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

Treatment of Pulmonary Granulomatosis with Polyangiitis (GPA)

For pulmonary GPA with severe manifestations (alveolar hemorrhage, respiratory failure, or other organ-threatening disease), initiate rituximab or cyclophosphamide combined with high-dose glucocorticoids for remission induction, followed by rituximab maintenance therapy to prevent relapse. 1, 2

Disease Severity Stratification

Treatment strategy depends critically on disease severity classification:

• Severe GPA is defined by Five-Factor Score (FFS) ≥1, presence of alveolar hemorrhage, rapidly progressive glomerulonephritis, or other organ/life-threatening manifestations 1, 2
• Non-severe GPA has FFS=0 and lacks organ-threatening features 1, 2

Pulmonary involvement with alveolar hemorrhage or respiratory compromise qualifies as severe disease requiring aggressive therapy 2.

Remission Induction for Severe Pulmonary GPA

Glucocorticoid Therapy

Initiate with pulsed intravenous methylprednisolone 500-1000 mg daily for 3 days (maximum total 3 grams), followed by high-dose oral prednisone 0.75-1 mg/kg/day. 1, 2

• A reduced-dose glucocorticoid regimen is conditionally recommended over standard-dose regimens, as it provides similar efficacy for the composite outcome of ESRD or death while reducing infection risk 1
• Taper prednisone to 5-7.5 mg/day by weeks 19-52, targeting 7.5-10 mg by 3 months 2

Immunosuppressive Agent Selection

Rituximab is conditionally recommended over cyclophosphamide for remission induction, particularly for relapsing disease or in patients wishing to preserve fertility. 1, 2

Rituximab dosing regimen:

• 375 mg/m² IV weekly for 4 weeks, OR
• 1000 mg IV on days 1 and 15 (two-dose protocol) 2, 3, 4

Cyclophosphamide alternative:

• 2 mg/kg/day oral (adjusted for renal function) OR
• 15 mg/kg IV pulse every 2-3 weeks 2
• Continue until remission achieved (typically 3-6 months maximum) 1, 5
• Critical caveat: Cyclophosphamide reduces ovarian reserve and causes male infertility, making rituximab preferable in young patients 2, 3

The evidence shows rituximab is non-inferior to cyclophosphamide for severe GPA and superior for relapsing disease 1, 2. However, patients with alveolar hemorrhage requiring mechanical ventilation were excluded from major trials, so cyclophosphamide retains the most extensive experience in this critical subset 5.

Remission Maintenance Therapy

After achieving remission, rituximab 500 mg IV every 6 months is the preferred maintenance agent, as it reduces relapse rates compared to traditional agents. 1, 2, 3

Alternative maintenance options in order of preference:

• Methotrexate 20-25 mg weekly 2
• Azathioprine 2 mg/kg/day 1, 2
• Mycophenolate mofetil 2000 mg/day 2
• Leflunomide 1

If remission was induced with cyclophosphamide, switch to a maintenance agent (rituximab, methotrexate, or azathioprine) after 3-6 months rather than continuing cyclophosphamide. 1, 5

Management of Relapsing Disease

For severe pulmonary relapse, re-induce with rituximab plus glucocorticoids. 1, 2

• Rituximab is particularly effective for relapsing disease and superior to cyclophosphamide in this setting 1, 6
• Consider switching to a different remission induction agent if the current regimen fails 1

Adjunctive Therapies

Plasma Exchange

Plasma exchange is NOT routinely recommended for all patients with severe GPA. 1

• Consider plasma exchange only for patients at highest risk of progression to ESRD (rapidly declining kidney function, dialysis-dependent) or with concurrent anti-glomerular basement membrane disease 1
• The evidence does not support routine use in alveolar hemorrhage alone 1

Pneumocystis Prophylaxis

All patients receiving rituximab or cyclophosphamide require trimethoprim-sulfamethoxazole prophylaxis against Pneumocystis jirovecii pneumonia. 2, 3

Critical Monitoring Parameters

During induction therapy:

• Complete blood count weekly 2
• Serum creatinine and urinalysis 2
• Infection surveillance (infection rates 25-28 per 100 patient-years with immunosuppression) 4

During maintenance:

• Birmingham Vasculitis Activity Score for disease activity 2
• ANCA titers (though unreliable as sole biomarker) 2
• Cardiovascular risk factors 2

Definition of Remission

Remission is defined as Birmingham Vasculitis Activity Score = 0, prednisone dose ≤7.5 mg/day, and absence of clinical signs or symptoms attributable to active disease. 2

Common Pitfalls

• Do not delay treatment in severe pulmonary GPA—mortality without treatment is 50% at 6 months 6
• Do not continue cyclophosphamide beyond 6 months due to cumulative toxicity; switch to maintenance agent 1, 5
• Do not rely on ANCA titers alone to guide treatment decisions; use clinical assessment 2
• Do not use mepolizumab for severe GPA—it is only indicated for non-severe disease or respiratory manifestations without systemic vasculitis 1