What does a positive test result for Anti-Neutrophil Cytoplasmic Antibodies (ANCA) indicate?

ANCA Antibodies Positive: Clinical Significance

A positive ANCA test primarily indicates ANCA-associated vasculitis (AAV), particularly granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), or eosinophilic granulomatosis with polyangiitis (EGPA), which are life-threatening systemic vasculitides requiring immediate immunosuppressive therapy. 1

Primary Disease Associations

ANCA-Associated Vasculitides (Most Important)

c-ANCA (PR3-ANCA) Pattern:

• Granulomatosis with polyangiitis (GPA): Present in 80-90% of active systemic disease, though sensitivity drops to 50% in limited forms or after corticosteroid therapy 1
• Microscopic polyangiitis (MPA): Found in 20-40% of cases 1
• Pauci-immune crescentic glomerulonephritis: Present in 20-40% 1
• EGPA: Detected in 35% of cases 1

p-ANCA (MPO-ANCA) Pattern:

• Microscopic polyangiitis: Most common association with MPO positivity in 35-40% of patients 2
• EGPA: Present in 35-77% of cases, particularly those with renal involvement 1, 2
• GPA: Approximately 5-10% of GPA cases show MPO-ANCA rather than typical PR3-ANCA 1, 2
• Pauci-immune necrotizing crescentic glomerulonephritis: Found in 20-40% 2

Critical Clinical Context

About 90% of patients with small-vessel vasculitis affecting the kidneys have ANCA directed against MPO or PR3, making this the diagnostic cornerstone. 3, 4 However, approximately 10% of true AAV patients are persistently ANCA-negative, requiring tissue biopsy for confirmation 4.

Key Clinical Manifestations Requiring ANCA Testing

Renal involvement (most critical):

• Microscopic hematuria with dysmorphic red blood cells and red cell casts 3, 2
• Moderate proteinuria (1-3 g/day) 3
• Rapidly declining GFR over days to weeks 3, 2

Respiratory tract involvement:

• Nasal crusting and bleeding, especially with disproportionate systemic unwellness 1
• Pulmonary nodules, infiltrates, or alveolar hemorrhage 3, 2
• Pulmonary-renal syndrome (10% of AAV patients, significantly increases mortality) 2, 4

Other manifestations:

• Peripheral neuropathy or mononeuritis multiplex 2, 4
• Palpable purpura indicating dermal small-vessel vasculitis 2, 4

Secondary Associations (Non-Vasculitic)

ANCA positivity can occur in other conditions, though with different clinical significance: 5, 6

• Inflammatory bowel disease (ulcerative colitis > Crohn's disease) 1, 5
• Autoimmune liver diseases (autoimmune hepatitis type 1) 5
• Rheumatoid arthritis 1, 6
• Systemic lupus erythematosus 6, 7
• Cystic fibrosis: 80% have atypical c-ANCA with BPI as target antigen 1
• Drug-induced vasculitis: Cocaine/levamisole can cause ANCA-positive vasculitis 1, 6
• Infections: Endocarditis with nephritis, chronic infections 5, 6
• Malignancies 6

Diagnostic Algorithm

When ANCA positivity is detected, proceed systematically:

1. Confirm with antigen-specific testing: High-quality antigen-specific immunoassays (ELISA) for both MPO-ANCA and PR3-ANCA are the gold standard, replacing indirect immunofluorescence 1, 3, 2

2. Assess for organ-threatening disease immediately:

   • Urinalysis with microscopy for dysmorphic RBCs and red cell casts 2, 4
   • Renal function (GFR) 2, 4
   • Chest imaging for pulmonary involvement 1
   • ESR and CRP (though 10% of AAV can have normal values) 4

3. Consider tissue biopsy: Kidney biopsy has 91.5% diagnostic yield in GPA and remains the gold standard 3, 2, 4

4. Do NOT delay treatment: The American College of Rheumatology recommends immediate initiation of remission induction therapy with rituximab or cyclophosphamide plus high-dose glucocorticoids in severe, organ-threatening disease without waiting for biopsy confirmation 3

Critical Pitfalls to Avoid

Negative ANCA does not exclude vasculitis: Sensitivity drops to 50% in limited GPA, after corticosteroid therapy, and 10-20% of WG/MPA patients are ANCA-negative 1, 7

Cocaine/levamisole mimics GPA: Both can present with midline nasal destruction and positive c-ANCA/PR3, requiring tissue cocaine levels and specific histopathologic features (massive apoptosis with caspase-3/9 expression) for differentiation 1

Delayed diagnosis is life-threatening: Diagnosis is often delayed by 6+ months, particularly with ENT symptoms (>8 months delay), rendering the condition potentially fatal 1

Prognostic Implications

MPO-ANCA versus PR3-ANCA has major treatment implications: MPO-ANCA patients have significantly lower relapse rates compared to PR3-ANCA patients, fundamentally altering maintenance therapy decisions 2. In MPO-AAV patients on dialysis without extrarenal manifestations, relapse risk is so low that maintenance immunosuppression risks may outweigh benefits 2.