What are the most notable trials and treatment regimens for ANCA (Antineutrophil Cytoplasmic Antibody)-associated vasculitis?

Notable Trials and Treatment Regimens for ANCA-Associated Vasculitis

Glucocorticoids in combination with rituximab or cyclophosphamide are the cornerstone of initial treatment for ANCA-associated vasculitis, with rituximab being superior for relapsing disease, particularly in PR3-ANCA positive patients. 1

Key Induction Therapy Trials

RAVE Trial (Rituximab vs. Cyclophosphamide)

• Multicenter, randomized, double-blind trial comparing rituximab (375 mg/m² weekly for 4 weeks) to oral cyclophosphamide (2 mg/kg/day) 2
• Demonstrated rituximab was non-inferior to cyclophosphamide for remission induction
• Key finding: Rituximab was superior for relapsing disease with 67% achieving remission vs. 42% in the cyclophosphamide group (p=0.01) 1, 2
• Post-hoc analysis showed superior remission rates with rituximab in PR3-ANCA subgroup (OR 2.11; 95% CI: 1.04-4.30) 1

RITUXVAS Trial

• Compared rituximab plus two cyclophosphamide pulses to standard cyclophosphamide regimen in patients with renal involvement 3
• Similar sustained remission rates: 76% in rituximab group vs. 82% in control group
• Similar adverse event profiles between groups 3

CYCLOPS Trial

• Compared oral vs. intravenous cyclophosphamide administration 1
• IV cyclophosphamide resulted in lower total cyclophosphamide exposure
• Lower rate of leukopenia with IV regimen
• However, more relapses occurred with IV cyclophosphamide during long-term follow-up 1

LoVAS Trial

• Compared reduced-dose prednisolone (0.5 mg/kg/day) vs. high-dose prednisolone (1 mg/kg/day) with rituximab 4
• Reduced-dose glucocorticoids were non-inferior in achieving remission
• Significantly fewer serious adverse events (18.8% vs. 36.9%) and serious infections (7.2% vs. 20.0%) in the reduced-dose group 1, 4

MYCYC Trial

• Compared mycophenolate mofetil (MMF) to cyclophosphamide for induction 1
• Similar remission rates for both PR3-ANCA and MPO-ANCA patients
• However, much higher relapse risk with MMF in PR3-ANCA patients 1

Maintenance Therapy Trials

MAINRITSAN Trial

• Evaluated rituximab for maintenance therapy
• Rituximab dosing: 500 mg × 2 at complete remission, and 500 mg at months 6,12, and 18 1

RITAZAREM Trial

• Studied rituximab in relapsing GPA/MPA with high remission rates (>90% by 4 months)
• Rituximab dosing: 1000 mg infusion after remission induction, and at months 4,8,12, and 16 1

Novel Therapeutic Approaches

ADVOCATE Trial

• Evaluated avacopan (C5a receptor antagonist) as a glucocorticoid-sparing agent
• Avacopan (30 mg twice daily) was non-inferior to prednisolone for remission induction
• Post-hoc analysis showed earlier reduction in albuminuria and improved kidney function with avacopan, especially in patients with eGFR <20 ml/min/1.73m² 1

Treatment Algorithm Based on Disease Presentation

1. For new-onset disease:

   • First-line: Glucocorticoids + rituximab or cyclophosphamide 1
   • Consider rituximab for PR3-ANCA positive patients (superior outcomes) 1
   • Consider cyclophosphamide for severe kidney disease (SCr >4 mg/dl) due to limited data for rituximab in this setting 1

2. For relapsing disease:

   • Rituximab is preferred (superior outcomes, especially in PR3-ANCA positive patients) 1
   • Rituximab achieves remission in 64-72% of patients with relapsing/refractory disease 5, 6

3. For maintenance therapy:

   • Options include rituximab, azathioprine, or MMF 1
   • Rituximab preferred for PR3-ANCA positive patients and those with relapsing disease 1
   • Azathioprine (1.5-2 mg/kg/day) is an alternative, especially with low baseline IgG 1

Glucocorticoid Regimens

• Traditional high-dose: Prednisolone/prednisone 1 mg/kg/day (max 60-80 mg/day) 1, 7
• Reduced-dose option: Prednisolone 0.5 mg/kg/day with rituximab (non-inferior efficacy with fewer adverse events) 1, 4
• PEXIVAS trial demonstrated that more rapid glucocorticoid tapering was as effective but safer in patients with GFR <50 ml/min/1.73m² 1

Treatment of Refractory Disease

• Options include:
  • Increasing glucocorticoids (IV or oral)
  • Adding rituximab if cyclophosphamide was used initially, or vice versa
  • Consider plasma exchange, especially for diffuse alveolar hemorrhage with hypoxemia 1

Monitoring for Disease Activity and Relapse

• ANCA positivity, increasing ANCA levels, or conversion from negative to positive may predict relapse 1
• Return of hematuria after initial resolution may indicate kidney relapse 1
• Regular monitoring of inflammatory markers (e.g., CRP) and kidney function is essential 1

The treatment landscape for ANCA-associated vasculitis has evolved significantly with these landmark trials, moving from cyclophosphamide-based regimens toward more targeted therapies like rituximab, with improved safety profiles and comparable or superior efficacy.