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

Treatment of Granulomatosis with Polyangiitis (Wegener's Disease)

For patients with severe GPA (defined by Five-Factor Score ≥1, renal insufficiency, alveolar hemorrhage, or peripheral neuropathy), initiate high-dose glucocorticoids combined with either rituximab or cyclophosphamide for remission induction, followed by maintenance therapy with rituximab, azathioprene, or methotrexate. 1, 2, 3

Disease Severity Stratification

Treatment decisions hinge on disease severity classification:

• Severe GPA is defined by Five-Factor Score ≥1 (renal insufficiency, proteinuria, cardiomyopathy, gastrointestinal involvement, CNS involvement), peripheral neuropathy, alveolar hemorrhage, or other organ/life-threatening manifestations 2, 3
• Non-severe GPA has FFS=0 and lacks organ-threatening features 3

The American College of Rheumatology emphasizes that treatment should not be delayed while awaiting kidney biopsy results if clinical presentation is compatible with small-vessel vasculitis and ANCA serology (MPO or PR3) is positive 1

Remission Induction for Severe GPA

Glucocorticoid Regimen

• Initiate with pulsed intravenous methylprednisolone 500-1000 mg daily for 3 days (maximum total 3g), followed by high-dose oral glucocorticoids (0.75-1 mg/kg/day or 1 mg/kg/day prednisone) 3, 4
• Taper prednisone to 5 mg/day by weeks 19-52, targeting 7.5-10 mg by 3 months 3

Immunosuppressive Agent Selection

Rituximab (preferred for relapsing disease and fertility preservation):

• 375 mg/m² intravenous infusion once weekly for 4 weeks 4, 1
• Administer methylprednisolone 100 mg IV (or equivalent) 30 minutes prior to each infusion to reduce infusion reactions 4
• Rituximab is non-inferior to cyclophosphamide and superior for relapsing disease 3, 5

Cyclophosphamide (extensive historical experience, particularly for alveolar hemorrhage requiring mechanical ventilation or dialysis-requiring RPGN):

• 2 mg/kg/day oral or 15 mg/kg IV pulse every 2-3 weeks, adjusted for renal function and white blood cell count 3, 6
• Continue for 3-6 months until remission is achieved 7, 5
• Mandatory Pneumocystis jirovecii prophylaxis with sulfamethoxazole-trimethoprim (800 mg-160 mg on alternate days or 400 mg-80 mg daily) 1

Critical Pitfall

Limited experience exists with rituximab in patients requiring mechanical ventilation for alveolar hemorrhage or dialysis for rapidly progressive glomerulonephritis, as these patients were excluded from major trials; cyclophosphamide remains the agent with greatest efficacy data in these settings 5

Maintenance Therapy

After achieving remission (defined as Birmingham Vasculitis Activity Score = 0 with prednisone ≤7.5 mg/day) 3:

Rituximab maintenance (preferred):

• 500 mg IV every 6 months, reducing relapse rates compared to unscheduled treatment 3, 2
• If induction was with rituximab, initiate maintenance within 24 weeks after last induction dose, but no sooner than 16 weeks 4

Alternative maintenance agents:

• Azathioprine 2 mg/kg/day 3, 6
• Methotrexate 20-25 mg weekly 3, 8
• Mycophenolate mofetil 2000 mg/day 3

The staged approach using cyclophosphamide for induction (3-6 months) followed by switching to methotrexate or azathioprine for maintenance achieves 93% complete remission rates with reduced cumulative cyclophosphamide toxicity 8, 6

Management of Refractory Disease

Refractory GPA is defined as unchanged or increased disease activity after 4 weeks of appropriate remission-induction therapy 1, 3

Before declaring refractoriness, verify:

• Accuracy of primary diagnosis 3
• Adequacy of treatment regimen and patient compliance 3
• Distinction between active disease versus irreversible damage using the Vasculitis Damage Index 3

For confirmed refractory disease: Switch to rituximab if cyclophosphamide was used initially, or vice versa 3, 5

Management of Relapsing Disease

Systemic relapse (recurrence of vasculitis manifestations):

• Re-induce with rituximab for patients relapsing on maintenance therapy 3
• Consider switching to a different immunomodulatory approach based on clinical features 3

Non-severe respiratory relapse (isolated ENT/sinus disease):

• Optimize topical therapies (nasal rinses, topical glucocorticoids) 1
• Increase oral glucocorticoids 3
• Consider functional endoscopic sinus surgery for relapsing ENT disease unresponsive to medical therapy 3

Essential Monitoring and Prophylaxis

Infection Prevention

• Screen for hepatitis B, HIV, and tuberculosis before initiating cyclophosphamide or rituximab 1
• Pneumocystis jirovecii prophylaxis mandatory with cyclophosphamide or rituximab 1
• Timely vaccination according to current recommendations before immunosuppression 1

Treatment Toxicity Surveillance

• Weekly complete blood count during cyclophosphamide induction 3
• Regular bladder cancer screening (urine cytology) in cyclophosphamide-treated patients 1
• Bone density assessment for patients on prolonged glucocorticoids 1
• Monitor for hypophosphatemia (occurs in 21% with rituximab, often transient at infusion time) 4

Disease Activity Monitoring

• Birmingham Vasculitis Activity Score 3
• Serum creatinine and urinalysis 3
• ANCA titers (though treatment decisions should not be based solely on titer changes) 1

Special Populations

Patients with stage 5 chronic kidney disease in remission: Evaluate for renal transplantation, as outcomes are similar to other transplant recipients with rare disease relapses in the transplanted kidney 1