What is the initial treatment approach for a patient with vasculitis, considering the variable presentation and potential severity of the condition?

Initial Treatment of Vasculitis

For patients with vasculitis, treatment must be stratified by disease severity: severe/generalized ANCA-associated vasculitis requires immediate combination therapy with cyclophosphamide and high-dose glucocorticoids, while nonsevere disease can be managed with methotrexate plus glucocorticoids. 1

Disease Severity Classification

The first critical step is categorizing disease severity, as this directly determines treatment intensity 1:

• Severe disease includes life- or organ-threatening manifestations: alveolar hemorrhage, glomerulonephritis (especially creatinine >500 μmol/L or 5.6 mg/dL), central nervous system vasculitis, mononeuritis multiplex, cardiac involvement, mesenteric ischemia, or limb/digit ischemia 1
• Generalized disease involves renal or other organ-threatening disease with creatinine <500 μmol/L (5.6 mg/dL) 1
• Nonsevere disease presents without life- or organ-threatening manifestations (e.g., rhinosinusitis, asthma, mild systemic symptoms, uncomplicated cutaneous disease, mild inflammatory arthritis) 1
• Localized disease affects only upper/lower respiratory tract without systemic involvement 1

Induction Therapy for Severe/Generalized Disease

Combination cyclophosphamide plus glucocorticoids is the standard induction regimen for severe and generalized vasculitis 1, 2:

Cyclophosphamide Administration

• Oral cyclophosphamide: 2 mg/kg/day (maximum 200 mg/day) for 3-6 months 1
• Intravenous cyclophosphamide: 15 mg/kg every 2 weeks for 3 doses, then every 3 weeks for at least 3 additional doses 1
• Pulsed IV cyclophosphamide may have lower cumulative toxicity but potentially higher relapse rates compared to continuous oral therapy 1

Glucocorticoid Regimen

• Initial therapy: IV methylprednisolone 500-1,000 mg/day for 1-3 days (or 30 mg/kg/day in children, maximum 1,000 mg/day) 1, 2
• Followed by oral prednisone: 1 mg/kg/day (maximum 60-80 mg/day in adults, 60 mg/day in children) with gradual tapering 1, 2
• Reduced-dose glucocorticoid regimens are now preferred over standard-dose regimens as they provide similar efficacy with decreased infection risk 1

Rituximab as Alternative

• Rituximab (375 mg/m² IV weekly for 4 weeks or 1,000 mg on days 1 and 15) is an alternative first-line agent, particularly for patients with fertility concerns or relapsing disease 1, 3
• However, cyclophosphamide is preferred over rituximab in patients with severe renal involvement (creatinine >2.0 mg/dL) 2

Treatment for Nonsevere Disease

For nonsevere ANCA-associated vasculitis, methotrexate plus glucocorticoids is preferred over cyclophosphamide or rituximab 1:

• Methotrexate: up to 25 mg/week (subcutaneous or oral) 1
• Glucocorticoids: high-dose oral glucocorticoids (prednisone 1 mg/kg/day) with tapering 1
• Methotrexate is favored due to lower toxicity compared to cyclophosphamide, with larger evidence base than rituximab for this population 1
• Rituximab may be preferred in specific situations: hepatic/renal dysfunction, recurrent relapses on methotrexate, or compliance concerns 1

Essential Supportive Measures

Mandatory prophylaxis must be implemented immediately 1, 4:

• Pneumocystis jirovecii prophylaxis: trimethoprim-sulfamethoxazole (co-trimoxazole) for all patients receiving immunosuppression 1, 4
• Bladder protection with cyclophosphamide: oral or IV mesna (2-mercaptoethanesulfonate sodium) to prevent hemorrhagic cystitis 1, 4
• Osteoporosis prophylaxis: calcium, vitamin D, and bisphosphonates for patients on long-term glucocorticoids 1, 5

Monitoring Parameters

Regular monitoring is essential to assess disease activity and drug toxicity 1, 2, 4:

• Complete blood count, renal function (creatinine, urinalysis), inflammatory markers (ESR, CRP), and ANCA levels 2, 4
• Blood glucose monitoring while on glucocorticoids 1, 4
• Persistent or recurrent hematuria indicates ongoing disease activity or relapse 2
• Rising ANCA titers or conversion from negative to positive may predict future relapse 2

Critical Pitfalls to Avoid

• Do not delay treatment while awaiting biopsy results in patients with clinical presentation compatible with ANCA vasculitis and positive serology, especially with rapidly deteriorating renal function 2
• Do not withhold treatment based solely on unfavorable histologic findings, as kidney recovery can occur even with advanced damage 2
• Do not use glucocorticoid monotherapy except in rare circumstances (e.g., isolated arthralgias), as combination therapy minimizes glucocorticoid exposure and improves outcomes 1
• Do not underestimate cyclophosphamide toxicity: monitor for leucopenia, declining renal function requiring dose adjustment, and long-term bladder cancer risk 1, 4

Transition to Maintenance Therapy

After achieving remission (typically 3-6 months), transition from cyclophosphamide to maintenance therapy 1, 2:

• Rituximab is preferred over azathioprine or methotrexate for maintenance after cyclophosphamide induction, with lower relapse rates 1
• Rituximab dosing for maintenance: 500 mg IV every 6 months or 1,000 mg IV every 4 months 1
• Azathioprine (up to 2 mg/kg/day) or methotrexate (up to 25 mg/week) are alternatives when rituximab is not available or contraindicated 1

Special Considerations

• Drug-induced vasculitis: withdrawal of the offending agent alone is often sufficient, obviating immunosuppression 6
• Hepatitis B or C-associated vasculitis: should be treated as pathogenetically separate entities with antiviral therapy 1
• Patients should ideally be managed at centers with vasculitis expertise, particularly for severe or refractory disease 2