Successful Treatment of Recalcitrant Pediatric Pemphigus Vulgaris With Rituximab

Abstract

Introduction Pemphigus vulgaris (PV) affecting the pediatric population is extremely rare, representing less than 3% of all PV cases. 1 Conventional treatment with systemic steroids with or without adjuvant immunosuppressants used in adult cases of PV is often employed. However, pediatric cases often present a therapeutic challenge given their increased susceptibility to systemic therapy’s associated risks. To date, no specific guidelines regarding treatment strategies in this patient population exist. We describe a 14-year-old Hispanic female patient with severe, recalcitrant PV with suboptimal treatment response to systemic steroids and intravenous immunoglobulin (IVIG) successfully treated with rituximab (RTX), showing control of disease in as early as 2 weeks after treatment initiation. To our knowledge, only 45 cases of pediatric PV successfully treated with RTX have been reported in the literature, highlighting its use as a safe therapeutic option in this patient population. 1 -17 Case Report A 14-year-old Hispanic female patient presented to our clinics for evaluation of 1-month history of multiple scattered flaccid vesicles and erosive lesions involving the trunk, extremities, and oral mucosa. Lesional and perilesional skin biopsy was obtained, confirming the diagnosis of PV. At this time, treatment with systemic oral corticosteroids (0.5 mg/kg/d) was initiated with significant improvement. However, within 1 month of therapy, the patient had a severe relapse of disease complicated by sepsis requiring hospitalization (Figure 1). Treatment with intravenous (IV) antibiotics and IV steroids (methylprednisolone 40 mg) was initiated. After control of disease was achieved approximately 2 weeks following IV steroids, the patient was transitioned to oral prednisone 60 mg and mycophenolate mofetil 500 mg daily. Given suboptimal treatment response and progressive disease, IVIG treatment (15 g/d [0.4 mg/kg/d]) for 5 days was administered. Despite the previous treatment regimen, the patient showed minimal improvement. In addition, the patient developed side effects from the therapy, including recurrent infections, Cushingoid features, hypertrichosis, and edema. To minimize ongoing prolonged steroid use, treatment with RTX (4 cycles of 375 mg/m2, 1 week apart) was initiated. Baseline laboratories prior to initial RTX cycle revealed elevated markers for CD19 and CD20 B cells (25.8%, 25.8%), decreased markers for CD4 T cells (33.4%) and elevated serum anti-desmoglein (dsg) 1 and 3 antibodies (189 U/mL and 122 U/mL, respectively). Our patient tolerated RTX therapy well with no adverse effects showing rapid clinical remission (no new lesions) in as early as 2 weeks after initial infusion (Figure 2). Following RTX therapy, our patient continued with sustained clinical remission while on low dose steroids. Following 6 months after RTX infusion, systemic steroids were successfully discontinued. At the last 18-month follow-up, our patient has remained disease free off all therapy, with serial serum anti-dsg 1/3 levels persisting below normal levels and no relapse episodes. Figure 1. Note multiple erosions and scattered flaccid bullae involving almost 100% of patient’s back. Figure 2. Significant re-epithelialization 4 weeks after the fourth cycle of rituximab. Note few scattered erosions and crusted plaques. Discussion Rituximab is a chimeric monoclonal antibody that targets the CD20 antigen present on the cell surface of B cells. 18 Despite its approval in adults with new-onset moderate to severe PV or those with recalcitrant disease, data regarding its use in pediatric cases of PV currently remain off-label. Rituximab appears to show promising results for the management of pediatric PV. 19 In 2019, Bilgic et al reviewed the literature describing a total of 30 cases of pediatric pemphigus (25 PV; 5 pemphigus foliaceous) successfully treated with RTX. 3 Since then, 21 more pediatric PV cases, including ours, have been described, resulting in 46 patients 1 -17 (Table 1). At diagnosis and at treatment initiation, mean age was 12.7 (range = 1.5-17) and 13.9 (range = 4.5-17) years, respectively. Following RTX therapy, patients were followed up for a mean period of 30 (range = 5-103) months. The most frequently used RTX dosing regimen in pediatric PV cases was 4 weekly infusions of 500 mg (n = 16), followed by 2 cycles of 500 mg infusions, 15 days apart (n = 9) and 4 weekly infusions of 375 mg/m2 body surface area (BSA) (n = 7), respectively. Table 1. Summary of Pediatric Cases of Pemphigus Vulgaris Treated With Rituximab. Total of patients, no. 46 Gender, no 21 F, 25 M Mean age at diagnosis, years (range) 12.7 (1.5-17) Mean age at initiation of RTX tx, years (range) 13.9 (4.5-17) Mean pre-dsg 1/3 levels, U/mL 453.5, 415.2 RTX dosing regimen  Body surface area dosing regimen   500 mg weekly × 4 wks 17   375 mg/m2 BSA weekly × 4 wks 7  Fixed dosing regimen   500 mg ×2, 2 wks apart 8   100 mg × 2, 2 wks apart 4   375 mg/m2 BSA × 2, 2 wks apart 6   375 mg/m2 BSA × 2, 30 days apart 1   300 mg/m2 BSA × 2, 2 wks apart 1   350 mg/m2 BSA × 2, 2 wks apart 2 Mean total follow-up, months (range) 30 (5-103) Clinical outcome at last follow-up, no  CR off T 21  CR on T 12  PR off T 4  PR on T 3  CR 3  PR 1  Not mentioned 1  Death 1 Reported AE, no 24  Infusion reaction (fever, chills, dyspnea, tachychardia, urticaria) 10  Angioedema 3  HSV 1  Infection (not specific, URI) 2  Sepsis 2 Relapse episodes, no 12 Mean post-dsg 1/3 levels, U/mL 30.4, 101.9 Abbreviations: AE, adverse effects; BSA, body surface area; F, female; M, male; Tx, treatment; RTX, rituximab; dsg, desmoglein; wks, weeks; CR off T, complete remission off therapy; CR on T, complete remission on therapy; PR off T, partial remission off therapy; PR on T, partial remission on therapy; CR, clinical remission; PR, partial remission; HSV, herpes simplex virus; URI, upper respiratory infection; no, number. Most cases (78%, n = 36) result in clinical remission following RTX therapy, with clinical outcome at last follow-up varying from complete remission (CR) requiring ongoing systemic immunosuppression (n = 12) to CR off all therapy (n = 21). In 2 cases, CR was reported as treatment outcome, but details regarding ongoing therapies were unclear. 4,12 Of all pediatric patients treated with RTX therapy, approximately 26% (n = 12) report a relapse of disease, the majority occurring within a mean period of 13 (range = 8-20) months after initial RTX therapy. Adverse effects associated with RTX were reported in approximately 35% of patients (n = 16). Of these, infusion reactions were the most commonly reported (mild infusion reactions, n = 12; angioedema, n = 3), followed by infections (n = 5). A summary of the reported cases, including clinical characteristics, treatment regimen, and outcome, is depicted in Table 2. Although pediatric patients treated with RTX are thought to have an increased risk of developing severe infections, sepsis was reported in only 2 cases, one of which resulted in death. 8,12 At 12 months after RTX therapy, our patient has achieved CR off all treatment with no reported adverse effects or relapse episodes. Whether or not patients benefit from additional maintenance RTX infusions during follow-up to ensure sustained clinical remission is still a subject of great debate. 3,4 In this review, a total of 18 patients received additional RTX infusions. In our case, at 6- and 12-month follow-up evaluations, our patient showed sustained clinical response; thus, additional maintenance infusions were deferred. Also, follow-up serum anti-dsg 1 and 3 antibody levels remained below normal limits and CD19 B-cell markers remained <1%, supporting sustained clinical response. Table 2. Pediatric Cases of Pemphigus Vulgaris Treated With Rituximab. Ref. Case no Sex/age at onset of PV (yrs) Previous TX AE due to previous TX Age at initiation of RTX (yrs) Indications for RTX/dosing regimen Adjuvant TX Additional RTX doses AE due to RTX Clinical outcome at last F/U visit Total F/U(months) Relapse Serum dsg1/3 levels (pre/post RTX) Our case 1 F/13 CS, TS, MMF, IVIG Sepsis, CUSH. hirsutism, edema 14 RD375 mg/m2 weekly for 4 wks TS, PSL (5-60 mg/d) N N CR off T 6 No 189 U/mL and 122 U/mL 25 U/mL and 17 U/mL Kianfar et al 1 2 M/14 CS, AZT, MMF, ILCS NR 17 RD500 mg weekly for 4 wks PSL (0.25 mg/kg/d) 1 cycle (4 infusions) N PR off T 103 Yes NM NM 3 F/14 CS, AZT CUSH, hirsutism acne, striae, osteopenia, ↑LFT 17 AE to previous tx/ 500 mg weekly for 4 wks PSL (0.1 mg/kg/d) N Chills and fever CR on T 18 No NM NM 4 F/14 None NR 14 Severe/500 mg weekly for 4 wks PSL (1 mg/kg/d) N N CR on T 28.5 Yes NM NM 5 F/16 None NR 16 Severe/500 mg weekly for 4 wks PSL (1.8 mg/kg/d) N Fever CR off T 58 No NM NM 6 M/17 None Dyspepsia 17 Severe, intolerance to PSL/500 mg weekly for 4 wks PSL (0.8 mg/kg/d) 1 cycle (4 infusions) Dyspnea PR on T 57 Yes NM NM 7 F/16 CS, AZT NR 17 RD/500 mg weekly for 4 wks PSL (0.5 mg/kg/d) 1 cycle (4 infusions) Dyspnea, rigor, tachycardia PR off T 51 Yes NM NM 8 F/16 CS, AZT, MMF ↑LFT 17 RD/500 mg weekly for 4 wks PSL (1.1 mg/kg/d) N N CR on T 102 Yes NM NM 9 F/17 None NR 17 Severe/500 mg weekly for 4 wks PSL (1.1 mg/kg/d) 2 infusions N PR on T 51.5 Yes NM NM 10 F/16 CS NR 17 RD/500 mg weekly, for example, 4 wks PSL (0.9 mg/kg/d) N Dyspnea CR on T 5 No NM NM 11 M/11 CS, AZT NR 11 RD/500 mg weekly for 2 wks PSL (2 mg/kg/d) 2 infusions Fever, infection CR off T 97 Yes 30 U/mL and 137 U/mL NM Broshtilova et al 2 12 F/14 CS, DAP CUSH, delayed growth, skin atrophy, striae, hirsutism, menstrual irregularity, infections 14 RD and due to AEs of previous therapy/2 dose of 375 mg/m2 30 days apart NM NM N CR 34 No 270 U/mL and 314 U/mL 255 U/mL and 251 U/mL (first infusion) 202 U/mL and 308 U/mL (second infusion) Bilgic-Temel et al 3 13 M/16 CS, AZA Psychosis, OP, wt gain 17 RD and severe adverse events/2 dose 1000 mg 15 days apart MP (0.5-1 mg/kg/d) 3 cycles of fixed dose (500 mg) N CR off T 60 No NM NM 14 M/14 CS, AZA, DAP, MMP, IVIG Cataract, lymphopenia 17 RD and adverse events/2 doses 1000 mg 15 days apart IVIG N N PR off T 49 No NM NM 15 M/13 CS, AZA, DAP NR 17 RD/2 dose 1000 mg 15 days apart DAP N N PR off T 60 No NM NM 16 F/9 CS, AZA, IVIG, DAP OP, anemia 13 RD and severe/2 dose 500 mg 15 days apart MP, AZA 3 cycles of fixed dose (500 mg) N CR off T 25 Yes NM NM 17 F/10 CS, IVIG, ILS, TS OP, wt gain, CUSH 11 RD and severe adverse events/375 mg/m2 weekly for 4 weeks MP, ILS, TS 3 cycles (2 doses of RTX of 375 mg/m2 weekly for 4 wks and 1 prophylactic dose of RTX of 375 mg/m2 weekly for 2 weeks) N CR off T 19 Yes NM NM Gupta et al 4 18 M/12 CS, AZA NR 12 RD, contraindication to steroids, severe/2 doses of 500 mg 2 wks apart CS (5-20 mg/d) N Infusion reaction (1) HZV (1) CR off T 12 No 31.8 U/mL and 17.1 U/mL 11.3 U/mL and 3.1 U/mL 19 F/9 CS, AZA Anemia 9 CS (5-20 mg/d) N CR off T 12 No 357 U/mL and 219 U/mL 98 U/mL and 77 U/mL 20 F/11 CS, CP NR 11 CP (50 mg/d), CS (5-20 mg/d) N CR on T 12 No 99.1 U/mL and 103.4 U/mL 3.4 U/mL and 6.7 U/mL 21 M/12 CS, CP NR 12 CP (50 mg/d), CS (5-20 mg/d) N CR on T 12 No 184.6 U/mL and 94 U/mL 80.5 U/mL and 64 U/mL 22 M/9 CS, AZA NR 9 CS (5-20 mg/d) N CR off T 12 No 150 U/mL and 10.8 U/mL 47 U/mL and 1.8 U/mL Salman et al 5 23 M/14 CS, AZA, IVIG, DAP Osteopenia, CUSH, ↑LFT 14 RD/2 doses of 375 mg/m2 15 days apart Low dose CS (0.1-0.2 mg/kg/d) 3 cycles N CR on T 24 No NM NM 24 M/16 CS, AZA, IVIG, MMF Cataracts, osteopenia, lymphopenia 16 RD/2 doses of 375 mg/m2 15 days apart Low dose CS (0.1-0.2 mg/kg/d) 1 cycles N CR off T 44 No NM NM Buch JY et al 6 25 F/11 CS, AZA Hyperglycemia, CUSH 11 RD/2 doses of 300 mg/m2 15 days apart 40 mg PSL 1 cycle N CR on T 12 1 patient relapsed (not specific) 20.2 U/mL and 143.4 U/mL 1.8 U/mL and 5.7 U/mL 26 M/11 CS, AZA CUSH, wt gain, HTN 12 RD/2 doses of 300 mg/m2 15 days apart 40 mg PSL N N CR on T 12 237 U/mL and 194.6 U/mL 64 U/mL and 94 U/mL 27 F/9 CS CUSH, wt gain 9 RD/2 doses of 300 mg/m2 15 days apart 40 mg PSL 1 cycle N CR on T 12 228 U/mL and 229 U/mL 47.3 U/mL and 2.5 U/mL Kincaid et al 7 28 F/4 CS, IVIG, AZA HTN, CUSH, delayed growth 4 and 5 RD/2 doses of 375 mg/m2 15 days apart CS, AZA 2 cycles Mild infusion reaction, urticaria, low-grade fever CR off T 24 Yes 320 U/mL NM Kong et al 8 29 M/9 CS, MTX, MMF, Cyp, DAP NR NM RD/2 doses of 750 mg/m2 2 wks apart MTX, CS, MMF 1 cycle Neutropenia and sepsis CR on T 25 No NM NM Vinay et al 9 30 M/NS CS, AZA, DAP NR 9 RD and severe/2 doses of 375 mg/m2 15 days apart CS (0.5-1 mg/kg/d) N Angioedema CR off T 36 No 1372.80 U/mL and 888.80 U/mL 0.5 U/mL and 14.22 U/mL 31 M/NS CS, AZA, DAP NR 11 Severe/2 doses of 375 mg/m2 15 days apart CS (0.5-1 mg/kg/d) N Infusion reaction CR off T 8 No 248.52 U/mL and 575.20 U/mL Lost to F/U 32 M/NS CS, AZA, DAP, MMF NR 17 RD and severe/2 doses of 500 mg/m2 15 days apart AZA (2 mg/kg/d), CS (0.5-1 mg/kg/d) N N CR off T 19 No 67.30 U/mL and 130.33 U/mL 7.56 U/mL and 4.48 U/mL 33 M/NS CS CUSH 17 RD and SEs of previous therapy/2 doses of 500 mg/m2 15 days apart AZA (2 mg/kg/d), CS (0.5-1 mg/kg/d) 1 cycle Infusion reaction CR on T 18 No 1148.46 U/mL and 116.09 U/mL 94.04 U/mL and 14.79 U/mL 34 F/NS CS NR 17 Severe/2 doses of 500 mg/m2 15 days apart CS (0.5-1 mg/kg/d) N N CR off T 17 No 1743.74 U/mL and 87.43 U/mL 18.10 U/mL and 0.86 U/mL 35 F/NS CS, AZA NR 13 RD/2 doses of 500 mg/m2 15 days apart CS (0.5-1 mg/kg/d) N Upper respiratory tract infection CR off T 14 No 165.11 U/mL and 340.25 U/mL 1.83 U/mL and 6.26 U/mL 36 M/NS CS, AZA NR 12 RD/2 doses of 500 mg/m2 15 days apart CS (0.5-1 mg/kg/d) 1 cycle Angioedema CR off T 12 No 107.11 U/mL and 134.81 U/mL 2.98 U/mL and 274.17 U/mL Didona et al 10 37 M/11 CS, IVIG Wt gain, CUSH. 11 RD/2 doses of 375 mg/m2 18 days apart NM N N CR 10 No NM NM 38 M/17 DP, AZA, MMF NR NM RD/2 doses of 500 mg/m2 15 days apart CS N N NM 12 NM NM NM Chen et al 11 39 M/17 CS, IVIG NR 17 RD/500 mg/m2 weekly for 4 wks CS N N CR off T NS NM NM NM Kanwar et al 12 40 M/9 CS, DP, AZA NR NM RD and severe/2 doses of 375 mg/m2 15 days apart PSL (1-1.5 mg/kg/d) N Angioedema CR off T 11.5 NM 1372.80 U/mL and 888.80 U/mL 0.12 U/mL and 742.40 U/mL 41 M/17 CS, CP NR NM RD and severe/2 doses of 1000 mg/m2 15 days apart PSL (1-1.5 mg/kg/d) N Sepsis Death N/A NM 95.73 U/mL and 25.60 U/mL NA Reguai et al 13 42 F/14 CS, IVIG Mood changes, acne, gastric ulcer 14 Severe AEs on previous therapy/375 mg/m2 weekly for 4 wks NM 2 cycles N CR off T 62 Yes 65 U/mL and 160 U/mL 2 U/mL and 44 U/m: Fuertes et al 14 43 M/1.5 CS, AZA, DAP, Gold CUSH 14 RD/375 mg/m2 weekly for 4 wks CS (prednisone 20 mg/d slowly tapered) N N CR 18 No 157 U/mL and 3 U/mL 10 U/mL and 1 U/mL Schmidt et al 15 44 F/17 CS, IVIG, MTX, AZA, MMF, NR NM RD/375 mg/m2 weekly for 4 wks MMF and MP N N CR off T 7 NM NM NM Schmidt et al 16 45 M/11.5 CS, AZA, DAP, MMF, CP, IVIG, MMF Osteopenia, infections, CUSH, growth delay 14 RD/375 mg/m2 weekly for 4 wks MMF (1-5 g/d), MP (12 mg/d), IVIG (10 g after 1st and 4th infusion) N N CR off T 24 No NM NM Kong et al 17 46 F/10 CS, AZA, MMF, IVIG, plasmapheresis Myelosuppression, infections 17 RD/375 mg/m2 weekly for 4 wks, then every 4 or 8 wks CS Y, 375 mg/m2/wk × 4 every 4-8 weeks N CR on T 17 NM 2079 U/mL and 4616 U/mL 33 U/mL and 564 U/mL Abbreviations: AE, adverse effects; AZA, azathioprine; CS, systemic corticosteroids; CP, cyclophosphamide; Cys, cyclosporine; CR off T, complete remission off therapy; CR on T, complete remission on therapy; CR, complete remission; CUSH, cushingoid; DAP, dapsone; Dsg, desmoglein; F/U, follow-up; IVIG, intravenous immunoglobulin; ILCS, intralesional steroids; LFT, liver function tests; MMF, mycophenolate mofetil; MTX, methotrexate; MP, methylprednisolone; NR, not reported; NM, not mentioned; OP, osteoporosis; PR on T, partial remission on therapy; PSL, prednisolone; Ref, references; RTX, rituximab; RD, refractory disease to conventional therapy; TS, topical steroids; wt, weight; wks, weeks. Conclusion We describe a 14-year-old Hispanic female patient who achieved sustained CR off treatment with no adverse effects or relapses reported at 18-month follow-up evaluation after successfully being treated with RTX. To our knowledge, CR off therapy has also been reported in 22 other cases. Given the vulnerability of this patient population, there is an increasing need for new therapeutic options. Our case is relevant because it supports the growing number of cases reporting successful treatment for pediatric PV using RTX. Physicians treating pediatric PV should be aware of the use of RTX as a therapeutic option in cases of recalcitrant pediatric PV, achieving prompt control of the disease. However, the need for randomized clinical trials to assess the role and efficacy of RTX on pediatric patients with PV remains. Author Contributions OCY and FC conceptualized and proposed the case report, edited the report, and provided guidance throughout. OYC, MS, VJG and FMR completed the literature review, wrote the first draft of the manuscript, and edited the report. MS, VJG, and FMR created the tables. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.