What is the recommended treatment regimen for vasculitis?

Treatment for Vasculitis

For ANCA-associated vasculitis, immediate combination therapy with high-dose glucocorticoids (prednisolone 1 mg/kg/day, maximum 60 mg) plus either rituximab (375 mg/m² weekly × 4 weeks) or cyclophosphamide (2 mg/kg/day oral or 15 mg/kg IV pulses) is the standard of care, with treatment selection based on disease severity, renal function, and patient-specific factors. 1, 2

Disease Severity Classification

Before initiating treatment, categorize ANCA-associated vasculitis by severity to guide therapy intensity 1:

• Localized disease: Upper/lower respiratory tract involvement without systemic symptoms 1
• Early systemic: Systemic involvement without organ-threatening features 1
• Generalized: Renal or organ-threatening disease with creatinine <500 μmol/L (5.6 mg/dL) 1
• Severe: Vital organ failure or creatinine >500 μmol/L (5.6 mg/dL) 1
• Refractory: Progressive disease despite glucocorticoids and cyclophosphamide 1

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

Induction Therapy for Severe/Generalized Disease

Glucocorticoid Dosing

Start prednisolone at 1 mg/kg/day (maximum 60 mg/day) immediately upon diagnosis. 1, 2

• Maintain high-dose for 1 month minimum before tapering 1
• Do not reduce below 15 mg/day for the first 3 months 1
• Taper to maintenance dose of 5-7.5 mg/day by 6 months 1
• Never use alternate-day glucocorticoid therapy—this significantly increases relapse risk 1, 2

For patients requiring rapid effect, add IV methylprednisolone 500-1000 mg/day for 3-5 days 1. Recent evidence suggests lower doses (250 mg) may be equally effective with fewer infections, though this remains controversial 3, 4.

Immunosuppressive Agent Selection

Choose between rituximab and cyclophosphamide based on these factors 1, 2:

Favor rituximab when:

• Relapsing disease (67% vs 42% remission rate compared to cyclophosphamide) 2, 5
• Younger patients concerned about fertility 1, 2
• PR3-ANCA positivity (higher relapse risk) 1

Favor cyclophosphamide when:

• Severe renal disease (creatinine >3.4 mg/dL or dialysis requirement) 1, 2
• Rapidly progressive renal failure 1
• Diffuse alveolar hemorrhage with hypoxemia 1

Specific Dosing Regimens

Rituximab: 1, 5

• 375 mg/m² IV weekly × 4 weeks, OR
• 1000 mg IV on days 1 and 15

Cyclophosphamide: 1

• Oral: 2 mg/kg/day for 3-6 months (reduce to 1.5 mg/kg/day if age >60 years; 1.0 mg/kg/day if age >70 years)
• IV pulses: 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)
• Reduce dose by 0.5 mg/kg/day (oral) or 2.5 mg/kg (IV) if GFR <30 mL/min/1.73 m² 1

For the most severe disease (dialysis-dependent, rapidly progressive renal failure, or severe pulmonary hemorrhage), consider combination rituximab plus cyclophosphamide. 1, 2

Induction Therapy for Non-Severe Disease

For early systemic or non-organ threatening disease, use methotrexate 20-25 mg/week (oral or parenteral) plus glucocorticoids as a less toxic alternative. 1

• Start at 15 mg/week and escalate to 20-25 mg/week over 1-2 months 1
• Do not use methotrexate if GFR <60 mL/min/1.73 m² 1, 2
• Supplement with folic acid 5 mg weekly 1
• May take longer to achieve remission compared to cyclophosphamide, especially with pulmonary involvement 1

Adjunctive Therapies

Plasma Exchange

Add plasma exchange (7 exchanges over 14 days) for patients with: 1

• Serum creatinine >3.4 mg/dL (>300 μmol/L) 1
• Dialysis requirement 1
• Rapidly increasing creatinine 1
• Diffuse alveolar hemorrhage with hypoxemia 1

Plasma exchange improves renal survival in severe renal disease 1.

Avacopan

Avacopan 30 mg twice daily can replace glucocorticoids in combination with rituximab or cyclophosphamide. 1

• Particularly beneficial for patients at high risk of glucocorticoid toxicity 1
• May provide greater GFR recovery in patients with lower baseline GFR 1

Mandatory Prophylaxis

All patients receiving cyclophosphamide must receive: 1

• Pneumocystis jiroveci prophylaxis: Trimethoprim-sulfamethoxazole 800/160 mg on alternate days or 400/80 mg daily (use pentamidine if contraindicated) 1
• Mesna (oral or IV) to prevent hemorrhagic cystitis by binding toxic acrolein metabolites 1
• Bone protection: Calcium, vitamin D, and bisphosphonates for glucocorticoid-induced osteoporosis 1, 2

Maintenance Therapy

Once remission is achieved (typically by 3-6 months), transition to maintenance therapy with rituximab OR azathioprine plus low-dose glucocorticoids. 1, 2

Maintenance Options

Rituximab (preferred for relapsing disease): 1, 5

• 500 mg IV every 6 months (MAINRITSAN protocol), OR
• 1000 mg IV every 4 months (RITAZAREM protocol)
• Reduces major relapse rate to 5% vs 29% with azathioprine 5

Azathioprine (first-line with strongest evidence): 1, 2

• 1.5-2 mg/kg/day for 18-24 months
• Then reduce to 1 mg/kg/day until 4 years after diagnosis
• Taper by 25 mg every 3 months thereafter 1

Alternative agents if azathioprine not tolerated: 1, 2

• Mycophenolate mofetil 2000 mg/day (divided doses) 1
• Methotrexate 20-25 mg/week (only if GFR >60 mL/min/1.73 m²) 1, 2

Glucocorticoid maintenance: 1, 2

• Continue at 5-7.5 mg/day for at least 18-24 months 1, 2
• Reduce by 1 mg every 2 months after 2 years 2

Duration of Maintenance Therapy

Continue maintenance therapy for minimum 18-24 months, with extended therapy to 4 years reducing relapse risk. 1, 2

Factors favoring extended maintenance (up to 4 years) 1:

• PR3-ANCA positivity
• Relapsing disease
• Persistent ANCA positivity or rising titers
• Pulmonary involvement

Refractory Disease

For patients failing standard therapy or experiencing relapse, rituximab achieves 91% remission rate in refractory AAV. 2, 5

Additional options for refractory disease 2:

• IV immunoglobulin (IVIG) 2 g/kg for short-term control (measure serum immunoglobulin first—risk of anaphylaxis in IgA deficiency)
• Increase immunosuppression intensity
• Consider experimental therapies in consultation with vasculitis centers

Monitoring Requirements

At every clinical visit, perform: 2

• Structured clinical assessment using Birmingham Vasculitis Activity Score (BVAS) 2
• Urinalysis with microscopy 2
• Complete metabolic panel, CBC 2
• ESR and CRP 2

For cyclophosphamide monitoring: 1

• CBC weekly initially, then every 2 weeks
• Dose adjustment or discontinuation if acute leukopenia or gradual decline occurs 1
• Investigate persistent unexplained hematuria in all patients with prior cyclophosphamide exposure due to bladder cancer risk 2

ANCA monitoring: 2

• Persistence, increase, or conversion from negative to positive may predict relapse 2
• Use to inform treatment decisions, particularly regarding maintenance duration 2

Critical Pitfalls to Avoid

• Never delay treatment awaiting biopsy in rapidly deteriorating patients 2
• Never use alternate-day glucocorticoid therapy 1, 2
• Never use methotrexate with GFR <60 mL/min/1.73 m² 1, 2
• Never omit Pneumocystis prophylaxis with cyclophosphamide 1
• Tobacco smokers on cyclophosphamide develop bladder cancer at lower doses and earlier than non-smokers—counsel smoking cessation aggressively 2
• Never provide inadequate initial immunosuppression in severe disease—this increases mortality risk 2

Special Populations

Pediatric patients (2-17 years): 5

• Rituximab 375 mg/m² IV weekly × 4 weeks
• IV methylprednisolone 30 mg/kg/day (maximum 1 g/day) × 3 doses before first rituximab infusion
• Oral prednisolone 1 mg/kg/day (maximum 60 mg/day) tapered to 0.2 mg/kg/day by month 6

Patients should be treated at centers with AAV management experience, particularly for severe or refractory disease. 2