Comparison of low - dose and standard - dose rituximab (rheumatoid arthritis protocol) in the treatment of pemphigus vulgaris: A retrospective observational study

INTRODUCTION

Pemphigus vulgaris (PV) is an autoimmune blistering disease characterized by immunoglobulin G autoantibodies against desmoglein 1 and 3, leading to acantholysis and intraepidermal blister formation. It predominantly affects middle-aged individuals and presents with painful mucosal erosions and flaccid bullae on the skin. Before the advent of corticosteroids, PV had a high mortality rate; however, despite improved survival, prolonged steroid use brings substantial adverse effects such as osteoporosis, diabetes, hypertension, and infections.

Rituximab, a chimeric monoclonal antibody against the CD20 antigen on B lymphocytes, has emerged as a targeted therapy with remarkable efficacy in PV. It depletes pathogenic B cells and leads to clinical and immunologic remission. Rituximab was approved by the Food and Drug Administration in 2018 for PV and was endorsed in guidelines as a first-line treatment in moderate-to-severe cases.

The two most widely used regimens are the lymphoma protocol (375 mg/m² weekly for 4 weeks) and the rheumatoid arthritis (RA) protocol (2 × 1000 mg given 2 weeks apart).^[1] Given the high cost and immunosuppressive burden of standard-dose regimens, various studies have explored lower dosing strategies. A low-dose regimen (2 × 500 mg) has shown promising results with comparable efficacy and better affordability in several retrospective and prospective studies.^[2-4] However, comparative data with full-dose regimens remain limited, particularly in Indian populations. This study aimed to compare the clinical outcomes, relapse rates, and safety of low-dose rituximab with the RA protocol in patients with moderate-to-severe PV.

MATERIALS AND METHODS

This retrospective, comparative observational study was conducted at a tertiary care center from 2022 to 2024. Fifty patients with histologically and immunologically confirmed PV were enrolled after obtaining ethical clearance and informed consent. Inclusion criteria comprised patients aged 18-65 years with biopsy and direct immunofluorescence-confirmed PV and moderate-to-severe disease activity. Patients were excluded if they had active infections, underlying malignancy, or were pregnant or lactating.

Participants were divided into two groups: Group A received low-dose rituximab (500 mg intravenously on day 0 and day 15), and Group B received the standard-dose RA protocol (1000 mg intravenously on day 0 and day 15). The choice of regimen was based on the physician’s discretion, availability of rituximab, and affordability of the patient.

Premedication included paracetamol, pheniramine, and hydrocortisone. All patients received oral corticosteroids, which were tapered over time, and a subset continued on azathioprine based on clinical judgment. For those demonstrating partial response or early relapse, a maintenance dose of rituximab was administered at 6 months. The primary outcome was the proportion of patients achieving complete remission (CR) off therapy at 6 months. Secondary outcomes included time to disease control, relapse rate at 12 months, cumulative corticosteroid dose, and safety profile.

The outcomes were defined according to the International Pemphigus Committee Consensus Group on definitions of endpoints and therapeutic response for pemphigus.^[5]

All statistical analyses were conducted using the Statistical Package for the Social Sciences version 25.0 (IBM Corp., Armonk, NY, USA). Continuous variables were expressed as mean ± standard deviation and compared using the independent t-test or Mann-Whitney U-test. Categorical variables were analyzed using the Chi-square or Fisher’s exact test. A P < 0.05 was considered statistically significant.

RESULTS

Of the 50 patients enrolled, 25 were treated with low-dose rituximab (Group A), and 25 with the standard-dose rituximab according to the RA protocol (Group B). Baseline data, including age, sex, duration of disease, previous therapies (steroids, immunosuppressants), and clinical severity according to pemphigus disease area index (PDAI) score, are summarized in Table 1. There was no statistically significant difference found in the baseline characteristics of both groups.

The CR rate was 80% (20 patients) in Group A and 84% (21 patients) in Group B. Remission off therapy at 6 months was achieved in 68% of patients in Group A and 72% in Group B. The average time to achieve disease control was 5.6 weeks in Group A and 4.9 weeks in Group B. All patients in both groups successfully discontinued systemic corticosteroids and immunosuppressants by the end of the 3^rd month.

Relapse was documented in 3 patients (12%) in the low-dose group and 2 patients (8%) in the full-dose group at 6 months. At 9 months, relapse occurred in 2 patients (8%) in the low-dose group and 1 patient (4%) in the full-dose group. By 12 months, the cumulative relapse rates were 20% for the low-dose group and 16% for the standard-dose group. The cumulative corticosteroid dose administered was 2.8 g in Group A and 2.6 g in Group B.

Adverse effects were observed in both groups. Minor infusion-related events, such as transient fever and chills, occurred in 2 patients in each group. One patient in Group B experienced an anaphylactic reaction during the second rituximab infusion, which was managed successfully. Another patient in Group B developed hepatotoxicity, with a tenfold increase in transaminase levels post-infusion, which normalized with conservative treatment. Clinical outcomes are summarized in Table 2.

DISCUSSION

This study retrospectively compared low-dose rituximab (2 × 500 mg) with the standard-dose rituximab according to the RA protocol (2 × 1000 mg) in the treatment of moderate-to-severe PV. Our findings demonstrate that both dosing regimens are highly effective in inducing remission, allowing early withdrawal of corticosteroids and immunosuppressants, and maintaining a favorable safety profile over 12 months. These results support the emerging body of evidence favoring the use of low-dose rituximab as a viable first-line option in PV.

In our study, both groups were comparable in terms of age, gender distribution, disease duration, prior treatment history, and disease severity. The absence of significant differences in these baseline characteristics ensures that outcome comparisons are unlikely to be confounded by initial disease severity or demographic disparities.

The mean time to disease control was 5.6 ± 1.2 weeks for the low-dose group and 4.9 ± 1.1 weeks for the RA protocol group (P < 0.001). Although statistically significant, the difference of 0.7 weeks (~5 days) is of questionable clinical relevance. The slightly faster control in the standard-dose group may be due to greater initial B-cell depletion. However, as per Kanagarajan et al., the marginal delay with low-dose therapy is often acceptable given the lower cost and similar long-term outcomes.^[6]

This also reflects its steroid-sparing potential, which is critical in minimizing long-term adverse effects such as osteoporosis, metabolic syndrome, and infections. The Ritux 3 trial also demonstrated that rituximab enabled rapid disease control and significantly reduced cumulative steroid exposure compared to corticosteroids alone.^[7]

CR rates were 80% in the low-dose group and 84% in the standard RA protocol group (P = 1.000). This similarity suggests that both regimens are effective in inducing disease control, aligning with findings from Gupta et al.^[4] and Kanagarajan et al., ^[6] who also observed no significant differences in complete remission (CR) between dosing strategies. The high remission rates in both arms reflect rituximab’s efficacy as a B-cell-targeted therapy in PV.

CR off therapy at 6 months was achieved in 68% of patients receiving low-dose therapy and 72% in the RA group (P = 1.000). This demonstrates that the lower cumulative rituximab dose can maintain remission after corticosteroid tapering in most patients. Singh et al. similarly reported that low-dose protocols sustain remission in a significant proportion of patients without continuous adjunctive immunosuppression.^[2]

Partial remission was seen in 20% of the low-dose group versus 16% of the RA group (P = 1.000). This small difference was not statistically significant. Patients in partial remission typically had residual, low-grade disease activity and often required additional immunomodulatory therapy or booster infusions.

These findings suggest that lower rituximab doses are sufficient to achieve clinical remission, particularly in patients with moderate disease severity. All patients in our study were able to discontinue corticosteroids and immunosuppressants by 12 weeks.

Mean time to relapse was 11.2 ± 2.4 months for the low-dose group and 12.8 ± 1.7 months for the RA group (P = 0.08), a non-significant difference. Both regimens demonstrated similar durability of remission, supporting low-dose rituximab as a viable long-term treatment option. These findings mirror Singh et al.,^[2] Kanwar et al.,^[3] and Kanagarajan et al.,^[6] who reported no significant difference in relapse timing between regimens.

When comparing relapse rates over time, our study demonstrated a stepwise increase in relapse between 6 and 12 months for both regimens. At 6 months, relapse was observed in 12% of patients on the low-dose protocol compared to 8% on the RA protocol, aligning with findings by Singh et al.^[2] and Kanwar et al.,^[3] who also reported slightly higher early relapse in low-dose arms. By 9 months, relapse rates were 8% and 4%, respectively, again comparable to Kanagarajan et al.,^[6] whose results showed 500 mg × 2 dosing with 6.9% relapse at 6 months and 13.8% at 9 months, versus 0% for the 1 g × 2 regimen at both time points.^[2,3,6]

Despite these differences, by 12 months the relapse gap narrowed considerably, suggesting that the majority of relapses occur within the first 9 months regardless of dose, and can be effectively managed with timely booster infusions.

These data reinforce that low-dose rituximab provides durable disease control in most patients, with a relapse pattern that is both predictable and manageable. This supports its use as a cost-effective first-line biologic in moderate PV, particularly in resource-limited settings.

Relapses were generally mild-to-moderate and were managed with low-dose rituximab boosters. Our approach is in line with Ahmed et al., although their protocol combined rituximab with IVIG.^[8]

Maintenance doses were required in 16% of the low-dose group versus 8% of the RA group (P = 0.663). While the proportion was higher in the low-dose group, the difference was not statistically significant. This trend might reflect the slightly earlier relapse tendency in some low-dose patients, as also suggested in earlier observational series.^[2,3,4,6] Safety was overall favorable, though notable adverse events occurred in the full-dose group. One patient developed anaphylaxis during the second rituximab dose. This aligns with delayed hypersensitivity reactions described in literature, attributed to immunoglobulin E-mediated or complement activation mechanisms after immune priming during the first infusion.^[9]

Another patient experienced a 10-fold increase in hepatic transaminases following the first dose. Although asymptomatic and reversible, this rare but serious complication has been previously reported in patients treated with rituximab for lymphoma and should prompt liver function monitoring in rituximab-treated patients. The exact mechanism of acute liver injury secondary to Rituximab infusion is not known; however, reactivation of Hepatitis B is postulated to be one of the factors causing it.^[10,11]

Comparison with other studies is summarized in Table 3.^[2-4,6]

An important practical aspect is the cost-effectiveness of the low-dose regimen. In our setting, the low-dose protocol nearly halved the cost of treatment while delivering comparable clinical outcomes. This aligns with the conclusions drawn by various studies, which highlighted the financial feasibility of low-dose rituximab in Indian populations.^[2-4,6] Furthermore, shorter infusion durations and reduced hospital resource utilization may enhance patient compliance and make therapy more accessible. With similar outcomes and fewer adverse events, low-dose regimens offer a pragmatic solution in resource-constrained settings. However, it is important to note that most patients in the low-dose group had moderate disease, and the generalizability of low-dose efficacy to severe PV remains limited.

CONCLUSION

Low-dose rituximab is comparable to the standard RA protocol in efficacy and relapse prevention in PV. It offers significant steroid-sparing benefits, reduced adverse effects, and greater affordability. It may be considered a first-line biologic option for moderate PV in Indian patients. Larger multicenter trials are needed to confirm these findings and optimize long-term dosing strategies.