What is the recommended treatment regimen for a patient with C‑ANCA‑positive granulomatosis with polyangiitis (formerly Wegener’s granulomatosis)?

Treatment of C-ANCA Positive Granulomatosis with Polyangiitis

For remission induction in C-ANCA positive GPA, treat with high-dose glucocorticoids combined with either rituximab OR cyclophosphamide, with rituximab strongly preferred for relapsing disease, women of childbearing age, or when cumulative cyclophosphamide exposure is a concern. 1, 2

Remission Induction Therapy

Glucocorticoid Regimen

• Initiate with pulse intravenous methylprednisolone 500-1000 mg daily for 3 days (maximum total 3g), followed by oral prednisone 0.75-1 mg/kg/day 3
• Taper prednisone to 5 mg/day by weeks 19-52, targeting 7.5-10 mg by 3 months 3

Immunosuppressive Agent Selection

Rituximab (Preferred Option):

• Standard induction: 375 mg/m² IV weekly for 4 weeks 2, 4
• Alternative regimen: 1,000 mg IV on days 1 and 15 4
• Rituximab is particularly preferred over cyclophosphamide in patients with relapsing disease, as it demonstrates superior efficacy in this population 1, 2
• Preserves fertility (no reported fertility concerns) 2, 4
• Mandatory Pneumocystis jirovecii prophylaxis with trimethoprim/sulfamethoxazole required 2, 3, 4

Cyclophosphamide (Alternative):

• Oral: 2 mg/kg/day for 3-6 months 3, 5
• IV pulse: 15 mg/kg every 2-3 weeks 3
• Causes reduced ovarian reserve, ovarian failure, and male infertility 2
• Cumulative doses above 36g associated with malignancy risk 1
• Requires Pneumocystis jirovecii prophylaxis 3

Adjunctive Therapy for Severe Disease

• Plasma exchange should be considered for serum creatinine ≥500 μmol/L (5.7 mg/dL) due to rapidly progressive glomerulonephritis 1
• Plasma exchange can also be considered for severe diffuse alveolar hemorrhage 1

Maintenance Therapy

Rituximab is superior to azathioprine for maintenance and should be preferred whenever possible. 2, 3

Rituximab Maintenance (Preferred)

• 500 mg IV every 6 months for 18 months to 4 years after achieving remission 1, 2, 4
• The MAINRITSAN trial demonstrated rituximab resulted in major relapses in only 3 patients versus 17 with azathioprine (hazard ratio 6.61, P=0.002) 2
• Monitor immunoglobulin levels every 6 months, as hypogammaglobulinemia occurs in 27-58% of patients 2
• Continue Pneumocystis prophylaxis throughout maintenance 2

Alternative Maintenance Agents (if rituximab unavailable/contraindicated)

• Azathioprine: 1.5-2 mg/kg/day 1, 3
• Methotrexate: 20-25 mg weekly (contraindicated if GFR <60 ml/min per 1.73 m²) 1, 3
• Mycophenolate mofetil: 2000 mg/day in divided doses 1, 3

Duration of Maintenance

• Minimum 18 months, optimal duration 18 months to 4 years after remission induction 1
• Maintenance therapy should be continued for at least 24 months following sustained remission 1

Relapse Management

Severe Relapse (Life- or Organ-Threatening)

• Treat according to initial induction guidelines with rituximab preferred over cyclophosphamide 1
• Rituximab is particularly effective for relapsing disease, especially in PR3-ANCA (C-ANCA) positive patients 1, 3

Non-Severe Relapse

• Increase glucocorticoids with or without azathioprine or mycophenolate mofetil 1
• Avoid cyclophosphamide for non-severe relapses to minimize cumulative toxicity 1
• Methotrexate can be used for non-severe relapses without contraindications 1

Refractory Disease

For patients refractory to initial therapy after 4 weeks or with <50% reduction in disease activity after 6 weeks, switch from cyclophosphamide to rituximab or vice versa. 1, 2, 3

• Before declaring refractoriness, verify primary diagnosis, treatment compliance, and distinguish active disease from irreversible damage 3
• Consider adding IV immunoglobulin or plasma exchange as alternatives 1
• Refer to expert centers for potential clinical trial enrollment 1

Critical Monitoring Parameters

Do NOT Use ANCA Titers to Guide Treatment

• Use structured clinical assessment rather than ANCA testing to inform treatment decisions 1, 2
• Changes in ANCA titer alone are not reliable measures of disease activity 1

Required Monitoring

• Complete blood count weekly during induction 3
• Serum creatinine and urinalysis regularly 3
• Immunoglobulin levels every 6 months during rituximab therapy 1, 2
• Screen for hepatitis B, HIV, and tuberculosis before initiating therapy 3
• Bladder cancer screening (urine cytology) for cyclophosphamide-treated patients 3
• Bone density assessment for prolonged glucocorticoid use 3
• Cardiovascular risk assessment periodically 1

Relapse Risk Factors in C-ANCA (PR3-ANCA) Patients

PR3-ANCA positivity (C-ANCA) is associated with significantly higher relapse risk compared to MPO-ANCA. 1, 2, 3

Additional high-risk features include:

• History of prior relapse 1
• ANCA positive at end of induction 1
• Rising ANCA titers 1
• Ear, nose, and throat disease 1
• Lower cyclophosphamide exposure 1
• Early immunosuppressive withdrawal 1

Patients with PR3-ANCA positivity may benefit from extended maintenance therapy duration beyond the minimum 18 months. 2

Common Pitfalls

• Do not delay treatment while awaiting kidney biopsy if clinical presentation is compatible with small-vessel vasculitis and ANCA serology is positive 3
• Do not use glucocorticoids alone; combined therapy is required for effective treatment 1
• Do not misinterpret irreversible damage as active disease requiring escalation of immunosuppression 3
• Do not exceed cumulative cyclophosphamide doses of 36g due to malignancy risk 1
• Do not use methotrexate in patients with GFR <60 ml/min per 1.73 m² 1