When should a patient with suspected vasculitis and symptoms such as hematuria, proteinuria, or respiratory tract symptoms undergo ANCA (Antineutrophil Cytoplasmic Antibodies) testing?

When to Order ANCA Testing

ANCA testing should be performed immediately in any patient presenting with clinical features suggesting small or medium vessel vasculitis, particularly when there is evidence of multi-organ involvement such as hematuria with red cell casts, proteinuria, pulmonary infiltrates, palpable purpura, peripheral neuropathy, or upper respiratory tract symptoms (nasal crusting, epistaxis, sinusitis). 1

Clinical Contexts Requiring ANCA Testing

High-Priority Indications (Test Immediately)

• Renal manifestations: Microscopic hematuria with dysmorphic red blood cells, red cell casts, moderate proteinuria (1-3 g/day), or rapidly declining GFR over days to weeks 2, 3, 4

• Pulmonary-renal syndrome: Simultaneous lung and kidney injury with alveolar hemorrhage, which affects 10% of ANCA-associated vasculitis patients and significantly increases mortality risk 2

• Upper respiratory tract involvement: Nasal crusting and bleeding, chronic rhinosinusitis, especially when patients feel disproportionately unwell relative to their symptoms 1

• Neurologic manifestations: Mononeuritis multiplex or other peripheral neuropathy patterns 2

• Dermatologic findings: Palpable purpura indicating dermal small-vessel vasculitis 2

• Pulmonary nodules or infiltrates: Particularly when accompanied by constitutional symptoms 1, 2

Specific Disease Contexts

• Eosinophilic granulomatosis with polyangiitis (EGPA) suspicion: Test in patients with asthma, chronic rhinosinusitis, and eosinophilia who develop end-organ involvement, particularly peripheral neuropathy, lung infiltrates, cardiomyopathy, or other complications 1

• Anti-GBM disease: ANCA testing is recommended in all patients with anti-glomerular basement membrane disease 5

• Idiopathic interstitial pneumonia: ANCA should be tested when this diagnosis is being considered 5

• Infective endocarditis with nephritis: Approximately 10% of patients with infective endocarditis develop ANCA, making testing relevant in this context 6, 5

Testing Methodology

Both indirect immunofluorescence (IIF) and antigen-specific immunoassays (ELISA for PR3-ANCA and MPO-ANCA) should be performed together for optimal diagnostic accuracy. 1

• High-quality antigen-specific immunoassays are increasingly replacing IIF as the primary screening method when new-onset vasculitis is suspected, as they provide superior sensitivity and specificity 2, 7

• The c-ANCA pattern is 99% specific with 73% sensitivity using combined IIF and ELISA techniques for active systemic granulomatosis with polyangiitis, though sensitivity drops to 50% in limited forms or after corticosteroid therapy 1, 8

• When one assay is negative but clinical suspicion remains high, testing should be repeated using a different assay methodology 7

Critical Timing Considerations

Do not delay ANCA testing when clinical suspicion is high, and do not wait for biopsy results before initiating treatment in severe, organ-threatening disease with compatible clinical features and positive ANCA. 3

• The combination of upper respiratory tract involvement, lower respiratory tract disease, palpable purpura, constitutional symptoms, positive ANCA, and glomerulonephritis with RBC casts is diagnostic for severe granulomatosis with polyangiitis 3

• Approximately 90% of patients with small-vessel vasculitis have ANCA directed against MPO or PR3, and a positive test with compatible clinical features is sufficient to begin treatment 2, 3, 4

• Kidney biopsy has a diagnostic yield of 91.5% in granulomatosis with polyangiitis but should not delay treatment initiation when clinical presentation strongly suggests ANCA-associated vasculitis 2, 3

Common Pitfalls to Avoid

• False positives occur: ANCA can be positive in drug-induced vasculitis (particularly levamisole-adulterated cocaine), infective endocarditis, autoimmune liver diseases, and inflammatory bowel diseases 6, 5

• ANCA-negative vasculitis exists: Approximately 10% of true ANCA-associated vasculitis patients are persistently ANCA-negative, requiring compatible clinical features and typically tissue biopsy confirmation 2

• Context matters: Routine ANCA testing is not recommended in patients with connective tissue diseases, malignancy, or during drug treatment unless specific vasculitis features are present 5

• Delayed diagnosis in ENT presentations: Patients presenting with eye symptoms have diagnostic delays exceeding 14 months, while ENT symptoms are associated with delays over 8 months, despite over half seeing an ENT surgeon prior to diagnosis 1