What is the initial treatment approach for a patient with Granulomatosis with polyangitis?

Initial Treatment for Granulomatosis with Polyangiitis

For newly diagnosed GPA, initiate rituximab (375 mg/m² IV weekly for 4 weeks) combined with high-dose glucocorticoids using a reduced-dose regimen, and do not delay treatment while awaiting biopsy confirmation if clinical presentation and positive PR3/MPO-ANCA are present. 1, 2

Disease Severity Stratification

Before initiating treatment, classify disease severity to guide therapeutic intensity 2:

• Severe disease: Organ-threatening or life-threatening manifestations including impaired renal function (eGFR <50 mL/min/1.73 m²), pulmonary hemorrhage, rapidly progressive glomerulonephritis, or other major organ involvement 3
• Non-severe disease: Constitutional symptoms or limited organ involvement without life-threatening features 2

Remission Induction Therapy

First-Line Treatment: Rituximab + Glucocorticoids

Rituximab is conditionally recommended over cyclophosphamide for remission induction based on the American College of Rheumatology/Vasculitis Foundation 2021 guidelines, showing at least equivalent efficacy with potentially fewer long-term toxicities 1, 2:

• Rituximab dosing: 375 mg/m² IV weekly for 4 consecutive weeks OR 1,000 mg IV on days 1 and 15 2, 4
• Glucocorticoid regimen: Begin with IV methylprednisolone pulse (1,000 mg daily for 1-3 days), followed by oral prednisone (1 mg/kg/day, maximum 80 mg/day) with rapid tapering 4
• Reduced-dose glucocorticoid protocol: Use a more rapid taper rate with lower cumulative dose during the first 6 months (approximately 40% of standard dosing) to minimize serious infections while maintaining efficacy 3, 1

Alternative: Cyclophosphamide + Glucocorticoids

Cyclophosphamide (2 mg/kg/day orally, adjusted for renal function) combined with glucocorticoids remains an option, particularly when rituximab is unavailable or contraindicated 4:

• Associated with higher rates of serious adverse effects including infertility and malignancy risk 5
• Consider preferentially in patients who previously failed rituximab 3

Plasma Exchange Considerations

Plasma exchange is NOT routinely recommended for all patients with severe GPA 3:

• Consider plasma exchange only in highly selected patients at high or moderate-high risk of progression to end-stage kidney disease (ESKD), particularly those requiring dialysis at presentation 3, 2
• Plasma exchange probably reduces 1-year ESKD risk by approximately 16% in high-risk patients requiring dialysis, but increases serious infection risk by 8.5% 3
• Do NOT use plasma exchange for pulmonary hemorrhage without renal involvement 3
• Plasma exchange has little or no effect on mortality or disease relapse 3

Essential Supportive Care and Prophylaxis

Pneumocystis Jirovecii Prophylaxis (MANDATORY)

All patients receiving rituximab or cyclophosphamide MUST receive PCP prophylaxis 2, 6:

• Trimethoprim-sulfamethoxazole: 800 mg-160 mg on alternate days OR 400 mg-80 mg daily 6
• This also provides protection against certain bacterial infections including some E. coli strains 6

Pre-Treatment Screening

Screen for chronic infections before initiating immunosuppression 2, 6:

• Hepatitis B surface antigen and core antibody
• Hepatitis C antibody
• HIV testing

Infusion Premedication

Premedicate before each rituximab infusion to mitigate infusion-related reactions 4:

• Antihistamine (e.g., diphenhydramine)
• Acetaminophen

Remission Maintenance Therapy

After achieving remission (typically by 6 months), transition to maintenance therapy 2:

• Rituximab is the preferred maintenance agent: 500 mg IV every 6 months for at least 18 months 3, 2
• Alternative maintenance agents (if rituximab intolerance): Methotrexate or azathioprine 3, 2
• Continue low-dose glucocorticoids during maintenance, tapering to the minimum effective dose 3

Monitoring During Treatment

Clinical Assessment

• Use validated tools such as Birmingham Vasculitis Activity Score (BVAS) to guide treatment decisions 2
• Do NOT adjust immunosuppression based on ANCA titers alone 3

High-Risk Features for Relapse

Monitor more closely in patients with 2:

• PR3-ANCA positivity
• Upper airway disease involvement
• Lung involvement
• History of prior relapse
• Persistent ANCA positivity

Post-Rituximab Monitoring

• Monitor immunoglobulin levels for hypogammaglobulinemia 2
• Long-term infection surveillance as standard practice 6

Critical Pitfalls to Avoid

• Never delay treatment initiation while awaiting kidney biopsy if clinical presentation is compatible with small vessel vasculitis and MPO/PR3-ANCA is positive—this can significantly worsen outcomes due to rapid disease progression 3, 1
• Do not use corticosteroids alone for remission induction—they are ineffective as monotherapy 3
• Avoid cyclophosphamide for non-severe relapses due to cumulative toxicity 3
• Do not omit PCP prophylaxis—this dramatically increases risk of life-threatening opportunistic infections 6