What is the initial treatment for Granulomatosis with Polyangiitis (GPA), formerly known as Wegener's granulomatosis?

Initial Treatment for Granulomatosis with Polyangiitis (GPA)

For remission induction of new-onset organ-threatening or life-threatening GPA, treatment with a combination of glucocorticoids and either cyclophosphamide OR rituximab is strongly recommended as the initial therapy. 1

Classification of Disease Severity

Treatment approach depends on disease severity:

Severe Disease (Organ or Life-Threatening)

• Five-Factor Score (FFS) ≥ 1
• Presence of:
  • Renal involvement with significant dysfunction
  • Pulmonary hemorrhage
  • Central nervous system involvement
  • Cardiac involvement
  • Gastrointestinal involvement
  • Other major organ dysfunction

Non-Severe Disease

• FFS = 0
• Absence of organ or life-threatening manifestations
• May include:
  • Mild systemic symptoms
  • Rhinosinusitis
  • Uncomplicated cutaneous disease
  • Mild inflammatory arthritis

Initial Treatment Algorithm

For Severe GPA:

1. Induction Therapy:

   • High-dose glucocorticoids:

     • IV methylprednisolone 500-1000 mg/day for 3-5 days, followed by
     • Oral prednisone 1 mg/kg/day (generally up to 80 mg/day)

   • PLUS ONE of the following:

     • Rituximab: 375 mg/m² IV weekly for 4 doses OR 1000 mg on days 1 and 15 1, 2
     • Cyclophosphamide: IV 15 mg/kg every 2 weeks for 3 doses, then every 3 weeks for at least 3 more doses OR oral 2 mg/kg/day for 3-6 months 1

2. After Remission (3-6 months):

   • Switch to maintenance therapy with:
     • Azathioprine (up to 2 mg/kg/day)
     • Methotrexate (up to 25 mg/week)
     • Rituximab (500 mg every 6 months)
   • Taper glucocorticoids to lowest effective dose

For Non-Severe GPA:

1. Induction Therapy:
   • Glucocorticoids (lower doses than for severe disease)
   • PLUS ONE of the following:
     • Methotrexate (up to 25 mg/week) 1
     • Mycophenolate mofetil (up to 1500 mg twice daily) 1

Evidence-Based Considerations

1. Rituximab vs. Cyclophosphamide:

   • Rituximab is conditionally recommended over cyclophosphamide for remission induction in severe GPA according to the 2021 ACR/Vasculitis Foundation guidelines 1
   • Rituximab has been shown to provide similar benefits to cyclophosphamide for remission induction in randomized controlled trials 1
   • Rituximab may be particularly preferred in:
     • Young patients concerned about fertility
     • Patients with relapsing disease after prior cyclophosphamide exposure
     • Patients with contraindications to cyclophosphamide

2. Methotrexate for Non-Severe Disease:

   • Methotrexate combined with glucocorticoids is effective for non-severe GPA 3
   • Should be avoided in patients with creatinine clearance <30 ml/min 1
   • Dose should be reduced in patients with creatinine clearance <60 ml/min 1

Common Pitfalls and Caveats

1. Disease Assessment:

   • Ensure accurate diagnosis with appropriate serologic testing (ANCA) and biopsy when possible
   • Correctly classify disease severity to guide treatment choice

2. Rituximab Considerations:

   • Limited experience with rituximab in patients with alveolar hemorrhage requiring mechanical ventilation or rapidly progressive glomerulonephritis requiring dialysis 4
   • Monitor for infusion reactions, especially with first infusion (12% of patients) 2

3. Cyclophosphamide Toxicity:

   • Monitor for cytopenias, hemorrhagic cystitis, and infection
   • Consider fertility preservation measures before starting therapy
   • Adjust dose based on age and renal function

4. Glucocorticoid Management:

   • Aim to taper glucocorticoids to minimize long-term toxicity
   • Pneumocystis jirovecii pneumonia prophylaxis recommended during induction therapy

5. Monitoring:

   • Regular assessment of disease activity using validated clinical tools
   • Do not change immunosuppression based on ANCA titer changes alone 1
   • Monitor for treatment-related complications and infections

By following this evidence-based approach to initial treatment of GPA, clinicians can effectively induce remission while minimizing treatment-related morbidity and mortality, ultimately improving patient outcomes and quality of life.