What is the treatment approach for a patient with chronic granulomatous polyangitis, particularly for those with impaired renal function and lung involvement?

Treatment of Granulomatosis with Polyangiitis (GPA)

For patients with chronic granulomatosis with polyangiitis (GPA) presenting with impaired renal function and lung involvement, rituximab combined with glucocorticoids is the preferred remission induction therapy, followed by rituximab maintenance therapy every 6 months. 1, 2, 3

Disease Severity Classification

The first critical step is determining disease severity, as this dictates the treatment algorithm:

• Severe disease is defined by the presence of organ-threatening or life-threatening manifestations including glomerulonephritis with impaired renal function (serum creatinine >4 mg/dL), pulmonary hemorrhage, or rapidly progressive glomerulonephritis 1
• Non-severe disease involves constitutional symptoms, upper airway disease, or limited organ involvement without immediate threat to organ function 1

Your patient with impaired renal function and lung involvement clearly falls into the severe disease category and requires aggressive remission induction therapy 1

Remission Induction Therapy for Severe GPA

First-Line Treatment: Rituximab + Glucocorticoids

Rituximab is conditionally recommended over cyclophosphamide for remission induction in severe GPA due to comparable efficacy with potentially fewer long-term toxicities, particularly regarding fertility preservation and malignancy risk 1, 2

Rituximab dosing for induction:

• 375 mg/m² IV weekly for 4 consecutive weeks 2, 3
• Alternative regimen: 1,000 mg IV on days 1 and 15 (two doses total) 2

Glucocorticoid regimen:

• IV methylprednisolone 1,000 mg daily for 1-3 days, followed by oral prednisone taper 3
• Reduced-dose glucocorticoid regimens are conditionally recommended over standard-dose regimens as they provide similar efficacy with decreased infection risk 1
• Begin glucocorticoids within 14 days prior to or concurrent with rituximab initiation 3

When to Consider Cyclophosphamide Instead

Cyclophosphamide may be preferred in specific scenarios 1:

• Severe glomerulonephritis with serum creatinine >4 mg/dL (354 μmol/L) 1
• Life-threatening alveolar hemorrhage requiring mechanical ventilation (limited rituximab data in this setting) 4
• Rapidly progressive glomerulonephritis requiring dialysis 4
• In these cases, consider combining two IV pulses of cyclophosphamide with rituximab 1

Plasma Exchange Considerations

Plasma exchange is NOT routinely recommended for all patients with severe GPA and renal involvement 1

However, plasma exchange should be considered in highly selected patients:

• Those at highest risk of progression to end-stage renal disease (ESRD) 1
• The benefit is most pronounced when baseline risk of ESRD is very high (118 fewer ESRD cases per 1,000 patients treated) 1
• Critical caveat: Plasma exchange increases the risk of severe infection (risk ratio 1.19), so the ESRD risk must outweigh infection risk 1
• Factors favoring plasma exchange include: rapidly declining kidney function, severe baseline renal impairment, and poor response to initial immunosuppression 1

Plasma exchange IS indicated if there is overlap with anti-glomerular basement membrane (anti-GBM) disease 1

Remission Maintenance Therapy

Once remission is achieved (defined as BVAS = 0), transition to maintenance therapy 2:

Rituximab is the preferred maintenance agent:

• 500 mg IV every 6 months 2, 3
• Initiate within 24 weeks after the last induction dose, but no sooner than 16 weeks 3
• Continue for at least 18 months, with duration extended based on relapse risk factors 1

Alternative maintenance agents (in order of preference) 1:

1. Rituximab (preferred)
2. Methotrexate or azathioprine
3. Mycophenolate mofetil or leflunomide

Continue low-dose glucocorticoids during maintenance as this reduces relapse rates (relapse rate 14% with continued glucocorticoids vs. 36% without) 1

Monitoring and Relapse Risk

Structured clinical assessment using validated tools (BVAS) should guide treatment decisions, NOT ANCA titers alone 1

• Perform urinalysis at every visit to screen for renal relapse 1
• ANCA levels may rise before relapse but should not trigger treatment changes in isolation—increase clinical monitoring frequency instead 1

High-risk features for relapse include 1:

• PR3-ANCA positivity (higher relapse risk than MPO-ANCA) 1
• Upper airway (ENT) disease involvement 1
• Lung involvement 1
• History of prior relapse 1
• Persistent ANCA positivity at end of induction 1

Patients with MPO-ANCA have worse renal prognosis despite lower relapse rates, with more severe tubulointerstitial inflammation and worse eGFR outcomes at 12 months 1

Essential Supportive Care

Pneumocystis jirovecii prophylaxis with trimethoprim-sulfamethoxazole is mandatory during rituximab therapy 2

Additional monitoring requirements 1:

• Screen for hepatitis B, hepatitis C, and HIV before initiating rituximab 1
• Monitor immunoglobulin levels post-rituximab for hypogammaglobulinemia 1
• Assess for infections at each visit, as infection is the leading cause of early mortality 5

Common Pitfalls to Avoid

1. Do not delay treatment while awaiting biopsy confirmation if clinical suspicion is high with positive PR3-ANCA—commence treatment and biopsy when feasible 1
2. Do not use ANCA titers alone to guide treatment escalation—rising ANCA without clinical disease activity warrants closer monitoring, not treatment changes 1
3. Do not stop maintenance therapy prematurely—minimum 18 months is required, with many patients requiring longer duration based on relapse risk 1
4. Do not forget infection prophylaxis—infections are the leading cause of death in the first year of treatment 5, 6
5. Re-evaluate the diagnosis if disease appears refractory—consider whether this is truly active vasculitis versus damage, infection, or alternative diagnosis 1