What is the recommended treatment approach for vasculitis in relation to the Advocate trial?

Treatment Approach for ANCA-Associated Vasculitis Based on the ADVOCATE Trial

Based on the ADVOCATE trial, avacopan should be considered as an adjunctive therapy to rituximab or cyclophosphamide for ANCA-associated vasculitis, particularly for patients who would benefit from reduced glucocorticoid exposure. 1

Current Standard Treatment Approach

The management of ANCA-associated vasculitis (AAV) follows a two-phase approach:

Remission Induction Phase

• First-line therapy: Combination of glucocorticoids with either:

  • Cyclophosphamide OR
  • Rituximab 2

• For organ-threatening or life-threatening disease:

  • Rituximab 375 mg/m² weekly for 4 weeks OR
  • Cyclophosphamide (oral or IV) 2, 3

• For non-organ-threatening disease:

  • Methotrexate (20-25 mg/week) OR
  • Mycophenolate mofetil 2

Maintenance Phase

• Preferred agents:

  • Azathioprine (first choice)
  • Rituximab
  • Methotrexate
  • Mycophenolate mofetil 2

• Duration: Minimum 24 months following sustained remission 2

The ADVOCATE Trial and Avacopan

The ADVOCATE trial evaluated avacopan (C5a receptor inhibitor) as a potential glucocorticoid-sparing agent in AAV treatment:

• Key findings:

  • Avacopan (30mg twice daily) was non-inferior to standard prednisone taper for remission at week 26 (72.3% vs 70.1%)
  • Avacopan was superior to prednisone for sustained remission at week 52 (65.7% vs 54.9%, p=0.007) 1, 4
  • Similar rates of serious adverse events between groups (37.3% with avacopan vs 39.0% with prednisone) 1

• Clinical implications:

  • Avacopan can potentially reduce or eliminate the need for high-dose glucocorticoids
  • Particularly beneficial for patients at high risk for glucocorticoid toxicity
  • May improve kidney function recovery in patients with low GFR (<30 ml/min/1.73m²) 2, 4

Treatment Algorithm Based on ADVOCATE Trial

1. Initial assessment:

   • Confirm diagnosis with ANCA testing and biopsy when possible
   • Assess disease severity and organ involvement
   • Evaluate risk factors for glucocorticoid toxicity 5

2. For severe/organ-threatening disease:

   • Standard approach: Rituximab OR cyclophosphamide + high-dose glucocorticoids
   • ADVOCATE-based approach: Rituximab OR cyclophosphamide + avacopan with reduced-dose or no glucocorticoids 2, 1

3. For patients with renal involvement:

   • Consider avacopan particularly for those with GFR <30 ml/min/1.73m² 2
   • For severe renal disease (SCr >3.4 mg/dl or rapidly increasing), consider plasma exchange 2

4. For diffuse alveolar hemorrhage:

   • Avacopan may be beneficial as adjunctive therapy with standard treatment
   • Consider plasma exchange for cases with hypoxemia 2, 6

Monitoring and Follow-up

• Regular assessment of disease activity using Birmingham Vasculitis Activity Score
• Monitor renal function, urinalysis, inflammatory markers, and ANCA levels
• Vigilance for treatment complications, especially infections 5
• Assess for comorbidities following remission induction 2

Caveats and Considerations

• The ADVOCATE trial did not address safety and efficacy beyond 52 weeks 1
• Access to avacopan may be limited in some regions 6
• Optimal glucocorticoid tapering regimen when using avacopan remains to be established 6
• Patients with AAV should be managed in centers with experience in vasculitis 2, 5

Special Populations

• For younger patients or those with fertility concerns, rituximab is preferred over cyclophosphamide 5
• For relapsing disease, consider switching from cyclophosphamide to rituximab or vice versa 2

The ADVOCATE trial represents a significant advancement in AAV treatment by demonstrating that avacopan can effectively reduce glucocorticoid exposure while maintaining or improving outcomes, particularly for sustained remission at one year.