What is the treatment for cutaneous Anti-Neutrophil Cytoplasmic Antibodies (ANCA) vasculitis?

Treatment of Cutaneous ANCA Vasculitis

For isolated cutaneous ANCA vasculitis without organ-threatening disease, initiate treatment with glucocorticoids combined with either methotrexate or azathioprine, reserving cyclophosphamide and rituximab for severe or refractory cases. 1

Disease Severity Assessment

The treatment approach must be stratified based on disease severity and extent of organ involvement 1:

• Localized cutaneous disease only: Skin manifestations without systemic organ involvement
• Generalized non-organ-threatening disease: Cutaneous involvement with constitutional symptoms but no vital organ compromise
• Severe organ-threatening disease: Cutaneous manifestations with renal involvement (creatinine >3.4 mg/dl), pulmonary hemorrhage, or other vital organ failure 1

Common pitfall: Cutaneous ANCA vasculitis can present as the initial manifestation of systemic disease, so thorough evaluation for renal, pulmonary, and other organ involvement is mandatory before selecting therapy 2, 3.

Treatment Algorithm by Disease Severity

Isolated Cutaneous or Non-Organ-Threatening Disease

First-line therapy 1, 4:

• Glucocorticoids: Prednisone 0.5-1 mg/kg/day (maximum 80 mg/day) with structured tapering 1
• Plus methotrexate: 15-25 mg/week (avoid if GFR <60 ml/min/1.73 m²) 1
• Alternative: Azathioprine 1.5-2 mg/kg/day if methotrexate contraindicated 1

Supportive measures 2, 4:

• Leg elevation and avoidance of prolonged standing
• NSAIDs for symptomatic relief
• Colchicine or dapsone for mild recurrent disease

Severe or Organ-Threatening Cutaneous Disease

Induction therapy 1:

Rituximab (preferred for most patients) 1:

• 375 mg/m² weekly for 4 weeks
• Plus glucocorticoids: Follow PEXIVAS reduced-dose regimen starting at 50-75 mg/day based on weight, with structured tapering to 5 mg/day by week 20 1

Cyclophosphamide (alternative option) 1:

• Oral: 2 mg/kg/day for 3 months (reduce to 1.5 mg/kg/day if age >60 years, 1.0 mg/kg/day if age >70 years) 1
• Intravenous: 15 mg/kg at weeks 0,2,4,7,10,13 (reduce to 12.5 mg/kg if age >60 years, 10 mg/kg if age >70 years) 1
• Dose adjustment: Reduce by 0.5 mg/kg/day (oral) or 2.5 mg/kg (IV) if GFR <30 ml/min/1.73 m² 1

Combination therapy for severe disease 1, 5:

• Rituximab 375 mg/m² weekly for 4 weeks plus cyclophosphamide 15 mg/kg at weeks 0 and 2 only
• This approach allows rapid glucocorticoid tapering and achieves remission in 84% by 5 months 5

Glucocorticoid-Sparing Strategy

Avacopan (C5a receptor antagonist) 1:

• 30 mg twice daily as alternative to glucocorticoids
• Combined with rituximab or cyclophosphamide induction
• Prioritize for: Patients at high risk for glucocorticoid toxicity (diabetes, osteoporosis, psychiatric history) or those with lower GFR who may benefit from greater renal recovery 1

Important consideration: Cumulative glucocorticoid doses directly correlate with toxicity burden, with mood disturbance and psychosis occurring early, while adrenal insufficiency presents later 6.

Maintenance Therapy After Remission

Following successful induction, transition to maintenance therapy 1:

Rituximab (preferred) 1:

• MAINRITSAN protocol: 500 mg × 2 at complete remission, then 500 mg at months 6,12, and 18
• OR RITAZAREM protocol: 1000 mg at remission, then at months 4,8,12, and 16 1

Azathioprine (alternative) 1:

• 1.5-2 mg/kg/day at complete remission
• Continue for 1 year, then decrease by 25 mg every 3 months
• Extend to 4 years total duration for high-relapse-risk patients 1

Mycophenolate mofetil (second-line alternative) 1:

• 2000 mg/day in divided doses for 2 years
• Consider for azathioprine-intolerant patients
• Caveat: Higher relapse rates in PR3-ANCA positive patients; more effective in MPO-ANCA positive patients 7

Glucocorticoids during maintenance 1:

• Continue 5-7.5 mg/day prednisone for 2 years
• Then reduce by 1 mg every 2 months 1

Optimal maintenance duration: 18 months to 4 years after induction of remission 1

Adjunctive Therapies

Infection prophylaxis (mandatory) 1:

• Trimethoprim/sulfamethoxazole 800/160 mg on alternate days or 400/80 mg daily for all patients receiving cyclophosphamide
• Alternatives if contraindicated: dapsone or atovaquone 1

Cyclophosphamide-specific precautions 1:

• MESNA (2-mercaptoethanesulfonate sodium) to prevent hemorrhagic cystitis
• Encourage high fluid intake on infusion days
• Antiemetic therapy with IV cyclophosphamide 1

Refractory or Relapsing Disease

For treatment failure or relapse 1:

• Re-induce with rituximab (preferred) 1
• If cyclophosphamide was used initially, switch to rituximab, or vice versa 1
• Consider plasma exchange for severe refractory disease 1
• Increase glucocorticoids (IV or oral) as bridge therapy 1

Emerging options for refractory cases 2, 4:

• Intravenous immunoglobulin
• Plasmapheresis
• Biologic agents (infliximab, though evidence limited) 2

Monitoring Requirements

During induction 1:

• Complete blood count weekly initially, then biweekly
• Renal function and urinalysis regularly
• Dose adjustment or discontinuation for leucopenia <4000/μL

During maintenance 1:

• Monitor for relapse risk factors: PR3-ANCA positivity, upper respiratory tract involvement, persistent ANCA positivity 1
• Regular assessment for infection (most common serious adverse event) 8

Critical distinction: Cutaneous ANCA vasculitis with pan-dermal small-vessel and subcutaneous muscular-vessel involvement on biopsy suggests underlying systemic disease (connective tissue disease, malignancy-associated vasculitis, or Behçet disease) requiring more aggressive systemic therapy 2.