Therapeutic Response with Rituximab and Intravenous Immunoglobulin in Recalcitrant Bullous Pemphigoid

Dear Editor, Bullous pemphigoid (BP) is a chronic, autoimmune blistering disease that primarily affects the elderly. It is characterized by the formation of subepidermal blisters and intense pruritus. Despite standard therapeutic approaches, some cases of BP can be recalcitrant, posing significant challenges in management.[1] Here, we present a case series of biopsy and DIF-proven recalcitrant BP cases that required multiple therapeutic strategies such as rituximab or intravenous immunoglobulin to achieve disease control. Cases 1 and 2: A 35-year-old female and a 60-year-old female with no comorbidities had a 7-month and 1-year history of moderate BP and severe BP according to the Bullous Pemphigoid Disease Area Index score, respectively. Patients remained unresponsive to systemic corticosteroids 1.5 mg/kg/day, azathioprine 100 mg OD, doxycycline 200 mg/day, and nicotinamide 1 g/day even after 6 months of therapy. Patients were then given injection rituximab according to the rheumatoid arthritis (RA) protocol 1000 mg 2 weeks apart and responded well after two doses of rituximab with marked reduction in the formation of new bullae and resolution of pruritus, with mean time to achieve disease control and to end of consolidation phase of 2.4 and 5.5 weeks, respectively. Complete remission was observed after 4.2 months post two doses of injection rituximab. Follow-up at 1-year postrituximab infusion showed sustained remission with no new lesions and minimal need for topical steroids. Case 3: A 63-year-old male known case of diabetes mellitus on tablet metformin 500 mg twice a day for 5 years, diagnosed with severe BP 6 months back. He remained recalcitrant to standard therapies; after the physician and cardiology opinion, the patient was given rituximab according to RA protocol. The patient achieved disease control by the 3rd week after the 2nd dose of rituximab and was maintained on azathioprine 50 mg daily and achieved complete remission after 2 months post 3rd dose of rituximab. Cases 4-6: A 31-year-old female, a 30-year-old female, and a 74-year-old male, all cases had no known comorbidities and remained recalcitrant 6 months post three doses of injections of rituximab. Patients were then administered intravenous immunoglobulin 2 g/kg over 5 days and all of them attained remission. The mean number of cycles required to achieve remission was two (range 1–3). The mean time to achieve complete remission post the last cycle was 1.6 months. All cases were followed up for 1 year without any relapse and were maintained on tablet azathioprine 50 mg/day [Figures 1 and 2].Figure 1: Multiple tense bullae, few with erythematous border, few erythematous to hyperpigmented urticarial plaques distributed over trunkFigure 2: (a) Improvement post 2 cycles of intravenous immunoglobulin (IVIG) (b) improvement post 2 cycles of IVIGNo major adverse events were reported in any of the patients. Minor adverse reactions like chills postinfusion were noted in one patient postrituximab infusion. Intravenous immunoglobulin (IVIG) was well-tolerated in this series, with only mild side effects such as headache and no serious adverse reactions. The details are summarized in Table 1.Table 1: Summary of the casesBP typically responds well to standard treatments such as topical and systemic corticosteroids, tetracycline antibiotics, and immunosuppressive agents. However, some patients exhibit recalcitrant disease requiring advanced therapeutic approaches. Rituximab, an anti-CD20 monoclonal antibody, and IVIG have emerged as an effective treatment for refractory BP. Standard rituximab doses approved for lymphomas (375 mg/m² weekly for 4 weeks) and RA (two infusions of 1000 mg repeated in 2 weeks) are the most commonly used protocols and have proven effective in pemphigus vulgaris (PV), BP, and other autoimmune bullous diseases. A low-dose rituximab protocol of two infusions of 500 mg has also been used for PV, demonstrating a good safety profile and therapeutic response. The lymphoma protocol was not found to be superior than the rest of the protocols, and the RA protocol is preferred due to the cost-effectiveness.[2] In this series, three patients responded adequately to injection rituximab which was given according to the RA protocol attaining complete remission and absence of any further relapses up to 1 year post the last dose with minimal need of adjuvant immunosuppressants and no major adverse effects. This was similar to the observations by Rashid et al. and Polansky et al. who reported a 74% and 75% remission rate, respectively, with minimal adverse effects.[3,4] Although, Shetty and Ahmed et al. reported complete response in 69% of the patients But the adverse effects were significant.[2] All the three patients who were recalcitrant to three doses of injection rituximab responded well to injection IVIG 2 g/kg achieving complete remission after a mean of two cycles. The mean time to achieve remission was 1.6 months post the last cycle. This was better than the response reported by Ujiie et al. in which the improvement rate evaluated according to BPDAI-based severity was 70.7%–84.3% at 15, 30, and 60–90 days, with the total BPDAI scores decreasing significantly.[5] The reduced efficacy of rituximab in BP patients could be attributed to the varied pathomechanisms involved such as the involvement of eosinophils, neutrophils, and mast cells, which are not directly targeted by rituximab. These cells play a major role in tissue damage and inflammation in BP. The chronic inflammatory nature of BP, driven by cytokines and complement activation, may not be fully controlled by B-cell depletion alone, and in addition to IgG, some patients with BP have circulating IgE autoantibodies against BP180, suggesting a broader immune response not addressed by B-cell-targeted therapies requiring other interventions such as dupilumab and IVIG. Lack of availability and higher cost are the major hindrances with dupilumab.[6,7] IVIG was proven to reduce disease severity in animal models of BP by directly modulating the production of IL-6 and IL-10, in addition to reducing pathogenic antibody levels by increasing pathogenic IgG clearance by saturating FcRn as well as neutralizing pathogenic IgG by anti-idiotypic antibodies. Hence, it is a promising intervention in patients recalcitrant to rituximab as a rescue therapy as well as to maintain a sustained remission with minimal side effects which was also observed in the present case series.[8] In this case series, the treatment response was assessed based on the reduction in BPDAI score. However, certain serological markers such as titers of anti-BP180 antigen can be used for diagnosis and monitoring the therapeutic response.[9] We conclude that rituximab alone is a promising therapy in recalcitrant BP and IVIG can be an effective and safe treatment option, particularly in patients recalcitrant to rituximab alone or those who are unable to tolerate other therapies. More studies are required with a higher sample size to standardize the protocols. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Authors’ contributions Literature search: P.A, S.B; Data acquisition: C.K, S.C; Manuscript preparation: C.K, S.C, P.A, S.B; Manuscript editing: P.A, S.B; Manuscript review: C.K, S.C. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.