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

Treatment of Granulomatosis with Polyangiitis (GPA)

For severe GPA with organ-threatening manifestations, initiate rituximab 375 mg/m² IV weekly for 4 weeks combined with pulsed IV methylprednisolone (500-1000 mg daily for 3 days) followed by high-dose oral prednisone (0.75-1 mg/kg/day), then maintain remission with rituximab 500 mg IV every 6 months. 1, 2, 3

Disease Severity Stratification

Before initiating treatment, classify disease severity to guide therapeutic intensity:

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

This distinction is critical because severe disease requires aggressive immunosuppression while non-severe disease may be managed with less intensive regimens.

Remission Induction for Severe GPA

Glucocorticoid Regimen

Start with pulsed IV methylprednisolone 500-1000 mg daily for 3 days (maximum total 3g), followed immediately by high-dose oral prednisone 0.75-1 mg/kg/day 1, 2. Begin tapering prednisone to 5 mg/day by weeks 19-52, with a target dose of 7.5-10 mg by 3 months 1.

Immunosuppressive Agent Selection

Rituximab is preferred over cyclophosphamide for the following reasons 1, 2:

• Superior efficacy in relapsing disease 1
• Preserves fertility, making it particularly important for younger patients 1
• Non-inferior to cyclophosphamide for new-onset disease 1

Rituximab dosing for induction: 375 mg/m² IV once weekly for 4 weeks 3, 2

Cyclophosphamide alternative: If rituximab is unavailable or contraindicated, use cyclophosphamide 2 mg/kg/day oral or 15 mg/kg IV pulse every 2-3 weeks until remission is achieved (usually within 6 months) 1. However, cyclophosphamide carries risks of leukopenia, infections, infertility, and increased malignancy 1.

Mandatory Prophylaxis

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

Maintenance Therapy

Once remission is achieved (defined as Birmingham Vasculitis Activity Score = 0, prednisone ≤7.5 mg/day, and absence of active disease symptoms 1, 2):

Rituximab 500 mg IV every 6 months is the preferred maintenance agent because it reduces relapse rates compared to traditional agents and unscheduled treatment 1, 2. Initiate maintenance within 24 weeks after the last induction infusion, but no sooner than 16 weeks 3.

Alternative Maintenance Options (in order of preference if rituximab unavailable):

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

The addition of a conventional maintenance agent (azathioprine, methotrexate, or mycophenolate) to rituximab and glucocorticoids decreases relapse incidence (hazard ratio 0.53) without increasing adverse events 4.

Management of Relapsing Disease

Severe Systemic Relapse

Re-induce with rituximab 375 mg/m² IV weekly for 4 weeks plus glucocorticoids 2. Rituximab is particularly effective and superior to cyclophosphamide in the relapsing setting 2.

If the patient previously failed rituximab, switch to cyclophosphamide 1.

Non-Severe Respiratory Relapse

Follow a stepwise approach 5:

1. Optimize topical therapies (bronchodilators) 5
2. Increase oral glucocorticoids with short courses of high-dose (0.5-1 mg/kg/day for 5-7 days) 5
3. Consider functional endoscopic sinus surgery for relapsing ENT disease unresponsive to medical therapy 5

Refractory Disease

Refractory GPA is defined as unchanged or increased disease activity after 4 weeks of appropriate remission-induction therapy 5.

Before declaring refractoriness, verify:

• Primary diagnosis is correct (exclude infections, malignancies) 5
• Treatment regimen was appropriate 5
• Patient compliance with therapy 5
• Active manifestations versus irreversible damage 5

For refractory systemic GPA despite glucocorticoids plus cyclophosphamide: Switch to rituximab 1

For refractory disease despite rituximab: Switch to cyclophosphamide 1

Adjunctive Therapies

Plasma Exchange

Plasma exchange is not routinely recommended for all patients with severe GPA 2. However, consider it for:

• Patients at highest risk of progression to end-stage renal disease 2
• Concurrent anti-glomerular basement membrane disease 2
• Severe refractory cases with diffuse alveolar hemorrhage or rapidly progressive glomerulonephritis when combined with rituximab 6, 7

The combination of rituximab with concurrent plasma exchange (every 2-3 days for 5 total treatments) may be beneficial for severe, treatment-refractory cases 6.

Critical Monitoring Parameters

During Induction:

• Complete blood count weekly 1
• Serum creatinine and urinalysis regularly 1
• Infection surveillance 1

During Maintenance:

• Birmingham Vasculitis Activity Score for disease activity 1, 2
• ANCA titers 1
• Cardiovascular risk factors 1

Specific Adverse Events to Monitor:

• With rituximab: Infusion reactions, infections, hypophosphatemia 3
• With cyclophosphamide: Leukopenia, infections, infertility, malignancy risk 1

Common Pitfalls and Caveats

• Do not delay treatment while awaiting biopsy confirmation if clinical suspicion is high with positive ANCA and organ-threatening manifestations 8
• Do not retreat with rituximab sooner than 16 weeks after the last infusion 3
• Distinguish between active disease and irreversible damage using the Vasculitis Damage Index to avoid unnecessary immunosuppression escalation 5
• Monitor for cardiovascular events as RA patients (and by extension, vasculitis patients) have increased cardiovascular risk; discontinue rituximab if serious cardiac events occur 3
• Premedicate before rituximab infusions with antihistamine and acetaminophen to mitigate infusion-related reactions 3