A 58-year-old man with a 6-month history of constitutional symptoms, palpable purpura on lower extremities, and glomerulonephritis is found to have elevated inflammatory markers and positive ANCA (c-ANCA with anti-PR3 antibodies). A diagnosis of granulomatosis with polyangiitis (GPA) is made. What is the drug of choice for induction therapy in this patient?

## Induction Therapy for GPA **Key Point:** Cyclophosphamide combined with corticosteroids remains the gold-standard induction regimen for generalized GPA with organ involvement (especially renal and pulmonary disease). ### Mechanism of Action Cyclophosphamide is an alkylating agent that causes profound immunosuppression through: - Direct DNA cross-linking in rapidly dividing B and T lymphocytes - Reduction of circulating ANCA-positive B cells - Prevention of ANCA-mediated vasculitis progression ### Induction vs. Maintenance Distinction | Phase | Drug | Duration | Goal | |-------|------|----------|------| | **Induction** | Cyclophosphamide + corticosteroids | 3–6 months | Achieve remission; suppress active vasculitis | | **Maintenance** | Azathioprine or rituximab | 12–24 months | Prevent relapse; reduce steroid burden | **High-Yield:** The EULAR/ERA-EDTA 2022 guidelines and most Indian institutional protocols recommend cyclophosphamide for: - Generalized GPA (multi-system involvement) - Severe renal disease (creatinine >1.5 mg/dL) - Pulmonary hemorrhage - CNS or cardiac involvement ### Corticosteroid Role Glucocorticoids (typically methylprednisolone IV pulses followed by oral prednisolone taper) are: - Mandatory adjuncts to cyclophosphamide - Provide rapid anti-inflammatory effect - Reduce initial disease activity while cyclophosphamide takes effect (2–4 weeks) **Clinical Pearl:** Rituximab (anti-CD20 monoclonal antibody) is now an acceptable alternative to cyclophosphamide for induction in some centres, especially for relapsing disease or if fertility preservation is critical. However, cyclophosphamide remains the reference standard for de novo generalized GPA. **Warning:** Cyclophosphamide carries significant toxicity (hemorrhagic cystitis, infertility, secondary malignancy, infection). Mesna is used for bladder protection, and prophylactic measures (hydration, frequent voiding) are essential. [cite:Harrison 21e Ch 319]