Classification: Three Phenotypes
ANCA-associated vasculitis (AAV) accounts for ~50% of pulmonary-renal syndrome cases. Three clinically and serologically distinct entities:
| Phenotype | ANCA Type | Associated Antigen | Prevalence | Key Features |
|---|---|---|---|---|
| GPA (Granulomatosis with Polyangiitis, formerly Wegener granulomatosis) | c-ANCA | Proteinase-3 (PR3) | 40-50% of AAV | Upper resp tract granulomas, pulmonary nodules, necrotizing GN |
| MPA (Microscopic Polyangiitis) | p-ANCA | Myeloperoxidase (MPO) | 40-50% of AAV | Pulmonary-renal syndrome, minimal extrapulmonary involvement, necrotizing GN |
| EGPA (Eosinophilic Granulomatosis with Polyangiitis, formerly Churg-Strauss) | p-ANCA (50%) | MPO or ANCA-negative | 10-15% of AAV | Asthma, eosinophilia, cardiac/GI involvement, later-onset vasculitis |
Serology-pathology mismatch: Don’t diagnose by serology alone. Biopsy remains gold standard. ~10% of confirmed AAV are ANCA-negative (especially EGPA).
Epidemiology & Presentation
Age & Demographics
- Peak incidence: 50-70 years old
- GPA: Slightly younger, more common in Whites
- MPA: Slightly older, no racial predominance
- EGPA: Most common in 40-50 year-olds
ANCA-Associated Vasculitis Clinical Spectrum
GPA (Granulomatosis with Polyangiitis) - Upper respiratory tract (90%): Sinusitis, nasal granulomas, saddle nose deformity - Lungs (85%): Nodules (often cavitary), infiltrates, hemoptysis - Kidneys (80%): RPGN, hematuria, RBC casts - Other: Eyes (scleritis), skin (palpable purpura), joints (arthritis), CNS (rare)
MPA (Microscopic Polyangiitis) - NO upper respiratory involvement (distinguishes from GPA) - Lungs (85%): Pulmonary hemorrhage (hemoptysis, pulmonary edema) - Kidneys (100%): RPGN (diagnostic hallmark) - Skin (40%): Palpable purpura, necrotizing vasculitis - GI (20%): Abdominal pain, bleeding - Systemic: Constitutional symptoms (fever, weight loss, arthralgia)
EGPA (Eosinophilic Granulomatosis with Polyangiitis) - Prodrome: Asthma (>90%), usually 5-10 years before vasculitis - Eosinophilia: Marked peripheral eosinophilia (>1.5 × 10⁹/L) diagnostic - Cardiac (50%): Myocarditis, pericarditis, heart failure - GI (60%): Abdominal pain, ischemia, perforation - Neuropathy (70%): Mononeuritis multiplex, distal symmetric polyneuropathy - Kidneys (40%): RPGN, but less severe than GPA/MPA; glomerulonephritis more pauci-immune
Pathophysiology: ANCA-Mediated Vascular Injury
The Four-Hit Model
Hit 1: Abnormal Neutrophil Priming - Genetic susceptibility genes (HLA-DPA1, HLA-DPB1, PR3, PRTN3 loci) - Environmental triggers (infections, drugs like hydralazine, propylthiouracil) - Neutrophils primed to express ANCA antigens on surface
Hit 2: ANCA Autoantibody Production - B cells produce anti-PR3 (c-ANCA, GPA) or anti-MPO (p-ANCA, MPA) - IgG1/IgG3 subclasses activate complement - Serum ANCA titer correlates with disease activity (especially PR3)
Hit 3: Neutrophil Activation & Degranulation - ANCA IgG crosslinks surface PR3/MPO → neutrophil activation - Fc receptor engagement amplifies activation - Neutrophil extracellular traps (NETs) release enzymes, exacerbating inflammation
Hit 4: Vascular Injury - Necrotizing vasculitis of small arteries, capillaries, venules - Direct endothelial injury from serine proteases (PR3, NE) - Complement activation (C5a, MAC), monocyte recruitment - Glomerular crescent formation if renal involvement
Diagnosis: Biopsy + ANCA Testing
ANCA Serology
c-ANCA (Cytoplasmic Pattern)
- Antigen: Proteinase-3 (PR3)
- Association: GPA (>90%), rarely MPA
- Method: Indirect immunofluorescence (staining pattern) + ELISA (antigen confirmation)
- Specificity: 95-99% if positive
- Sensitivity: 90% in generalized GPA; <50% in localized disease (confined to upper resp)
p-ANCA (Perinuclear Pattern)
- Antigen: Myeloperoxidase (MPO)
- Association: MPA (90%), EGPA (50%), vasculitis-associated GN
- Specificity: 95-99% if positive
- Sensitivity: 80% in MPA, 50% in EGPA
ANCA-Negative AAV
- ~10% of confirmed AAV cases (especially EGPA)
- Diagnosis: Clinical features + compatible pathology on biopsy
- Don’t exclude AAV if high suspicion and negative ANCA
Drug-induced ANCA vasculitis: Hydralazine, propylthiouracil (PTU), sulfasalazine, minocycline → MPO-ANCA vasculitis (typically p-ANCA). Discontinue drug; vasculitis usually resolves without immunosuppression over weeks-months.
Kidney Biopsy (Gold Standard for Renal Involvement)
Light Microscopy: - Segmental fibrinoid necrosis (crescent formation) - Necrosis of capillary wall without immune complex deposition - Crescent types: Cellular (early, reversible), fibrocellular (intermediate), fibrous (end-stage, irreversible) - Pauci-immune pattern (minimal immune complex)
Immunofluorescence: - Pauci-immune (minimal IgG, IgM, IgA, C3) - Hallmark of ANCA-GN - C3 may be present if secondary complement activation - Full-house IF rules OUT AAV, suggests lupus instead
Electron Microscopy: - Minimal electron-dense deposits (pauci-immune) - Rarefaction of capillary wall, fibrin material
Other Diagnostic Clues
| Test | Findings | Significance |
|---|---|---|
| CBC | Anemia (chronic disease), elevated WBC if active | Non-specific |
| CMP | Elevated Cr, AKI pattern | GN activity |
| UA | Hematuria, RBC casts, proteinuria | GN activity |
| Chest X-ray | Pulmonary nodules (GPA), infiltrates (MPA/EGPA), eosinophilic infiltrates (EGPA) | Often diagnostic for GPA |
| ESR/CRP | Markedly elevated | Indicates inflammation; high ESR predicts relapse |
| Complement | Normal (hallmark) | Helps distinguish from lupus (low complement) |
| Cryoglobulins | Negative | Distinguishes from mixed cryoglobulinemia |
ANCA-Associated GN Classification (Pathologic Findings)
| Class | % Glomeruli Sclerosed | % Glomeruli with Crescents | Prognosis | Treatment |
|---|---|---|---|---|
| Focal | <50% | <50% | Best | Standard induction |
| Crescentic | <50% | 50-75% | Intermediate | Aggressive induction |
| Sclerotic | >50% | Variable | Worst | Supportive care, no reversal expected |
Sclerotic ANCA-GN: If >80% of glomeruli sclerosed at biopsy, prognosis for renal recovery poor. Immunosuppression unlikely to help; focus on preventing further deterioration.
Treatment Algorithm
Remission Induction (3-6 Months)
Goal: Achieve complete remission (Cr stable, UA normalized, ANCA becoming negative or titer declining, no systemic symptoms).
Standard Induction: Rituximab Preferred (RAVE Trial)
RAVE Trial (2010): Rituximab non-inferior to cyclophosphamide for remission induction (64% vs. 53% at 6 months) and superior in relapsing disease (67% vs. 42%); adverse-event rates did not differ between arms, so rituximab is preferred chiefly to avoid cyclophosphamide gonadal and bladder toxicity [1]
Rituximab-based induction: - Rituximab: 1000 mg IV × 2 infusions 2 weeks apart (or 375 mg/m² weekly × 4 weeks) - Corticosteroids: IV methylprednisolone 1000 mg × 3 days (or 500-750 mg/day × 3 days), then prednisone 1 mg/kg daily (max 80 mg) taper over 3-6 months to 5-10 mg/day - Induction duration: 3-6 months to remission
Advantages: - Non-inferior to cyclophosphamide for remission induction (64% vs. 53% at 6 months in RAVE) [1] - Less infertility risk (especially in women) — avoids cyclophosphamide gonadal toxicity - Avoids cumulative cyclophosphamide dose limits and bladder toxicity (RAVE found no difference in overall adverse-event rates) [1] - Can repeat doses if relapse
Monitoring: - Monthly: CBC (CD19 cells should become undetectable), ANCA titer, Cr, UA - Assess for sterile pyuria, infections
Alternative Induction: Cyclophosphamide (If Rituximab Contraindicated)
NIH vs Euro-Lupus Dosing: - NIH: 500-1000 mg/m² IV monthly × 3-6 months - Euro-Lupus: 500 mg fixed dose IV monthly × 6 months (equivalent efficacy, lower cumulative toxicity)
Corticosteroids: Same as rituximab regimen above
Monitoring: Monthly CBC, Cr, UA; mesna prophylaxis (0.6 mg per mg CYC) for hemorrhagic cystitis
Complementary Therapy
Complement Inhibition (Avacopan)
ADVOCATE Trial (2021): Avacopan (C5a receptor antagonist) replaced the prednisone taper on background rituximab or cyclophosphamide — non-inferior (not faster) for remission at week 26 (72.3% vs. 70.1%, P=0.24 for superiority) and superior for sustained remission at week 52 (65.7% vs. 54.9%, P=0.007); glucocorticoid-sparing [2]
Avacopan dosing: - 30 mg orally twice daily (three 10 mg capsules BID), as used in ADVOCATE and per the FDA label [2] - Mechanism: Blocks C5a (complement amplification loop); reduces crescent formation
Benefits: - Substantially reduced glucocorticoid exposure — this is the primary rationale [2] - Higher sustained remission at 52 weeks vs. prednisone taper [2] - Serious adverse events were comparable between arms (37.3% vs. 39.0%) [2]
Cost/Access: Expensive; use if available or severe disease
Remission Maintenance (≥18-24 Months)
Goal: Maintain remission on minimal immunosuppression to prevent relapse (50% risk without maintenance) while minimizing long-term toxicity.
Rituximab-Based Maintenance
- Fixed-schedule rituximab: 500 mg IV every 6 months (MAINRITSAN trials)
- Alternative: Rituximab doses based on B-cell recovery (CD19 reappearance)
- Duration: Minimum 18-24 months; some trials used ≥3 years
- Prednisone: Taper to 5-7.5 mg daily (continue indefinitely at low dose)
Azathioprine-Based Maintenance (Older Standard)
- Azathioprine: 1.5-2.5 mg/kg daily
- Prednisone: 5-10 mg daily
- Duration: ≥18-24 months (≥2 years preferred)
- Disadvantage: Higher relapse rates than rituximab
- Use if: Rituximab contraindicated or cost prohibitive
Maintenance Without Rituximab Infusions
- If CYC used for induction, switch to azathioprine or MMF for maintenance
Special Scenarios
ANCA-GN with Pulmonary Hemorrhage
- Immediate life threat: Hemoptysis + hypoxia
- Management:
- Urgent immunosuppression (induction as above)
- Consider plasma exchange (debate persists, but some benefit if Hb <7 or O₂ requirement high)
- High-dose IV methylprednisolone 1000 mg × 3-7 days
- Intubation if severe respiratory failure
- PEXIVAS Trial (2020): Plasma exchange vs. no plasma exchange on background immunosuppression — no significant difference in the primary outcome of death or ESKD (28.4% vs. 31.0%; HR 0.86, 95% CI 0.65–1.13), and results were similar across subgroups, so PEXIVAS does not support a benefit in fulminant presentations. The same trial found reduced-dose glucocorticoids non-inferior to standard-dose with fewer serious infections [3]
ANCA-Negative Pauci-Immune RPGN
- ~10% of pauci-immune RPGN are ANCA-negative
- Diagnosis: Clinical features + biopsy findings (pauci-immune crescents)
- Treatment: Same as ANCA+ RPGN
- Prognosis: Variable; some respond well, others more aggressive
Localized GPA (Upper Respiratory Only)
- No systemic/renal involvement at diagnosis
- ANCA: Often negative or low-titer c-ANCA
- Management: Observation or low-dose rituximab (rituximab 375 mg/m² × 4 weeks)
- Close follow-up: Monitor for systemic progression (monthly UA, Cr, ANCA)
- Risk of progression: 50% progress to generalized disease if untreated
Relapsing ANCA Vasculitis
- 40-50% relapse rate during or after maintenance therapy
- Predictors of relapse: PR3-ANCA (higher risk), persistent ANCA seropositivity, male sex
- Management:
- If on maintenance rituximab: Increase frequency (q 4 months vs. q 6 months)
- If on azathioprine: Switch to rituximab maintenance
- Assess adherence to medications
- Exclude infection, drug-induced vasculitis
Clinical Pearls & Pitfalls
ANCA-negative pauci-immune RPGN: Don’t miss these! 10-15% of confirmed AAV are ANCA-negative. Biopsy is diagnostic. Clinical features + pauci-immune crescents sufficient for diagnosis and treatment initiation.
PR3-ANCA vs. MPO-ANCA relapse risk: PR3-ANCA (GPA) patients have ~50% relapse risk; MPO-ANCA (MPA) have ~30% relapse risk. Higher relapse risk in PR3 justifies longer maintenance (2-3 years vs. 18 months).
Monitoring ANCA titers: Persistently positive or rising ANCA during remission predicts imminent relapse. However, negative ANCA doesn’t exclude relapse (15% of relapses are ANCA-negative). Monitor clinical features more than serology.
EGPA cardiac involvement: Myocarditis with reduced EF is ominous sign in EGPA. Requires intensive induction (CYC often preferred over rituximab if severe cardiac disease). Echocardiography baseline screening recommended.
Infection risk with rituximab induction: Opportunistic infections (PCP, CMV, listeria) can occur during B-cell depletion. Screen for TB; consider PCP prophylaxis (TMP-SMX) if CD4 <500. Monitor for symptoms closely.
Landmark Trials
[1] RAVE Trial (2010): Rituximab vs. cyclophosphamide for ANCA-associated vasculitis induction. NEJM. 2010;363(3):221–232. PMID: 20647199
[2] ADVOCATE Trial (2021): Avacopan vs. prednisone taper, both on background rituximab or cyclophosphamide. NEJM. 2021;384(7):599–609. PMID: 33596356
[3] PEXIVAS Trial (2020): Plasma exchange and two glucocorticoid dosing regimens in severe ANCA-associated vasculitis (eGFR <50 mL/min/1.73 m² or diffuse pulmonary hemorrhage). NEJM. 2020;382(7):622–631. PMID: 32053298