Initial Treatment Regimen for Granulomatosis with Polyangiitis (GPA)
For severe GPA (defined by Five-Factor Score ≥1, organ-threatening manifestations, or life-threatening disease), initiate pulsed intravenous methylprednisolone 500-1000 mg daily for 3 days followed by high-dose oral glucocorticoids (0.75-1 mg/kg/day) combined with either rituximab (1000 mg on days 1 and 15) or cyclophosphamide (2 mg/kg/day adjusted for renal function) until remission is achieved, typically within 6 months. 1, 2, 3
Disease Severity Stratification
Before initiating treatment, classify disease severity to determine the appropriate regimen:
Severe GPA is defined by any of the following 1, 2:
- Five-Factor Score (FFS) ≥1 (includes renal insufficiency with creatinine >1.58 mg/dL, proteinuria >1g/day, cardiomyopathy, gastrointestinal involvement, or CNS involvement)
- Peripheral neuropathy
- Alveolar hemorrhage
- Other organ-threatening or life-threatening manifestations (mesenteric ischemia, limb digital ischemia, severe eye disease)
Non-severe GPA is characterized by FFS=0 and absence of the above manifestations 1, 2
Induction Therapy for Severe GPA
Glucocorticoid Component
Begin with pulsed intravenous methylprednisolone 500-1000 mg daily for 1-3 days (maximum total dose 3 grams), followed immediately by high-dose oral prednisone at 0.75-1 mg/kg/day (not exceeding 80 mg/day) 1, 2, 3. The glucocorticoid dose should be tapered according to a pre-specified protocol once remission begins 1.
Immunosuppressive Agent Selection
Rituximab is the preferred first-line agent for most patients with severe GPA, particularly those with 1, 2, 3:
- Relapsing disease (where rituximab demonstrates superior efficacy compared to cyclophosphamide)
- Childbearing potential (male or female)
- Previous cyclophosphamide exposure at cumulative doses associated with increased complication risk
Dosing: Rituximab 375 mg/m² once weekly for 4 weeks OR 1000 mg on days 1 and 15 3. Both regimens achieve comparable remission rates of approximately 64% at 6 months 3.
Cyclophosphamide remains an acceptable alternative with the following considerations 1, 2:
- Administered at 2 mg/kg/day orally (adjusted for renal function, age, and white blood cell count) OR as intravenous pulses (0.6 g/m² every 2 weeks for 1 month, then every 4 weeks)
- Continue until remission is achieved, typically within 6 months; may extend to 9-12 months for patients with slow but steady improvement
- Achieves remission rates of approximately 53% at 6 months 3
Critical Comparison: Rituximab vs Cyclophosphamide
The RAVE trial (GPA/MPA Study 1) demonstrated non-inferiority of rituximab to cyclophosphamide for achieving complete remission at 6 months 3. Importantly, rituximab showed superiority in the relapsing disease subgroup, making it the preferred choice for patients with prior disease activity 3, 4. The FDA label confirms that 64% of rituximab-treated patients achieved complete remission (BVAS=0, off glucocorticoids) at 6 months compared to 53% with cyclophosphamide 3.
Premedication and Supportive Care
All patients receiving rituximab should be premedicated with antihistamine and acetaminophen prior to each infusion 3. Pneumocystis jirovecii pneumonia (PCP) prophylaxis is conditionally recommended for all patients receiving rituximab or cyclophosphamide 1.
Induction Therapy for Non-Severe GPA
For patients with non-severe disease (FFS=0, no organ-threatening manifestations), glucocorticoids alone may be sufficient 1. However, this approach is associated with high relapse rates once glucocorticoids are tapered, and close monitoring is essential 1.
Treatment Duration and Monitoring
Continue induction therapy until remission is achieved, defined as Birmingham Vasculitis Activity Score (BVAS) of 0 3. Complete remission at 6 months is achieved in 64% of rituximab-treated patients and 53% of cyclophosphamide-treated patients 3. For patients who achieve remission at 6 months, sustained remission at 12 months occurs in 44% of rituximab-treated patients versus 38% of cyclophosphamide-treated patients 3.
Common Pitfalls and Caveats
Avoid dosing immunosuppressive therapy based solely on ANCA titers, as this approach is not supported by evidence and may lead to inappropriate treatment escalation or de-escalation 1.
Do not routinely add plasma exchange to induction therapy for all patients with glomerulonephritis 1. While plasma exchange may reduce the risk of end-stage renal disease in patients with severe renal involvement (creatinine ≥5.8 mg/dL), it increases infection risk and does not improve mortality 1. Reserve plasma exchange for patients at highest risk of progression to ESRD who accept the increased infection risk 1.
Monitor for infusion-related reactions with rituximab, which occur in 12% of patients after the first infusion but decrease to 1% by the fourth infusion 3. Cardiovascular monitoring is essential, as serious cardiac events can occur during infusion 3.
Cyclophosphamide carries significant toxicity risks including leukopenia (27% of patients), infections, infertility, and increased malignancy risk 2, 3. Dose adjustments for renal function and age are mandatory 3.
Transition to Maintenance Therapy
Once remission is achieved, transition to maintenance therapy is essential to prevent relapse. Maintenance therapy should be continued for 24-48 months following induction of remission 1. For patients initially treated with cyclophosphamide, switch to azathioprine or rituximab for maintenance 3. For patients initially treated with rituximab, continue rituximab 500 mg every 6 months for maintenance 2.