When is ANCA (antineutrophil cytoplasmic antibody) testing indicated for suspected ANCA‑associated vasculitis?

When to Order ANCA Testing

ANCA testing should be performed in all patients presenting with clinical features suggesting small-vessel vasculitis, including glomerulonephritis (hematuria with dysmorphic RBCs, red cell casts, proteinuria, rapidly declining GFR), pulmonary-renal syndrome, peripheral neuropathy, palpable purpura, or upper respiratory tract manifestations (chronic sinusitis, nasal crusting/bleeding, subglottic stenosis). 1, 2

Primary Clinical Indications

Renal Manifestations

• Rapidly progressive glomerulonephritis: Microscopic hematuria with dysmorphic red blood cells, red cell casts, moderate proteinuria (1-3 g/day), and rapidly declining GFR over days to weeks 1
• Acute kidney injury with serum creatinine >4 mg/dL (>354 μmol/L) requires urgent ANCA testing 2
• Approximately 90% of patients with small-vessel vasculitis or necrotizing crescentic glomerulonephritis have detectable ANCA 1

Pulmonary-Renal Syndrome

• Simultaneous lung and kidney injury with alveolar hemorrhage is a critical indication for immediate ANCA testing 1, 3
• This presentation affects 10% of AAV patients and carries increased mortality risk 3
• Testing should include both ANCA and anti-GBM antibodies, as positive anti-GBM requires urgent plasma exchange 1

Upper Respiratory Tract Disease

• Granulomatosis with polyangiitis (GPA): Persistent nasal bleeding, crusting, obstruction, septal perforation, chronic rhinosinusitis, or subglottic inflammation 1, 2
• In GPA limited to the sinonasal tract, ANCA can be negative (sensitivity drops to 50% in limited forms), making diagnosis challenging 1, 2
• PR3-ANCA is detected in 80-90% of GPA patients with systemic disease 1

Eosinophilic Granulomatosis with Polyangiitis (EGPA)

• ANCA testing should be performed in all patients with suspected EGPA 1
• Test when patients present with adult-onset asthma, chronic rhinosinusitis with eosinophilic nasal polyps, peripheral eosinophilia, and end-organ involvement (peripheral neuropathy, lung infiltrates, cardiomyopathy, purpura) 1, 2
• ANCA is detectable in only 30-40% of EGPA patients, with most being MPO-ANCA positive 1

Other Vasculitis Manifestations

• Peripheral neuropathy, particularly mononeuritis multiplex 2, 3
• Palpable purpura indicating dermal small-vessel vasculitis 2, 3
• Multi-organ involvement with constitutional symptoms and elevated inflammatory markers (CRP, ESR) 2, 3

Testing Methodology

Recommended Approach

• Use high-quality antigen-specific immunoassays (ELISA) for PR3-ANCA and MPO-ANCA as the primary screening method 1
• The 2017 international consensus statement recommends this approach over indirect immunofluorescence (IIF) alone 1
• If immunoassay is negative but clinical suspicion remains high, perform a second test (another immunoassay and/or IIF) 1

Combined Testing Strategy

• Both IIF and antigen-specific ELISA should be performed together for optimal diagnostic accuracy 2, 3
• C-ANCA pattern has 99% specificity with 73% sensitivity using combined IIF and ELISA for active systemic GPA 2
• Best diagnostic performance is obtained when IIF is combined with PR3 and MPO-specific ELISAs 4

Critical Clinical Caveats

ANCA-Negative Disease

• Approximately 10% of patients with true AAV are persistently ANCA-negative 1, 3
• ANCA negativity does not exclude AAV diagnosis 1
• These patients require compatible clinical features and typically tissue biopsy confirmation 2, 3
• ANCA-negative patients occur more frequently in EGPA (60-70% are ANCA-negative) 1

False Positives

• ANCA can be found in inflammatory bowel disease, autoimmune hepatitis, primary sclerosing cholangitis, rheumatoid arthritis, systemic lupus erythematosus, infections, and drug-induced conditions 1, 5
• Cocaine and levamisole (cocaine adulterant) can cause ANCA-positive vasculitis 1
• Diagnosis should never be made on ANCA serology alone - requires compatible clinical manifestations 1

When NOT to Delay Treatment

• If clinical presentation is compatible with small-vessel vasculitis and MPO-ANCA or PR3-ANCA is positive, do not delay immunosuppressive therapy while waiting for biopsy results, especially in rapidly deteriorating patients 1, 2
• This is particularly critical in pulmonary-renal syndrome or rapidly progressive glomerulonephritis 1, 2

When ANCA Testing Is NOT Essential

• Not essential at initial ENT/secondary care presentation for chronic rhinosinusitis with abnormal or normal endoscopy 1
• Should be considered only after failure of appropriate medical therapy for chronic rhinosinusitis 1
• Not indicated in isolated chronic rhinosinusitis without systemic features or treatment failure 1

Additional Diagnostic Considerations

Complementary Testing

• Anti-GBM antibodies should be tested in pulmonary-renal syndrome, as patients with anti-GBM/AAV overlap have lower renal survival 1
• Urinalysis with microscopy for dysmorphic RBCs and red cell casts is essential 2, 3
• Inflammatory markers (CRP, ESR), complete blood count, comprehensive metabolic panel 3

Tissue Biopsy

• Kidney biopsy has 91.5% diagnostic yield in GPA and provides prognostic information 1, 2
• Biopsy remains the gold standard, particularly in ANCA-negative cases with high clinical suspicion 1, 3
• In the context of positive MPO or PR3-ANCA with compatible clinical picture, immediate biopsy may not be necessary and should not delay treatment 1

Management Setting

• Patients with suspected or confirmed ANCA-associated vasculitis should be managed at centers with vasculitis expertise to ensure rapid diagnostic capabilities and appropriate treatment modalities 1, 2, 3