What is the initial treatment for a patient with small vessel vasculitis?

Treatment for Small Vessel Vasculitis

Immediate combination therapy with high-dose glucocorticoids (prednisolone 1 mg/kg/day, maximum 60 mg/day) plus either cyclophosphamide (2 mg/kg/day oral or IV pulses) or rituximab (375 mg/m² weekly for 4 weeks) is the standard initial treatment for small vessel vasculitis, with treatment selection based on disease severity and organ involvement. 1, 2

Disease Categorization Guides Treatment Intensity

Before initiating therapy, categorize ANCA-associated vasculitis by severity using the EUVAS classification system: 3, 1

• Localized: Upper/lower respiratory tract disease without systemic involvement
• Early systemic: Any manifestations without organ-threatening disease
• Generalized: Renal or organ-threatening disease (creatinine <500 μmol/L)
• Severe: Renal or vital organ failure (creatinine >500 μmol/L)
• Refractory: Progressive disease unresponsive to standard therapy

Induction Therapy by Disease Severity

Generalized or Severe Disease (Organ-Threatening)

Cyclophosphamide plus glucocorticoids remains the cornerstone for severe disease: 3, 1

• Cyclophosphamide: 2 mg/kg/day oral (maximum 200 mg/day) OR intravenous pulses 3, 2
• Prednisolone: 1 mg/kg/day (maximum 60 mg/day), maintained at high dose for 1 month, then tapered to ≥15 mg/day for first 3 months 3, 1
• IV methylprednisolone pulses may be added when rapid effect is needed 3

Rituximab is equally effective and preferred in specific circumstances: 1, 2

• Dose: 375 mg/m² weekly for 4 weeks 1, 4
• Achieves 64% complete remission at 6 months, non-inferior to cyclophosphamide 1, 4
• Preferred for: relapsing disease (67% vs 42% remission with cyclophosphamide), younger patients with fertility concerns, or cyclophosphamide intolerance 1, 2

Early Systemic or Non-Organ-Threatening Disease

Methotrexate plus glucocorticoids offers a less toxic alternative: 3, 1

• Methotrexate: Start 15 mg/week, escalate to 20-25 mg/week over 1-2 months (oral or parenteral) 3
• Prednisolone: Same dosing as above (1 mg/kg/day) 3
• Takes longer to achieve remission compared to cyclophosphamide, particularly with pulmonary involvement 3
• Contraindicated if GFR <60 mL/min/1.73 m² 2

Essential Adjunctive Therapies

Mandatory Prophylaxis

Pneumocystis jiroveci prophylaxis is required for all patients receiving cyclophosphamide: 3, 1

• Trimethoprim/sulfamethoxazole 800/160 mg on alternate days OR 400/80 mg daily 3, 1
• Pentamidine if contraindication exists, though less cost-effective 3

Mesna (2-mercaptoethanesulfonate sodium) for bladder protection: 3, 1

• Binds toxic acrolein metabolite from cyclophosphamide 3
• Given with pulse cyclophosphamide; may benefit continuous oral therapy 3
• Critical caveat: Tobacco smokers develop bladder cancer at lower cyclophosphamide doses and earlier than non-smokers 2

Osteoporosis prophylaxis per local guidelines for all patients on long-term glucocorticoids 3, 5

Plasma Exchange for Severe Renal Disease

Add plasma exchange for patients with: 3

• Serum creatinine >500 μmol/L (5.65 mg/dL) 3
• Dialysis requirement 1
• Diffuse alveolar hemorrhage with hypoxemia 1

This improves renal survival in severe renal disease 3

Transition to Maintenance Therapy

Once remission is achieved (typically 3-6 months), transition to maintenance therapy: 1, 2

• Glucocorticoids: Taper to 5-7.5 mg/day for 2 years, then reduce by 1 mg every 2 months 1, 2
• First-line maintenance agent - Azathioprine: 1.5-2 mg/kg/day for 18-24 months, then decrease to 1 mg/kg/day until 4 years after diagnosis 1, 5
• Alternative maintenance options: Rituximab (500 mg at remission and months 6,12,18), mycophenolate mofetil, methotrexate, or leflunomide 1, 5, 2

Minimum maintenance duration is 18-24 months, with extended therapy to 4 years reducing relapse risk 2

Management of Refractory Disease

For patients failing standard therapy or experiencing relapse: 1, 2

• Rituximab achieves 91% remission rate in refractory ANCA-associated vasculitis 1, 2
• Intravenous immunoglobulin (IVIG) 2 gm/kg for short-term control 1, 2
  • Critical safety measure: Check serum immunoglobulin levels first due to anaphylaxis risk in IgA deficiency 1

Monitoring Requirements

At every clinical visit perform: 1, 5

• Structured clinical assessment using validated tools (Birmingham Vasculitis Activity Score) 2
• Urinalysis with microscopy 2
• Basic laboratory tests: CBC, comprehensive metabolic panel, ESR, CRP 2

Investigate persistent unexplained hematuria immediately in all patients with prior cyclophosphamide exposure due to bladder cancer risk, which can occur months to years after treatment 1, 5, 2

Critical Pitfalls to Avoid

Do not delay treatment while awaiting biopsy results in rapidly deteriorating patients with positive ANCA serology 2

Avoid alternate-day glucocorticoid therapy, which increases relapse risk 2

Recognize relapse predictors to guide monitoring intensity: 6

• Anti-PR3 antibody positivity (hazard ratio 1.87) 6
• Lung involvement (hazard ratio 1.71) 6
• Upper respiratory tract disease (hazard ratio 1.73) 6
• Patients with all 3 risk factors have 73% relapse rate vs 26% with none 6

Treatment resistance is more common in: 6

• Female patients 6
• Black ethnicity 6
• Severe kidney disease at presentation (odds ratio 1.28 per 100 μmol/L creatinine elevation) 6

The mortality stakes are high: Untreated systemic vasculitis carries 40-46% five-year mortality in patients with poor prognostic factors, making delays in proven immunosuppressive therapy potentially fatal 1, 5