When is rituximab indicated for pemphigus vulgaris?

Indications for Rituximab in Pemphigus Vulgaris

Rituximab is indicated as first-line therapy in combination with short-term prednisolone for newly diagnosed moderate-to-severe pemphigus vulgaris, achieving 89% complete remission off all treatment at 2 years compared to 34% with prednisolone alone. 1, 2

First-Line Treatment (Preferred Indication)

Rituximab combined with short-term prednisolone (0.5–1 mg/kg/day for 3–6 months) is now the recommended initial therapy for newly diagnosed moderate-to-severe pemphigus vulgaris, representing a paradigm shift from historical practice where rituximab was reserved only for refractory cases. 1, 2 This approach is FDA-approved for adult patients with moderate-to-severe pemphigus vulgaris. 3

Key Evidence Supporting First-Line Use:

• 89% of treatment-naïve patients achieved complete remission off all treatment at 2 years versus 34% with prednisolone alone (P < 0.0001). 1
• Fewer severe adverse events occurred in the rituximab arm, primarily because prednisolone doses were substantially lower and shorter in duration. 1
• Early rituximab use prevents the cumulative toxicity of prolonged high-dose corticosteroids, which historically caused significant morbidity. 2

Refractory Disease (Secondary Indication)

Rituximab is indicated when patients fail to achieve adequate disease control with conventional therapy (systemic corticosteroids plus conventional immunosuppressants such as azathioprine or mycophenolate mofetil). 1

Efficacy in Refractory Cases:

• Remission rates of 74–87% after a single rituximab cycle in patients who failed conventional therapy. 1
• Up to 86% remission in refractory disease following one treatment cycle. 1
• Rituximab reduced monthly prednisone intake by 73% in patients who failed conventional adjuvant therapy, bringing steroid requirements down to levels comparable with treatment-responsive patients. 4

Contraindications to Systemic Corticosteroids

Rituximab combined with high-potency topical corticosteroids can be considered as first-line therapy in patients with contraindications to systemic corticosteroids (e.g., uncontrolled diabetes, severe osteoporosis, active infections). 5 In a small case series, this approach achieved complete healing in a mean of 15 weeks without severe adverse effects. 5

Relapse After Initial Remission

Relapse occurs in 40–65% of patients, typically 13–17 months after rituximab treatment (range 13–145 months). 1, 2 Repeat rituximab cycles using the same protocol are indicated for relapse management and can effectively re-induce remission. 2, 6

Critical Pre-Treatment Requirements

Before initiating rituximab, the following screening is mandatory:

• Hepatitis B screening (HBsAg and anti-HBc) is required before treatment, as HBV reactivation can be fatal. 2, 7, 3
• Chest radiograph and IGRA testing to evaluate for active or latent tuberculosis. 2, 7
  • If IGRA-positive, initiate latent TB treatment and delay rituximab for at least 1 month after starting anti-tubercular therapy. 7
• Complete blood count with differential and platelets before the first dose. 3
• Baseline immunoglobulin levels (IgG, IgM, IgA) should be measured. 2

Dosing Protocol for Pemphigus Vulgaris

The pemphigus-specific protocol differs from lymphoma and rheumatoid arthritis protocols:

• Induction: 1 g on days 0 and 14 (two infusions two weeks apart). 1, 6
• Maintenance: 0.5 g at 12 and 18 months in the landmark trial. 1
• Alternative lymphoma protocol: 375 mg/m² weekly for 4 weeks. 8

Expected Clinical Timeline

• Clinical improvement begins within 6 weeks of the first rituximab infusion. 1, 2, 6
• Complete healing of lesions averages 15 weeks (range 3–8 weeks). 2, 5
• Mean time to disease control is 11 months, with remission achieved at a mean of 58 months. 1, 2, 6

Combination with Conventional Immunosuppressants

When adding rituximab, adjuvant immunosuppressants (azathioprine, mycophenolate mofetil) must be dose-reduced to minimize infection risk—do not continue full-dose conventional therapy. 2, 6 For tacrolimus specifically, reduce to 2–3 mg/day targeting trough levels of 6 ng/mL. 2

Critical Pitfalls to Avoid

• Do not delay rituximab until after multiple failed conventional therapies in appropriate candidates; early use provides superior outcomes (89% vs 34% remission) and fewer adverse effects. 2
• Do not maintain full-dose conventional immunosuppressants when adding rituximab, as this creates excessive immunosuppression and raises severe infection risk. 2, 6
• Do not skip hepatitis B screening—reactivation can be fatal. 2, 3
• Do not administer rituximab as IV push or bolus—only as IV infusion with appropriate premedication and monitoring for severe infusion reactions. 3

Monitoring During Treatment

• CBC with differential and platelets every 2–4 weeks initially, then at 2–4 month intervals. 2, 3
• Monthly monitoring for TB symptoms during treatment and for at least 12 months after completion (fever, night sweats, weight loss, persistent cough, hemoptysis). 7
• Consider PCP prophylaxis when using triple immunosuppression or with additional risk factors. 2, 6

Special Populations

Pediatric patients aged 6 months and older with pemphigus vulgaris can receive rituximab, though the primary indication in this age group is for mature B-cell NHL/B-AL. 3 The infusion rate for pediatric patients should be initiated at 0.5 mg/kg/hr (maximum 50 mg/hr). 3