What is the management approach for patients with Behcet's disease who test positive for cytoplasmic anti-neutrophil cytoplasmic antibodies (c-ANCA)?

Management of Behçet's Disease with Positive c-ANCA

Patients with Behçet's disease who test positive for c-ANCA should be treated according to ANCA-associated vasculitis protocols with a combination of glucocorticoids and either cyclophosphamide or rituximab for remission induction, followed by maintenance therapy with azathioprine, rituximab, methotrexate, or mycophenolate mofetil.

Understanding c-ANCA in Behçet's Disease

• c-ANCA positivity in Behçet's disease is uncommon but significant, as it may indicate:
  • Overlap with ANCA-associated vasculitis (AAV) 1
  • Higher risk of vascular involvement, particularly in upper extremities and visceral arteries 2
  • Potential for pauci-immune glomerulonephritis 3, 4

Diagnostic Approach

1. Confirm the diagnosis:

   • Biopsy of affected tissue is strongly recommended to establish diagnosis 5, 1
   • Test for both PR3-ANCA and MPO-ANCA using high-quality antigen-specific assays 1
   • Perform comprehensive organ assessment to determine extent of involvement

2. Disease activity assessment:

   • Use validated tools like Birmingham Vasculitis Activity Score (BVAS) 1
   • Classify disease as organ-threatening/life-threatening or non-organ-threatening 5
   • Evaluate for specific organ involvement, particularly renal and vascular manifestations

Treatment Algorithm

For Organ-Threatening or Life-Threatening Disease:

1. Remission Induction:

   • Combination of glucocorticoids and either cyclophosphamide OR rituximab 5
   • Glucocorticoids: High-dose prednisone 1 mg/kg/day or IV pulse 1
   • Cyclophosphamide: 2 mg/kg/day oral or intermittent IV 1
   • Rituximab: 375 mg/m² IV weekly for 4 doses or 1,000 mg on days 1 and 15 1
   • Duration: Typically 3-6 months until remission is achieved

2. For patients with severe renal involvement:

   • Consider plasma exchange for patients with serum creatinine ≥500 mmol/L (5.7 mg/dL) due to rapidly progressive glomerulonephritis 5
   • Plasma exchange may also be considered for severe diffuse alveolar hemorrhage 5

For Non-Organ-Threatening Disease:

• Combination of glucocorticoids and either methotrexate or mycophenolate mofetil 5

Maintenance Therapy:

• Continue treatment with low-dose glucocorticoids and either azathioprine, rituximab, methotrexate, or mycophenolate mofetil 5
• Maintain therapy for at least 24 months following induction of sustained remission 5

Monitoring and Follow-up

1. Regular clinical assessment:

   • Structured clinical assessment rather than ANCA testing should guide treatment decisions 5
   • Monitor for disease activity using validated tools (BVAS, VDI) 1
   • Perform urinalysis at each visit to screen for infection, renal relapse, or bladder complications 5

2. Laboratory monitoring:

   • Inflammatory markers and renal function: Every 1-3 months 5
   • Complete blood count and liver function: Similar intervals to screen for drug toxicity 5
   • Immunoglobulin levels: Prior to each course of rituximab and in patients with recurrent infection 5

3. Prophylaxis:

   • Provide Pneumocystis jirovecii pneumonia prophylaxis for patients receiving rituximab or cyclophosphamide 5

Special Considerations

• Refractory disease: For patients not responding to initial therapy, switch from cyclophosphamide to rituximab or vice versa 5
• Cardiovascular risk: Perform periodic assessment of cardiovascular risk 5
• Bladder cancer surveillance: Investigate persistent unexplained hematuria, especially in patients with prior cyclophosphamide exposure 5
• Renal transplantation: Can be considered in end-stage renal disease with good outcomes reported 3

Important Caveats

• Do not base treatment decisions on ANCA titer results alone 5
• Do not delay treatment while waiting for biopsy results in ANCA-positive patients with compatible clinical presentation, especially in rapidly deteriorating patients 1
• Patients with Behçet's disease and c-ANCA positivity should be managed in close collaboration with, or at, centers of expertise in vasculitis 5