What is the recommended treatment regimen for a patient with Granulomatosis with Polyangiitis (GPA)?

Treatment of Granulomatosis with Polyangiitis (GPA)

For active severe GPA, initiate rituximab 375 mg/m² IV weekly for 4 weeks OR cyclophosphamide (2 mg/kg/day oral or 15 mg/kg IV pulse every 2-3 weeks), both combined with high-dose glucocorticoids (methylprednisolone 500-1000 mg IV daily for 3 days, then oral prednisone 0.75-1 mg/kg/day). 1, 2

Disease Severity Classification

Severe GPA is defined by:

• Five-Factor Score (FFS) ≥1 1
• Presence of organ-threatening or life-threatening manifestations including:
  • Rapidly progressive glomerulonephritis (serum creatinine >3.4 mg/dL or requiring dialysis) 1, 3
  • Diffuse alveolar hemorrhage with hypoxemia 1, 3
  • Peripheral neuropathy 1
  • Other critical organ involvement 1

Non-severe GPA is characterized by:

• FFS = 0 1
• Absence of the above organ-threatening features 1
• May include ENT manifestations, arthralgia, or constitutional symptoms 1

Induction Therapy for Severe GPA

Glucocorticoid Regimen

Administer methylprednisolone 500-1000 mg IV daily for 3 consecutive days (maximum cumulative 3 grams), followed by oral prednisone based on weight: 1, 3, 2

• <50 kg: 50 mg/day 3
• 50-75 kg: 60 mg/day 3

• 75 kg: 75 mg/day 3

Taper prednisone to 5 mg/day by weeks 19-52. 3 Target dose of 7.5-10 mg by 3 months, though this may take up to 5 months in practice. 4

Immunosuppressive Agent Selection

Rituximab (preferred for most patients): 1, 2

• Dose: 375 mg/m² IV weekly for 4 weeks 1, 2
• Premedication: Methylprednisolone 100 mg IV (or equivalent) 30 minutes before each infusion 2
• Advantages: Superior for relapsing disease, preserves fertility, non-inferior to cyclophosphamide 4, 1
• Monitoring: Watch for infusion reactions (12% with first infusion, decreasing to 1% by fourth), infections (62% any infection, 11% serious), hypophosphatemia, and hypogammaglobulinemia 2, 5

Cyclophosphamide (alternative option): 1, 4

• Oral: 2 mg/kg/day (adjusted for renal function and age) 4, 1
• IV pulse: 15 mg/kg every 2-3 weeks (preferred to reduce toxicity) 4
• Duration: Continue until remission achieved, typically within 6 months 1
• Prophylaxis required: Trimethoprim/sulfamethoxazole 800/160 mg alternate days for Pneumocystis jirovecii 4
• Supportive care: MESNA for hemorrhagic cystitis prevention, antiemetics, adequate hydration 4
• Cautions: Leukopenia, infections, infertility, malignancy risk 4, 1

Plasma Exchange Considerations

Consider plasma exchange in addition to standard therapy for: 1, 3

• Serum creatinine >3.4 mg/dL 3
• Dialysis-dependent renal failure 3
• Diffuse alveolar hemorrhage with hypoxemia 3, 6
• Concomitant anti-GBM disease 3

Protocol: Perform every 2-3 days for 5-7 total treatments. 6 Note that the PEXIVAS trial showed no mortality benefit for routine plasma exchange, but it remains an option for critically ill patients not responding to standard therapy. 4, 3

Maintenance Therapy

After achieving remission, transition to maintenance therapy: 1, 4

Rituximab maintenance (preferred): 1

• Dose: 500 mg IV every 6 months 1, 2
• Initiation timing: Within 24 weeks after last induction dose, but no sooner than 16 weeks 2
• Duration: Continue for 18 months to 4 years 3
• Evidence: Reduces relapse rates compared to unscheduled treatment 1

Alternative maintenance agents (if rituximab unavailable): 4, 7

• Azathioprine 2 mg/kg/day 4
• Methotrexate 20-25 mg weekly 4
• Mycophenolate mofetil 2000 mg/day 4

Important caveat: Adding a conventional maintenance agent (azathioprine, methotrexate, or mycophenolate) to rituximab reduces relapse risk (HR 0.53) without increasing adverse events. 7

Treatment of Non-Severe GPA

For non-severe disease, use glucocorticoids plus methotrexate, azathioprine, or mycophenolate mofetil. 1 Rituximab may be considered for patients with contraindications to conventional agents or those wishing to preserve fertility. 4, 1

Management of Refractory Disease

For patients failing initial cyclophosphamide therapy: 1, 8

• Switch to rituximab 375 mg/m² weekly for 4 weeks 1
• Consider combination low-dose cyclophosphamide with rituximab for severe renal involvement 8
• Add plasma exchange for rapidly progressive glomerulonephritis 6, 8

For patients relapsing on maintenance therapy: 1

• Re-induce with rituximab (pulse IV or high-dose oral glucocorticoids + rituximab) 4
• Consider switching to a different immunomodulatory approach based on clinical features 4

Critical Monitoring Parameters

During induction: 1, 2

• Complete blood count weekly (watch for leukopenia with cyclophosphamide) 4
• Serum creatinine and urinalysis 1
• Infection surveillance (leading cause of death in first year: 48%) 3
• CD19+ B cell depletion with rituximab 5
• Immunoglobulin levels (risk of hypogammaglobulinemia with rituximab) 5

During maintenance: 1

• Disease activity assessment using Birmingham Vasculitis Activity Score 4
• ANCA titers (though not used to guide treatment decisions) 4
• Cardiovascular risk factors and treatment-related complications 4

Definition of Remission

Remission is defined as: 4

• Birmingham Vasculitis Activity Score = 0 4
• Maximum prednisone dose ≤7.5 mg/day 4
• Absence of clinical signs or symptoms attributable to active disease 4

Common Pitfalls to Avoid

• Do not delay treatment in suspected severe GPA while awaiting biopsy confirmation—empiric therapy should begin immediately for organ-threatening disease. 3
• Do not use lower glucocorticoid starting doses (<0.5 mg/kg/day) in life-threatening manifestations like alveolar hemorrhage. 3
• Do not routinely use plasma exchange for all severe GPA—reserve for specific indications listed above. 4, 3
• Do not stop rituximab maintenance prematurely—continue for at least 18 months to prevent relapse. 3
• Do not overlook infection prophylaxis—Pneumocystis prophylaxis is mandatory with cyclophosphamide. 4