What is the initial treatment approach for a patient with granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis?

Initial Treatment of Granulomatosis with Polyangiitis (GPA)

For severe GPA (defined by organ- or life-threatening manifestations), initiate pulsed intravenous methylprednisolone 500-1000 mg daily for 3 days followed by high-dose oral glucocorticoids (0.75-1 mg/kg/day) combined with either rituximab (1-gram IV infusions 2 weeks apart) or cyclophosphamide (0.6 g/m² IV pulses), with rituximab preferred for relapsing disease and fertility preservation. 1, 2

Disease Severity Stratification

The first critical step is determining disease severity, which dictates the treatment approach:

Severe GPA is defined by:

• Five-Factor Score (FFS) ≥1, which includes renal insufficiency (creatinine >1.58 mg/dl), proteinuria >1 g/day, cardiomyopathy, gastrointestinal involvement, or central nervous system involvement 1
• Presence of peripheral neuropathy, alveolar hemorrhage, rapidly progressive glomerulonephritis, or other organ/life-threatening manifestations 1, 3

Non-severe GPA is characterized by FFS=0 and absence of the above manifestations 1

Induction Therapy for Severe GPA

Glucocorticoid Component

All patients with severe GPA require aggressive glucocorticoid therapy:

• Pulsed IV methylprednisolone: 500-1000 mg daily for 3 days (maximum total 3 grams) 1
• Followed by oral prednisone: 0.75-1 mg/kg/day (not exceeding 80 mg/day), with pre-specified tapering to 5-7.5 mg/day by weeks 19-52 1, 2

Immunosuppressive Agent Selection

Two equally effective options exist for severe GPA:

Rituximab (preferred in most situations):

• Dosing: 375 mg/m² IV once weekly for 4 weeks OR 1-gram IV infusions separated by 2 weeks 1, 2
• Advantages: Superior for relapsing disease, preserves fertility, non-inferior efficacy to cyclophosphamide 1, 2
• Evidence: The REOVAS trial demonstrated rituximab achieved 64% complete remission at 6 months in severe GPA, comparable to cyclophosphamide (53%) 2
• Monitoring: Watch for infusion reactions, infections, and hypophosphatemia 1

Cyclophosphamide (alternative option):

• Dosing: 0.6 g/m² IV pulses every 2 weeks for 1 month, then every 4 weeks OR 2 mg/kg/day oral 1, 2
• Duration: Continue until remission achieved (usually within 6 months); longer induction (up to 9-12 months) reserved for slow responders 1
• Monitoring: Weekly complete blood count, requires Pneumocystis jirovecii prophylaxis 1
• Toxicities: Leukopenia, infections, infertility, increased malignancy risk 1

Critical Clinical Decision Point

When to choose rituximab over cyclophosphamide:

• Relapsing disease (rituximab is superior) 1, 3
• Women of childbearing age (fertility preservation) 1
• Patients with prior cyclophosphamide exposure 4

When cyclophosphamide may be preferred:

• Very limited experience exists with rituximab in patients requiring mechanical ventilation for alveolar hemorrhage or dialysis for rapidly progressive glomerulonephritis—cyclophosphamide has the most extensive evidence in these critical situations 4

Induction Therapy for Non-Severe GPA

For non-severe GPA, glucocorticoids alone may be sufficient 1

• High-dose oral glucocorticoids (0.75-1 mg/kg/day) with tapering
• Some patients may benefit from methotrexate combined with glucocorticoids for limited, non-life-threatening disease 5

Essential Adjunctive Measures

All patients require:

• Pneumocystis jirovecii prophylaxis when receiving rituximab or cyclophosphamide 1, 3
• Pre-medication with antihistamine and acetaminophen prior to rituximab infusion 2
• Urgent treatment initiation: Do not delay immunosuppression while awaiting kidney biopsy if clinical presentation and positive MPO/PR3-ANCA serology are consistent with GPA 6

Monitoring During Induction

Critical parameters to monitor:

• Complete blood count weekly 1
• Serum creatinine and urinalysis 1
• Birmingham Vasculitis Activity Score (BVAS) for disease activity 2
• Infection surveillance 1

Definition of Remission

Remission is achieved when:

• BVAS = 0 1, 2
• Prednisone dose ≤7.5 mg/day 1, 2
• Absence of clinical signs or symptoms attributable to active disease 1

Common Pitfalls to Avoid

• Do not base treatment decisions solely on ANCA titers—treat based on clinical disease activity 3
• Do not delay treatment waiting for biopsy confirmation if clinical presentation and serology are consistent with GPA 6
• Do not combine rituximab and cyclophosphamide—if one fails, switch to the other rather than combining 3
• Do not use cyclophosphamide, rituximab, or mycophenolate in pregnant patients—use only glucocorticoids, IV immunoglobulins, or azathioprine 7