. Basic infectious disease tests including Epstein–Barr virus and cytomegalovirus were all negative. Nonstress test and fetal sonography revealed perfect biophysical profile scoring of her fetus, mild polyhydramnios (maximum vertical pocket of amnion: 8.3 cm), and an estimated fetal body weight (EFBW) of 1663 g (+ 0.8 standard deviation [SD]). However, splenomegaly was detected by additional abdominal sonography. Although HELLP syndrome or AFLP was suspected upon admission according to liver dysfunction and low platelet count at third trimester and termination of pregnancy could be possible, her clinical course and examination results did not match well to Sibai’s criteria for HELLP syndrome [5] and Swansea’s criteria for AFLP [6]. Moreover, her general condition and fetal status did not require urgent intervention. Considering the findings such as mild fever, elevated ferritin level, high level of IL-18, splenomegaly, and good fetal status, she was ultimately diagnosed with recurrence flare of AOSD by us and some rheumatologists. Thus, systemic steroid pulse therapy (first dose: 250 mg of methylprednisolone [mPSL] for 3 days) was initiated and switched to oral prednisolone (PSL) thereafter. Additionally, the patient was carefully followed up by frequent laboratory tests and transabdominal fetal sonography. Figure 1 illustrates her clinical course after hospitalization at 30 gestational weeks. Clinical AOSD findings such as fever, liver dysfunction, and high ferritin level were well controlled for 3 weeks after the initiation of systemic steroid therapy; hence, the oral PSL dosage was gradually reduced. However, another steroid pulse therapy was needed for the second flare of AOSD that happened at her 33 gestational weeks with elevated liver enzymes and rash on her trunk. In her clinical course, although with maintained uneventful fetal status, the growth of the fetus had been gradually restricted, resulting in intrauterine growth restriction (IUGR). At 36 weeks and 0 days of gestation, she had irregular uterine contractions without apparent infectious findings, and preterm premature rupture of membrane (pPROM). Finally, she spontaneously delivered a female infant transvaginally at 36 weeks and 3 days of gestation. Her infant had a low birth weight (2440 g) but was very healthy; the Apgar score was 9/10, and pH of the umbilical artery was 7.312. Moreover, no abnormal findings of the amniotic fluid at delivery and no pathological features in her placenta and umbilical cord were found. At 12 days postpartum, she had elevated ferritin levels and extremely low platelet count, indicating the third AOSD flare by a rheumatologist; thus, the dosage of oral PSL was increased and maintained for months. During her follow-up checkup as an outpatient by rheumatologists at 1 year postpartum, her C-reactive protein (CRP) and ferritin levels were within the reference range, and her platelet count gradually increased, indicating a well-controlled AOSD.
Table 2 Laboratory findings
Value Reference intervals, unit
T-Bil 0.7 0.4–1.5, mg/dl
AST 491 13–30, U/L
ALT 438 7–23, U/L
LDH 653 124–222, U/L
γ-GTP 10 9–32, U/L
BUN 6.4 8.0–20.0, mg/dl
Cre 0.58 0.46–0.79, mg/dl
BS 84 80–110, mg/dl
UA 3.3 2.6–7.0, mg/dl
CRP 1.81 0.00–0.14, mg/dl
TG 163 30–149, mg/dl
Ferritin 281 5–157, ng/ml
WBC 2980 3300–8600, /μl
RBC 3.93 3.86–4.92, × 106/μl
Hb 10.7 11.6–14.8, g/dl
Ht 32.5 35.1–44.4, %
Plt 108 158–348, × 103 /μl
PT-INR 0.89 0.90–1.10
APTT 33 25–35, seconds
Fib 407 200–400, mg/dl
AT III 96 80–130, %
Urinary protein 0.33 0.02–0.12, g/day
IL-18 175,116 0–211, pg/ml
Aldolase 30.6 2.5–7.5, U/L
Fig. 1 Clinical course, laboratory data, and treatment of the patient. Initial mPSL pulse therapy was provided for 3 days after 30 weeks and 5 days of gestation and then switched to oral PSL therapy. At 33 weeks and 0 days of gestation, another pulse therapy was provided for the second flare. EFBW was restricted gradually from − 0.6 SD to − 1.5 SD. At 36 weeks and 0 days of gestation, this patient started irregular uterine contractions and finally delivered a healthy infant spontaneously at 36 weeks and 3 days of gestation. At 12 days postpartum, she experienced the third flare, and oral PSL therapy was maintained
Discussion and conclusions
The flare of AOSD in pregnancy was first reported in 1980 by Stein et al. [7]. Currently, nearly 30 reports about AOSD associated with pregnancy have been published [3, 4, 7–32]. Hence, we reviewed the cases of AOSD complications during pregnancy [3, 4, 7–32]. A total of 53 flares in 47 pregnant women, including our case, have been recorded. The clinical course of AOSD during pregnancy consists of three types: first-onset type, which refers to the first onset of AOSD related to pregnancy [3, 4, 7, 8, 11, 12, 14, 17–25, 28–30, 32], recurrent-flare type, which refers to a recurrent flare related to pregnancy with previous AOSD diagnosis [4, 7, 9, 13, 14, 16, 25, 31], and no-flare type, which is only a complication with no flare related to pregnancy [4, 9, 10, 14, 15, 17, 26, 27]. In the literature review, the cases were divided into these three types shown in Table 3 and our case belongs to the recurrent-flare type.
Table 3 Review of pregnancy cases with adult onset Still’s disease classified into three types
Total: 47 pregnant women and 53 pregnancies
First onset (Number = 26) Recurrent flare (Number = 13) No flare (Number = 14)
Age at pregnancy (year), Median [IQR] 29 [25–33] (1 unknown case) 31 [29–34] 27 [26–30] (1 unknown case)
Parity, %
Primigravida 50 (8/16) 80 (8/10) 69.2 (9/13)
Multigravida 50 (8/16) 20 (2/10) 30.8 (4/13)
Unknown, number 10 3 1
Timing of flare, %
1st trimester 24 (6/25) 23.1 (3/13) –
2nd trimester 52 (13/25) 38.5 (5/13) –
3rd trimester 8 (2/25) 7.7 (1/13) –
Postpartum 16 (4/25) 30.8 (4/13) –
Unknown, number 1 0 –
Major symptoms and complications, %
Fever 95.7 (22/23) 70 (7/10) –
Arthralgia, Arthritis 91.3 (21/23) 60 (6/10) –
Erythema, Rash 78.3 (18/23) 50 (5/10) –
Sore throat 65.2 (15/23) 30 (3/10) –
Lymphadenopathy 60.9 (14/23) 10 (1/10) –
Hepatomegaly, Liver dysfunction 34.8 (8/23) 30 (3/10) –
Splenomegaly 34.8 (8/23) 10 (1/10) –
HLH 8.7 (2/23) 10 (1/10) –
Unknown, number 3 3 –
Major treatment, %
Corticosteroid 82.6 (19/23) 69.2 (9/13) 28.6 (4/14)
Anakinra 13.0 (3/23) 7.7 (1/13) 28.6 (4/14)
IVIg 17.4 (4/23) 7.7 (1/13) 7.1 (1/14)
NSAIDs 21.7 (5/23) 7.7 (1/13) 14.3 (2/14)
HCQ 4.3 (1/23) 15.4 (2/13) 7.1 (1/14)
No medication – – 57.1 (8/14)
Unknown, number 3 0 0
Delivery, %
Transvaginal 66.7 (12/18) 50 (4/8) 62.5 (5/8)
Cesarean section 22.2 (4/18) 50 (4/8) 25 (2/8)
Abortion 11.1 (2/18) 0 (0/8) 12.5 (1/8)
Unknown, number 8 5 6
Major obstetrical and perinatal complications, %
Preterm birth 32 (8/25) 33.3 (4/12) 16.7 (2/12)
IUGR 8 (2/25) 41.7 (5/12) 8.3 (1/12)
pPROM 12 (3/25) 8.3 (1/12) 8.3 (1/12)
No major complication 48 (12/25) 41.7 (5/12) 50 (6/12)
Others, number 2 for OHD, 1 for neonatal HLH, 1 for preeclampsia, and 1 for neonatal death for IRDS 1 for GDM, and 1 for OHD 1 for neonatal HLH, 1 for GDM, and 1 for HDP
Unknown, number 1 1 2
The median age of patients at pregnancy was almost 30 years (median [interquartile range (IQR)]: 29 [25–33], 31 [29–34], and 27 [26–30] for the first-onset, recurrent-flare, and no-flare types, respectively), indicating that women with AOSD during pregnancy were younger than the general population at first diagnosis [1]. Regarding parity, AOSD flare mainly happens among primigravida patients, with the recurrent-flare type obtaining the highest rate (83.3%), although all patients in this type are in clinical remission at conception [4, 7, 9, 13, 14, 16, 25, 31]. Our case was also in clinical remission and did not require any medication at conception.
Most likely, the AOSD flare occurred until second trimester and at postpartum, with limited reports of flare at third trimester; the first-onset type was found only in two cases [21, 24] and the recurrent-flare type in one case, which is our case. Although AOSD flare occurring at third trimester is extremely rare, the clinical symptoms of AOSD are similar to those of HELLP syndrome and AFLP, suggesting that close attention to perinatal management is crucial. Generally, the Yamaguchi criteria [2] is adopted for the diagnosing AOSD (Table 1). However, we needed to assess AOSD recurrence in a comprehensive way by considering the clinical features and laboratory findings because no criteria for the diagnosis of AOSD recurrence are currently available. In fact, the review showed that most of the major symptoms of AOSD detected in the recurrent-flare type are relatively fewer than in the first-onset type. In addition, the major symptoms and findings of AOSD are elevated liver enzyme, leukocytosis, and sometimes abdominal pain or nausea, which are difficult to distinguish from HELLP syndrome or AFLP, particularly in cases with flare occurring at third trimester. Elevated ferritin [2] and IL-18 [33], which are reportedly biomarkers of AOSD activity, are considered better diagnostic markers than any other markers. Specific AOSD features such as fever, splenomegaly, and typical rash can support the possibility of AOSD. Izuka et al. recently reported that elevated serum aldolase can be a useful biomarker of AOSD [34]. In our case, the serum aldolase level was high (30.6 U/L), which supported the diagnosis of recurrent AOSD flare. Finally, we and some rheumatologists comprehensively diagnosed the patient with AOSD recurrence flare in consideration of the AOSD findings such as elevated ferritin, IL-18, and aldolase levels, splenomegaly, and uneventful fetal status.
AOSD treatments generally include PSL/mPSL, nonsteroidal anti-inflammatory agents (NSAIDs) and in more severe cases, methotrexate, anakinra (interleukin-1 [IL-1] inhibitor), intravenous immune globulin (IVIg), cyclosporine, or tacrolimus. However, selecting the appropriate medication for pregnant patients entails some limitations. Jamilloux Y et al. recommended corticosteroids as the first treatment choice, and IVIg and IL-1 inhibitor as the second treatment choice for AOSD [35]. Our review also showed that corticosteroid was mainly used, followed by IL-1 inhibitor and IVIg. In Japan, where most of the IL-1 antagonists have not yet been approved, tacrolimus may be a reasonable second choice for severe AOSD flare in pregnancy, and some successful management cases reported to have used this medication during pregnancy [11, 23]. In our case, twice mPSL pulse therapy followed by oral PSL was chosen; consequently, pregnancy was maintained until 36 gestational weeks.
In almost one-third of cases in both the first-onset and recurrent-flare types, the main obstetrical complication was preterm birth. Some reports showed that other autoimmune diseases or autoinflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis, occurring during pregnancy are risk factors for preterm birth, and maternal disease activity contributes to the increased risk of preterm delivery [36–38]. Furthermore, long-term steroidal use is another risk factor for preterm birth [37, 38]. Our review results showed that the incidence of preterm delivery in both the first-onset and recurrent-flare types of AOSD was almost twice higher than that in the no-flare type. Therefore, the high disease activity of AOSD and long-term use of systemic steroids may be possible reasons for the high incidence of preterm delivery in patients with AOSD. Our case also delivered prematurely, with high disease activity and long-term systemic steroid use including twice steroid pulse therapies. Hemophagocytic lymphohistiocytosis (HLH) is also a severe and crucial complication of AOSD. HLH was diagnosed in some cases having the first-onset and recurrent-flare types and in neonatal cases delivered from mothers with AOSD, even in clinical remission. Meanwhile, we believe that in general, the overall severity of AOSD during pregnancy may be better than the HELLP syndrome and AFLP. In fact, lethal complication was only found in one case wherein a premature fetus died at 28 weeks old because of infantile respiratory distress syndrome (IRDS) in the first-onset type, as reported by Green et al. in 1982 [8]. Therefore, with the cooperation of rheumatologists and pediatricians, pregnant patients with AOSD can maintain their pregnancy by paying special attention to prematurity, fetal growth, and HLH, even if the case is in clinical remission.
The relationship of pathogenesis between AOSD and pregnancy remains unclear. Ida A et al. reported that serum IL-18 levels were significantly elevated in pregnant women from the first trimester until the onset of labor than in nonpregnant women [39]. They noticed further increment of serum IL-18 levels after labor, lasting until at least the third day of postpartum. This result parallels the clinical feature of AOSD in pregnancy, that is, AOSD flares are likely to happen in the first/second trimester and postpartum. Considering that our case had also prominently high IL-18 levels, IL-18 elevation may cause the flare of AOSD during pregnancy, suggesting that pregnancy may be a risk factor of AOSD. Therefore, the serum IL-18 levels as a follow-up during pregnancy may be a useful predictive and diagnostic marker of AOSD flare; however, further investigations are required.
From the abovementioned consideration, patients with AOSD can be pregnant and continue pregnancy safely while under treatment, considering that the prognosis of pregnant women with AOSD and their fetuses is favorable in previous cases. Furthermore, for a safer pregnancy in patients complicated with AOSD, we, as obstetricians, need tight cooperation with rheumatologists and pediatricians for the sufficient control of AOSD activity and perinatal care and should provide enough explanation to patients on the risks of flares during pregnancy. Moreover, we conduct frequent laboratory tests and careful follow-up in preparation for flares, premature birth, and HLH. If the flare happens at third trimester, as in our case, we need to differentiate AOSD from HELLP syndrome and AFLP because of the similarity of laboratory data and physical findings. Fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for the differentiation from HELLP syndrome and AFLP.
To our knowledge, this report is the first to present the recurrent flare of AOSD during pregnancy at third trimester. However, we need to further investigate on the proper management of pregnant women with AOSD.
Abbreviations
AOSDAdult-onset Still’s disease
TNF-αTumor necrosis factor-α
IL-6Interleukin-6
IL-18Interleukin-18
HELLPHemolysis, elevated liver enzymes and low platelet count
AFLPAcute fatty liver of pregnancy
GDMGestational diabetes mellitus
EFBWEstimated fetal body weight
SDStandard deviation
mPSLMethylprednisolone
PSLPrednisolone
IUGRIntrauterine growth restriction
pPROMPreterm premature rupture of membrane
CRPC-reactive protein
IQRInterquartile range
NSAIDsNonsteroidal anti-inflammatory agents
IL-1Interleukin-1
IVIgIntravenous immune globulin
HLHHemophagocytic lymphohistiocytosis
IRDSInfantile respiratory distress syndrome
NVDNormal vaginal delivery
T-BilTotal bilirubin
ASTAspartate aminotransferase
ALTAlanine aminotransferase
LDHLactate dehydrogenase
γ-GTPγ-glutamyl transpeptidase
BUNBlood urea nitrogen
CreCreatinine
BSBlood sugar
TGTriglyceride
WBCWhite blood cell
RBCRed blood cell
HbHemoglobin
HtHematocrit
PltPlatelet
PT-INRProthrombin-time international normalized ratio
APTTActivated partial thromboplastin time
FibFibrinogen
AT IIIAntithrombin III
HCQHydroxychloroquine
OHDOligohydramnios
HDPHypertensive disorders of pregnancy
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Acknowledgements
The authors would like to thank Enago (www.enago.jp) for the English language review.
Authors’ contributions
SH collected and interpreted the patient’s data, collected previous reports and wrote the first draft of this paper. MS and HO also interpreted the data and revised the first draft. SI and HY also revised the first draft and support the data collection. All authors approved the final manuscript.
Authors’ information
SH was a junior resident of the Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan at the time of this work. Now, SH belongs to the Department of Obstetrics and Gynecology, the Jikei University School of Medicine.
Funding
All authors had no funding support related to this report.
Availability of data and materials
The datasets that support the findings about this case are available from the corresponding author, SH, on reasonable request.
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 of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33627085 | 19,473,663 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Death'. | Clinical course of IPF in Italian patients during 12 months of observation: results from the FIBRONET observational study.
BACKGROUND
FIBRONET was an observational, multicentre, prospective cohort study investigating the baseline characteristics, clinical course of disease and use of antifibrotic treatment in Italian patients with idiopathic pulmonary fibrosis (IPF).
METHODS
Patients aged ≥ 40 years diagnosed with IPF within the previous 3 months at 20 Italian centres were consecutively enrolled and followed up for 12 months, with evaluations at 3, 6, 9 and 12 months. The primary objective was to describe the clinical course of IPF over 12 months of follow-up, including changes in lung function measured by % predicted forced vital capacity (FVC% predicted).
RESULTS
209 patients (82.3% male, mean age 69.54 ± 7.43 years) were enrolled. Mean FVC% predicted was relatively preserved at baseline (80.01%). The mean time between IPF diagnosis and initiation of antifibrotic therapy was 6.38 weeks; 72.3% of patients received antifibrotic therapy within the first 3 months of follow-up, and 83.9% within 12 months of follow-up. Mean FVC% predicted was 80.0% at baseline and 82.2% at 12 months, and 47.4% of patients remained stable (i.e. had no disease progression) in terms of FVC% predicted during the study.
CONCLUSIONS
FIBRONET is the first prospective, real-life, observational study of patients with IPF in Italy. The short time between diagnosis and initiation of antifibrotic therapy, and the stable lung function between baseline and 12 months, suggest that early diagnosis and prompt initiation of antifibrotic therapy may preserve lung function in patients with IPF.
BACKGROUND
NCT02803580.
Background
The interstitial lung diseases (ILDs), a heterogeneous group of over 200 distinct diseases, include a subgroup of diseases known as the idiopathic interstitial pneumonias (IIPs) [1, 2]. The most common IIP is idiopathic pulmonary fibrosis (IPF) [1], a progressive, and ultimately fatal, disease characterised by progressive fibrosis of the lung parenchyma and subsequent decline in lung function, and defined by a usual interstitial pattern on high-resolution computed tomography (HRCT) [3–5]. IPF shows a variable rate of progression and the disease course may include acute, life-threatening exacerbations [6, 7]. The disease is more frequent in men than in women and is usually diagnosed in people aged over 50 years, particularly in those with a history of smoking [3]. Prior to the availability of antifibrotic treatment, the prognosis for IPF was poor (3–6 years) [8–10].
Diagnosing IPF in clinical practice can be challenging, as symptoms often appear similar to those of more common respiratory diseases, such as chronic obstructive pulmonary disease. This contributes to a delay in diagnosis, which is usually made 6–24 months after initial symptoms [11–13], but can be made even later (> 3 years) [14]. In 2011, simplified and updated criteria for the diagnosis and management of IPF were published by the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Latin American Thoracic Society (ALAT); this document was updated again in 2018 [3, 15]. Early diagnosis is important as it enables earlier treatment and, potentially, improvement of long-term clinical outcomes. There is currently no therapy that reverses or cures the lung damage associated with IPF; however, two antifibrotic drugs (pirfenidone [Roche] and nintedanib [Boehringer Ingelheim]) are licensed for the treatment of IPF, both of which can slow the decline in lung function [16, 17]. Despite the availability of these drugs, many patients diagnosed with IPF are not treated with an antifibrotic. According to one survey of 290 respiratory physicians in Europe, 40% of patients with a confirmed diagnosis of IPF in Italy, Spain, France, Germany and the UK do not receive treatment with an approved antifibrotic [18].
The epidemiology of IPF in Italy has not been thoroughly investigated. Two regional studies estimated the annual incidence of IPF to be between 2.5 and 5.3 cases per 100,000 person-years in Lombardy, and between 7.5 and 25.6 per 100,000 person-years in Lazio [19, 20]. In another national study of 1,104,037 patients with IPF in the Italian primary care setting between 2002 and 2017, the incidence of IPF based on health database records was estimated to be 1.25–3.77 [21]. However, epidemiological studies of IPF are widely acknowledged as challenging due to changes in IPF diagnostic criteria over time and modifications to the IPF coding systems used in administrative databases (a common source of epidemiological data), as well as differences in study design, methodology and study populations in clinical trials [22].
Long-term data on the natural course of IPF in Italy are scarce, and there is limited information on patient characteristics and disease management. However, a growing body of real-world evidence from Italy suggests that pirfenidone and nintedanib can attenuate the decline in lung function in patients with IPF [23, 24], and data from other real-world studies in Europe and Australia suggest that antifibrotic treatment may prolong survival [10, 25, 26]. Integrating evidence from randomised controlled trials with real-life evidence has become increasingly important for the respiratory physician, since real-life studies are not limited by strict selection criteria and therefore approximate the general patient population more accurately [27]. Adding to the existing body of real-life evidence in Italy, the primary objective of this study was to describe the baseline characteristics, the clinical course of the disease (in terms of changes in lung function, including forced vital capacity [FVC]% predicted) and the use of antifibrotic treatment in a group of Italian patients with IPF, during 12 months of observation.
Methods
Study design
This was an Italian, observational, multicentre, prospective cohort study enrolling approximately 200 patients meeting the inclusion/exclusion criteria described below over 18 months. Patients were followed up for 1 year, undergoing three follow-up evaluations after 3 (± 1.5), 6 (± 1.5) and 9 (± 1.5) months (as per current clinical practice in Italy for the management of patients with IPF), and a final follow-up visit at 12 (± 1.5) months. In total, 20 pulmonary centres, managing the majority of patients with IPF in Italy, were involved in the study.
Inclusion and exclusion criteria
Patients were included if they were aged ≥ 40 years, with a diagnosis of IPF confirmed by a physician during the previous 3 months (based on 2011 ATS/ERS/JRS/ALAT guidelines, as this study was started before the 2018 update) [3] and an assessment of IPF based on HRCT, or HRCT and surgical lung biopsy if required and available. Patients were excluded if they were participants in other clinical trials or other IPF or ILD registries, were scheduled to receive a lung transplant within the next 6 months, or were pregnant or breastfeeding. The protocol was approved in July 2015 by an institutional review board/ethics committee (107/2015/PO del registry EC), and written informed consent was obtained for all patients.
Outcomes
The primary objective was to describe the clinical course of IPF in a group of patients in Italy by assessing symptoms, lung function and exercise tolerance during 12 months of observation. Of these, change in FVC% predicted as a measure of lung function was our primary endpoint of interest. Key secondary endpoints included patient characteristics at enrolment in terms of key socio-demographic data, IPF risk factors, comorbidities, acute IPF exacerbations, and hospitalisations and other medical visits. Health-related quality of life was assessed by the St. George’s Respiratory Questionnaire (SGRQ), originally developed to measure the impact of obstructive airway disease on overall health, daily life and perceived well-being [28]. The SGRQ scale ranges from 0–100, with higher scores indicating greater limitations. In addition, treatment-related data were collected (time from diagnosis to treatment initiation, as well as percentage of patients receiving antifibrotic therapy at each follow-up time point).
Statistics
Missing data for patients lost to follow-up were not imputed for the primary analysis, although two additional sensitivity analyses were performed using a ‘last observation carried forward’ approach. In the first analysis set, evaluable patients were those with FVC% predicted available at baseline and who underwent pulmonary function tests (PFTs) at one or more follow-up visit. In the second analysis set, evaluable patients were those with FVC% predicted available at baseline and who underwent PFTs at 6-, 9- or 12-month follow-up.
Descriptive analyses included means, medians, quantiles, proportions and contingency tables, according to the nature of the variables. As a dispersion measurement, the standard deviation (SD) and the interquartile range were calculated. Statistical analyses were performed on evaluable patients, defined as those with known gender who fulfilled inclusion/exclusion criteria and completed at least one of the following evaluations at enrolment: IPF symptoms, lung function and 6-min walk test. For analysis of follow-up data, only patients who completed Visit 2 (3 months), Visit 3 (6 months), Visit 4 (9 months) and Visit 5 (12 months) were considered. Patients needing lung transplantation were not excluded from the analyses or analysed separately.
Results
Patient characteristics
Patients were enrolled between 30 November 2015 and 6 April 2017. In total, 209 patients were evaluable for analysis at enrolment. IPF was diagnosed using HRCT in all patients (100.0%). Other diagnostic procedures included spirometry (27.8%), bronchoalveolar lavage (19.1%), cryobiopsy (8.1%), surgical lung biopsy (6.7%) and transbronchial biopsy (5.3%). Nineteen of the 20 participating centres had at least one patient evaluable at the 12-month follow-up visit. A high proportion of patients were evaluable at each time point: 191 (91.4%) at 3 months, 172 (82.3%) at 6 months, 161 (77.0%) at 9 months, and 174 (83.3%) at 12 months (Table 1). During the 12-month observation period, 36 patients (17.2%) withdrew from the study. Of these, there were 13 (6.2%) deaths, 19 (9.1%) lost to follow-up, three (1.4%) who withdrew consent, one (0.5%) who was included in a clinical trial and one (0.5%) who withdrew for other reasons (a patient could withdraw from the study for more than one reason).Table 1 Patient disposition
n (%)
Enrolled 209 (100)
Evaluable at enrolment 209 (100)
Performed V2 (3 ± 1.5 months) 191 (91.4)
Performed V3 (6 ± 1.5 months) 172 (82.3)
Performed V4 (9 ± 1.5 months) 161 (77.0)
Performed V5 (12 ± 1.5 months) 174 (83.3)
Withdrawn patients 36 (17.2)
Inclusion in clinical trial 1 (0.5)
Consent withdrawal (from patient or legally accepted representative) 3 (1.4)
Lost to follow-up 19 (9.1)
Death 13 (6.2)
Other cause of discontinuation 1 (0.5)
The mean (± SD) number of months between baseline and follow-up visits was 3.24 (± 0.58) months for V2 follow-up, 6.26 (± 0.58) months for V3 follow-up, 9.16 (± 0.61) months for V4 follow-up, and 12.32 (± 0.66) months for V5 follow-up
SD standard deviation, V Visit
Most patients (82.8%) were male. The mean age at enrolment (± 1 SD) was 69.54 (± 7.43) years, and all patients were Caucasian/white. The mean (± SD) weight (kg) was 77.95 (± 13.18) and the mean (± SD) height (cm) was 166.88 (± 8.36). According to the body mass index (BMI), 50 (29.9%) participants were classified as obese (BMI ≥ 30), 81 (48.5%) as overweight (BMI 25–29.9), 34 (20.4%) as normal weight (BMI 18.5–24.9) and 2 (1.2%) as underweight (BMI < 18.5). At baseline, nine patients (4.3%) were receiving nintedanib and 24 (11.5%) pirfenidone.
The most frequently reported comorbidities were arterial hypertension (n = 103, 49.3%), gastroesophageal reflux disease (n = 49, 23.4%), diabetes mellitus (n = 45, 21.5%), atherothrombotic disease including coronary heart disease (n = 27, 12.9%), and benign prostatic hypertrophy (n = 25, 12.0%) (Table 2). The majority of patients were former smokers (n = 138, 66.0%) and a small proportion (n = 9, 4.3%) were current smokers. The median (25th–75th percentile) estimated amount of tobacco consumed by former and current smokers was 30 (14–40) packs per year for a median (25th–75th percentile) of 30 (20–40) years. Seventy patients (34.0%) reported previous exposure to environmental risk factors (e.g. metal dust, asbestos) (Table 3). Two patients (1.0%) had been exposed to amiodarone, and 25 (12.0%) had a family history of pulmonary fibrosis.Table 2 Comorbidities at enrolment
n (%)
N of patients with at least one comorbidity 171 (81.8)
Anxiety/depression 12 (5.7)
Arterial hypertension 103 (49.3)
Atherothrombotic disease, including coronary heart disease 27 (12.9)
Atrial fibrillation 9 (4.3)
Benign prostatic hypertrophy 25 (12.0)
Cerebrovascular disease (carotid stenosis, stroke) 13 (6.2)
Deep venous thrombosis (DVT) 1 (0.5)
Diabetes mellitus 45 (21.5)
Emphysema 8 (3.8)
Gastroesophageal reflux disease 49 (23.4)
Hypercholesterolaemia 17 (8.1)
Lung cancer 1 (0.5)
Peripheral arterial disease (symptomatic or ankle brachial index < 0.8) 2 (1.0)
Pulmonary hypertension 6 (2.9)
Renal insufficiency 5 (2.4)
Other 80 (38.3)
Previous myocardial infarction 23 (11.0)
Percentages calculated out of total number of evaluable patients. A patient could have more than one comorbidity
Table 3 IPF risk factors and family history for pulmonary fibrosis
N = 209
Exposure to environmental risk factors
No 136 (65.1)
Yes 70 (33.5)
Not known 3 (1.4)
Metal dust 27 (12.9)
Wood dust 9 (4.3)
Solvents 15 (7.2)
Oils 6 (2.9)
Asbestos 17 (8.1)
Quartz dust 2 (1.0)
Farming 2 (1.0)
Livestock dust 1 (0.5)
Vegetable dust 4 (1.9)
Other 12 (5.7)
Exposure to amiodarone
No 207 (99.0)
Yes 2 (1.0)
Family history
No 183 (87.6)
Yes 25 (12.0)
Not known 1 (0.5)
IPF idiopathic pulmonary fibrosis
The mean (± SD) number of months from first IPF diagnosis to inclusion in the study was 1.01 (± 1.05), and the mean (± SD) number of years from first IPF symptoms to inclusion in the study was 2.14 (± 2.45). At first IPF diagnosis, the mean (± SD) age was 69.46 (± 7.43) years.
Results: primary endpoints
IPF symptoms and exercise tolerance
At baseline, 184/209 evaluable patients (88.0%) had symptoms of IPF. The most frequent symptom at baseline was cough (59.8%), followed by fatigue (54.1%) and dyspnoea (18.2%). At 12 months (n = 174), the frequencies of these symptoms were 30.5%, 32.2% and 4.6%, respectively. Dizziness and chest pain (evaluated separately) were reported in < 5% of patients at baseline and 12 months. The mean (± SD) 6-min walk distance was 395.70 (± 121.70) metres at baseline, and 411.70 (± 108.90) metres at 12 months. No sensitivity analyses were applied to the longitudinal data for either symptoms or exercise tolerance.
Lung function
At baseline, 140/196 evaluable patients (71.4%) had FVC predicted ≥ 70% (Fig. 1) and 59/196 (30.1%) had FVC predicted ≥ 90% (suggesting very early diagnosis). In the whole group, FVC% predicted did not decline over time: the mean (± SD) FVC% predicted was 80.01% (± 19.23) at baseline and 82.17% (± 20.93) at 12-month follow-up (Fig. 2). Considering the relative change of FVC% predicted at 12 months versus baseline, 52.6% of evaluable patients (70/133) were classified as ‘decliners’ (> 0% decrease in FVC% predicted). Of these, 24.1% decreased by 0– < 5%, 12.0% decreased by 5– < 10%, and 16.5% decreased by ≥ 10%. The remaining patients (63/133; 47.4%) were classified as ‘non-decliners’ (> 0% increase in FVC% predicted). Of these, 15.0% increased by 0– < 5%, 15.0% increased by 5– < 10%, and 17.3% increased by ≥ 10% (Table 4). In the first sensitivity analysis (imputation of missing values for patients with values at baseline and any follow-up), mean FVC% predicted (± SD) was 80.18% (± 20.41) at 12-month follow-up (for 183 evaluable patients). In the second sensitivity analysis (imputation of missing values for patients with values at baseline and 6-, 9- or 12-month follow-up), mean FVC% predicted (± SD) was 80.12% (± 20.31) at 12-month follow-up (for 173 evaluable patients) (Additional file 1: Table S1). The sensitivity analyses had a marginal impact on the overall results: the proportion of decliners ranged between 52.0% and 53.0%, very close to the proportion observed in the primary analysis (52.6%). Along with spirometry measurements, diffusing capacity of the lung for carbon monoxide (DLCO) remained stable during observation. The mean (± SD) DLCO% predicted at baseline and 3, 6, 9 and 12 months’ follow-up was 51.68% (± 13.52), 51.27% (± 14.75), 49.71% (± 13.23), 50.27% (± 16.58) and 50.91% (± 15.65) respectively.Fig. 1 FVC% predicted at baseline. Percentages calculated from the total number of evaluable patients with available FVC predicted at baseline (n = 196). FVC forced vital capacity
Fig. 2 Mean change in FVC% predicted (± SD) during 12 months of observation. FVC forced vital capacity, SD standard deviation
Table 4 FVC% predicted relative change from baseline to 12 months
N = 133
Decliners (decrease in FVC% predicted) 70 (52.6%)
0– < 5% 32 (24.1%)
5– < 10% 16 (12.0%)
10– < 15% 8 (6.0%)
≥ 15% 14 (10.5%)
Non-decliners (increase in FVC% predicted) 63 (47.4%)
0– < 5% 20 (15.0%)
5– < 10% 20 (15.0%)
≥ 10% 23 (17.3%)
FVC forced vital capacity
Results: secondary endpoints
Use of antifibrotic and other therapy during study
A total of 33 patients (15.8%) were receiving antifibrotic treatment at baseline (within the 3 months prior to enrolment), and the overall proportion of treated patients increased during the observation period: 72.3% (n = 138) at 3 months, 80.8% (n = 139) at 6 months, and 83.9% (n = 146) at 12 months. The majority of evaluable patients began antifibrotic treatment early in the study (within 3 months prior to enrolment, or within the first 3 months of the study), with only eight patients initiating treatment later and 28/146 evaluable patients (16.1%) receiving no antifibrotic therapy at 1 year. The mean time from diagnosis to initiation of treatment was 6.38 weeks.
Non-antifibrotic therapy was primarily long-term oxygen therapy but was not frequently used: 3.3%, 8.4%, 8.1% and 8.6% at baseline, 3, 6, and 12 months, respectively. No patients were listed for lung transplantation at baseline, and the transplantation rate remained low throughout the study: 2.6% (n = 5) at 3 months, 1.2% (n = 2) at 6 months, and 0.6% (n = 1) at 12 months. Adherence to antifibrotic medications (according to 4-item Morisky Medication Adherence Scale score) was good, with no relevant changes over time: mean (± SD) 3.70 (± 0.65) at baseline, 3.65 (± 0.74) at 6 months, and 3.56 (± 0.75) at 12 months.
Health-related quality of life
The median (25th–75th percentile) SGRQ total score at baseline was 39.82 (23.40–56.49), and was worst in the ‘symptoms’ (42.26 [27.29–57.98]) and ‘activities’ (54.39 [35.80–72.89]) subcategories, and highest in the ‘impacts on daily life’ (28.16 [12.26–47.09]) subcategory (Additional file 1: Figure S1). After 12 months of follow-up, SGRQ scores were similar to baseline in all subcategories (Additional file 1: Table S2). No sensitivity analyses were performed on these data.
Hospitalisation, emergency room admission and other medical visits
Thirteen patients (6.2%) had at least one hospitalisation, with a total of 14 hospitalisations recorded. Ten patients (4.8%) had a total of 15 admissions to the emergency room. 29.7% of patients (62/209) had at least one medical visit, the most frequent of which were visits to the general practitioner (GP) clinic (n = 48, 23.0%), followed by the pulmonologist clinic (n = 23, 11.0%) (Additional file 1: Figure S2). Considering patients who visited a clinic, the mean (± SD) number of GP and pulmonologist visits per patient was 1.60 (± 0.82) and 1.61 (± 0.92), respectively. During the study, 121 patients (57.9%) underwent laboratory examinations at pre-specified follow-up visits, mainly due to the required surveillance for antifibrotic therapy or to monitor IPF progression (especially liver function tests, blood count tests, HRCT and unscheduled spirometry).
Acute IPF exacerbations and adverse events
In total, 15 patients (7.2% of those evaluable at enrolment) had at least one exacerbation during the observation period. There were 18 exacerbations reported (seven mild, seven moderate and four severe, according to clinical judgement). Five patients (2.4%) had one mild exacerbation, seven patients (3.3%) had one moderate exacerbation, two patients (1.0%) had one severe exacerbation, one patient (0.5%) had two severe exacerbations and one patient (0.5%) had two mild exacerbations. The 1-year Kaplan–Meier estimate of the probability of an exacerbation was 6.5%.
Safety was not one of the primary or secondary objectives of this study. However, 17 serious adverse events were recorded in total, 11 of which were fatal (Additional file 1: Table S3). In addition to these 11 deaths, 2 further deaths occurred during the observation period. No sensitivity analyses were performed on these data.
Discussion
The main socio-demographic and clinical characteristics of Italian patients in this real-world study are consistent with those previously described in the literature (Additional file 1: Table S4). At baseline, mean FVC% predicted was relatively preserved in FIBRONET (80.01%). This is similar to another real-world study of 128 Italian patients with IPF, in which mean FVC% predicted was 75.0% at baseline and 74.0% after 1 year of treatment with pirfenidone [28], and slightly higher than in a study of 41 Italian patients with advanced IPF (60.3% at baseline and 58.0% after 6 months) [24]. Almost half of the patients in FIBRONET (47.4%) remained stable (i.e. had no disease progression) in terms of FVC% predicted during 12 months of observation.
These results are consistent with findings from previous clinical trials in IPF. In a post hoc analysis of FVC (mL) change from baseline at Week 52 in the INPULSIS® and INPULSIS®-ON trials, 191 patients (36.8%) in the nintedanib group and 62 patients (18.0%) in the placebo group showed no decline in FVC [29]. In the sample of 624 patients with IPF who met the criteria for enrolment in the CAPACITY® or ASCEND® trials and were assigned to placebo, 91% of patients showed either no decline or a < 10% decline in the first 6 months of the study [30]. Another observational study conducted in 20 ILD expert centres in Germany (INSIGHTS-IPF) also found that FVC was relatively stable over the first 12 months of antifibrotic treatment, in line with our findings [25]. Although several clinical trials and real-world experiences show that a proportion of patients has either no decline or < 10% decline in FVC during 12 months of observation, it is not appropriate to describe such patients as having ‘stable disease’ since IPF is by nature a progressive disease. The SGRQ total score at baseline (39.82) in our study was slightly lower (suggesting less of an impact on quality of life) than the scores in the Australian registry (44.3) and INSIGHT registry (47.7) [26]. The changes in SGRQ total score over approximately 1 year were small in both the Australian and INSIGHT registry [31, 32]. At 12 months, we observed fewer patients reporting cough, fatigue and dyspnoea, although it is unknown if this was influenced by patient drop-outs or related to the treatment.
Antifibrotic therapy
An earlier diagnosis of IPF allows earlier treatment and, potentially, improvement of long-term clinical outcomes. Despite the available scientific data from clinical trials, post hoc analyses, long-term safety studies and real-world experiences, the question of when to start and when to stop treatment with antifibrotics is still under debate. In IPF, particularly when the disease is diagnosed at an early stage, ‘wait and watch’ is a common approach. This is largely due to the lack of awareness of both patients and physicians regarding the progression of the disease and its prognosis. In FIBRONET, the mean (± SD) number of years between the first symptoms of IPF and study enrolment was 2.14 (± 2.45), whereas on average, only 6.38 weeks elapsed between IPF diagnosis and initiation of antifibrotic therapy. We speculate that the short time between diagnosis and initiation of antifibrotic therapy, combined with relatively preserved lung function at baseline (FVC 80.01%), is a possible explanation for the relatively stable lung function observed over 52 weeks in our study (47.4% with marginal or no decline in FVC% predicted after 12 months of observation).
The proportion of patients receiving antifibrotic treatment increased over the course of the study (15.8% at baseline, 72.3% at 3 months, 80.8% at 6 months, and 83.9% at 12 months). The overall proportion of patients receiving antifibrotic treatment in this study is much higher compared with Finnish and Swedish IPF registry studies conducted between 2014 and 2016, in which the percentage of patients receiving antifibrotic therapy over a 3-year period was 29.6% and 69.4%, respectively [33]. A survey of French pulmonologists treating patients with IPF in 2014 found 31% of physicians treated patients with antifibrotics [34]. The differences may be explained by different types of centres participating in registry activities, i.e. expert centres in the management of ILD in the FIBRONET study, compared with perhaps a broader range of centres participating in the Finnish and Swedish registries. Differences in reimbursement for antifibrotic drugs between countries may also explain some of these differences (see Pesonen et al. [33]). Lastly, Italy has a relatively well-established and strong ILD community within a universal healthcare system, which may influence prescription rates.
Limitations
FIBRONET was a descriptive, observational study in which patients were prospectively followed for 1 year, so neither causality nor treatment association was evaluated, and possible confounders were not assessed. The number of patients enrolled into our study is not as large as some other registries, but we believe it provides a useful representation of the Italian population. One limitation of our study is the high number of patients lost to follow-up (76 patients [36.4%] with missing FVC data at 12-month follow-up), which may have biased the results, since patients with greater disease progression may not have been healthy enough to attend their follow-up visits. In order to minimise selection bias, patient sampling was based on consecutive enrolment, and every effort was made to select sites across a variety of geographic regions. The patients in this study were all treated at specialist centres, and the results may therefore not be comparable with other real-world studies involving non-specialist centres. However, since the specialist centres that were selected treat the majority of patients with IPF in Italy, our study does reflect the healthcare setting for most patients in that country. Lastly, we did not collect data on treatments used by patients other than nintedanib and pirfenidone during the observation period.
Conclusions
FIBRONET is one of the largest prospective real-world studies of Italian patients with IPF and is unique in that it was designed to prospectively describe the clinical course of IPF in terms of changes in lung function in an Italian real-world context. The results of this study suggest that early diagnosis of IPF, enabling early initiation of antifibrotic therapy, may be associated with preserved lung function in patients with IPF. These results add some relevant data to the body of observational, real-life, long-term data on the natural course of IPF in Italy, which currently are limited.
Supplementary Information
Additional file 1. Additional tables and figures.
Abbreviations
ALATLatin American Thoracic Society
ATSAmerican Thoracic Society
BMIBody mass index
ERSEuropean Respiratory Society
FVCForced vital capacity
HRCTHigh-resolution computed tomography
IIPIdiopathic interstitial pneumonia
ILDInterstitial lung disease
IPFIdiopathic pulmonary fibrosis
JRSJapanese Respiratory Society
PFTPulmonary function test
SDStandard deviation
SGRQSt. George’s Respiratory Questionnaire
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Supplementary Information
The online version contains supplementary material available at 10.1186/s12931-021-01643-w.
Acknowledgements
The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). No authors received compensation related to the development of this manuscript. Writing assistance, supported financially by Boehringer Ingelheim, was provided by Chester Trinick of MediTech Media during the development of this manuscript. The authors were fully responsible for all content and editorial decisions, had access to all data, were involved in all stages of development and have approved the final version. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy, as well as intellectual property considerations.
The FIBRONET study group includes a total of 20 members:
Prof. Carlo VANCHERI, Regional Referral Center for Rare Lung Diseases, University Hospital “Policlinico G. Rodolico”, Department of Clinical and Experimental Medicine, University of Catania, Catania—Italy
Prof.ssa Sara TOMASSETTI, Department of Experimental and Clinical Medicine, Careggi University Hospital, Firenze—Italy
Prof. Sergio HARARI, Department of Clinical Sciences and Community Health, University of Milan; Department of Medicine, Ospedale San Giuseppe, Milano—Italy
Prof. Alberto PESCI, U.O. di Clinica Pneumologica, Azienda Ospedaliera San Gerardo, Monza—Italy
Prof. Carlo ALBERA, S.C. Pneumologia U., A.O.U. Città della Scienza e della Salute (Molinette), University of Torino—Italy
Prof.ssa Paola ROTTOLI, U.O.C. di Pneumologia Universitaria, A.O.U. Senese Le Scotte, Siena—Italy
Prof.ssa Marialuisa Bocchino Clinica Malattie dell’Apparato Respiratorio, Università Federico II, Napoli—Italy
Prof.ssa Anna Agnese STANZIOLA, Clinica Malattie dell’Apparato Respiratorio, Università Federico II, Napoli—Italy
Prof. Fabrizio LUPPI, U.O. di Clinica Pneumologica, Azienda Ospedaliera San Gerardo, Monza—Italy
Dr. Alfredo SEBASTIANI, U.O.C. Pneumologia e Infettivologia Respiratoria, A.O. San Camillo Forlanini, Roma—Italy
Prof. Donato LACEDONIA Pneumologia 4, Ospedale Colonnello D’Avanzo, Foggia—Italy
Prof. Patrizio VITULO, Servizio di Pneumologia, ISMETT di Palermo, Palermo—Italy
Dr.ssa Laura TAVANTI, U.O. di Pneumologia A.O.U. Pisana, Pisa—Italy
Prof. Andrea VIANELLO, A.O.U. di Padova, Dip. Immunologia Clinica ed Ematologia, University-Hospital, Padova—Italy
Prof.ssa Marina SAETTA, Pneumologia Clinica, University Hospital, Padova—Italy
Dr. Stefano MARINARI, U.O.C. di Pneumologia, Ospedale Clinicizzato Santissima Annunziata, Chieti—Italy
Prof. Pietro PIRINA, Pneumotisiologia Clinica Pneumologica, Policlinico Universitario di Sassari, Sassari—Italy
Prof. Salvatore VALENTE, Unità complessa di Pneumologia, Policlinico Gemelli, Roma—Italy
Dr. Tiberio OGGIONNI, Pneumologia, Policlinico San Matteo, Pavia—Italy
Prof. Stefano GASPARINI, Dip. Pneumologia, Ospedali Riuniti di Ancona, Ancona—Italy
Authors’ contributions
All authors had access to the data and contributed to the drafting and revision of the article. All authors read and approved the final manuscript.
Funding
The FIBRONET study was funded by Boehringer Ingelheim International GmbH.
Availability of data and materials
To ensure independent interpretation of clinical study results, Boehringer Ingelheim grants all external authors access to all relevant material, including participant-level clinical study data, and relevant material as needed by them to fulfil their role and obligations as authors under the International Committee of Medical Journal Editors (ICMJE) criteria.
Furthermore, clinical study documents (e.g. study report, study protocol, statistical analysis plan) and participant clinical study data are available to be shared after publication of the primary manuscript in a peer-reviewed journal and if regulatory activities are complete and other criteria met per the BI Policy on Transparency and Publication of Clinical Study Data: https://trials.boehringer-ingelheim.com/.
Prior to providing access, documents will be examined, and, if necessary, redacted and the data will be de-identified, to protect the personal data of study participants and personnel, and to respect the boundaries of the informed consent of the study participants.
Clinical Study Reports and Related Clinical Documents can also be requested via the link https://trials.boehringer-ingelheim.com/. All requests will be governed by a Document Sharing Agreement.
Bona fide, qualified scientific and medical researchers may request access to de-identified, analysable participant clinical study data with corresponding documentation describing the structure and content of the datasets. Upon approval, and governed by a Data Sharing Agreement, data are shared in a secured data-access system for a limited period of 1 year, which may be extended upon request.
Researchers should use the https://trials.boehringer-ingelheim.com/ link to request access to study data.
Ethics approval and consent to participate
The study protocol was approved in July 2015 by an institutional review board/ethics committee (107/2015/PO del registry EC), and written informed consent was obtained for all patients.
Consent for publication
Not applicable.
Competing interests
BC was an employee of Boehringer Ingelheim (Italy) at the time of this study. GC is an employee of Boehringer Ingelheim. SR is an employee of MediNeos Observational Research (Modena, Italy). AP has received personal (speaker/advisory board) fees from Boehringer Ingelheim and Roche, and his research activity is partially supported by project Premia. SH has acted as a clinical trial investigator, participated in scientific advisory boards, and delivered lectures for Boehringer Ingelheim, Roche and Actelion. He has also received research grants from Boehringer Ingelheim. CA has acted as a clinical trial investigator for Boehringer Ingelheim and Roche, participated in scientific advisory boards for Boehringer Ingelheim, Roche, MSD, Fibrogen and GSK, and received research grants from Boehringer Ingelheim and Roche. CV has received research grants and personal fees from Boehringer Ingelheim and Roche. VP has received personal fees from Boehringer Ingelheim. RRM has nothing to disclose. | NINTEDANIB, PIRFENIDONE | DrugsGivenReaction | CC BY | 33627105 | 19,008,138 | 2021-02-24 |
What was the outcome of reaction 'Death'? | Clinical course of IPF in Italian patients during 12 months of observation: results from the FIBRONET observational study.
BACKGROUND
FIBRONET was an observational, multicentre, prospective cohort study investigating the baseline characteristics, clinical course of disease and use of antifibrotic treatment in Italian patients with idiopathic pulmonary fibrosis (IPF).
METHODS
Patients aged ≥ 40 years diagnosed with IPF within the previous 3 months at 20 Italian centres were consecutively enrolled and followed up for 12 months, with evaluations at 3, 6, 9 and 12 months. The primary objective was to describe the clinical course of IPF over 12 months of follow-up, including changes in lung function measured by % predicted forced vital capacity (FVC% predicted).
RESULTS
209 patients (82.3% male, mean age 69.54 ± 7.43 years) were enrolled. Mean FVC% predicted was relatively preserved at baseline (80.01%). The mean time between IPF diagnosis and initiation of antifibrotic therapy was 6.38 weeks; 72.3% of patients received antifibrotic therapy within the first 3 months of follow-up, and 83.9% within 12 months of follow-up. Mean FVC% predicted was 80.0% at baseline and 82.2% at 12 months, and 47.4% of patients remained stable (i.e. had no disease progression) in terms of FVC% predicted during the study.
CONCLUSIONS
FIBRONET is the first prospective, real-life, observational study of patients with IPF in Italy. The short time between diagnosis and initiation of antifibrotic therapy, and the stable lung function between baseline and 12 months, suggest that early diagnosis and prompt initiation of antifibrotic therapy may preserve lung function in patients with IPF.
BACKGROUND
NCT02803580.
Background
The interstitial lung diseases (ILDs), a heterogeneous group of over 200 distinct diseases, include a subgroup of diseases known as the idiopathic interstitial pneumonias (IIPs) [1, 2]. The most common IIP is idiopathic pulmonary fibrosis (IPF) [1], a progressive, and ultimately fatal, disease characterised by progressive fibrosis of the lung parenchyma and subsequent decline in lung function, and defined by a usual interstitial pattern on high-resolution computed tomography (HRCT) [3–5]. IPF shows a variable rate of progression and the disease course may include acute, life-threatening exacerbations [6, 7]. The disease is more frequent in men than in women and is usually diagnosed in people aged over 50 years, particularly in those with a history of smoking [3]. Prior to the availability of antifibrotic treatment, the prognosis for IPF was poor (3–6 years) [8–10].
Diagnosing IPF in clinical practice can be challenging, as symptoms often appear similar to those of more common respiratory diseases, such as chronic obstructive pulmonary disease. This contributes to a delay in diagnosis, which is usually made 6–24 months after initial symptoms [11–13], but can be made even later (> 3 years) [14]. In 2011, simplified and updated criteria for the diagnosis and management of IPF were published by the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Latin American Thoracic Society (ALAT); this document was updated again in 2018 [3, 15]. Early diagnosis is important as it enables earlier treatment and, potentially, improvement of long-term clinical outcomes. There is currently no therapy that reverses or cures the lung damage associated with IPF; however, two antifibrotic drugs (pirfenidone [Roche] and nintedanib [Boehringer Ingelheim]) are licensed for the treatment of IPF, both of which can slow the decline in lung function [16, 17]. Despite the availability of these drugs, many patients diagnosed with IPF are not treated with an antifibrotic. According to one survey of 290 respiratory physicians in Europe, 40% of patients with a confirmed diagnosis of IPF in Italy, Spain, France, Germany and the UK do not receive treatment with an approved antifibrotic [18].
The epidemiology of IPF in Italy has not been thoroughly investigated. Two regional studies estimated the annual incidence of IPF to be between 2.5 and 5.3 cases per 100,000 person-years in Lombardy, and between 7.5 and 25.6 per 100,000 person-years in Lazio [19, 20]. In another national study of 1,104,037 patients with IPF in the Italian primary care setting between 2002 and 2017, the incidence of IPF based on health database records was estimated to be 1.25–3.77 [21]. However, epidemiological studies of IPF are widely acknowledged as challenging due to changes in IPF diagnostic criteria over time and modifications to the IPF coding systems used in administrative databases (a common source of epidemiological data), as well as differences in study design, methodology and study populations in clinical trials [22].
Long-term data on the natural course of IPF in Italy are scarce, and there is limited information on patient characteristics and disease management. However, a growing body of real-world evidence from Italy suggests that pirfenidone and nintedanib can attenuate the decline in lung function in patients with IPF [23, 24], and data from other real-world studies in Europe and Australia suggest that antifibrotic treatment may prolong survival [10, 25, 26]. Integrating evidence from randomised controlled trials with real-life evidence has become increasingly important for the respiratory physician, since real-life studies are not limited by strict selection criteria and therefore approximate the general patient population more accurately [27]. Adding to the existing body of real-life evidence in Italy, the primary objective of this study was to describe the baseline characteristics, the clinical course of the disease (in terms of changes in lung function, including forced vital capacity [FVC]% predicted) and the use of antifibrotic treatment in a group of Italian patients with IPF, during 12 months of observation.
Methods
Study design
This was an Italian, observational, multicentre, prospective cohort study enrolling approximately 200 patients meeting the inclusion/exclusion criteria described below over 18 months. Patients were followed up for 1 year, undergoing three follow-up evaluations after 3 (± 1.5), 6 (± 1.5) and 9 (± 1.5) months (as per current clinical practice in Italy for the management of patients with IPF), and a final follow-up visit at 12 (± 1.5) months. In total, 20 pulmonary centres, managing the majority of patients with IPF in Italy, were involved in the study.
Inclusion and exclusion criteria
Patients were included if they were aged ≥ 40 years, with a diagnosis of IPF confirmed by a physician during the previous 3 months (based on 2011 ATS/ERS/JRS/ALAT guidelines, as this study was started before the 2018 update) [3] and an assessment of IPF based on HRCT, or HRCT and surgical lung biopsy if required and available. Patients were excluded if they were participants in other clinical trials or other IPF or ILD registries, were scheduled to receive a lung transplant within the next 6 months, or were pregnant or breastfeeding. The protocol was approved in July 2015 by an institutional review board/ethics committee (107/2015/PO del registry EC), and written informed consent was obtained for all patients.
Outcomes
The primary objective was to describe the clinical course of IPF in a group of patients in Italy by assessing symptoms, lung function and exercise tolerance during 12 months of observation. Of these, change in FVC% predicted as a measure of lung function was our primary endpoint of interest. Key secondary endpoints included patient characteristics at enrolment in terms of key socio-demographic data, IPF risk factors, comorbidities, acute IPF exacerbations, and hospitalisations and other medical visits. Health-related quality of life was assessed by the St. George’s Respiratory Questionnaire (SGRQ), originally developed to measure the impact of obstructive airway disease on overall health, daily life and perceived well-being [28]. The SGRQ scale ranges from 0–100, with higher scores indicating greater limitations. In addition, treatment-related data were collected (time from diagnosis to treatment initiation, as well as percentage of patients receiving antifibrotic therapy at each follow-up time point).
Statistics
Missing data for patients lost to follow-up were not imputed for the primary analysis, although two additional sensitivity analyses were performed using a ‘last observation carried forward’ approach. In the first analysis set, evaluable patients were those with FVC% predicted available at baseline and who underwent pulmonary function tests (PFTs) at one or more follow-up visit. In the second analysis set, evaluable patients were those with FVC% predicted available at baseline and who underwent PFTs at 6-, 9- or 12-month follow-up.
Descriptive analyses included means, medians, quantiles, proportions and contingency tables, according to the nature of the variables. As a dispersion measurement, the standard deviation (SD) and the interquartile range were calculated. Statistical analyses were performed on evaluable patients, defined as those with known gender who fulfilled inclusion/exclusion criteria and completed at least one of the following evaluations at enrolment: IPF symptoms, lung function and 6-min walk test. For analysis of follow-up data, only patients who completed Visit 2 (3 months), Visit 3 (6 months), Visit 4 (9 months) and Visit 5 (12 months) were considered. Patients needing lung transplantation were not excluded from the analyses or analysed separately.
Results
Patient characteristics
Patients were enrolled between 30 November 2015 and 6 April 2017. In total, 209 patients were evaluable for analysis at enrolment. IPF was diagnosed using HRCT in all patients (100.0%). Other diagnostic procedures included spirometry (27.8%), bronchoalveolar lavage (19.1%), cryobiopsy (8.1%), surgical lung biopsy (6.7%) and transbronchial biopsy (5.3%). Nineteen of the 20 participating centres had at least one patient evaluable at the 12-month follow-up visit. A high proportion of patients were evaluable at each time point: 191 (91.4%) at 3 months, 172 (82.3%) at 6 months, 161 (77.0%) at 9 months, and 174 (83.3%) at 12 months (Table 1). During the 12-month observation period, 36 patients (17.2%) withdrew from the study. Of these, there were 13 (6.2%) deaths, 19 (9.1%) lost to follow-up, three (1.4%) who withdrew consent, one (0.5%) who was included in a clinical trial and one (0.5%) who withdrew for other reasons (a patient could withdraw from the study for more than one reason).Table 1 Patient disposition
n (%)
Enrolled 209 (100)
Evaluable at enrolment 209 (100)
Performed V2 (3 ± 1.5 months) 191 (91.4)
Performed V3 (6 ± 1.5 months) 172 (82.3)
Performed V4 (9 ± 1.5 months) 161 (77.0)
Performed V5 (12 ± 1.5 months) 174 (83.3)
Withdrawn patients 36 (17.2)
Inclusion in clinical trial 1 (0.5)
Consent withdrawal (from patient or legally accepted representative) 3 (1.4)
Lost to follow-up 19 (9.1)
Death 13 (6.2)
Other cause of discontinuation 1 (0.5)
The mean (± SD) number of months between baseline and follow-up visits was 3.24 (± 0.58) months for V2 follow-up, 6.26 (± 0.58) months for V3 follow-up, 9.16 (± 0.61) months for V4 follow-up, and 12.32 (± 0.66) months for V5 follow-up
SD standard deviation, V Visit
Most patients (82.8%) were male. The mean age at enrolment (± 1 SD) was 69.54 (± 7.43) years, and all patients were Caucasian/white. The mean (± SD) weight (kg) was 77.95 (± 13.18) and the mean (± SD) height (cm) was 166.88 (± 8.36). According to the body mass index (BMI), 50 (29.9%) participants were classified as obese (BMI ≥ 30), 81 (48.5%) as overweight (BMI 25–29.9), 34 (20.4%) as normal weight (BMI 18.5–24.9) and 2 (1.2%) as underweight (BMI < 18.5). At baseline, nine patients (4.3%) were receiving nintedanib and 24 (11.5%) pirfenidone.
The most frequently reported comorbidities were arterial hypertension (n = 103, 49.3%), gastroesophageal reflux disease (n = 49, 23.4%), diabetes mellitus (n = 45, 21.5%), atherothrombotic disease including coronary heart disease (n = 27, 12.9%), and benign prostatic hypertrophy (n = 25, 12.0%) (Table 2). The majority of patients were former smokers (n = 138, 66.0%) and a small proportion (n = 9, 4.3%) were current smokers. The median (25th–75th percentile) estimated amount of tobacco consumed by former and current smokers was 30 (14–40) packs per year for a median (25th–75th percentile) of 30 (20–40) years. Seventy patients (34.0%) reported previous exposure to environmental risk factors (e.g. metal dust, asbestos) (Table 3). Two patients (1.0%) had been exposed to amiodarone, and 25 (12.0%) had a family history of pulmonary fibrosis.Table 2 Comorbidities at enrolment
n (%)
N of patients with at least one comorbidity 171 (81.8)
Anxiety/depression 12 (5.7)
Arterial hypertension 103 (49.3)
Atherothrombotic disease, including coronary heart disease 27 (12.9)
Atrial fibrillation 9 (4.3)
Benign prostatic hypertrophy 25 (12.0)
Cerebrovascular disease (carotid stenosis, stroke) 13 (6.2)
Deep venous thrombosis (DVT) 1 (0.5)
Diabetes mellitus 45 (21.5)
Emphysema 8 (3.8)
Gastroesophageal reflux disease 49 (23.4)
Hypercholesterolaemia 17 (8.1)
Lung cancer 1 (0.5)
Peripheral arterial disease (symptomatic or ankle brachial index < 0.8) 2 (1.0)
Pulmonary hypertension 6 (2.9)
Renal insufficiency 5 (2.4)
Other 80 (38.3)
Previous myocardial infarction 23 (11.0)
Percentages calculated out of total number of evaluable patients. A patient could have more than one comorbidity
Table 3 IPF risk factors and family history for pulmonary fibrosis
N = 209
Exposure to environmental risk factors
No 136 (65.1)
Yes 70 (33.5)
Not known 3 (1.4)
Metal dust 27 (12.9)
Wood dust 9 (4.3)
Solvents 15 (7.2)
Oils 6 (2.9)
Asbestos 17 (8.1)
Quartz dust 2 (1.0)
Farming 2 (1.0)
Livestock dust 1 (0.5)
Vegetable dust 4 (1.9)
Other 12 (5.7)
Exposure to amiodarone
No 207 (99.0)
Yes 2 (1.0)
Family history
No 183 (87.6)
Yes 25 (12.0)
Not known 1 (0.5)
IPF idiopathic pulmonary fibrosis
The mean (± SD) number of months from first IPF diagnosis to inclusion in the study was 1.01 (± 1.05), and the mean (± SD) number of years from first IPF symptoms to inclusion in the study was 2.14 (± 2.45). At first IPF diagnosis, the mean (± SD) age was 69.46 (± 7.43) years.
Results: primary endpoints
IPF symptoms and exercise tolerance
At baseline, 184/209 evaluable patients (88.0%) had symptoms of IPF. The most frequent symptom at baseline was cough (59.8%), followed by fatigue (54.1%) and dyspnoea (18.2%). At 12 months (n = 174), the frequencies of these symptoms were 30.5%, 32.2% and 4.6%, respectively. Dizziness and chest pain (evaluated separately) were reported in < 5% of patients at baseline and 12 months. The mean (± SD) 6-min walk distance was 395.70 (± 121.70) metres at baseline, and 411.70 (± 108.90) metres at 12 months. No sensitivity analyses were applied to the longitudinal data for either symptoms or exercise tolerance.
Lung function
At baseline, 140/196 evaluable patients (71.4%) had FVC predicted ≥ 70% (Fig. 1) and 59/196 (30.1%) had FVC predicted ≥ 90% (suggesting very early diagnosis). In the whole group, FVC% predicted did not decline over time: the mean (± SD) FVC% predicted was 80.01% (± 19.23) at baseline and 82.17% (± 20.93) at 12-month follow-up (Fig. 2). Considering the relative change of FVC% predicted at 12 months versus baseline, 52.6% of evaluable patients (70/133) were classified as ‘decliners’ (> 0% decrease in FVC% predicted). Of these, 24.1% decreased by 0– < 5%, 12.0% decreased by 5– < 10%, and 16.5% decreased by ≥ 10%. The remaining patients (63/133; 47.4%) were classified as ‘non-decliners’ (> 0% increase in FVC% predicted). Of these, 15.0% increased by 0– < 5%, 15.0% increased by 5– < 10%, and 17.3% increased by ≥ 10% (Table 4). In the first sensitivity analysis (imputation of missing values for patients with values at baseline and any follow-up), mean FVC% predicted (± SD) was 80.18% (± 20.41) at 12-month follow-up (for 183 evaluable patients). In the second sensitivity analysis (imputation of missing values for patients with values at baseline and 6-, 9- or 12-month follow-up), mean FVC% predicted (± SD) was 80.12% (± 20.31) at 12-month follow-up (for 173 evaluable patients) (Additional file 1: Table S1). The sensitivity analyses had a marginal impact on the overall results: the proportion of decliners ranged between 52.0% and 53.0%, very close to the proportion observed in the primary analysis (52.6%). Along with spirometry measurements, diffusing capacity of the lung for carbon monoxide (DLCO) remained stable during observation. The mean (± SD) DLCO% predicted at baseline and 3, 6, 9 and 12 months’ follow-up was 51.68% (± 13.52), 51.27% (± 14.75), 49.71% (± 13.23), 50.27% (± 16.58) and 50.91% (± 15.65) respectively.Fig. 1 FVC% predicted at baseline. Percentages calculated from the total number of evaluable patients with available FVC predicted at baseline (n = 196). FVC forced vital capacity
Fig. 2 Mean change in FVC% predicted (± SD) during 12 months of observation. FVC forced vital capacity, SD standard deviation
Table 4 FVC% predicted relative change from baseline to 12 months
N = 133
Decliners (decrease in FVC% predicted) 70 (52.6%)
0– < 5% 32 (24.1%)
5– < 10% 16 (12.0%)
10– < 15% 8 (6.0%)
≥ 15% 14 (10.5%)
Non-decliners (increase in FVC% predicted) 63 (47.4%)
0– < 5% 20 (15.0%)
5– < 10% 20 (15.0%)
≥ 10% 23 (17.3%)
FVC forced vital capacity
Results: secondary endpoints
Use of antifibrotic and other therapy during study
A total of 33 patients (15.8%) were receiving antifibrotic treatment at baseline (within the 3 months prior to enrolment), and the overall proportion of treated patients increased during the observation period: 72.3% (n = 138) at 3 months, 80.8% (n = 139) at 6 months, and 83.9% (n = 146) at 12 months. The majority of evaluable patients began antifibrotic treatment early in the study (within 3 months prior to enrolment, or within the first 3 months of the study), with only eight patients initiating treatment later and 28/146 evaluable patients (16.1%) receiving no antifibrotic therapy at 1 year. The mean time from diagnosis to initiation of treatment was 6.38 weeks.
Non-antifibrotic therapy was primarily long-term oxygen therapy but was not frequently used: 3.3%, 8.4%, 8.1% and 8.6% at baseline, 3, 6, and 12 months, respectively. No patients were listed for lung transplantation at baseline, and the transplantation rate remained low throughout the study: 2.6% (n = 5) at 3 months, 1.2% (n = 2) at 6 months, and 0.6% (n = 1) at 12 months. Adherence to antifibrotic medications (according to 4-item Morisky Medication Adherence Scale score) was good, with no relevant changes over time: mean (± SD) 3.70 (± 0.65) at baseline, 3.65 (± 0.74) at 6 months, and 3.56 (± 0.75) at 12 months.
Health-related quality of life
The median (25th–75th percentile) SGRQ total score at baseline was 39.82 (23.40–56.49), and was worst in the ‘symptoms’ (42.26 [27.29–57.98]) and ‘activities’ (54.39 [35.80–72.89]) subcategories, and highest in the ‘impacts on daily life’ (28.16 [12.26–47.09]) subcategory (Additional file 1: Figure S1). After 12 months of follow-up, SGRQ scores were similar to baseline in all subcategories (Additional file 1: Table S2). No sensitivity analyses were performed on these data.
Hospitalisation, emergency room admission and other medical visits
Thirteen patients (6.2%) had at least one hospitalisation, with a total of 14 hospitalisations recorded. Ten patients (4.8%) had a total of 15 admissions to the emergency room. 29.7% of patients (62/209) had at least one medical visit, the most frequent of which were visits to the general practitioner (GP) clinic (n = 48, 23.0%), followed by the pulmonologist clinic (n = 23, 11.0%) (Additional file 1: Figure S2). Considering patients who visited a clinic, the mean (± SD) number of GP and pulmonologist visits per patient was 1.60 (± 0.82) and 1.61 (± 0.92), respectively. During the study, 121 patients (57.9%) underwent laboratory examinations at pre-specified follow-up visits, mainly due to the required surveillance for antifibrotic therapy or to monitor IPF progression (especially liver function tests, blood count tests, HRCT and unscheduled spirometry).
Acute IPF exacerbations and adverse events
In total, 15 patients (7.2% of those evaluable at enrolment) had at least one exacerbation during the observation period. There were 18 exacerbations reported (seven mild, seven moderate and four severe, according to clinical judgement). Five patients (2.4%) had one mild exacerbation, seven patients (3.3%) had one moderate exacerbation, two patients (1.0%) had one severe exacerbation, one patient (0.5%) had two severe exacerbations and one patient (0.5%) had two mild exacerbations. The 1-year Kaplan–Meier estimate of the probability of an exacerbation was 6.5%.
Safety was not one of the primary or secondary objectives of this study. However, 17 serious adverse events were recorded in total, 11 of which were fatal (Additional file 1: Table S3). In addition to these 11 deaths, 2 further deaths occurred during the observation period. No sensitivity analyses were performed on these data.
Discussion
The main socio-demographic and clinical characteristics of Italian patients in this real-world study are consistent with those previously described in the literature (Additional file 1: Table S4). At baseline, mean FVC% predicted was relatively preserved in FIBRONET (80.01%). This is similar to another real-world study of 128 Italian patients with IPF, in which mean FVC% predicted was 75.0% at baseline and 74.0% after 1 year of treatment with pirfenidone [28], and slightly higher than in a study of 41 Italian patients with advanced IPF (60.3% at baseline and 58.0% after 6 months) [24]. Almost half of the patients in FIBRONET (47.4%) remained stable (i.e. had no disease progression) in terms of FVC% predicted during 12 months of observation.
These results are consistent with findings from previous clinical trials in IPF. In a post hoc analysis of FVC (mL) change from baseline at Week 52 in the INPULSIS® and INPULSIS®-ON trials, 191 patients (36.8%) in the nintedanib group and 62 patients (18.0%) in the placebo group showed no decline in FVC [29]. In the sample of 624 patients with IPF who met the criteria for enrolment in the CAPACITY® or ASCEND® trials and were assigned to placebo, 91% of patients showed either no decline or a < 10% decline in the first 6 months of the study [30]. Another observational study conducted in 20 ILD expert centres in Germany (INSIGHTS-IPF) also found that FVC was relatively stable over the first 12 months of antifibrotic treatment, in line with our findings [25]. Although several clinical trials and real-world experiences show that a proportion of patients has either no decline or < 10% decline in FVC during 12 months of observation, it is not appropriate to describe such patients as having ‘stable disease’ since IPF is by nature a progressive disease. The SGRQ total score at baseline (39.82) in our study was slightly lower (suggesting less of an impact on quality of life) than the scores in the Australian registry (44.3) and INSIGHT registry (47.7) [26]. The changes in SGRQ total score over approximately 1 year were small in both the Australian and INSIGHT registry [31, 32]. At 12 months, we observed fewer patients reporting cough, fatigue and dyspnoea, although it is unknown if this was influenced by patient drop-outs or related to the treatment.
Antifibrotic therapy
An earlier diagnosis of IPF allows earlier treatment and, potentially, improvement of long-term clinical outcomes. Despite the available scientific data from clinical trials, post hoc analyses, long-term safety studies and real-world experiences, the question of when to start and when to stop treatment with antifibrotics is still under debate. In IPF, particularly when the disease is diagnosed at an early stage, ‘wait and watch’ is a common approach. This is largely due to the lack of awareness of both patients and physicians regarding the progression of the disease and its prognosis. In FIBRONET, the mean (± SD) number of years between the first symptoms of IPF and study enrolment was 2.14 (± 2.45), whereas on average, only 6.38 weeks elapsed between IPF diagnosis and initiation of antifibrotic therapy. We speculate that the short time between diagnosis and initiation of antifibrotic therapy, combined with relatively preserved lung function at baseline (FVC 80.01%), is a possible explanation for the relatively stable lung function observed over 52 weeks in our study (47.4% with marginal or no decline in FVC% predicted after 12 months of observation).
The proportion of patients receiving antifibrotic treatment increased over the course of the study (15.8% at baseline, 72.3% at 3 months, 80.8% at 6 months, and 83.9% at 12 months). The overall proportion of patients receiving antifibrotic treatment in this study is much higher compared with Finnish and Swedish IPF registry studies conducted between 2014 and 2016, in which the percentage of patients receiving antifibrotic therapy over a 3-year period was 29.6% and 69.4%, respectively [33]. A survey of French pulmonologists treating patients with IPF in 2014 found 31% of physicians treated patients with antifibrotics [34]. The differences may be explained by different types of centres participating in registry activities, i.e. expert centres in the management of ILD in the FIBRONET study, compared with perhaps a broader range of centres participating in the Finnish and Swedish registries. Differences in reimbursement for antifibrotic drugs between countries may also explain some of these differences (see Pesonen et al. [33]). Lastly, Italy has a relatively well-established and strong ILD community within a universal healthcare system, which may influence prescription rates.
Limitations
FIBRONET was a descriptive, observational study in which patients were prospectively followed for 1 year, so neither causality nor treatment association was evaluated, and possible confounders were not assessed. The number of patients enrolled into our study is not as large as some other registries, but we believe it provides a useful representation of the Italian population. One limitation of our study is the high number of patients lost to follow-up (76 patients [36.4%] with missing FVC data at 12-month follow-up), which may have biased the results, since patients with greater disease progression may not have been healthy enough to attend their follow-up visits. In order to minimise selection bias, patient sampling was based on consecutive enrolment, and every effort was made to select sites across a variety of geographic regions. The patients in this study were all treated at specialist centres, and the results may therefore not be comparable with other real-world studies involving non-specialist centres. However, since the specialist centres that were selected treat the majority of patients with IPF in Italy, our study does reflect the healthcare setting for most patients in that country. Lastly, we did not collect data on treatments used by patients other than nintedanib and pirfenidone during the observation period.
Conclusions
FIBRONET is one of the largest prospective real-world studies of Italian patients with IPF and is unique in that it was designed to prospectively describe the clinical course of IPF in terms of changes in lung function in an Italian real-world context. The results of this study suggest that early diagnosis of IPF, enabling early initiation of antifibrotic therapy, may be associated with preserved lung function in patients with IPF. These results add some relevant data to the body of observational, real-life, long-term data on the natural course of IPF in Italy, which currently are limited.
Supplementary Information
Additional file 1. Additional tables and figures.
Abbreviations
ALATLatin American Thoracic Society
ATSAmerican Thoracic Society
BMIBody mass index
ERSEuropean Respiratory Society
FVCForced vital capacity
HRCTHigh-resolution computed tomography
IIPIdiopathic interstitial pneumonia
ILDInterstitial lung disease
IPFIdiopathic pulmonary fibrosis
JRSJapanese Respiratory Society
PFTPulmonary function test
SDStandard deviation
SGRQSt. George’s Respiratory Questionnaire
Publisher's Note
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Supplementary Information
The online version contains supplementary material available at 10.1186/s12931-021-01643-w.
Acknowledgements
The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). No authors received compensation related to the development of this manuscript. Writing assistance, supported financially by Boehringer Ingelheim, was provided by Chester Trinick of MediTech Media during the development of this manuscript. The authors were fully responsible for all content and editorial decisions, had access to all data, were involved in all stages of development and have approved the final version. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy, as well as intellectual property considerations.
The FIBRONET study group includes a total of 20 members:
Prof. Carlo VANCHERI, Regional Referral Center for Rare Lung Diseases, University Hospital “Policlinico G. Rodolico”, Department of Clinical and Experimental Medicine, University of Catania, Catania—Italy
Prof.ssa Sara TOMASSETTI, Department of Experimental and Clinical Medicine, Careggi University Hospital, Firenze—Italy
Prof. Sergio HARARI, Department of Clinical Sciences and Community Health, University of Milan; Department of Medicine, Ospedale San Giuseppe, Milano—Italy
Prof. Alberto PESCI, U.O. di Clinica Pneumologica, Azienda Ospedaliera San Gerardo, Monza—Italy
Prof. Carlo ALBERA, S.C. Pneumologia U., A.O.U. Città della Scienza e della Salute (Molinette), University of Torino—Italy
Prof.ssa Paola ROTTOLI, U.O.C. di Pneumologia Universitaria, A.O.U. Senese Le Scotte, Siena—Italy
Prof.ssa Marialuisa Bocchino Clinica Malattie dell’Apparato Respiratorio, Università Federico II, Napoli—Italy
Prof.ssa Anna Agnese STANZIOLA, Clinica Malattie dell’Apparato Respiratorio, Università Federico II, Napoli—Italy
Prof. Fabrizio LUPPI, U.O. di Clinica Pneumologica, Azienda Ospedaliera San Gerardo, Monza—Italy
Dr. Alfredo SEBASTIANI, U.O.C. Pneumologia e Infettivologia Respiratoria, A.O. San Camillo Forlanini, Roma—Italy
Prof. Donato LACEDONIA Pneumologia 4, Ospedale Colonnello D’Avanzo, Foggia—Italy
Prof. Patrizio VITULO, Servizio di Pneumologia, ISMETT di Palermo, Palermo—Italy
Dr.ssa Laura TAVANTI, U.O. di Pneumologia A.O.U. Pisana, Pisa—Italy
Prof. Andrea VIANELLO, A.O.U. di Padova, Dip. Immunologia Clinica ed Ematologia, University-Hospital, Padova—Italy
Prof.ssa Marina SAETTA, Pneumologia Clinica, University Hospital, Padova—Italy
Dr. Stefano MARINARI, U.O.C. di Pneumologia, Ospedale Clinicizzato Santissima Annunziata, Chieti—Italy
Prof. Pietro PIRINA, Pneumotisiologia Clinica Pneumologica, Policlinico Universitario di Sassari, Sassari—Italy
Prof. Salvatore VALENTE, Unità complessa di Pneumologia, Policlinico Gemelli, Roma—Italy
Dr. Tiberio OGGIONNI, Pneumologia, Policlinico San Matteo, Pavia—Italy
Prof. Stefano GASPARINI, Dip. Pneumologia, Ospedali Riuniti di Ancona, Ancona—Italy
Authors’ contributions
All authors had access to the data and contributed to the drafting and revision of the article. All authors read and approved the final manuscript.
Funding
The FIBRONET study was funded by Boehringer Ingelheim International GmbH.
Availability of data and materials
To ensure independent interpretation of clinical study results, Boehringer Ingelheim grants all external authors access to all relevant material, including participant-level clinical study data, and relevant material as needed by them to fulfil their role and obligations as authors under the International Committee of Medical Journal Editors (ICMJE) criteria.
Furthermore, clinical study documents (e.g. study report, study protocol, statistical analysis plan) and participant clinical study data are available to be shared after publication of the primary manuscript in a peer-reviewed journal and if regulatory activities are complete and other criteria met per the BI Policy on Transparency and Publication of Clinical Study Data: https://trials.boehringer-ingelheim.com/.
Prior to providing access, documents will be examined, and, if necessary, redacted and the data will be de-identified, to protect the personal data of study participants and personnel, and to respect the boundaries of the informed consent of the study participants.
Clinical Study Reports and Related Clinical Documents can also be requested via the link https://trials.boehringer-ingelheim.com/. All requests will be governed by a Document Sharing Agreement.
Bona fide, qualified scientific and medical researchers may request access to de-identified, analysable participant clinical study data with corresponding documentation describing the structure and content of the datasets. Upon approval, and governed by a Data Sharing Agreement, data are shared in a secured data-access system for a limited period of 1 year, which may be extended upon request.
Researchers should use the https://trials.boehringer-ingelheim.com/ link to request access to study data.
Ethics approval and consent to participate
The study protocol was approved in July 2015 by an institutional review board/ethics committee (107/2015/PO del registry EC), and written informed consent was obtained for all patients.
Consent for publication
Not applicable.
Competing interests
BC was an employee of Boehringer Ingelheim (Italy) at the time of this study. GC is an employee of Boehringer Ingelheim. SR is an employee of MediNeos Observational Research (Modena, Italy). AP has received personal (speaker/advisory board) fees from Boehringer Ingelheim and Roche, and his research activity is partially supported by project Premia. SH has acted as a clinical trial investigator, participated in scientific advisory boards, and delivered lectures for Boehringer Ingelheim, Roche and Actelion. He has also received research grants from Boehringer Ingelheim. CA has acted as a clinical trial investigator for Boehringer Ingelheim and Roche, participated in scientific advisory boards for Boehringer Ingelheim, Roche, MSD, Fibrogen and GSK, and received research grants from Boehringer Ingelheim and Roche. CV has received research grants and personal fees from Boehringer Ingelheim and Roche. VP has received personal fees from Boehringer Ingelheim. RRM has nothing to disclose. | Fatal | ReactionOutcome | CC BY | 33627105 | 19,008,138 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumomediastinum'. | Successful thrombolysis of normotensive pulmonary embolism with life-threatening hypoxia in a young man with Klinefelter syndrome.
Klinefelter syndrome (KS) affects males born with an additional X chromosome giving the genotype 47XXY classically. This syndrome has primary features of infertility and hypogonadism along with other features including a genetically hypercoagulable state. When associated with other risk factors, KS further increases the risk of venous thromboembolism and could result in life-threatening pulmonary embolism (PE). There should be a lower threshold in suspecting PE as a cause of acute respiratory failure in this patient group and thrombolysis should be considered early in normotensive PE with severe hypoxia for best patient outcomes. Furthermore, clinicians should be cautious in managing testosterone therapy in patients with KS and additional thromboembolic risk factors.
Background
Klinefelter syndrome (KS) is considered to be the most common sex chromosome disorder. An Australian prevalence study had reported a rate of 223 per 100 000 males, with up to 50% of cases remaining undiagnosed.1 Affected males have an additional X chromosome leading to poor development of male secondary sexual characteristics. Other than these phenotypic changes, these patients are more prone to cardiovascular, endocrine and psychiatric disorders.2 KS is also considered to be a genetically hypercoagulable state where affected individuals have been shown to be four times more likely to have venous thromboembolism (VTE).2 The standardised incidence ratio for VTE is reported to be highest before 30 years of age at 12%.3 The current hypothesis for this hypercoagulable state is the presence of increased levels of plasminogen activator inhibitor 1 (PAI-1) in KS, related to obesity and low testosterone levels. Despite this, a study by Zitzmann et al did not demonstrate a change in PAI-1 levels in patients who are treated with testosterone therapy.4 Other hypotheses for the hypercoagulable state seen in this patient group include an increase in factor VIII and IX levels due to the genes coding for these factors being located on the X chromosome. A case series of six KS patients with deep venous thrombosis (DVT) has shown elevated factor VIII levels, but this was not significantly different from a control population with VTE.5
The Pulmonary Embolism International Thrombolysis Study (PEITHO) trial demonstrated that fibrinolytic therapy in patients with intermediate-severity pulmonary embolism (PE) prevented haemodynamic decompensation but increased the risk of major haemorrhage and stroke.6 A third of the patients in the PEITHO trial complained of persisting dyspnoea at 3-month follow-up, but over 80% had only low or intermediate probability of persisting or new-onset pulmonary hypertension at echocardiographic follow-up. Based on these data, the latest guidelines for PE by the European Society of Cardiology do not recommend routine thrombolysis for intermediate-risk PE. On the other hand, a small randomised trial of 83 patients suggested that thrombolysis in submassive PE improved the functional capacity at 3 months compared with anticoagulation alone.7
Here, we report a case of a young man with KS presenting with submassive PE complicated by pneumomediastinum and pneumopericardium with severe hypoxic respiratory failure prompting successful thrombolysis with good functional outcomes.
Case presentation
A young man in his mid-20s with KS presented to the emergency department with fluctuating generalised ill health and worsening shortness of breath for 2 weeks. He had an associated persistent dry cough and mild subjective fevers. He denied any pleuritic chest pain and could not recall any preceding calf tenderness and had no identifiable risk factors for VTE except his father having experienced an unprovoked DVT in the past with a negative thrombophilia screen. The patient had been diagnosed with KS at the age of 18 months with XXYY karyotype while being investigated for developmental delay and has been on testosterone replacement since the age of 15 years with a current testosterone regimen of intramuscular testosterone undecanoate 1000 mg at 3 monthly interval. He was otherwise healthy.
On examination, he was of a lean build with a well-grown beard. He was tachypnoeic (up to 40 breaths/min), tachycardic (up to 140 beats/min), and peripherally and centrally cyanosed. His blood pressure remained stable over 100/60 mm Hg. He had occasional crepitations on bilateral lung fields. His oxygen saturation (SPO2) on room air was 74% and was promptly commenced on a non-rebreather with improvement of SPO2 to 85%.
Investigations
Arterial blood gas performed on admission demonstrated type 1 respiratory failure with PaO2 of 52 mm Hg. ECG showed tachycardia with S1-Q3-T3 pattern. An urgent CT pulmonary angiogram (CTPA) was performed on high suspicion of PE. This demonstrated a completely occluded left main pulmonary artery with a large embolus and another embolus in the right main pulmonary artery extending into the right middle and lower lobe arteries extensively and to the upper lobe arteries to a lesser extent. CTPA further demonstrated pneumomediastinum and pneumopericardium (figure 1). Closer evaluation of his CTPA revealed alveolar rupture leading to pneumomediastinum and pneumopericardium which was attributed to barotrauma from the persistent dry cough.
Figure 1 Bilateral pulmonary embolism with pneumomediastinum and pneumopericardium.
Bedside echocardiogram demonstrated ballooning of the right ventricle, suggestive of significant pulmonary hypertension and his troponin I was elevated at 162 ng/L (<21 ng/L).
Treatment
He was at high risk according to the simplified PE severity index with a 30-day mortality prediction of 8.9%. Due to the high oxygen requirement and severity of clot burden with persistent tachycardia and right ventricular strain, it was decided to thrombolyse him. He received intravenous alteplase 10 mg loading followed by a 90 mg infusion. His saturation improved gradually over a 6-hour period up to 100% on room air. He received therapeutic dose subcutaneous enoxaparin for 7 days following thrombolysis and was changed to oral apixaban 5 mg two times per day for life-long therapy on discharge.
Outcome and follow-up
His testosterone level was 25.4 nmol/L (normal range 10–35 nmol/L). This was 9 weeks after his regular testosterone undecanoate therapy. He was noted to be polycythaemic with a haemoglobin level of 209 g/L and haematocrit of 0.63. The elevated erythropoietin level at 42 mIU/mL (normal range 5–25 mIU/mL) suggests secondary polycythaemia. His haemoglobin level and haematocrit improved to 152 g/L and 0.45, respectively, at the time of discharge. A thrombophilia screen was negative for any secondary causes including JAK2 mutation, antiphospholipid antibodies, anti nuclear antibody, extractable nuclear antigen, vasculitis screening, homocysteine level and prothrombotic gene mutations.
On follow-up at 3 months, he had returned to his baseline functional capacity and his repeat echocardiogram showed complete resolution of right ventricular strain with normal cardiac function. In the long-term management of his testosterone replacement therapy, it was decided to recommence his testosterone only when the serum testosterone level falls below 10 nmol/L.
Discussion
Our patient had multiple risk factors for VTE. KS is known to increase the risk of VTE. He had a family history of unprovoked DVT, although the thrombophilia screening for both him and his father could not identify a hereditary cause. His polycythaemia could have predisposed him to VTE and was likely multifactorial from hypoxia, dehydration and testosterone therapy. The fact that he tolerated an SPO2 down to 74% in the community was remarkable and we postulate that the secondary polycythaemic response may have allowed him to tolerate such severe hypoxia. Although he was not hypotensive, severe hypoxic respiratory failure with signs of right ventricular strain prompted the decision for thrombolysis. Current guidance for PE thrombolysis mostly depends on failed haemodynamics and suggests close monitoring and consideration of rescue thrombolysis for cases like our patient.8 Several researchers have highlighted the need for thrombolysis in severe hypoxic respiratory failure with preserved haemodynamics.9 10 Percutaneous catheter-directed therapy is currently recommended for haemodynamically unstable PE with contraindications for thrombolysis.8 As our patient did not have any contraindications for thrombolysis, this was not considered. Our patient clearly improved with thrombolysis with normalisation of his oxygenation from SPO2 of 74%–100% within hours and his full recovery without any evidence of pulmonary hypertension speaks to the dramatic improvement achieved with this therapy. Polycythaemia is one of the most common side effects of testosterone therapy.11 Regardless of this, a systematic review of six randomised trials and five observational studies failed to show an association between testosterone therapy and thromboembolism.12 Despite this, provided the multiple risk factors our patient had for VTE, it was decided to minimise any risk testosterone-related polycythaemia could cause by targeting his testosterone therapy towards the lower limit of normal.
Learning points
Clinicians should be cognisant about the hypercoagulable state of Klinefelter syndrome, especially when the patient has other risk factors for venous thromboembolism (VTE).
We propose that clinicians use a cautious and closely supervised approach to testosterone replacement therapy in patients with other risk factors for VTE.
Clinicians should be aware of the current limitations for thrombolysis recommendations in pulmonary embolism (PE) which entirely depend on haemodynamic instability, and should carefully explore the need for thrombolysis in normotensive PE with refractory hypoxic respiratory failure on a case-by-case basis, which in our case led to optimum patient outcomes both in the short and long term.
Twitter: @jkndmiththinda
Contributors: NDMJK managed the acute presentation of the case and continues to follow up the case. JG provided Endocrinology input in management. NDMJK did the initial literature review, composed the original draft and prepared the images. JG contributed with literature review and provided critical feedback to the manuscript. All authors contributed to editing and finalising the manuscript and have given final approval to the version submitted and are accountable for the content submitted.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | TESTOSTERONE UNDECANOATE | DrugsGivenReaction | CC BY-NC | 33627349 | 19,038,559 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumopericardium'. | Successful thrombolysis of normotensive pulmonary embolism with life-threatening hypoxia in a young man with Klinefelter syndrome.
Klinefelter syndrome (KS) affects males born with an additional X chromosome giving the genotype 47XXY classically. This syndrome has primary features of infertility and hypogonadism along with other features including a genetically hypercoagulable state. When associated with other risk factors, KS further increases the risk of venous thromboembolism and could result in life-threatening pulmonary embolism (PE). There should be a lower threshold in suspecting PE as a cause of acute respiratory failure in this patient group and thrombolysis should be considered early in normotensive PE with severe hypoxia for best patient outcomes. Furthermore, clinicians should be cautious in managing testosterone therapy in patients with KS and additional thromboembolic risk factors.
Background
Klinefelter syndrome (KS) is considered to be the most common sex chromosome disorder. An Australian prevalence study had reported a rate of 223 per 100 000 males, with up to 50% of cases remaining undiagnosed.1 Affected males have an additional X chromosome leading to poor development of male secondary sexual characteristics. Other than these phenotypic changes, these patients are more prone to cardiovascular, endocrine and psychiatric disorders.2 KS is also considered to be a genetically hypercoagulable state where affected individuals have been shown to be four times more likely to have venous thromboembolism (VTE).2 The standardised incidence ratio for VTE is reported to be highest before 30 years of age at 12%.3 The current hypothesis for this hypercoagulable state is the presence of increased levels of plasminogen activator inhibitor 1 (PAI-1) in KS, related to obesity and low testosterone levels. Despite this, a study by Zitzmann et al did not demonstrate a change in PAI-1 levels in patients who are treated with testosterone therapy.4 Other hypotheses for the hypercoagulable state seen in this patient group include an increase in factor VIII and IX levels due to the genes coding for these factors being located on the X chromosome. A case series of six KS patients with deep venous thrombosis (DVT) has shown elevated factor VIII levels, but this was not significantly different from a control population with VTE.5
The Pulmonary Embolism International Thrombolysis Study (PEITHO) trial demonstrated that fibrinolytic therapy in patients with intermediate-severity pulmonary embolism (PE) prevented haemodynamic decompensation but increased the risk of major haemorrhage and stroke.6 A third of the patients in the PEITHO trial complained of persisting dyspnoea at 3-month follow-up, but over 80% had only low or intermediate probability of persisting or new-onset pulmonary hypertension at echocardiographic follow-up. Based on these data, the latest guidelines for PE by the European Society of Cardiology do not recommend routine thrombolysis for intermediate-risk PE. On the other hand, a small randomised trial of 83 patients suggested that thrombolysis in submassive PE improved the functional capacity at 3 months compared with anticoagulation alone.7
Here, we report a case of a young man with KS presenting with submassive PE complicated by pneumomediastinum and pneumopericardium with severe hypoxic respiratory failure prompting successful thrombolysis with good functional outcomes.
Case presentation
A young man in his mid-20s with KS presented to the emergency department with fluctuating generalised ill health and worsening shortness of breath for 2 weeks. He had an associated persistent dry cough and mild subjective fevers. He denied any pleuritic chest pain and could not recall any preceding calf tenderness and had no identifiable risk factors for VTE except his father having experienced an unprovoked DVT in the past with a negative thrombophilia screen. The patient had been diagnosed with KS at the age of 18 months with XXYY karyotype while being investigated for developmental delay and has been on testosterone replacement since the age of 15 years with a current testosterone regimen of intramuscular testosterone undecanoate 1000 mg at 3 monthly interval. He was otherwise healthy.
On examination, he was of a lean build with a well-grown beard. He was tachypnoeic (up to 40 breaths/min), tachycardic (up to 140 beats/min), and peripherally and centrally cyanosed. His blood pressure remained stable over 100/60 mm Hg. He had occasional crepitations on bilateral lung fields. His oxygen saturation (SPO2) on room air was 74% and was promptly commenced on a non-rebreather with improvement of SPO2 to 85%.
Investigations
Arterial blood gas performed on admission demonstrated type 1 respiratory failure with PaO2 of 52 mm Hg. ECG showed tachycardia with S1-Q3-T3 pattern. An urgent CT pulmonary angiogram (CTPA) was performed on high suspicion of PE. This demonstrated a completely occluded left main pulmonary artery with a large embolus and another embolus in the right main pulmonary artery extending into the right middle and lower lobe arteries extensively and to the upper lobe arteries to a lesser extent. CTPA further demonstrated pneumomediastinum and pneumopericardium (figure 1). Closer evaluation of his CTPA revealed alveolar rupture leading to pneumomediastinum and pneumopericardium which was attributed to barotrauma from the persistent dry cough.
Figure 1 Bilateral pulmonary embolism with pneumomediastinum and pneumopericardium.
Bedside echocardiogram demonstrated ballooning of the right ventricle, suggestive of significant pulmonary hypertension and his troponin I was elevated at 162 ng/L (<21 ng/L).
Treatment
He was at high risk according to the simplified PE severity index with a 30-day mortality prediction of 8.9%. Due to the high oxygen requirement and severity of clot burden with persistent tachycardia and right ventricular strain, it was decided to thrombolyse him. He received intravenous alteplase 10 mg loading followed by a 90 mg infusion. His saturation improved gradually over a 6-hour period up to 100% on room air. He received therapeutic dose subcutaneous enoxaparin for 7 days following thrombolysis and was changed to oral apixaban 5 mg two times per day for life-long therapy on discharge.
Outcome and follow-up
His testosterone level was 25.4 nmol/L (normal range 10–35 nmol/L). This was 9 weeks after his regular testosterone undecanoate therapy. He was noted to be polycythaemic with a haemoglobin level of 209 g/L and haematocrit of 0.63. The elevated erythropoietin level at 42 mIU/mL (normal range 5–25 mIU/mL) suggests secondary polycythaemia. His haemoglobin level and haematocrit improved to 152 g/L and 0.45, respectively, at the time of discharge. A thrombophilia screen was negative for any secondary causes including JAK2 mutation, antiphospholipid antibodies, anti nuclear antibody, extractable nuclear antigen, vasculitis screening, homocysteine level and prothrombotic gene mutations.
On follow-up at 3 months, he had returned to his baseline functional capacity and his repeat echocardiogram showed complete resolution of right ventricular strain with normal cardiac function. In the long-term management of his testosterone replacement therapy, it was decided to recommence his testosterone only when the serum testosterone level falls below 10 nmol/L.
Discussion
Our patient had multiple risk factors for VTE. KS is known to increase the risk of VTE. He had a family history of unprovoked DVT, although the thrombophilia screening for both him and his father could not identify a hereditary cause. His polycythaemia could have predisposed him to VTE and was likely multifactorial from hypoxia, dehydration and testosterone therapy. The fact that he tolerated an SPO2 down to 74% in the community was remarkable and we postulate that the secondary polycythaemic response may have allowed him to tolerate such severe hypoxia. Although he was not hypotensive, severe hypoxic respiratory failure with signs of right ventricular strain prompted the decision for thrombolysis. Current guidance for PE thrombolysis mostly depends on failed haemodynamics and suggests close monitoring and consideration of rescue thrombolysis for cases like our patient.8 Several researchers have highlighted the need for thrombolysis in severe hypoxic respiratory failure with preserved haemodynamics.9 10 Percutaneous catheter-directed therapy is currently recommended for haemodynamically unstable PE with contraindications for thrombolysis.8 As our patient did not have any contraindications for thrombolysis, this was not considered. Our patient clearly improved with thrombolysis with normalisation of his oxygenation from SPO2 of 74%–100% within hours and his full recovery without any evidence of pulmonary hypertension speaks to the dramatic improvement achieved with this therapy. Polycythaemia is one of the most common side effects of testosterone therapy.11 Regardless of this, a systematic review of six randomised trials and five observational studies failed to show an association between testosterone therapy and thromboembolism.12 Despite this, provided the multiple risk factors our patient had for VTE, it was decided to minimise any risk testosterone-related polycythaemia could cause by targeting his testosterone therapy towards the lower limit of normal.
Learning points
Clinicians should be cognisant about the hypercoagulable state of Klinefelter syndrome, especially when the patient has other risk factors for venous thromboembolism (VTE).
We propose that clinicians use a cautious and closely supervised approach to testosterone replacement therapy in patients with other risk factors for VTE.
Clinicians should be aware of the current limitations for thrombolysis recommendations in pulmonary embolism (PE) which entirely depend on haemodynamic instability, and should carefully explore the need for thrombolysis in normotensive PE with refractory hypoxic respiratory failure on a case-by-case basis, which in our case led to optimum patient outcomes both in the short and long term.
Twitter: @jkndmiththinda
Contributors: NDMJK managed the acute presentation of the case and continues to follow up the case. JG provided Endocrinology input in management. NDMJK did the initial literature review, composed the original draft and prepared the images. JG contributed with literature review and provided critical feedback to the manuscript. All authors contributed to editing and finalising the manuscript and have given final approval to the version submitted and are accountable for the content submitted.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | TESTOSTERONE UNDECANOATE | DrugsGivenReaction | CC BY-NC | 33627349 | 19,038,559 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Polycythaemia'. | Successful thrombolysis of normotensive pulmonary embolism with life-threatening hypoxia in a young man with Klinefelter syndrome.
Klinefelter syndrome (KS) affects males born with an additional X chromosome giving the genotype 47XXY classically. This syndrome has primary features of infertility and hypogonadism along with other features including a genetically hypercoagulable state. When associated with other risk factors, KS further increases the risk of venous thromboembolism and could result in life-threatening pulmonary embolism (PE). There should be a lower threshold in suspecting PE as a cause of acute respiratory failure in this patient group and thrombolysis should be considered early in normotensive PE with severe hypoxia for best patient outcomes. Furthermore, clinicians should be cautious in managing testosterone therapy in patients with KS and additional thromboembolic risk factors.
Background
Klinefelter syndrome (KS) is considered to be the most common sex chromosome disorder. An Australian prevalence study had reported a rate of 223 per 100 000 males, with up to 50% of cases remaining undiagnosed.1 Affected males have an additional X chromosome leading to poor development of male secondary sexual characteristics. Other than these phenotypic changes, these patients are more prone to cardiovascular, endocrine and psychiatric disorders.2 KS is also considered to be a genetically hypercoagulable state where affected individuals have been shown to be four times more likely to have venous thromboembolism (VTE).2 The standardised incidence ratio for VTE is reported to be highest before 30 years of age at 12%.3 The current hypothesis for this hypercoagulable state is the presence of increased levels of plasminogen activator inhibitor 1 (PAI-1) in KS, related to obesity and low testosterone levels. Despite this, a study by Zitzmann et al did not demonstrate a change in PAI-1 levels in patients who are treated with testosterone therapy.4 Other hypotheses for the hypercoagulable state seen in this patient group include an increase in factor VIII and IX levels due to the genes coding for these factors being located on the X chromosome. A case series of six KS patients with deep venous thrombosis (DVT) has shown elevated factor VIII levels, but this was not significantly different from a control population with VTE.5
The Pulmonary Embolism International Thrombolysis Study (PEITHO) trial demonstrated that fibrinolytic therapy in patients with intermediate-severity pulmonary embolism (PE) prevented haemodynamic decompensation but increased the risk of major haemorrhage and stroke.6 A third of the patients in the PEITHO trial complained of persisting dyspnoea at 3-month follow-up, but over 80% had only low or intermediate probability of persisting or new-onset pulmonary hypertension at echocardiographic follow-up. Based on these data, the latest guidelines for PE by the European Society of Cardiology do not recommend routine thrombolysis for intermediate-risk PE. On the other hand, a small randomised trial of 83 patients suggested that thrombolysis in submassive PE improved the functional capacity at 3 months compared with anticoagulation alone.7
Here, we report a case of a young man with KS presenting with submassive PE complicated by pneumomediastinum and pneumopericardium with severe hypoxic respiratory failure prompting successful thrombolysis with good functional outcomes.
Case presentation
A young man in his mid-20s with KS presented to the emergency department with fluctuating generalised ill health and worsening shortness of breath for 2 weeks. He had an associated persistent dry cough and mild subjective fevers. He denied any pleuritic chest pain and could not recall any preceding calf tenderness and had no identifiable risk factors for VTE except his father having experienced an unprovoked DVT in the past with a negative thrombophilia screen. The patient had been diagnosed with KS at the age of 18 months with XXYY karyotype while being investigated for developmental delay and has been on testosterone replacement since the age of 15 years with a current testosterone regimen of intramuscular testosterone undecanoate 1000 mg at 3 monthly interval. He was otherwise healthy.
On examination, he was of a lean build with a well-grown beard. He was tachypnoeic (up to 40 breaths/min), tachycardic (up to 140 beats/min), and peripherally and centrally cyanosed. His blood pressure remained stable over 100/60 mm Hg. He had occasional crepitations on bilateral lung fields. His oxygen saturation (SPO2) on room air was 74% and was promptly commenced on a non-rebreather with improvement of SPO2 to 85%.
Investigations
Arterial blood gas performed on admission demonstrated type 1 respiratory failure with PaO2 of 52 mm Hg. ECG showed tachycardia with S1-Q3-T3 pattern. An urgent CT pulmonary angiogram (CTPA) was performed on high suspicion of PE. This demonstrated a completely occluded left main pulmonary artery with a large embolus and another embolus in the right main pulmonary artery extending into the right middle and lower lobe arteries extensively and to the upper lobe arteries to a lesser extent. CTPA further demonstrated pneumomediastinum and pneumopericardium (figure 1). Closer evaluation of his CTPA revealed alveolar rupture leading to pneumomediastinum and pneumopericardium which was attributed to barotrauma from the persistent dry cough.
Figure 1 Bilateral pulmonary embolism with pneumomediastinum and pneumopericardium.
Bedside echocardiogram demonstrated ballooning of the right ventricle, suggestive of significant pulmonary hypertension and his troponin I was elevated at 162 ng/L (<21 ng/L).
Treatment
He was at high risk according to the simplified PE severity index with a 30-day mortality prediction of 8.9%. Due to the high oxygen requirement and severity of clot burden with persistent tachycardia and right ventricular strain, it was decided to thrombolyse him. He received intravenous alteplase 10 mg loading followed by a 90 mg infusion. His saturation improved gradually over a 6-hour period up to 100% on room air. He received therapeutic dose subcutaneous enoxaparin for 7 days following thrombolysis and was changed to oral apixaban 5 mg two times per day for life-long therapy on discharge.
Outcome and follow-up
His testosterone level was 25.4 nmol/L (normal range 10–35 nmol/L). This was 9 weeks after his regular testosterone undecanoate therapy. He was noted to be polycythaemic with a haemoglobin level of 209 g/L and haematocrit of 0.63. The elevated erythropoietin level at 42 mIU/mL (normal range 5–25 mIU/mL) suggests secondary polycythaemia. His haemoglobin level and haematocrit improved to 152 g/L and 0.45, respectively, at the time of discharge. A thrombophilia screen was negative for any secondary causes including JAK2 mutation, antiphospholipid antibodies, anti nuclear antibody, extractable nuclear antigen, vasculitis screening, homocysteine level and prothrombotic gene mutations.
On follow-up at 3 months, he had returned to his baseline functional capacity and his repeat echocardiogram showed complete resolution of right ventricular strain with normal cardiac function. In the long-term management of his testosterone replacement therapy, it was decided to recommence his testosterone only when the serum testosterone level falls below 10 nmol/L.
Discussion
Our patient had multiple risk factors for VTE. KS is known to increase the risk of VTE. He had a family history of unprovoked DVT, although the thrombophilia screening for both him and his father could not identify a hereditary cause. His polycythaemia could have predisposed him to VTE and was likely multifactorial from hypoxia, dehydration and testosterone therapy. The fact that he tolerated an SPO2 down to 74% in the community was remarkable and we postulate that the secondary polycythaemic response may have allowed him to tolerate such severe hypoxia. Although he was not hypotensive, severe hypoxic respiratory failure with signs of right ventricular strain prompted the decision for thrombolysis. Current guidance for PE thrombolysis mostly depends on failed haemodynamics and suggests close monitoring and consideration of rescue thrombolysis for cases like our patient.8 Several researchers have highlighted the need for thrombolysis in severe hypoxic respiratory failure with preserved haemodynamics.9 10 Percutaneous catheter-directed therapy is currently recommended for haemodynamically unstable PE with contraindications for thrombolysis.8 As our patient did not have any contraindications for thrombolysis, this was not considered. Our patient clearly improved with thrombolysis with normalisation of his oxygenation from SPO2 of 74%–100% within hours and his full recovery without any evidence of pulmonary hypertension speaks to the dramatic improvement achieved with this therapy. Polycythaemia is one of the most common side effects of testosterone therapy.11 Regardless of this, a systematic review of six randomised trials and five observational studies failed to show an association between testosterone therapy and thromboembolism.12 Despite this, provided the multiple risk factors our patient had for VTE, it was decided to minimise any risk testosterone-related polycythaemia could cause by targeting his testosterone therapy towards the lower limit of normal.
Learning points
Clinicians should be cognisant about the hypercoagulable state of Klinefelter syndrome, especially when the patient has other risk factors for venous thromboembolism (VTE).
We propose that clinicians use a cautious and closely supervised approach to testosterone replacement therapy in patients with other risk factors for VTE.
Clinicians should be aware of the current limitations for thrombolysis recommendations in pulmonary embolism (PE) which entirely depend on haemodynamic instability, and should carefully explore the need for thrombolysis in normotensive PE with refractory hypoxic respiratory failure on a case-by-case basis, which in our case led to optimum patient outcomes both in the short and long term.
Twitter: @jkndmiththinda
Contributors: NDMJK managed the acute presentation of the case and continues to follow up the case. JG provided Endocrinology input in management. NDMJK did the initial literature review, composed the original draft and prepared the images. JG contributed with literature review and provided critical feedback to the manuscript. All authors contributed to editing and finalising the manuscript and have given final approval to the version submitted and are accountable for the content submitted.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | TESTOSTERONE UNDECANOATE | DrugsGivenReaction | CC BY-NC | 33627349 | 19,038,559 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary embolism'. | Successful thrombolysis of normotensive pulmonary embolism with life-threatening hypoxia in a young man with Klinefelter syndrome.
Klinefelter syndrome (KS) affects males born with an additional X chromosome giving the genotype 47XXY classically. This syndrome has primary features of infertility and hypogonadism along with other features including a genetically hypercoagulable state. When associated with other risk factors, KS further increases the risk of venous thromboembolism and could result in life-threatening pulmonary embolism (PE). There should be a lower threshold in suspecting PE as a cause of acute respiratory failure in this patient group and thrombolysis should be considered early in normotensive PE with severe hypoxia for best patient outcomes. Furthermore, clinicians should be cautious in managing testosterone therapy in patients with KS and additional thromboembolic risk factors.
Background
Klinefelter syndrome (KS) is considered to be the most common sex chromosome disorder. An Australian prevalence study had reported a rate of 223 per 100 000 males, with up to 50% of cases remaining undiagnosed.1 Affected males have an additional X chromosome leading to poor development of male secondary sexual characteristics. Other than these phenotypic changes, these patients are more prone to cardiovascular, endocrine and psychiatric disorders.2 KS is also considered to be a genetically hypercoagulable state where affected individuals have been shown to be four times more likely to have venous thromboembolism (VTE).2 The standardised incidence ratio for VTE is reported to be highest before 30 years of age at 12%.3 The current hypothesis for this hypercoagulable state is the presence of increased levels of plasminogen activator inhibitor 1 (PAI-1) in KS, related to obesity and low testosterone levels. Despite this, a study by Zitzmann et al did not demonstrate a change in PAI-1 levels in patients who are treated with testosterone therapy.4 Other hypotheses for the hypercoagulable state seen in this patient group include an increase in factor VIII and IX levels due to the genes coding for these factors being located on the X chromosome. A case series of six KS patients with deep venous thrombosis (DVT) has shown elevated factor VIII levels, but this was not significantly different from a control population with VTE.5
The Pulmonary Embolism International Thrombolysis Study (PEITHO) trial demonstrated that fibrinolytic therapy in patients with intermediate-severity pulmonary embolism (PE) prevented haemodynamic decompensation but increased the risk of major haemorrhage and stroke.6 A third of the patients in the PEITHO trial complained of persisting dyspnoea at 3-month follow-up, but over 80% had only low or intermediate probability of persisting or new-onset pulmonary hypertension at echocardiographic follow-up. Based on these data, the latest guidelines for PE by the European Society of Cardiology do not recommend routine thrombolysis for intermediate-risk PE. On the other hand, a small randomised trial of 83 patients suggested that thrombolysis in submassive PE improved the functional capacity at 3 months compared with anticoagulation alone.7
Here, we report a case of a young man with KS presenting with submassive PE complicated by pneumomediastinum and pneumopericardium with severe hypoxic respiratory failure prompting successful thrombolysis with good functional outcomes.
Case presentation
A young man in his mid-20s with KS presented to the emergency department with fluctuating generalised ill health and worsening shortness of breath for 2 weeks. He had an associated persistent dry cough and mild subjective fevers. He denied any pleuritic chest pain and could not recall any preceding calf tenderness and had no identifiable risk factors for VTE except his father having experienced an unprovoked DVT in the past with a negative thrombophilia screen. The patient had been diagnosed with KS at the age of 18 months with XXYY karyotype while being investigated for developmental delay and has been on testosterone replacement since the age of 15 years with a current testosterone regimen of intramuscular testosterone undecanoate 1000 mg at 3 monthly interval. He was otherwise healthy.
On examination, he was of a lean build with a well-grown beard. He was tachypnoeic (up to 40 breaths/min), tachycardic (up to 140 beats/min), and peripherally and centrally cyanosed. His blood pressure remained stable over 100/60 mm Hg. He had occasional crepitations on bilateral lung fields. His oxygen saturation (SPO2) on room air was 74% and was promptly commenced on a non-rebreather with improvement of SPO2 to 85%.
Investigations
Arterial blood gas performed on admission demonstrated type 1 respiratory failure with PaO2 of 52 mm Hg. ECG showed tachycardia with S1-Q3-T3 pattern. An urgent CT pulmonary angiogram (CTPA) was performed on high suspicion of PE. This demonstrated a completely occluded left main pulmonary artery with a large embolus and another embolus in the right main pulmonary artery extending into the right middle and lower lobe arteries extensively and to the upper lobe arteries to a lesser extent. CTPA further demonstrated pneumomediastinum and pneumopericardium (figure 1). Closer evaluation of his CTPA revealed alveolar rupture leading to pneumomediastinum and pneumopericardium which was attributed to barotrauma from the persistent dry cough.
Figure 1 Bilateral pulmonary embolism with pneumomediastinum and pneumopericardium.
Bedside echocardiogram demonstrated ballooning of the right ventricle, suggestive of significant pulmonary hypertension and his troponin I was elevated at 162 ng/L (<21 ng/L).
Treatment
He was at high risk according to the simplified PE severity index with a 30-day mortality prediction of 8.9%. Due to the high oxygen requirement and severity of clot burden with persistent tachycardia and right ventricular strain, it was decided to thrombolyse him. He received intravenous alteplase 10 mg loading followed by a 90 mg infusion. His saturation improved gradually over a 6-hour period up to 100% on room air. He received therapeutic dose subcutaneous enoxaparin for 7 days following thrombolysis and was changed to oral apixaban 5 mg two times per day for life-long therapy on discharge.
Outcome and follow-up
His testosterone level was 25.4 nmol/L (normal range 10–35 nmol/L). This was 9 weeks after his regular testosterone undecanoate therapy. He was noted to be polycythaemic with a haemoglobin level of 209 g/L and haematocrit of 0.63. The elevated erythropoietin level at 42 mIU/mL (normal range 5–25 mIU/mL) suggests secondary polycythaemia. His haemoglobin level and haematocrit improved to 152 g/L and 0.45, respectively, at the time of discharge. A thrombophilia screen was negative for any secondary causes including JAK2 mutation, antiphospholipid antibodies, anti nuclear antibody, extractable nuclear antigen, vasculitis screening, homocysteine level and prothrombotic gene mutations.
On follow-up at 3 months, he had returned to his baseline functional capacity and his repeat echocardiogram showed complete resolution of right ventricular strain with normal cardiac function. In the long-term management of his testosterone replacement therapy, it was decided to recommence his testosterone only when the serum testosterone level falls below 10 nmol/L.
Discussion
Our patient had multiple risk factors for VTE. KS is known to increase the risk of VTE. He had a family history of unprovoked DVT, although the thrombophilia screening for both him and his father could not identify a hereditary cause. His polycythaemia could have predisposed him to VTE and was likely multifactorial from hypoxia, dehydration and testosterone therapy. The fact that he tolerated an SPO2 down to 74% in the community was remarkable and we postulate that the secondary polycythaemic response may have allowed him to tolerate such severe hypoxia. Although he was not hypotensive, severe hypoxic respiratory failure with signs of right ventricular strain prompted the decision for thrombolysis. Current guidance for PE thrombolysis mostly depends on failed haemodynamics and suggests close monitoring and consideration of rescue thrombolysis for cases like our patient.8 Several researchers have highlighted the need for thrombolysis in severe hypoxic respiratory failure with preserved haemodynamics.9 10 Percutaneous catheter-directed therapy is currently recommended for haemodynamically unstable PE with contraindications for thrombolysis.8 As our patient did not have any contraindications for thrombolysis, this was not considered. Our patient clearly improved with thrombolysis with normalisation of his oxygenation from SPO2 of 74%–100% within hours and his full recovery without any evidence of pulmonary hypertension speaks to the dramatic improvement achieved with this therapy. Polycythaemia is one of the most common side effects of testosterone therapy.11 Regardless of this, a systematic review of six randomised trials and five observational studies failed to show an association between testosterone therapy and thromboembolism.12 Despite this, provided the multiple risk factors our patient had for VTE, it was decided to minimise any risk testosterone-related polycythaemia could cause by targeting his testosterone therapy towards the lower limit of normal.
Learning points
Clinicians should be cognisant about the hypercoagulable state of Klinefelter syndrome, especially when the patient has other risk factors for venous thromboembolism (VTE).
We propose that clinicians use a cautious and closely supervised approach to testosterone replacement therapy in patients with other risk factors for VTE.
Clinicians should be aware of the current limitations for thrombolysis recommendations in pulmonary embolism (PE) which entirely depend on haemodynamic instability, and should carefully explore the need for thrombolysis in normotensive PE with refractory hypoxic respiratory failure on a case-by-case basis, which in our case led to optimum patient outcomes both in the short and long term.
Twitter: @jkndmiththinda
Contributors: NDMJK managed the acute presentation of the case and continues to follow up the case. JG provided Endocrinology input in management. NDMJK did the initial literature review, composed the original draft and prepared the images. JG contributed with literature review and provided critical feedback to the manuscript. All authors contributed to editing and finalising the manuscript and have given final approval to the version submitted and are accountable for the content submitted.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | TESTOSTERONE UNDECANOATE | DrugsGivenReaction | CC BY-NC | 33627349 | 19,038,559 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary hypertension'. | Successful thrombolysis of normotensive pulmonary embolism with life-threatening hypoxia in a young man with Klinefelter syndrome.
Klinefelter syndrome (KS) affects males born with an additional X chromosome giving the genotype 47XXY classically. This syndrome has primary features of infertility and hypogonadism along with other features including a genetically hypercoagulable state. When associated with other risk factors, KS further increases the risk of venous thromboembolism and could result in life-threatening pulmonary embolism (PE). There should be a lower threshold in suspecting PE as a cause of acute respiratory failure in this patient group and thrombolysis should be considered early in normotensive PE with severe hypoxia for best patient outcomes. Furthermore, clinicians should be cautious in managing testosterone therapy in patients with KS and additional thromboembolic risk factors.
Background
Klinefelter syndrome (KS) is considered to be the most common sex chromosome disorder. An Australian prevalence study had reported a rate of 223 per 100 000 males, with up to 50% of cases remaining undiagnosed.1 Affected males have an additional X chromosome leading to poor development of male secondary sexual characteristics. Other than these phenotypic changes, these patients are more prone to cardiovascular, endocrine and psychiatric disorders.2 KS is also considered to be a genetically hypercoagulable state where affected individuals have been shown to be four times more likely to have venous thromboembolism (VTE).2 The standardised incidence ratio for VTE is reported to be highest before 30 years of age at 12%.3 The current hypothesis for this hypercoagulable state is the presence of increased levels of plasminogen activator inhibitor 1 (PAI-1) in KS, related to obesity and low testosterone levels. Despite this, a study by Zitzmann et al did not demonstrate a change in PAI-1 levels in patients who are treated with testosterone therapy.4 Other hypotheses for the hypercoagulable state seen in this patient group include an increase in factor VIII and IX levels due to the genes coding for these factors being located on the X chromosome. A case series of six KS patients with deep venous thrombosis (DVT) has shown elevated factor VIII levels, but this was not significantly different from a control population with VTE.5
The Pulmonary Embolism International Thrombolysis Study (PEITHO) trial demonstrated that fibrinolytic therapy in patients with intermediate-severity pulmonary embolism (PE) prevented haemodynamic decompensation but increased the risk of major haemorrhage and stroke.6 A third of the patients in the PEITHO trial complained of persisting dyspnoea at 3-month follow-up, but over 80% had only low or intermediate probability of persisting or new-onset pulmonary hypertension at echocardiographic follow-up. Based on these data, the latest guidelines for PE by the European Society of Cardiology do not recommend routine thrombolysis for intermediate-risk PE. On the other hand, a small randomised trial of 83 patients suggested that thrombolysis in submassive PE improved the functional capacity at 3 months compared with anticoagulation alone.7
Here, we report a case of a young man with KS presenting with submassive PE complicated by pneumomediastinum and pneumopericardium with severe hypoxic respiratory failure prompting successful thrombolysis with good functional outcomes.
Case presentation
A young man in his mid-20s with KS presented to the emergency department with fluctuating generalised ill health and worsening shortness of breath for 2 weeks. He had an associated persistent dry cough and mild subjective fevers. He denied any pleuritic chest pain and could not recall any preceding calf tenderness and had no identifiable risk factors for VTE except his father having experienced an unprovoked DVT in the past with a negative thrombophilia screen. The patient had been diagnosed with KS at the age of 18 months with XXYY karyotype while being investigated for developmental delay and has been on testosterone replacement since the age of 15 years with a current testosterone regimen of intramuscular testosterone undecanoate 1000 mg at 3 monthly interval. He was otherwise healthy.
On examination, he was of a lean build with a well-grown beard. He was tachypnoeic (up to 40 breaths/min), tachycardic (up to 140 beats/min), and peripherally and centrally cyanosed. His blood pressure remained stable over 100/60 mm Hg. He had occasional crepitations on bilateral lung fields. His oxygen saturation (SPO2) on room air was 74% and was promptly commenced on a non-rebreather with improvement of SPO2 to 85%.
Investigations
Arterial blood gas performed on admission demonstrated type 1 respiratory failure with PaO2 of 52 mm Hg. ECG showed tachycardia with S1-Q3-T3 pattern. An urgent CT pulmonary angiogram (CTPA) was performed on high suspicion of PE. This demonstrated a completely occluded left main pulmonary artery with a large embolus and another embolus in the right main pulmonary artery extending into the right middle and lower lobe arteries extensively and to the upper lobe arteries to a lesser extent. CTPA further demonstrated pneumomediastinum and pneumopericardium (figure 1). Closer evaluation of his CTPA revealed alveolar rupture leading to pneumomediastinum and pneumopericardium which was attributed to barotrauma from the persistent dry cough.
Figure 1 Bilateral pulmonary embolism with pneumomediastinum and pneumopericardium.
Bedside echocardiogram demonstrated ballooning of the right ventricle, suggestive of significant pulmonary hypertension and his troponin I was elevated at 162 ng/L (<21 ng/L).
Treatment
He was at high risk according to the simplified PE severity index with a 30-day mortality prediction of 8.9%. Due to the high oxygen requirement and severity of clot burden with persistent tachycardia and right ventricular strain, it was decided to thrombolyse him. He received intravenous alteplase 10 mg loading followed by a 90 mg infusion. His saturation improved gradually over a 6-hour period up to 100% on room air. He received therapeutic dose subcutaneous enoxaparin for 7 days following thrombolysis and was changed to oral apixaban 5 mg two times per day for life-long therapy on discharge.
Outcome and follow-up
His testosterone level was 25.4 nmol/L (normal range 10–35 nmol/L). This was 9 weeks after his regular testosterone undecanoate therapy. He was noted to be polycythaemic with a haemoglobin level of 209 g/L and haematocrit of 0.63. The elevated erythropoietin level at 42 mIU/mL (normal range 5–25 mIU/mL) suggests secondary polycythaemia. His haemoglobin level and haematocrit improved to 152 g/L and 0.45, respectively, at the time of discharge. A thrombophilia screen was negative for any secondary causes including JAK2 mutation, antiphospholipid antibodies, anti nuclear antibody, extractable nuclear antigen, vasculitis screening, homocysteine level and prothrombotic gene mutations.
On follow-up at 3 months, he had returned to his baseline functional capacity and his repeat echocardiogram showed complete resolution of right ventricular strain with normal cardiac function. In the long-term management of his testosterone replacement therapy, it was decided to recommence his testosterone only when the serum testosterone level falls below 10 nmol/L.
Discussion
Our patient had multiple risk factors for VTE. KS is known to increase the risk of VTE. He had a family history of unprovoked DVT, although the thrombophilia screening for both him and his father could not identify a hereditary cause. His polycythaemia could have predisposed him to VTE and was likely multifactorial from hypoxia, dehydration and testosterone therapy. The fact that he tolerated an SPO2 down to 74% in the community was remarkable and we postulate that the secondary polycythaemic response may have allowed him to tolerate such severe hypoxia. Although he was not hypotensive, severe hypoxic respiratory failure with signs of right ventricular strain prompted the decision for thrombolysis. Current guidance for PE thrombolysis mostly depends on failed haemodynamics and suggests close monitoring and consideration of rescue thrombolysis for cases like our patient.8 Several researchers have highlighted the need for thrombolysis in severe hypoxic respiratory failure with preserved haemodynamics.9 10 Percutaneous catheter-directed therapy is currently recommended for haemodynamically unstable PE with contraindications for thrombolysis.8 As our patient did not have any contraindications for thrombolysis, this was not considered. Our patient clearly improved with thrombolysis with normalisation of his oxygenation from SPO2 of 74%–100% within hours and his full recovery without any evidence of pulmonary hypertension speaks to the dramatic improvement achieved with this therapy. Polycythaemia is one of the most common side effects of testosterone therapy.11 Regardless of this, a systematic review of six randomised trials and five observational studies failed to show an association between testosterone therapy and thromboembolism.12 Despite this, provided the multiple risk factors our patient had for VTE, it was decided to minimise any risk testosterone-related polycythaemia could cause by targeting his testosterone therapy towards the lower limit of normal.
Learning points
Clinicians should be cognisant about the hypercoagulable state of Klinefelter syndrome, especially when the patient has other risk factors for venous thromboembolism (VTE).
We propose that clinicians use a cautious and closely supervised approach to testosterone replacement therapy in patients with other risk factors for VTE.
Clinicians should be aware of the current limitations for thrombolysis recommendations in pulmonary embolism (PE) which entirely depend on haemodynamic instability, and should carefully explore the need for thrombolysis in normotensive PE with refractory hypoxic respiratory failure on a case-by-case basis, which in our case led to optimum patient outcomes both in the short and long term.
Twitter: @jkndmiththinda
Contributors: NDMJK managed the acute presentation of the case and continues to follow up the case. JG provided Endocrinology input in management. NDMJK did the initial literature review, composed the original draft and prepared the images. JG contributed with literature review and provided critical feedback to the manuscript. All authors contributed to editing and finalising the manuscript and have given final approval to the version submitted and are accountable for the content submitted.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | TESTOSTERONE UNDECANOATE | DrugsGivenReaction | CC BY-NC | 33627349 | 19,038,559 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory failure'. | Successful thrombolysis of normotensive pulmonary embolism with life-threatening hypoxia in a young man with Klinefelter syndrome.
Klinefelter syndrome (KS) affects males born with an additional X chromosome giving the genotype 47XXY classically. This syndrome has primary features of infertility and hypogonadism along with other features including a genetically hypercoagulable state. When associated with other risk factors, KS further increases the risk of venous thromboembolism and could result in life-threatening pulmonary embolism (PE). There should be a lower threshold in suspecting PE as a cause of acute respiratory failure in this patient group and thrombolysis should be considered early in normotensive PE with severe hypoxia for best patient outcomes. Furthermore, clinicians should be cautious in managing testosterone therapy in patients with KS and additional thromboembolic risk factors.
Background
Klinefelter syndrome (KS) is considered to be the most common sex chromosome disorder. An Australian prevalence study had reported a rate of 223 per 100 000 males, with up to 50% of cases remaining undiagnosed.1 Affected males have an additional X chromosome leading to poor development of male secondary sexual characteristics. Other than these phenotypic changes, these patients are more prone to cardiovascular, endocrine and psychiatric disorders.2 KS is also considered to be a genetically hypercoagulable state where affected individuals have been shown to be four times more likely to have venous thromboembolism (VTE).2 The standardised incidence ratio for VTE is reported to be highest before 30 years of age at 12%.3 The current hypothesis for this hypercoagulable state is the presence of increased levels of plasminogen activator inhibitor 1 (PAI-1) in KS, related to obesity and low testosterone levels. Despite this, a study by Zitzmann et al did not demonstrate a change in PAI-1 levels in patients who are treated with testosterone therapy.4 Other hypotheses for the hypercoagulable state seen in this patient group include an increase in factor VIII and IX levels due to the genes coding for these factors being located on the X chromosome. A case series of six KS patients with deep venous thrombosis (DVT) has shown elevated factor VIII levels, but this was not significantly different from a control population with VTE.5
The Pulmonary Embolism International Thrombolysis Study (PEITHO) trial demonstrated that fibrinolytic therapy in patients with intermediate-severity pulmonary embolism (PE) prevented haemodynamic decompensation but increased the risk of major haemorrhage and stroke.6 A third of the patients in the PEITHO trial complained of persisting dyspnoea at 3-month follow-up, but over 80% had only low or intermediate probability of persisting or new-onset pulmonary hypertension at echocardiographic follow-up. Based on these data, the latest guidelines for PE by the European Society of Cardiology do not recommend routine thrombolysis for intermediate-risk PE. On the other hand, a small randomised trial of 83 patients suggested that thrombolysis in submassive PE improved the functional capacity at 3 months compared with anticoagulation alone.7
Here, we report a case of a young man with KS presenting with submassive PE complicated by pneumomediastinum and pneumopericardium with severe hypoxic respiratory failure prompting successful thrombolysis with good functional outcomes.
Case presentation
A young man in his mid-20s with KS presented to the emergency department with fluctuating generalised ill health and worsening shortness of breath for 2 weeks. He had an associated persistent dry cough and mild subjective fevers. He denied any pleuritic chest pain and could not recall any preceding calf tenderness and had no identifiable risk factors for VTE except his father having experienced an unprovoked DVT in the past with a negative thrombophilia screen. The patient had been diagnosed with KS at the age of 18 months with XXYY karyotype while being investigated for developmental delay and has been on testosterone replacement since the age of 15 years with a current testosterone regimen of intramuscular testosterone undecanoate 1000 mg at 3 monthly interval. He was otherwise healthy.
On examination, he was of a lean build with a well-grown beard. He was tachypnoeic (up to 40 breaths/min), tachycardic (up to 140 beats/min), and peripherally and centrally cyanosed. His blood pressure remained stable over 100/60 mm Hg. He had occasional crepitations on bilateral lung fields. His oxygen saturation (SPO2) on room air was 74% and was promptly commenced on a non-rebreather with improvement of SPO2 to 85%.
Investigations
Arterial blood gas performed on admission demonstrated type 1 respiratory failure with PaO2 of 52 mm Hg. ECG showed tachycardia with S1-Q3-T3 pattern. An urgent CT pulmonary angiogram (CTPA) was performed on high suspicion of PE. This demonstrated a completely occluded left main pulmonary artery with a large embolus and another embolus in the right main pulmonary artery extending into the right middle and lower lobe arteries extensively and to the upper lobe arteries to a lesser extent. CTPA further demonstrated pneumomediastinum and pneumopericardium (figure 1). Closer evaluation of his CTPA revealed alveolar rupture leading to pneumomediastinum and pneumopericardium which was attributed to barotrauma from the persistent dry cough.
Figure 1 Bilateral pulmonary embolism with pneumomediastinum and pneumopericardium.
Bedside echocardiogram demonstrated ballooning of the right ventricle, suggestive of significant pulmonary hypertension and his troponin I was elevated at 162 ng/L (<21 ng/L).
Treatment
He was at high risk according to the simplified PE severity index with a 30-day mortality prediction of 8.9%. Due to the high oxygen requirement and severity of clot burden with persistent tachycardia and right ventricular strain, it was decided to thrombolyse him. He received intravenous alteplase 10 mg loading followed by a 90 mg infusion. His saturation improved gradually over a 6-hour period up to 100% on room air. He received therapeutic dose subcutaneous enoxaparin for 7 days following thrombolysis and was changed to oral apixaban 5 mg two times per day for life-long therapy on discharge.
Outcome and follow-up
His testosterone level was 25.4 nmol/L (normal range 10–35 nmol/L). This was 9 weeks after his regular testosterone undecanoate therapy. He was noted to be polycythaemic with a haemoglobin level of 209 g/L and haematocrit of 0.63. The elevated erythropoietin level at 42 mIU/mL (normal range 5–25 mIU/mL) suggests secondary polycythaemia. His haemoglobin level and haematocrit improved to 152 g/L and 0.45, respectively, at the time of discharge. A thrombophilia screen was negative for any secondary causes including JAK2 mutation, antiphospholipid antibodies, anti nuclear antibody, extractable nuclear antigen, vasculitis screening, homocysteine level and prothrombotic gene mutations.
On follow-up at 3 months, he had returned to his baseline functional capacity and his repeat echocardiogram showed complete resolution of right ventricular strain with normal cardiac function. In the long-term management of his testosterone replacement therapy, it was decided to recommence his testosterone only when the serum testosterone level falls below 10 nmol/L.
Discussion
Our patient had multiple risk factors for VTE. KS is known to increase the risk of VTE. He had a family history of unprovoked DVT, although the thrombophilia screening for both him and his father could not identify a hereditary cause. His polycythaemia could have predisposed him to VTE and was likely multifactorial from hypoxia, dehydration and testosterone therapy. The fact that he tolerated an SPO2 down to 74% in the community was remarkable and we postulate that the secondary polycythaemic response may have allowed him to tolerate such severe hypoxia. Although he was not hypotensive, severe hypoxic respiratory failure with signs of right ventricular strain prompted the decision for thrombolysis. Current guidance for PE thrombolysis mostly depends on failed haemodynamics and suggests close monitoring and consideration of rescue thrombolysis for cases like our patient.8 Several researchers have highlighted the need for thrombolysis in severe hypoxic respiratory failure with preserved haemodynamics.9 10 Percutaneous catheter-directed therapy is currently recommended for haemodynamically unstable PE with contraindications for thrombolysis.8 As our patient did not have any contraindications for thrombolysis, this was not considered. Our patient clearly improved with thrombolysis with normalisation of his oxygenation from SPO2 of 74%–100% within hours and his full recovery without any evidence of pulmonary hypertension speaks to the dramatic improvement achieved with this therapy. Polycythaemia is one of the most common side effects of testosterone therapy.11 Regardless of this, a systematic review of six randomised trials and five observational studies failed to show an association between testosterone therapy and thromboembolism.12 Despite this, provided the multiple risk factors our patient had for VTE, it was decided to minimise any risk testosterone-related polycythaemia could cause by targeting his testosterone therapy towards the lower limit of normal.
Learning points
Clinicians should be cognisant about the hypercoagulable state of Klinefelter syndrome, especially when the patient has other risk factors for venous thromboembolism (VTE).
We propose that clinicians use a cautious and closely supervised approach to testosterone replacement therapy in patients with other risk factors for VTE.
Clinicians should be aware of the current limitations for thrombolysis recommendations in pulmonary embolism (PE) which entirely depend on haemodynamic instability, and should carefully explore the need for thrombolysis in normotensive PE with refractory hypoxic respiratory failure on a case-by-case basis, which in our case led to optimum patient outcomes both in the short and long term.
Twitter: @jkndmiththinda
Contributors: NDMJK managed the acute presentation of the case and continues to follow up the case. JG provided Endocrinology input in management. NDMJK did the initial literature review, composed the original draft and prepared the images. JG contributed with literature review and provided critical feedback to the manuscript. All authors contributed to editing and finalising the manuscript and have given final approval to the version submitted and are accountable for the content submitted.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | TESTOSTERONE UNDECANOATE | DrugsGivenReaction | CC BY-NC | 33627349 | 19,038,559 | 2021-02-24 |
What was the administration route of drug 'TESTOSTERONE UNDECANOATE'? | Successful thrombolysis of normotensive pulmonary embolism with life-threatening hypoxia in a young man with Klinefelter syndrome.
Klinefelter syndrome (KS) affects males born with an additional X chromosome giving the genotype 47XXY classically. This syndrome has primary features of infertility and hypogonadism along with other features including a genetically hypercoagulable state. When associated with other risk factors, KS further increases the risk of venous thromboembolism and could result in life-threatening pulmonary embolism (PE). There should be a lower threshold in suspecting PE as a cause of acute respiratory failure in this patient group and thrombolysis should be considered early in normotensive PE with severe hypoxia for best patient outcomes. Furthermore, clinicians should be cautious in managing testosterone therapy in patients with KS and additional thromboembolic risk factors.
Background
Klinefelter syndrome (KS) is considered to be the most common sex chromosome disorder. An Australian prevalence study had reported a rate of 223 per 100 000 males, with up to 50% of cases remaining undiagnosed.1 Affected males have an additional X chromosome leading to poor development of male secondary sexual characteristics. Other than these phenotypic changes, these patients are more prone to cardiovascular, endocrine and psychiatric disorders.2 KS is also considered to be a genetically hypercoagulable state where affected individuals have been shown to be four times more likely to have venous thromboembolism (VTE).2 The standardised incidence ratio for VTE is reported to be highest before 30 years of age at 12%.3 The current hypothesis for this hypercoagulable state is the presence of increased levels of plasminogen activator inhibitor 1 (PAI-1) in KS, related to obesity and low testosterone levels. Despite this, a study by Zitzmann et al did not demonstrate a change in PAI-1 levels in patients who are treated with testosterone therapy.4 Other hypotheses for the hypercoagulable state seen in this patient group include an increase in factor VIII and IX levels due to the genes coding for these factors being located on the X chromosome. A case series of six KS patients with deep venous thrombosis (DVT) has shown elevated factor VIII levels, but this was not significantly different from a control population with VTE.5
The Pulmonary Embolism International Thrombolysis Study (PEITHO) trial demonstrated that fibrinolytic therapy in patients with intermediate-severity pulmonary embolism (PE) prevented haemodynamic decompensation but increased the risk of major haemorrhage and stroke.6 A third of the patients in the PEITHO trial complained of persisting dyspnoea at 3-month follow-up, but over 80% had only low or intermediate probability of persisting or new-onset pulmonary hypertension at echocardiographic follow-up. Based on these data, the latest guidelines for PE by the European Society of Cardiology do not recommend routine thrombolysis for intermediate-risk PE. On the other hand, a small randomised trial of 83 patients suggested that thrombolysis in submassive PE improved the functional capacity at 3 months compared with anticoagulation alone.7
Here, we report a case of a young man with KS presenting with submassive PE complicated by pneumomediastinum and pneumopericardium with severe hypoxic respiratory failure prompting successful thrombolysis with good functional outcomes.
Case presentation
A young man in his mid-20s with KS presented to the emergency department with fluctuating generalised ill health and worsening shortness of breath for 2 weeks. He had an associated persistent dry cough and mild subjective fevers. He denied any pleuritic chest pain and could not recall any preceding calf tenderness and had no identifiable risk factors for VTE except his father having experienced an unprovoked DVT in the past with a negative thrombophilia screen. The patient had been diagnosed with KS at the age of 18 months with XXYY karyotype while being investigated for developmental delay and has been on testosterone replacement since the age of 15 years with a current testosterone regimen of intramuscular testosterone undecanoate 1000 mg at 3 monthly interval. He was otherwise healthy.
On examination, he was of a lean build with a well-grown beard. He was tachypnoeic (up to 40 breaths/min), tachycardic (up to 140 beats/min), and peripherally and centrally cyanosed. His blood pressure remained stable over 100/60 mm Hg. He had occasional crepitations on bilateral lung fields. His oxygen saturation (SPO2) on room air was 74% and was promptly commenced on a non-rebreather with improvement of SPO2 to 85%.
Investigations
Arterial blood gas performed on admission demonstrated type 1 respiratory failure with PaO2 of 52 mm Hg. ECG showed tachycardia with S1-Q3-T3 pattern. An urgent CT pulmonary angiogram (CTPA) was performed on high suspicion of PE. This demonstrated a completely occluded left main pulmonary artery with a large embolus and another embolus in the right main pulmonary artery extending into the right middle and lower lobe arteries extensively and to the upper lobe arteries to a lesser extent. CTPA further demonstrated pneumomediastinum and pneumopericardium (figure 1). Closer evaluation of his CTPA revealed alveolar rupture leading to pneumomediastinum and pneumopericardium which was attributed to barotrauma from the persistent dry cough.
Figure 1 Bilateral pulmonary embolism with pneumomediastinum and pneumopericardium.
Bedside echocardiogram demonstrated ballooning of the right ventricle, suggestive of significant pulmonary hypertension and his troponin I was elevated at 162 ng/L (<21 ng/L).
Treatment
He was at high risk according to the simplified PE severity index with a 30-day mortality prediction of 8.9%. Due to the high oxygen requirement and severity of clot burden with persistent tachycardia and right ventricular strain, it was decided to thrombolyse him. He received intravenous alteplase 10 mg loading followed by a 90 mg infusion. His saturation improved gradually over a 6-hour period up to 100% on room air. He received therapeutic dose subcutaneous enoxaparin for 7 days following thrombolysis and was changed to oral apixaban 5 mg two times per day for life-long therapy on discharge.
Outcome and follow-up
His testosterone level was 25.4 nmol/L (normal range 10–35 nmol/L). This was 9 weeks after his regular testosterone undecanoate therapy. He was noted to be polycythaemic with a haemoglobin level of 209 g/L and haematocrit of 0.63. The elevated erythropoietin level at 42 mIU/mL (normal range 5–25 mIU/mL) suggests secondary polycythaemia. His haemoglobin level and haematocrit improved to 152 g/L and 0.45, respectively, at the time of discharge. A thrombophilia screen was negative for any secondary causes including JAK2 mutation, antiphospholipid antibodies, anti nuclear antibody, extractable nuclear antigen, vasculitis screening, homocysteine level and prothrombotic gene mutations.
On follow-up at 3 months, he had returned to his baseline functional capacity and his repeat echocardiogram showed complete resolution of right ventricular strain with normal cardiac function. In the long-term management of his testosterone replacement therapy, it was decided to recommence his testosterone only when the serum testosterone level falls below 10 nmol/L.
Discussion
Our patient had multiple risk factors for VTE. KS is known to increase the risk of VTE. He had a family history of unprovoked DVT, although the thrombophilia screening for both him and his father could not identify a hereditary cause. His polycythaemia could have predisposed him to VTE and was likely multifactorial from hypoxia, dehydration and testosterone therapy. The fact that he tolerated an SPO2 down to 74% in the community was remarkable and we postulate that the secondary polycythaemic response may have allowed him to tolerate such severe hypoxia. Although he was not hypotensive, severe hypoxic respiratory failure with signs of right ventricular strain prompted the decision for thrombolysis. Current guidance for PE thrombolysis mostly depends on failed haemodynamics and suggests close monitoring and consideration of rescue thrombolysis for cases like our patient.8 Several researchers have highlighted the need for thrombolysis in severe hypoxic respiratory failure with preserved haemodynamics.9 10 Percutaneous catheter-directed therapy is currently recommended for haemodynamically unstable PE with contraindications for thrombolysis.8 As our patient did not have any contraindications for thrombolysis, this was not considered. Our patient clearly improved with thrombolysis with normalisation of his oxygenation from SPO2 of 74%–100% within hours and his full recovery without any evidence of pulmonary hypertension speaks to the dramatic improvement achieved with this therapy. Polycythaemia is one of the most common side effects of testosterone therapy.11 Regardless of this, a systematic review of six randomised trials and five observational studies failed to show an association between testosterone therapy and thromboembolism.12 Despite this, provided the multiple risk factors our patient had for VTE, it was decided to minimise any risk testosterone-related polycythaemia could cause by targeting his testosterone therapy towards the lower limit of normal.
Learning points
Clinicians should be cognisant about the hypercoagulable state of Klinefelter syndrome, especially when the patient has other risk factors for venous thromboembolism (VTE).
We propose that clinicians use a cautious and closely supervised approach to testosterone replacement therapy in patients with other risk factors for VTE.
Clinicians should be aware of the current limitations for thrombolysis recommendations in pulmonary embolism (PE) which entirely depend on haemodynamic instability, and should carefully explore the need for thrombolysis in normotensive PE with refractory hypoxic respiratory failure on a case-by-case basis, which in our case led to optimum patient outcomes both in the short and long term.
Twitter: @jkndmiththinda
Contributors: NDMJK managed the acute presentation of the case and continues to follow up the case. JG provided Endocrinology input in management. NDMJK did the initial literature review, composed the original draft and prepared the images. JG contributed with literature review and provided critical feedback to the manuscript. All authors contributed to editing and finalising the manuscript and have given final approval to the version submitted and are accountable for the content submitted.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Intramuscular | DrugAdministrationRoute | CC BY-NC | 33627349 | 19,038,559 | 2021-02-24 |
What was the outcome of reaction 'Pneumomediastinum'? | Successful thrombolysis of normotensive pulmonary embolism with life-threatening hypoxia in a young man with Klinefelter syndrome.
Klinefelter syndrome (KS) affects males born with an additional X chromosome giving the genotype 47XXY classically. This syndrome has primary features of infertility and hypogonadism along with other features including a genetically hypercoagulable state. When associated with other risk factors, KS further increases the risk of venous thromboembolism and could result in life-threatening pulmonary embolism (PE). There should be a lower threshold in suspecting PE as a cause of acute respiratory failure in this patient group and thrombolysis should be considered early in normotensive PE with severe hypoxia for best patient outcomes. Furthermore, clinicians should be cautious in managing testosterone therapy in patients with KS and additional thromboembolic risk factors.
Background
Klinefelter syndrome (KS) is considered to be the most common sex chromosome disorder. An Australian prevalence study had reported a rate of 223 per 100 000 males, with up to 50% of cases remaining undiagnosed.1 Affected males have an additional X chromosome leading to poor development of male secondary sexual characteristics. Other than these phenotypic changes, these patients are more prone to cardiovascular, endocrine and psychiatric disorders.2 KS is also considered to be a genetically hypercoagulable state where affected individuals have been shown to be four times more likely to have venous thromboembolism (VTE).2 The standardised incidence ratio for VTE is reported to be highest before 30 years of age at 12%.3 The current hypothesis for this hypercoagulable state is the presence of increased levels of plasminogen activator inhibitor 1 (PAI-1) in KS, related to obesity and low testosterone levels. Despite this, a study by Zitzmann et al did not demonstrate a change in PAI-1 levels in patients who are treated with testosterone therapy.4 Other hypotheses for the hypercoagulable state seen in this patient group include an increase in factor VIII and IX levels due to the genes coding for these factors being located on the X chromosome. A case series of six KS patients with deep venous thrombosis (DVT) has shown elevated factor VIII levels, but this was not significantly different from a control population with VTE.5
The Pulmonary Embolism International Thrombolysis Study (PEITHO) trial demonstrated that fibrinolytic therapy in patients with intermediate-severity pulmonary embolism (PE) prevented haemodynamic decompensation but increased the risk of major haemorrhage and stroke.6 A third of the patients in the PEITHO trial complained of persisting dyspnoea at 3-month follow-up, but over 80% had only low or intermediate probability of persisting or new-onset pulmonary hypertension at echocardiographic follow-up. Based on these data, the latest guidelines for PE by the European Society of Cardiology do not recommend routine thrombolysis for intermediate-risk PE. On the other hand, a small randomised trial of 83 patients suggested that thrombolysis in submassive PE improved the functional capacity at 3 months compared with anticoagulation alone.7
Here, we report a case of a young man with KS presenting with submassive PE complicated by pneumomediastinum and pneumopericardium with severe hypoxic respiratory failure prompting successful thrombolysis with good functional outcomes.
Case presentation
A young man in his mid-20s with KS presented to the emergency department with fluctuating generalised ill health and worsening shortness of breath for 2 weeks. He had an associated persistent dry cough and mild subjective fevers. He denied any pleuritic chest pain and could not recall any preceding calf tenderness and had no identifiable risk factors for VTE except his father having experienced an unprovoked DVT in the past with a negative thrombophilia screen. The patient had been diagnosed with KS at the age of 18 months with XXYY karyotype while being investigated for developmental delay and has been on testosterone replacement since the age of 15 years with a current testosterone regimen of intramuscular testosterone undecanoate 1000 mg at 3 monthly interval. He was otherwise healthy.
On examination, he was of a lean build with a well-grown beard. He was tachypnoeic (up to 40 breaths/min), tachycardic (up to 140 beats/min), and peripherally and centrally cyanosed. His blood pressure remained stable over 100/60 mm Hg. He had occasional crepitations on bilateral lung fields. His oxygen saturation (SPO2) on room air was 74% and was promptly commenced on a non-rebreather with improvement of SPO2 to 85%.
Investigations
Arterial blood gas performed on admission demonstrated type 1 respiratory failure with PaO2 of 52 mm Hg. ECG showed tachycardia with S1-Q3-T3 pattern. An urgent CT pulmonary angiogram (CTPA) was performed on high suspicion of PE. This demonstrated a completely occluded left main pulmonary artery with a large embolus and another embolus in the right main pulmonary artery extending into the right middle and lower lobe arteries extensively and to the upper lobe arteries to a lesser extent. CTPA further demonstrated pneumomediastinum and pneumopericardium (figure 1). Closer evaluation of his CTPA revealed alveolar rupture leading to pneumomediastinum and pneumopericardium which was attributed to barotrauma from the persistent dry cough.
Figure 1 Bilateral pulmonary embolism with pneumomediastinum and pneumopericardium.
Bedside echocardiogram demonstrated ballooning of the right ventricle, suggestive of significant pulmonary hypertension and his troponin I was elevated at 162 ng/L (<21 ng/L).
Treatment
He was at high risk according to the simplified PE severity index with a 30-day mortality prediction of 8.9%. Due to the high oxygen requirement and severity of clot burden with persistent tachycardia and right ventricular strain, it was decided to thrombolyse him. He received intravenous alteplase 10 mg loading followed by a 90 mg infusion. His saturation improved gradually over a 6-hour period up to 100% on room air. He received therapeutic dose subcutaneous enoxaparin for 7 days following thrombolysis and was changed to oral apixaban 5 mg two times per day for life-long therapy on discharge.
Outcome and follow-up
His testosterone level was 25.4 nmol/L (normal range 10–35 nmol/L). This was 9 weeks after his regular testosterone undecanoate therapy. He was noted to be polycythaemic with a haemoglobin level of 209 g/L and haematocrit of 0.63. The elevated erythropoietin level at 42 mIU/mL (normal range 5–25 mIU/mL) suggests secondary polycythaemia. His haemoglobin level and haematocrit improved to 152 g/L and 0.45, respectively, at the time of discharge. A thrombophilia screen was negative for any secondary causes including JAK2 mutation, antiphospholipid antibodies, anti nuclear antibody, extractable nuclear antigen, vasculitis screening, homocysteine level and prothrombotic gene mutations.
On follow-up at 3 months, he had returned to his baseline functional capacity and his repeat echocardiogram showed complete resolution of right ventricular strain with normal cardiac function. In the long-term management of his testosterone replacement therapy, it was decided to recommence his testosterone only when the serum testosterone level falls below 10 nmol/L.
Discussion
Our patient had multiple risk factors for VTE. KS is known to increase the risk of VTE. He had a family history of unprovoked DVT, although the thrombophilia screening for both him and his father could not identify a hereditary cause. His polycythaemia could have predisposed him to VTE and was likely multifactorial from hypoxia, dehydration and testosterone therapy. The fact that he tolerated an SPO2 down to 74% in the community was remarkable and we postulate that the secondary polycythaemic response may have allowed him to tolerate such severe hypoxia. Although he was not hypotensive, severe hypoxic respiratory failure with signs of right ventricular strain prompted the decision for thrombolysis. Current guidance for PE thrombolysis mostly depends on failed haemodynamics and suggests close monitoring and consideration of rescue thrombolysis for cases like our patient.8 Several researchers have highlighted the need for thrombolysis in severe hypoxic respiratory failure with preserved haemodynamics.9 10 Percutaneous catheter-directed therapy is currently recommended for haemodynamically unstable PE with contraindications for thrombolysis.8 As our patient did not have any contraindications for thrombolysis, this was not considered. Our patient clearly improved with thrombolysis with normalisation of his oxygenation from SPO2 of 74%–100% within hours and his full recovery without any evidence of pulmonary hypertension speaks to the dramatic improvement achieved with this therapy. Polycythaemia is one of the most common side effects of testosterone therapy.11 Regardless of this, a systematic review of six randomised trials and five observational studies failed to show an association between testosterone therapy and thromboembolism.12 Despite this, provided the multiple risk factors our patient had for VTE, it was decided to minimise any risk testosterone-related polycythaemia could cause by targeting his testosterone therapy towards the lower limit of normal.
Learning points
Clinicians should be cognisant about the hypercoagulable state of Klinefelter syndrome, especially when the patient has other risk factors for venous thromboembolism (VTE).
We propose that clinicians use a cautious and closely supervised approach to testosterone replacement therapy in patients with other risk factors for VTE.
Clinicians should be aware of the current limitations for thrombolysis recommendations in pulmonary embolism (PE) which entirely depend on haemodynamic instability, and should carefully explore the need for thrombolysis in normotensive PE with refractory hypoxic respiratory failure on a case-by-case basis, which in our case led to optimum patient outcomes both in the short and long term.
Twitter: @jkndmiththinda
Contributors: NDMJK managed the acute presentation of the case and continues to follow up the case. JG provided Endocrinology input in management. NDMJK did the initial literature review, composed the original draft and prepared the images. JG contributed with literature review and provided critical feedback to the manuscript. All authors contributed to editing and finalising the manuscript and have given final approval to the version submitted and are accountable for the content submitted.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33627349 | 19,038,559 | 2021-02-24 |
What was the outcome of reaction 'Pneumopericardium'? | Successful thrombolysis of normotensive pulmonary embolism with life-threatening hypoxia in a young man with Klinefelter syndrome.
Klinefelter syndrome (KS) affects males born with an additional X chromosome giving the genotype 47XXY classically. This syndrome has primary features of infertility and hypogonadism along with other features including a genetically hypercoagulable state. When associated with other risk factors, KS further increases the risk of venous thromboembolism and could result in life-threatening pulmonary embolism (PE). There should be a lower threshold in suspecting PE as a cause of acute respiratory failure in this patient group and thrombolysis should be considered early in normotensive PE with severe hypoxia for best patient outcomes. Furthermore, clinicians should be cautious in managing testosterone therapy in patients with KS and additional thromboembolic risk factors.
Background
Klinefelter syndrome (KS) is considered to be the most common sex chromosome disorder. An Australian prevalence study had reported a rate of 223 per 100 000 males, with up to 50% of cases remaining undiagnosed.1 Affected males have an additional X chromosome leading to poor development of male secondary sexual characteristics. Other than these phenotypic changes, these patients are more prone to cardiovascular, endocrine and psychiatric disorders.2 KS is also considered to be a genetically hypercoagulable state where affected individuals have been shown to be four times more likely to have venous thromboembolism (VTE).2 The standardised incidence ratio for VTE is reported to be highest before 30 years of age at 12%.3 The current hypothesis for this hypercoagulable state is the presence of increased levels of plasminogen activator inhibitor 1 (PAI-1) in KS, related to obesity and low testosterone levels. Despite this, a study by Zitzmann et al did not demonstrate a change in PAI-1 levels in patients who are treated with testosterone therapy.4 Other hypotheses for the hypercoagulable state seen in this patient group include an increase in factor VIII and IX levels due to the genes coding for these factors being located on the X chromosome. A case series of six KS patients with deep venous thrombosis (DVT) has shown elevated factor VIII levels, but this was not significantly different from a control population with VTE.5
The Pulmonary Embolism International Thrombolysis Study (PEITHO) trial demonstrated that fibrinolytic therapy in patients with intermediate-severity pulmonary embolism (PE) prevented haemodynamic decompensation but increased the risk of major haemorrhage and stroke.6 A third of the patients in the PEITHO trial complained of persisting dyspnoea at 3-month follow-up, but over 80% had only low or intermediate probability of persisting or new-onset pulmonary hypertension at echocardiographic follow-up. Based on these data, the latest guidelines for PE by the European Society of Cardiology do not recommend routine thrombolysis for intermediate-risk PE. On the other hand, a small randomised trial of 83 patients suggested that thrombolysis in submassive PE improved the functional capacity at 3 months compared with anticoagulation alone.7
Here, we report a case of a young man with KS presenting with submassive PE complicated by pneumomediastinum and pneumopericardium with severe hypoxic respiratory failure prompting successful thrombolysis with good functional outcomes.
Case presentation
A young man in his mid-20s with KS presented to the emergency department with fluctuating generalised ill health and worsening shortness of breath for 2 weeks. He had an associated persistent dry cough and mild subjective fevers. He denied any pleuritic chest pain and could not recall any preceding calf tenderness and had no identifiable risk factors for VTE except his father having experienced an unprovoked DVT in the past with a negative thrombophilia screen. The patient had been diagnosed with KS at the age of 18 months with XXYY karyotype while being investigated for developmental delay and has been on testosterone replacement since the age of 15 years with a current testosterone regimen of intramuscular testosterone undecanoate 1000 mg at 3 monthly interval. He was otherwise healthy.
On examination, he was of a lean build with a well-grown beard. He was tachypnoeic (up to 40 breaths/min), tachycardic (up to 140 beats/min), and peripherally and centrally cyanosed. His blood pressure remained stable over 100/60 mm Hg. He had occasional crepitations on bilateral lung fields. His oxygen saturation (SPO2) on room air was 74% and was promptly commenced on a non-rebreather with improvement of SPO2 to 85%.
Investigations
Arterial blood gas performed on admission demonstrated type 1 respiratory failure with PaO2 of 52 mm Hg. ECG showed tachycardia with S1-Q3-T3 pattern. An urgent CT pulmonary angiogram (CTPA) was performed on high suspicion of PE. This demonstrated a completely occluded left main pulmonary artery with a large embolus and another embolus in the right main pulmonary artery extending into the right middle and lower lobe arteries extensively and to the upper lobe arteries to a lesser extent. CTPA further demonstrated pneumomediastinum and pneumopericardium (figure 1). Closer evaluation of his CTPA revealed alveolar rupture leading to pneumomediastinum and pneumopericardium which was attributed to barotrauma from the persistent dry cough.
Figure 1 Bilateral pulmonary embolism with pneumomediastinum and pneumopericardium.
Bedside echocardiogram demonstrated ballooning of the right ventricle, suggestive of significant pulmonary hypertension and his troponin I was elevated at 162 ng/L (<21 ng/L).
Treatment
He was at high risk according to the simplified PE severity index with a 30-day mortality prediction of 8.9%. Due to the high oxygen requirement and severity of clot burden with persistent tachycardia and right ventricular strain, it was decided to thrombolyse him. He received intravenous alteplase 10 mg loading followed by a 90 mg infusion. His saturation improved gradually over a 6-hour period up to 100% on room air. He received therapeutic dose subcutaneous enoxaparin for 7 days following thrombolysis and was changed to oral apixaban 5 mg two times per day for life-long therapy on discharge.
Outcome and follow-up
His testosterone level was 25.4 nmol/L (normal range 10–35 nmol/L). This was 9 weeks after his regular testosterone undecanoate therapy. He was noted to be polycythaemic with a haemoglobin level of 209 g/L and haematocrit of 0.63. The elevated erythropoietin level at 42 mIU/mL (normal range 5–25 mIU/mL) suggests secondary polycythaemia. His haemoglobin level and haematocrit improved to 152 g/L and 0.45, respectively, at the time of discharge. A thrombophilia screen was negative for any secondary causes including JAK2 mutation, antiphospholipid antibodies, anti nuclear antibody, extractable nuclear antigen, vasculitis screening, homocysteine level and prothrombotic gene mutations.
On follow-up at 3 months, he had returned to his baseline functional capacity and his repeat echocardiogram showed complete resolution of right ventricular strain with normal cardiac function. In the long-term management of his testosterone replacement therapy, it was decided to recommence his testosterone only when the serum testosterone level falls below 10 nmol/L.
Discussion
Our patient had multiple risk factors for VTE. KS is known to increase the risk of VTE. He had a family history of unprovoked DVT, although the thrombophilia screening for both him and his father could not identify a hereditary cause. His polycythaemia could have predisposed him to VTE and was likely multifactorial from hypoxia, dehydration and testosterone therapy. The fact that he tolerated an SPO2 down to 74% in the community was remarkable and we postulate that the secondary polycythaemic response may have allowed him to tolerate such severe hypoxia. Although he was not hypotensive, severe hypoxic respiratory failure with signs of right ventricular strain prompted the decision for thrombolysis. Current guidance for PE thrombolysis mostly depends on failed haemodynamics and suggests close monitoring and consideration of rescue thrombolysis for cases like our patient.8 Several researchers have highlighted the need for thrombolysis in severe hypoxic respiratory failure with preserved haemodynamics.9 10 Percutaneous catheter-directed therapy is currently recommended for haemodynamically unstable PE with contraindications for thrombolysis.8 As our patient did not have any contraindications for thrombolysis, this was not considered. Our patient clearly improved with thrombolysis with normalisation of his oxygenation from SPO2 of 74%–100% within hours and his full recovery without any evidence of pulmonary hypertension speaks to the dramatic improvement achieved with this therapy. Polycythaemia is one of the most common side effects of testosterone therapy.11 Regardless of this, a systematic review of six randomised trials and five observational studies failed to show an association between testosterone therapy and thromboembolism.12 Despite this, provided the multiple risk factors our patient had for VTE, it was decided to minimise any risk testosterone-related polycythaemia could cause by targeting his testosterone therapy towards the lower limit of normal.
Learning points
Clinicians should be cognisant about the hypercoagulable state of Klinefelter syndrome, especially when the patient has other risk factors for venous thromboembolism (VTE).
We propose that clinicians use a cautious and closely supervised approach to testosterone replacement therapy in patients with other risk factors for VTE.
Clinicians should be aware of the current limitations for thrombolysis recommendations in pulmonary embolism (PE) which entirely depend on haemodynamic instability, and should carefully explore the need for thrombolysis in normotensive PE with refractory hypoxic respiratory failure on a case-by-case basis, which in our case led to optimum patient outcomes both in the short and long term.
Twitter: @jkndmiththinda
Contributors: NDMJK managed the acute presentation of the case and continues to follow up the case. JG provided Endocrinology input in management. NDMJK did the initial literature review, composed the original draft and prepared the images. JG contributed with literature review and provided critical feedback to the manuscript. All authors contributed to editing and finalising the manuscript and have given final approval to the version submitted and are accountable for the content submitted.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33627349 | 19,038,559 | 2021-02-24 |
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