What are the latest updates on rituximab (including standard‑dose, low‑dose, and ultra‑low‑dose regimens, maintenance timing, B‑cell monitoring, safety precautions, pediatric considerations, and alternative therapies) for first‑line treatment of moderate‑to‑severe pemphigus vulgaris and pemphigus foliaceus in dermatology?

Rituximab in Dermatology: Latest Updates for Pemphigus Management

First-Line Treatment Paradigm Shift

Rituximab combined with short-term prednisolone (0.5–1 mg/kg/day for 3–6 months) is now recommended as first-line therapy for newly diagnosed moderate-to-severe pemphigus vulgaris and pemphigus foliaceus, achieving 89% complete remission off all treatment at 2 years compared to only 34% with prednisolone alone. 1, 2

This represents a fundamental departure from historical practice where rituximab was reserved for refractory cases. 2 The superiority is dramatic—89% vs. 28% remission rates specifically in pemphigus vulgaris patients (P < 0.0001), with fewer severe adverse events due to lower cumulative corticosteroid exposure. 1

Dosing Protocols

Standard-Dose Regimen

• Pemphigus-specific protocol: 2 × 1,000 mg infusions given 2 weeks apart (days 0 and 14) 3, 4
• This differs from the older rheumatoid arthritis protocol and is the current standard 3

Low-Dose Alternative

• 500 mg × 2 infusions (2 weeks apart) demonstrated effectiveness in a British Journal of Dermatology study, with all 15 patients responding to therapy 5
• Eight patients achieved complete remission in median 5 weeks, seven achieved partial remission in median 34.5 weeks 5
• This low-dose approach may be considered for cost-effectiveness, though long-term comparative studies are needed 5

Maintenance Dosing

• For patients requiring retreatment: 500 mg at 6-month intervals or repeated full dosing (1,000 mg × 2) based on clinical need 6
• Median time to relapse after first cycle is 15 months (95% CI, 10.3–19.7 months) 6

Expected Clinical Timeline

• Clinical improvement begins within 6 weeks of rituximab administration 1, 2, 7
• Complete healing of skin and mucosal lesions averages 15 weeks (range 3–8 weeks) 2, 7, 8
• Mean time to disease control: 11 months; mean time to remission: 58 months 1, 2, 3

Relapse Patterns and Management

• Relapse occurs in 40–65% of patients, typically at 13–17 months (range 13–145 months) after rituximab 1, 2, 3, 7
• Patients who relapse benefit from additional cycles of rituximab using the same protocol 6
• In a JAMA Dermatology study, 89% of patients achieved complete remission (61% off all treatment, 28% on minimal adjuvant therapy) at final follow-up with repeated cycles as needed 6

Combination with Immunosuppressants

Adjuvant immunosuppressive drugs (azathioprine, mycophenolate mofetil) can be continued but MUST be dose-reduced to minimize infection risk. 1, 2, 3

• For tacrolimus specifically: reduce to 2–3 mg/day targeting trough levels of 6 ng/mL 2
• Critical pitfall: Do NOT continue full-dose conventional immunosuppressants when adding rituximab—dose reduction is mandatory to prevent severe infections 2, 3

B-Cell Monitoring

• Peripheral blood CD19-positive B lymphocytes drop to <1% after first infusion and remain undetectable in patients with sustained remission 4, 5
• B-cell depletion persists throughout the study period (up to 168 days documented) 4
• Sustained B-cell depletion correlates with maintained remission 5

Mandatory Pre-Treatment Screening

Hepatitis B

• Perform hepatitis B screening before rituximab initiation—reactivation can be fatal 2, 3

Tuberculosis

• Obtain chest radiograph to evaluate for active or latent tuberculosis 2, 3
• If IGRA-positive: initiate latent TB treatment and delay rituximab for at least 1 month after starting anti-tubercular therapy 2
• Monitor for TB symptoms monthly during treatment and for at least 12 months after completion 2

Baseline Immunoglobulins

• Measure baseline immunoglobulin levels (IgG, IgM, IgA) before starting rituximab 2

Monitoring Protocol During Treatment

• Complete blood count every 2–4 weeks initially after starting rituximab 2
• Liver and renal function tests regularly 2
• Consider PCP prophylaxis when using triple immunosuppression or with additional risk factors 2, 3

Infection Management

• Temporarily discontinue tacrolimus or other immunosuppressants if serious infection develops requiring antibiotics 2, 3
• Resume at reduced doses once infection resolves 3
• In the Japanese multicenter trial, pneumonia was the only serious adverse event causally related to rituximab (1 of 20 patients) 4

Alternative Approaches for Special Scenarios

Rituximab-Resistant Cases

• Novel anti-CD20 agents like veltuzumab (subcutaneous, 2 injections 2 weeks apart) may benefit rituximab-resistant patients 1, 2, 7
• One case report showed complete remission sustained for 2 years with veltuzumab after multiple failed rituximab cycles 1

Immunoadsorption Combination

• Consider immunoadsorption combined with rituximab, which can reduce circulating desmoglein antibody levels by up to 95% 2, 7
• Administered daily over three consecutive days 7

Topical Corticosteroid Alternative

• For patients with contraindications to systemic corticosteroids: rituximab combined with high-potency topical corticosteroids achieved mean healing time of 15 weeks in 5 patients 8
• This approach avoided systemic corticosteroid adverse effects entirely 8
• Two patients with 42- and 48-month follow-up remained relapse-free 8

Pediatric Considerations

The evidence provided does not include specific pediatric dosing protocols or safety data. Clinical decisions for pediatric pemphigus should extrapolate from adult data with appropriate weight-based adjustments and heightened monitoring.

Efficacy Compared to Conventional Therapy

• Meta-analysis of 578 pemphigus patients: 76% achieved remission following a single cycle of rituximab, with 39% able to discontinue adjuvant treatments 1
• In refractory disease specifically: remission rates up to 86% following a single cycle 1
• Japanese multicenter trial: 75% remission rate (55% complete, 20% partial) in refractory pemphigus 4

Critical Pitfalls to Avoid

1. Do NOT delay rituximab until after multiple failed conventional therapies in appropriate candidates—early use provides better outcomes (89% vs. 34% remission) and fewer adverse effects 1, 2

2. Do NOT continue full-dose conventional immunosuppressants when adding rituximab—this creates excessive immunosuppression and severe infection risk 1, 2, 3

3. Do NOT skip hepatitis B screening—reactivation is potentially fatal 2, 3

4. Do NOT assume the rheumatoid arthritis dosing protocol is optimal—the pemphigus-specific protocol (2 × 1,000 mg) is preferred 3