What is the treatment for Granulomatosis with Polyangiitis (GPA)?

Treatment of Granulomatosis with Polyangiitis (GPA)

The treatment of Granulomatosis with Polyangiitis requires a stratified approach based on disease severity, with high-dose glucocorticoids as the cornerstone of therapy and cyclophosphamide or rituximab added for severe disease. 1

Disease Classification and Treatment Stratification

Treatment strategies for GPA are tailored based on disease severity:

• Severe GPA: Defined by Five-Factor Score (FFS) ≥1 or presence of peripheral neuropathy, alveolar hemorrhage, or other organ/life-threatening manifestations 2
• Non-severe GPA: Defined by FFS=0 and absence of peripheral neuropathy, alveolar hemorrhage, or other organ/life-threatening manifestations 2

Induction Therapy

For Severe GPA:

• Initial treatment: Pulsed intravenous glucocorticoids (methylprednisolone 500-1000 mg daily for 3 days, maximum total 3g) followed by high-dose oral glucocorticoids (0.75-1 mg/kg/day) 2
• Plus one of the following:
  • Cyclophosphamide: Administered until remission is achieved (usually within 6 months); longer induction periods (up to 9-12 months) for patients who improve slowly 2
  • Rituximab: 1-gram pulses 2 weeks apart, comparable efficacy to cyclophosphamide in patients with FFS ≥1 2, 3

For Non-Severe GPA:

• Glucocorticoids alone: Usually sufficient to induce remission (93% remission rate in prospective trials) 2
• Consider adding mepolizumab: Particularly effective for respiratory manifestations in relapsing or refractory disease without organ-threatening manifestations 2, 1

Maintenance Therapy

For Severe GPA:

• Recommended options (in combination with tapered glucocorticoids):
  • Rituximab: 500 mg every 6 months shown to reduce relapse rates compared to unscheduled treatment 2, 1
  • Mepolizumab: Particularly effective for respiratory manifestations 2, 1
  • Traditional DMARDs: Including azathioprine, methotrexate, or leflunomide 2, 1

For Non-Severe GPA:

• Glucocorticoids alone or with mepolizumab: Taper to minimum effective dose to reduce toxicity 2, 1
• Consider traditional DMARDs: Despite limited evidence, often used in clinical practice 2

Management of Refractory Disease

• For refractory systemic GPA despite induction with glucocorticoids plus cyclophosphamide:
  • Switch to rituximab 2
• For refractory asthma/ENT disease without systemic manifestations:
  • Add mepolizumab (300 mg every 4 weeks, or consider 100 mg for limited respiratory manifestations) 2
• Alternative options for non-responders:
  • Other IL-5 inhibitors (benralizumab, reslizumab) 2, 1
  • Plasma exchange or intravenous immunoglobulin therapy 2

Special Considerations

• Respiratory manifestations: Optimize inhaled therapy for patients with active asthma or ENT involvement 2, 1
• Relapse management: Distinguish between systemic relapse (requiring aggressive immunosuppression) and respiratory relapse (may respond to optimized inhaled therapy and/or mepolizumab) 2, 1
• Glucocorticoid toxicity: Prioritize glucocorticoid-sparing strategies, as patients with GPA are often exposed to high cumulative doses 2

Monitoring and Follow-up

• Regular assessment of disease activity using clinical parameters 1
• Monitor for treatment-related complications:
  • With rituximab: Infusion reactions (12% with first infusion), infections (62%), hypophosphatemia (21%) 3
  • With cyclophosphamide: Leukopenia, infections, infertility, increased malignancy risk 4

Pitfalls and Caveats

• Diagnostic reassessment: Before labeling disease as refractory, re-evaluate diagnosis, treatment appropriateness, patient compliance, and distinguish active disease from irreversible damage 2
• Limited evidence in severe presentations: Rituximab has limited data in patients with alveolar hemorrhage requiring mechanical ventilation or rapidly progressive glomerulonephritis requiring dialysis 5
• Relapse risk: Even after successful induction therapy, early relapses are common (35% within first year), particularly respiratory manifestations 2
• Multidisciplinary approach: Essential for optimal management, involving rheumatologists, pulmonologists, otolaryngologists, and nephrologists 1