What is the initial treatment for a patient with ANCA (Antineutrophil Cytoplasmic Antibody)-associated vasculitis?

Initial Treatment for ANCA-Associated Vasculitis

The initial treatment for ANCA-associated vasculitis is glucocorticoids combined with either rituximab or cyclophosphamide, and treatment should be initiated immediately without waiting for kidney biopsy confirmation if the clinical presentation and positive MPO- or PR3-ANCA serology are compatible with vasculitis. 1

Immediate Treatment Initiation

• Do not delay immunosuppressive therapy while awaiting kidney biopsy results in patients with clinical presentation compatible with small-vessel vasculitis and positive ANCA serology, especially in those who are rapidly deteriorating 1
• Treatment should begin based on clinical presentation and positive MPO- or PR3-ANCA serology alone 1
• Patients should ideally be managed at centers with experience in AAV management 1

Choosing Between Rituximab and Cyclophosphamide

The 2024 KDIGO guidelines provide the most current evidence-based approach for selecting initial therapy:

For severe renal impairment:

• Cyclophosphamide is strongly preferred when serum creatinine >4 mg/dL (>354 μmol/L) 1
• Cyclophosphamide is also preferred for rapidly declining glomerular filtration rate or patients requiring dialysis 1
• In this setting, consider combining 2 intravenous pulses of cyclophosphamide with rituximab 1

For less severe disease:

• Rituximab is equally effective when serum creatinine <4 mg/dL 1
• Rituximab may be preferred in relapsing disease based on superior responses in this population 2

Glucocorticoid Regimen

The 2024 KDIGO guidelines support reduced glucocorticoid dosing based on the PEXIVAS trial, which demonstrated that lower cumulative doses (40% of standard at 6 months) reduced serious infections without compromising efficacy 1:

Weight-based tapering schedule:

• Week 1: 50 mg (<50 kg), 60 mg (50-75 kg), 75 mg (>75 kg) 1
• Week 2: 25 mg (<50 kg), 30 mg (50-75 kg), 40 mg (>75 kg) 1
• Weeks 3-4: 20 mg (<50 kg), 25 mg (50-75 kg), 30 mg (>75 kg) 1
• Continue tapering to 5 mg daily by weeks 19-20, then maintain 5 mg through week 52 1

For severe presentations:

• Initial pulse intravenous methylprednisolone 500-1000 mg/day for 1-3 days can be administered 3, 4

Specific Immunosuppressive Dosing

Rituximab options:

• 375 mg/m² weekly for 4 weeks, OR 1, 4
• 1 g at weeks 0 and 2 1

Cyclophosphamide options:

• Intravenous: 15 mg/kg at weeks 0,2,4,7,10,13 1, 3
  • Dose reduction required for age >60 years or GFR <30 mL/min/1.73 m² 3
• Oral: 2 mg/kg/day (maximum 200 mg/day) for 3-6 months 1

Route selection considerations:

• Intravenous preferred for patients with lower white blood cell counts, ready access to infusion centers, or adherence concerns 1
• Oral preferred when cost is a factor or infusion access is limited 1

Mandatory Supportive Measures

Pneumocystis jirovecii prophylaxis is mandatory:

• Trimethoprim-sulfamethoxazole 800/160 mg on alternate days OR 400/80 mg daily 3, 5, 6
• Required for all patients receiving cyclophosphamide or rituximab 3, 5, 6

For cyclophosphamide administration:

• Antiemetic therapy should be routinely administered with intravenous cyclophosphamide 3
• High fluid intake or intravenous fluids on infusion days to prevent hemorrhagic cystitis 3

Adjunctive Plasma Exchange

The 2022 BMJ guidelines and PEXIVAS trial showed that plasma exchange did not reduce the composite outcome of death or end-stage kidney disease in severe AAV 1:

• Conditionally recommended against routine use 1
• Consider for specific high-risk scenarios: diffuse alveolar hemorrhage with hypoxemia, serum creatinine >3.4 mg/dL, or patients requiring dialysis 3, 5

Monitoring Strategy

• Regular assessment of renal function, urinalysis, inflammatory markers, and ANCA levels for disease activity monitoring 3, 5
• ANCA positivity, increasing ANCA levels, or conversion from negative to positive may predict future relapse and should inform treatment decisions 1

Transition to Maintenance Therapy

• After achieving remission, transition from cyclophosphamide to less toxic maintenance agents 3, 5
• Maintenance options: rituximab, azathioprine, methotrexate, or mycophenolate mofetil 3, 5
• Rituximab is preferred for relapsing disease due to lower cumulative toxicity 5

Common Pitfalls to Avoid

• Do not wait for biopsy confirmation in rapidly deteriorating patients with compatible clinical presentation and positive ANCA serology 1
• Do not use standard high-dose glucocorticoids when reduced-dose regimens have equivalent efficacy with fewer serious infections 1, 7
• Do not forget Pneumocystis prophylaxis, as serious infections are a major cause of morbidity and mortality 3, 5, 8
• Do not use rituximab monotherapy in severe renal impairment (creatinine >4 mg/dL) without considering cyclophosphamide or combination therapy 1