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

Treatment of ANCA-Positive Vasculitis

Initiate treatment immediately with glucocorticoids combined with either rituximab or cyclophosphamide—do not delay for kidney biopsy confirmation if clinical presentation and positive MPO- or PR3-ANCA serology are compatible with vasculitis. 1

Immediate Treatment Initiation

• Begin immunosuppressive therapy based on clinical presentation and positive ANCA serology alone, especially in rapidly deteriorating patients 1
• Treatment should be started without waiting for histologic confirmation when the clinical picture is consistent with ANCA-associated vasculitis 1
• Patients should ideally be managed at centers with experience in AAV management 1

Choosing the Induction Agent

The choice between rituximab and cyclophosphamide depends primarily on disease severity and renal function:

Use Cyclophosphamide When:

• Serum creatinine >4 mg/dL (>354 μmol/L) 1, 2
• Rapidly declining glomerular filtration rate requiring dialysis 1, 2
• Severe glomerulonephritis with significant renal impairment 2

Use Rituximab When:

• Serum creatinine <4 mg/dL (less severe renal disease) 1
• PR3-ANCA positivity (rituximab is preferred) 2
• Relapsing disease (rituximab achieves >90% remission rates by 4 months) 2

Consider Combination Therapy:

• For severe glomerulonephritis with serum creatinine >4 mg/dL, combining 2 intravenous pulses of cyclophosphamide with rituximab may be considered 2

Specific Immunosuppressive Dosing

Rituximab Dosing:

• Standard protocol: 375 mg/m² weekly for 4 weeks 3, 1
• Alternative protocol: 1,000 mg at weeks 0 and 2 1

Cyclophosphamide Dosing:

Intravenous route:

• 15 mg/kg at weeks 0,2,4,7,10,13 (additional doses at weeks 16,19,21,24 if required) 3, 1
• Age-based dose reductions: 12.5 mg/kg for age >60 years; 10 mg/kg for age >70 years 3
• Renal dose adjustment: Reduce by 2.5 mg/kg for GFR <30 ml/min/1.73 m² 3

Oral route:

• 2 mg/kg/day for 3 months, continue for ongoing activity to maximum of 6 months 3, 1
• Age-based dose reductions: 1.5 mg/kg/day for age >60 years; 1.0 mg/kg/day for age >70 years 3
• Renal dose adjustment: Reduce by 0.5 mg/kg/day for GFR <30 ml/min/1.73 m² 3

Glucocorticoid Regimen

Use the reduced-dose PEXIVAS protocol with weight-based tapering over 52 weeks: 1, 2

• 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

Glucocorticoid Alternative:

• Avacopan 30 mg twice daily may replace glucocorticoids in patients at high risk of glucocorticoid toxicity, particularly those with GFR <30 mL/min/1.73 m² or lower baseline GFR (who may benefit from greater GFR recovery) 3, 2

Adjunctive Plasma Exchange

Consider plasma exchange for: 3, 1

• Serum creatinine >3.4 mg/dL (>300 mmol/L) 3, 1
• Patients requiring dialysis or with rapidly increasing serum creatinine 3, 1
• Diffuse alveolar hemorrhage with hypoxemia 3, 1

Mandatory Supportive Care

Pneumocystis Prophylaxis:

• Trimethoprim-sulfamethoxazole is mandatory for all patients receiving cyclophosphamide or rituximab 1, 2
• Dosing: 800/160 mg on alternate days or 400/80 mg daily 1

Cyclophosphamide-Specific Measures:

• Antiemetic therapy should be routinely administered with intravenous cyclophosphamide 1
• High fluid intake or intravenous fluids on infusion day to prevent hemorrhagic cystitis 1

Bone Protection:

• Calcium, vitamin D, and bisphosphonates should be administered to all patients on glucocorticoids 2

Monitoring During Induction

• Complete blood count weekly during induction 2
• Adjust cyclophosphamide dose for leucopenia <4,000/μL 2
• Monitor ANCA levels, as persistence, increase, or conversion from negative to positive predicts relapse risk 2

Transition to Maintenance Therapy

After achieving remission (typically by 3-6 months), transition to maintenance therapy: 3

Preferred Maintenance Options:

• Rituximab (preferred agent) 2

  • MAINRITSAN scheme: 500 mg × 2 at complete remission, then 500 mg at months 6,12, and 18 3
  • RITAZAREM scheme: 1,000 mg after induction, then at months 4,8,12, and 16 3

• Azathioprine with low-dose glucocorticoids 3

  • 1.5-2 mg/kg/day at complete remission 3
  • Decrease by 25 mg every 3 months after 1 year 3

Maintenance Duration:

• 18 months to 4 years after induction of remission 3, 2
• Low-dose glucocorticoids (5-7.5 mg/day) should be continued for 2 years, then slowly reduced by 1 mg every 2 months 3

Alternative Maintenance Agents:

• Mycophenolate mofetil 2,000 mg/day (divided doses) for 2 years at complete remission 3
• Methotrexate (contraindicated if GFR <60 mL/min/1.73 m²) 3, 2

Critical Pitfalls to Avoid

• Never delay treatment waiting for biopsy results in patients with compatible clinical presentation and positive ANCA 1
• Do not use methotrexate if GFR <60 mL/min/1.73 m² 3, 2
• Do not discontinue maintenance therapy prematurely—minimum duration is 18 months 2
• In severe renal disease with serum creatinine >4 mg/dL, limited data support rituximab monotherapy; cyclophosphamide or combination therapy should be considered 2
• Patients with PR3-ANCA positivity have higher relapse risk and benefit from rituximab-based strategies 2

Management of Relapsing Disease

• Reinitiate induction therapy, preferably with rituximab 3, 2
• Rituximab achieves >90% remission rates by 4 months in relapsing GPA/MPA patients 2
• If cyclophosphamide was used initially, switch to rituximab for relapse; if rituximab was used, consider adding cyclophosphamide or plasma exchange 3