Introduction
Pemphigus is an autoimmune blistering disorder caused by antibodies against desmoglein antigens in the epidermis. It is clinically characterized by cutaneous blisters/erosions and/or mucosal ulcers and histopathologically by intraepidermal acantholytic vesicles and blisters [1]. The disease has a chronic remitting and relapsing course and is potentially fatal in the absence of proper treatment. It has conventionally been treated with systemic glucocorticosteroid (GCS) and adjuvant immunosuppressant drugs which although effective in controlling the disease, carry serious long-term adverse effects and complications [2].
Biosimilar rituximab (RTX) which initially was employed in patients, in whom GCS were contraindicated, has now been recommended as the first-line treatment option in moderate to severe pemphigus [3]. It provides prolonged periods of remission as compared to the conventional treatment and overcomes the adverse effects associated with prolonged GCS and oral immunosuppressant therapy. Biosimilar RTX acts by selectively depleting the autoantibody producing CD-20 positive B-lymphocytes. The cell depletion occurs by three main mechanisms: induction of apoptosis, complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Since RTX has no action against CD-20 negative B-cells and terminally differentiated plasma cells, B-cell regeneration occurs from hemopoietic stem cells into the peripheral circulation thereby repopulating the autoantibody producing B-cell pool which is believed to be responsible for relapse after RTX therapy [4, 5].
The successful use of RTX in Indian pemphigus patients was first reported in 2011 by Kanwar et al. [2]. Over the last decade, its use in pemphigus management has steadily increased with more data accumulating from many centers across India [6–14].
Objective
In this study, we share the clinical practice experience of biosimilar RTX therapy in pemphigus patients treated at our center and also review other studies conducted on Indian pemphigus patients.
Material and methods
Study design
This was a retrospective, descriptive cohort study conducted at a tertiary care hospital in North India over a period of 4 years. The study protocol was reviewed and approved by the Institute Ethics Committee (intramural).
Study population
Details of pemphigus patients who received treatment at our center from 2018 to 2022 were screened and data of patients who received RTX therapy were retrieved for retrospective analysis. The diagnosis of pemphigus was clinical, confirmed by histopathology and immunofluorescence study. Elisa for antibodies against desmoglein 1/3 (DSG 1/3) could not be done due to non-availability at our center. Data pertaining to patient characteristics, disease characteristics, treatment history and RTX efficacy and safety were extracted and recorded for analysis (fig. 1).
Intervention
All patients underwent laboratory testing (complete hemogram, liver and renal function tests), chest X-ray, Mantoux test, viral markers (HbsAg, anti-HCV, HIV-1&2), ECG and echocardiography. Premedication was administered half an hour before RTX infusion with pantoprazole 40 mg (IV), pheniramine maleate 22.75 mg (IV), hydrocortisone 100 mg
(IV) and a tablet of paracetamol 500 mg. RTX was administered as per the rheumatoid arthritis (RA) protocol at a dose of 1 gm for two doses at 2 weeks’ interval. After the infusion, patients were started on oral GCS and immunosuppressants. Steroids were started at a dose of 0.5–1 mg/kg/day and tapered as per disease activity and severity.
Outcome measures
Response to treatment was assessed based on consensus statement on definitions of disease, endpoints, and therapeutic response for pemphigus [15]. Treatment outcome was analyzed using early and late endpoints:
• End of consolidation phase (ECP): when no new lesions have developed for a minimum of 2 weeks and approximately 80% of the lesions have healed.
• Complete remission (CR) on minimal therapy (CR on): when there is an absence of new and/or established lesions for at least 2 months while the patient is receiving prednisolone ≤ 10 mg/day and/or minimal adjuvant therapy.
• Complete remission (CR) off therapy (CR off): when there are no new and/or established lesions while being off all systemic therapy for at least 2 months.
• Partial remission off therapy (PR off): presence of transient new lesions that heal within 1 week without treatment and while the patient is off all systemic therapy for at least 2 months.
• Partial remission on minimal therapy (PR on): the presence of transient new lesions that heal within 1 week while the patient is receiving minimal therapy, including topical steroids.
• Relapse: relapse is the extension of established lesions or the appearance of more than three new lesions per month which do not heal spontaneously within a week after disease control.
Results
A total of 20 pemphigus patients received RTX therapy over a period of 4 years. Four cases were excluded due to incomplete records. Data of 16 pemphigus patients (13 pemphigus vulgaris, 2 mucosal pemphigus vulgaris and 1 pemphigus foliaceus) were retrieved and retrospectively analyzed. There were 4 (25%) males and 12 (75%) females with a mean age of 34.81 ±1.87 years (range: 19–60 years). The average duration of disease before RTX administration was 12.68 ±13.31 months (range: 1–48 months). Hypothyroidism (25%), diabetes mellitus (18.75%), and hypertension (12.5%) were the most common comorbidities present. Thirteen (81.25%) patients had involvement of more than one anatomic region. In 2 patients, only the trunk was involved and in one patient, only the lower limb was involved. Oral mucosa was involved in 15 (93.75%) patients out of whom 2 (12.5%) patients had involvement of more than one mucosal site. The other mucosae involved were genital, nasal and ocular. The body surface area involvement was < 5% in 8 (50%) patients, 5–10% in 6 (37.5%) patients and > 10% in 2 (12.5%) patients while Nikolsky’s sign was negative in 10 (62.5%) patients and positive in 6 (37.5%) patients (table 1).
RTX was administered as the first line of treatment in 3 (18.75%) patients and as the 2nd line of treatment in 13 (81.25%) patients. The latter group included patients who had developed side effects of previous treatments (68.75%), had inadequate response to previous treatments (56.25%) or had a comorbidity which contraindicated the use of prolonged GCS administration (31.25%). Of these 13 patients, 7 (53.84%) patients were shifted from intravenous GCS pulse therapy, 5 (38.46%) from oral GCS with oral immunosuppressant (ISA) and 1 from oral GCS treatment (7.69%) to RTX therapy. In patients shifted from pulse therapy, the average number of pulses received before RTX therapy were 12. All the patients received an adjuvant with biosimilar RTX. Of these, 9 (64.28%) patients received mycophenolate mofetil, 4 (28.57%) received azathioprine and 3 (21.42%) received cyclophosphamide.
After RTX infusion, the oral GCS dose could be tapered and stopped in an average time of 3.21 months. ECP was achieved in a mean duration of 2.03 ±1.08 months (range: 2 weeks–4 months). Duration of follow up after RTX infusion ranged from 7 months to 48 months with an average of 16.25 ±10.91 months. At the last follow up, 6 (37.5%) patients were in complete remission off therapy (CR off), 6 (37.5%) in complete remission on therapy (CR on) and 4 (25%) in partial remission on minimal therapy (PR on) (figs. 2, 3). The average time to achieve CR off, CR on and PR on was 15.33 ±5.75, 14.16 ±6.01 and 12.25 ±1.70 months, respectively (table 2). Lesions over the head and neck region were found to be more persistent and recalcitrant in patients who achieved partial remission. All patients were continued on adjuvant ISA for at least one year even if they achieved CR off earlier. One patient developed relapse at 18 months and was given a booster RTX infusion following which the patient attained CR on.
RTX infusion was generally well tolerated and uneventful in majority of the patients. Only minor side effects were noted including chills, headaches, palpitations, dizziness, and urticarial rash.
Discussion
Pemphigus is an immunobullous group of autoimmune blistering disorders which can be serious and life-threatening. The conventional treatment for this group of disorders is daily GCS with or without oral ISA. In India, dexamethasone cyclophosphamide pulse therapy (DCP) and its modifications, devised by Pasricha et al. has also been a commonly implied therapeutic regime for pemphigus patients [16]. Although DCP therapy has been proposed to overcome the complications seen with chronic GCS therapy, it is limited by the long duration of treatment, repeated hospitalizations, non-compliance and overall high economic burden in the long run. This results in poor quality of life and increased burden of the disease on the family [17, 18].
With the global rising trend of biosimilar RTX use in the management of pemphigus, documentation of its safety and efficacy in Indian patients has also been increasing [6–14, 19]. A comprehensive review of previous studies reporting the efficacy of RTX in Indian pemphigus patients is given in table 3. Most of these studies are retrospective in design with the number of study participants varying from 10 to 114. Rheumatoid arthritis protocol is the most commonly employed dosing regimen in these studies similar to our study. The duration of follow up ranged from 8.35 months to 42.7 months with clinically good outcomes being documented in all the studies [6–14]. Our study also confirms the effectiveness and safety of RTX in pemphigus patients. The end of consolidation phase could be achieved within just 2 weeks to 3.5 months with majority (75%) of the patients achieving complete remission. Steroids were tapered and stopped in a short average time of 3.21 months, which is important as many of our patients had developed complications of steroid therapy from previous treatments or had comorbidities contraindicating their long-term use. Cutaneous lesions were the first to heal followed by oral erosions. Lesions over the head and neck region especially the scalp, however, were found to be less responsive in patients who achieved partial remission. Relapse was seen in just one patient in our study cohort. Safety of RTX was also confirmed in our study with the absence of any serious adverse effects.
RTX has emerged as an effective steroid sparing treatment option in recent times and is increasingly used as a front line in pemphigus management [19–21]. In fact, it has now been recommended as the first line of treatment in the management of moderate to severe pemphigus. Its advantages over the conventional treatment regimen including rapid and prolonged remission and shorter hospital stay, makes it a suitable first-line option in the treatment of pemphigus. It has been found to be more cost effective than DCP therapy commonly administered in moderate to severe cases of pemphigus patients in India. However, the high upfront cost of therapy in the Indian setting still limits its use as the first-line treatment.
Another important aspect of RTX therapy in the Indian scenario is the high prevalence of latent and active tuberculosis in the population. RTX acts by suppressing the humoral immunity whereas tuberculosis infection is primarily mediated by innate and cellular immune response. Alkadi et al. in their study concluded that there is no need of screening patients for tuberculosis before RTX therapy, especially in endemic areas [22]. However, long-term GCS before RTX therapy or maintenance GCS doses after RTX therapy in pemphigus patients, necessitates screening for tuberculosis. QuantiFERON-TB Gold Plus has emerged as an important tool for detection of latent tuberculosis infection as studied by Jałowska et al. [23]. Its use in tuberculosis endemic countries like India is limited by its cost and availability.
Conclusions
We conclude from our study findings that biosimilar RTX is a safe and effective treatment option for pemphigus patients. We also propose based on experience of our center that in developing countries and resource-poor settings where affordability can be a limiting issue, biosimilar RTX should be employed as the first line of treatment in patients who can afford it or as the second line in those with recalcitrant disease, relapse and comorbidities. This study is limited by its retrospective nature, small sample size and lack of data on markers of immunological remission.
Funding
No external funding.
Ethical approval
Approval number: IEC/GMCJ/2023/1309.
Conflict of interest
The authors declare no conflict of interest.
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