What is the evidence for Rituximab (rituximab) in treating Antineutrophil Cytoplasmic Antibody (ANCA)-associated vasculitis?

Rituximab in ANCA-Associated Vasculitis

Rituximab is equally effective to cyclophosphamide for remission induction in severe ANCA-associated vasculitis and is superior for relapsing disease, making it a first-line treatment option alongside glucocorticoids. 1, 2

Remission Induction for Severe Disease

For active, severe GPA/MPA, rituximab should be used as first-line therapy with glucocorticoids, particularly in relapsing disease, women of childbearing age, or when cyclophosphamide poses risks. 1, 2

Evidence from Landmark Trials

• The RAVE trial demonstrated rituximab non-inferiority to cyclophosphamide for remission induction, with 64% of rituximab patients achieving remission off prednisone at 6 months versus 53% with cyclophosphamide 2
• Rituximab was superior in relapsing disease: 67% remission rate versus 42% with cyclophosphamide (P=0.01) 2
• The RITUXVAS trial confirmed rituximab non-inferiority to cyclophosphamide even in severe renal vasculitis and alveolar hemorrhage 1, 3
• Both trials used rituximab 375 mg/m² weekly for 4 consecutive weeks 1, 2

Dosing Regimens for Induction

• Standard regimen: 375 mg/m² IV weekly for 4 weeks 1, 4
• Alternative regimen: 1,000 mg IV on days 1 and 15 (two doses) 4
• All patients receive concurrent high-dose glucocorticoids with subsequent tapering 1

Remission Maintenance Therapy

Rituximab is superior to azathioprine for maintenance therapy and should be preferred whenever possible. 1, 4

MAINRITSAN Trial Evidence

• The MAINRITSAN trial compared rituximab 500 mg every 6 months versus azathioprine for maintenance after cyclophosphamide induction 1
• Major relapses occurred in only 3 rituximab patients versus 17 azathioprine patients at month 28 1
• Renal relapses: 0/3 in rituximab group versus 8/17 in azathioprine group 1

Maintenance Dosing

• 500 mg IV every 6 months for at least 18 months 1, 4
• The MAINRITSAN protocol: 500 mg at complete remission, then at months 6,12, and 18 4
• Optimal duration remains uncertain, with recent data suggesting possible extension to 4 years 5

Refractory Disease

For patients refractory to cyclophosphamide, switch to rituximab; for those refractory to rituximab, switch to cyclophosphamide. 1

• Rituximab has proven particularly useful in refractory disease previously treated with cyclophosphamide 1
• Patients with refractory renal disease have the greatest chance of improvement with rituximab 1
• Retro-orbital disease poses a particular challenge and may respond less favorably 1
• These patients should be managed in conjunction with expert centers 1

Special Populations and Considerations

Fertility Preservation

• Rituximab is preferable to cyclophosphamide in patients wishing to preserve reproductive potential 1, 4
• Cyclophosphamide causes reduced ovarian reserve, ovarian failure, and male infertility 1
• Long-term effects of rituximab on fertility have not been studied, but no concerns have been reported 1

EGPA (Eosinophilic Granulomatosis with Polyangiitis)

• Evidence for rituximab in EGPA is less robust than for GPA/MPA 4
• A retrospective analysis showed 34% complete remission at 6 months and 49% at 12 months in EGPA 1
• For severe EGPA relapse after cyclophosphamide, rituximab is conditionally recommended over repeat cyclophosphamide 1

Safety and Monitoring

Mandatory Prophylaxis

• Pneumocystis jirovecii prophylaxis with trimethoprim/sulfamethoxazole (800/160 mg on alternate days or 400/80 mg daily) is required during rituximab therapy 1, 4
• Alternatives include dapsone or atovaquone if trimethoprim/sulfamethoxazole is contraindicated 1

Baseline and Follow-up Monitoring

• Baseline: IgG, IgA, IgM levels, complete blood count, renal function, urinalysis with 24-hour proteinuria, hepatitis B and C screening 6
• Monitor immunoglobulin levels every 6 months during rituximab therapy 6
• Prolonged hypogammaglobulinemia (IgG or IgM below normal for ≥4 months) occurred in 16.4% of patients 7

Adverse Events

• Severe adverse events occurred in 42% of rituximab patients versus 36% with cyclophosphamide in RITUXVAS 3
• Infectious complications occurred in 15% of patients, leading to 5% mortality in one series 8
• Infusion-related reactions are generally mild to moderate 7
• Anti-rituximab antibodies develop in 23% of GPA/MPA patients by 18 months, though clinical relevance is unclear 7

Common Pitfalls to Avoid

• Do not use ANCA titers to guide treatment changes; use structured clinical assessment instead 1
• Do not delay rituximab treatment in severe disease to discuss fertility—have the discussion but proceed with treatment 1
• Do not assume rituximab is safer than cyclophosphamide—severe adverse event rates are similar 3
• Ensure pneumococcal vaccination before rituximab when possible—only 19% received it in one study 8
• Do not confuse ANCA-associated vasculitis with IgA vasculitis—rituximab has no guideline support for IgA vasculitis 6, 9