What is the classification and treatment of Anti-Neutrophil Cytoplasmic Antibodies (ANCA) vasculitis?

ANCA Vasculitis Classification

Primary Classification Systems

ANCA-associated vasculitis (AAV) is classified using the Chapel Hill Consensus Conference (CHCC) definitions combined with ACR criteria, which categorize disease by vessel size, clinical phenotype, and ANCA serotype. 1

The three main subtypes of AAV are:

1. Granulomatosis with Polyangiitis (GPA)

• Characterized by necrotizing granulomatous inflammation plus vasculitis 1
• Predominantly affects small to medium vessels 1
• Most commonly associated with PR3-ANCA (proteinase-3) and cytoplasmic ANCA (C-ANCA) 1
• Classic manifestations include destructive sinonasal lesions, pulmonary nodules, and pauci-immune glomerulonephritis 1
• Prevalence: 24-157 cases per million in European populations 1

2. Microscopic Polyangiitis (MPA)

• Characterized by vasculitis without granulomatous inflammation 1
• Affects small vessels 1
• Most commonly associated with MPO-ANCA (myeloperoxidase) and perinuclear ANCA (P-ANCA) 1
• Classic manifestations include rapidly progressive pauci-immune glomerulonephritis and alveolar hemorrhage 1
• Prevalence: 0-66 cases per million in Europe, 86 cases per million in Japan 1

3. Eosinophilic Granulomatosis with Polyangiitis (EGPA)

• Characterized by eosinophilic tissue infiltration plus vasculitis 1
• Affects small to medium vessels 1
• Only 40% of patients are ANCA-positive 1
• Classic manifestations include asthma, peripheral eosinophilia, and peripheral neuropathy 1
• Prevalence: 2-38 cases per million in European populations 1

Disease Severity Classification (EUVAS Criteria)

AAV should be categorized by disease severity to guide treatment decisions: 1

• Localized: Upper and/or lower respiratory tract disease without systemic involvement or constitutional symptoms 1
• Early Systemic: Any systemic involvement without organ-threatening or life-threatening disease 1
• Generalized: Renal or other organ-threatening disease with serum creatinine <500 μmol/L (5.6 mg/dL) 1
• Severe: Renal or other vital organ failure with serum creatinine >500 μmol/L (5.6 mg/dL) 1
• Refractory: Progressive disease unresponsive to glucocorticoids and cyclophosphamide 1

Diagnostic Approach

Serologic Testing

• High-quality antigen-specific immunoassays for MPO-ANCA and PR3-ANCA are the preferred screening method 1
• Approximately 90% of patients with small-vessel vasculitis have detectable ANCA 1
• 10% of AAV patients are persistently ANCA-negative but are treated similarly to ANCA-positive patients 1

Histopathologic Confirmation

• Biopsy showing necrotizing vasculitis, granulomatous inflammation, or pauci-immune glomerulonephritis is the gold standard 1
• In patients with positive PR3-ANCA or MPO-ANCA and compatible clinical presentation, treatment should not be delayed waiting for biopsy results, especially in rapidly deteriorating patients 1
• Kidney biopsy diagnostic yield in GPA can be as high as 91.5% 1

Surrogate Markers (When Biopsy Unavailable)

The following support AAV diagnosis in ANCA-positive patients without confirmatory biopsy: 1

• Fixed pulmonary infiltrates, nodules, or cavitations
• Subglottic stenosis
• Retro-orbital granuloma
• Red cell casts or dysmorphic erythrocytes in urine
• Diffuse alveolar hemorrhage
• Mononeuritis multiplex
• Episcleritis

Treatment Framework

Severe/Generalized Disease (GPA/MPA)

Rituximab is conditionally recommended over cyclophosphamide for remission induction 1, 2

• Rituximab dosing: 375 mg/m² weekly for 4 weeks 3
• Combined with reduced-dose glucocorticoid regimen to minimize toxicity 2
• Pneumocystis jirovecii prophylaxis is mandatory 2

Remission Maintenance

Rituximab is the preferred agent for maintenance therapy after achieving remission 2

• Dosing: 500 mg every 6 months for 18 months 3

Non-Severe EGPA

Mepolizumab is recommended for non-severe EGPA 1

Critical Pitfalls to Avoid

• Do not delay treatment in ANCA-positive patients with compatible clinical presentation while awaiting biopsy, particularly in rapidly deteriorating patients 1
• Do not use ANCA subtype alone for classification—up to 30% of MPA patients are PR3-ANCA positive without typical GPA features 1
• Do not forget to exclude infections (especially bacterial endocarditis) and malignancies that can mimic AAV before intensifying immunosuppression 4
• Do not omit Pneumocystis jirovecii prophylaxis in patients receiving rituximab or high-dose immunosuppression 2, 4
• Patients should be managed at centers with AAV expertise, access to rapid ANCA testing, rituximab availability, plasma exchange capability, and intensive care/dialysis facilities 1