What are alternative treatments for Granulomatosis with Polyangiitis (GPA), formerly known as Wegener's, in place of Rituxan (rituximab)?

Alternative Treatments for Granulomatosis with Polyangiitis (GPA) Instead of Rituximab

Cyclophosphamide combined with glucocorticoids is the primary alternative to rituximab for treating GPA, with proven efficacy in both remission induction and severe disease manifestations. 1

Remission Induction for Severe Disease

For organ-threatening or life-threatening GPA, cyclophosphamide plus glucocorticoids is equally effective to rituximab for remission induction. 1 The 2024 EULAR guidelines and 2021 ACR guidelines both recommend either agent as first-line therapy, with rituximab being non-inferior to cyclophosphamide in randomized controlled trials (RAVE and RITUXVAS). 1

Cyclophosphamide Dosing Options:

• Intravenous pulse regimen: 15 mg/kg every 2 weeks for 3 doses, then every 3 weeks 1
• Daily oral regimen: 2 mg/kg/day 1
• Alternative IV regimen: 0.5-1.0 g/m² monthly (though less evidence for GPA compared to lupus nephritis) 1

Both IV pulse and daily oral cyclophosphamide have similar efficacy; the choice depends on patient preference and compliance considerations. 1 In children, IV cyclophosphamide may be preferred to facilitate compliance and limit toxicity. 1

Critical Cyclophosphamide Safety Measures:

• Antiemetic therapy should be routinely administered with IV cyclophosphamide 1
• MESNA (2-mercaptoethanesulfonate sodium) should be given orally or IV to bind acrolein, a toxic metabolite that causes hemorrhagic cystitis 1
• Encourage high fluid intake on infusion days to dilute metabolites in urine 1
• Pneumocystis jirovecii prophylaxis with trimethoprim/sulfamethoxazole (800/160 mg alternate days or 400/80 mg daily) is mandatory 1
• Monitor blood counts regularly; dose adjustments may be necessary for leucopenia 1

Important Cyclophosphamide Toxicity Considerations:

Cyclophosphamide causes reduced ovarian reserve, ovarian failure, and male infertility, with risks increasing with cumulative doses. 1, 2 This makes rituximab preferable in patients wishing to preserve fertility. 1 Long-term risks include hemorrhagic cystitis and malignancy (bladder cancer). 1, 2

Non-Severe Disease Alternatives

For non-organ-threatening or non-life-threatening GPA, methotrexate or mycophenolate mofetil can be considered as alternatives to rituximab, always combined with glucocorticoids. 1

• Methotrexate has established efficacy for inducing and maintaining remission in non-severe GPA 3
• Mycophenolate mofetil is an acceptable alternative when rituximab and methotrexate are contraindicated 1

Maintenance Therapy Alternatives

After achieving remission with cyclophosphamide (typically given for 3-6 months), switch to azathioprine or methotrexate for maintenance therapy. 1, 3

Maintenance Options:

• Azathioprine: Standard maintenance agent with extensive long-term experience 1
• Methotrexate: Alternative maintenance option with proven efficacy 1
• Mycophenolate mofetil: Can be considered for maintenance 1

Important caveat: Rituximab is superior to azathioprine for maintenance therapy (MAINRITSAN trial showed major relapses in only 3 patients with rituximab vs 17 with azathioprine, HR 6.61, P=0.002). 4 However, when rituximab is unavailable or contraindicated, azathioprine remains an acceptable alternative. 1

Adjunctive Therapies

Avacopan

Avacopan (a C5a receptor antagonist) combined with cyclophosphamide may be considered as part of a glucocorticoid-sparing strategy. 1 This allows substantial reduction in glucocorticoid exposure while maintaining efficacy.

Plasma Exchange

Plasma exchange may be considered for patients with serum creatinine >300 µmol/L (approximately 3.4 mg/dL) due to active glomerulonephritis. 1 However, routine use for alveolar hemorrhage is not recommended. 1

Glucocorticoid Regimen

All induction regimens require oral glucocorticoids starting at 50-75 mg prednisolone equivalent daily (depending on body weight), with stepwise reduction to achieve 5 mg daily by 4-5 months. 1

When Cyclophosphamide is Specifically Preferred

Cyclophosphamide should be strongly considered over rituximab in:

• Patients with the most severe disease (serum creatinine >4.0 mg/dL or mechanical ventilation from alveolar hemorrhage), as these patients were excluded from the RAVE trial comparing rituximab to cyclophosphamide 1
• Patients who previously failed rituximab therapy 1
• Settings where cost restrictions mandate cyclophosphamide use 1

Refractory Disease Management

For patients refractory to initial therapy, switch from cyclophosphamide to rituximab or vice versa. 1, 4 A thorough reassessment should exclude infection, malignancy, and ensure treatment compliance before declaring refractoriness. 1

Common Pitfalls to Avoid

• Do not use ANCA titers alone to guide treatment changes; use structured clinical assessment instead 1, 4, 5
• Do not delay treatment in severe disease to discuss fertility preservation, though this discussion should occur 1
• Do not withhold cyclophosphamide from elderly patients solely based on age; adjust dosing and monitor meticulously 1
• Do not forget infection prophylaxis: Pneumocystis prophylaxis is mandatory with cyclophosphamide 1
• Do not use monthly IV cyclophosphamide regimens (as in lupus nephritis) without recognizing less robust evidence for GPA compared to the every-2-week-then-every-3-week regimen 1