# ANCA-Associated Vasculitis: Diagnosis, Classification, and Treatment

**Avacopan evidence and regulatory update:** The ADVOCATE article was retracted on 29 June 2026; its reported efficacy and comparative-safety results should not be used as established evidence. On 27 April 2026, FDA's CDER proposed withdrawal of TAVNEOS approval because a valid demonstration of efficacy could no longer be established and material facts in the application were untrue. FDA also identified serious liver-injury concerns. This is a proposed withdrawal, not a completed US withdrawal; FDA advises clinicians and patients to discuss available treatment options while the process is pending. [Retraction notice](https://pubmed.ncbi.nlm.nih.gov/42377355/) · [FDA notice, 27 April 2026](https://www.fda.gov/drugs/drug-alerts-and-statements/cder-proposes-withdraw-approval-tavneos).

## 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 |

Key Point

**Serology-pathology mismatch**: Don’t diagnose by serology alone. Biopsy remains gold standard. ~10% of confirmed AAV are ANCA-negative (especially EGPA).

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## 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

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## 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

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## 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

High-Yield Board Point

**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 |

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## 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 |

High-Yield Board Point

**Sclerotic ANCA-GN**: If \>80% of glomeruli sclerosed at biopsy, prognosis for renal recovery poor. Immunosuppression unlikely to help; focus on preventing further deterioration.

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## 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

#### **Avacopan: Historical ADVOCATE Evidence Retracted**

**Historical study:** ADVOCATE (2021) compared the C5a receptor inhibitor avacopan with a prednisone taper on background rituximab or cyclophosphamide \[2\]. The article was retracted in June 2026.

**Evidence interpretation:** Its originally reported remission, steroid-sparing, and comparative-safety findings must not be taught as established benefits. Use current regulatory advice and independently supported treatment options when planning induction therapy.

**Current decision:** Retraction of this article does not establish lack of benefit or resolve evidence from other studies. Avacopan use requires reassessment of independent evidence and current prescribing, regulatory, and guideline information. [Read the retraction notice](https://pubmed.ncbi.nlm.nih.gov/42377355/).

### 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

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## 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

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## Clinical Pearls & Pitfalls

Clinical Pearl

**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.

High-Yield Board Point

**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).

Key Point

**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.

Clinical Pearl

**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.

High-Yield Board Point

**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.

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## Landmark Trials

\[1\] **RAVE Trial** (2010): Rituximab vs. cyclophosphamide for ANCA-associated vasculitis induction. *NEJM.* 2010;363(3):221–232. PMID: 20647199

\[2\] **\[RETRACTED — historical citation\]** Jayne DRW, Merkel PA, Schall TJ, Bekker P; ADVOCATE Study Group. Avacopan for the Treatment of ANCA-Associated Vasculitis. *N Engl J Med.* 2021;384:599–609. [PMID 33596356](https://pubmed.ncbi.nlm.nih.gov/33596356/). Retracted 29 June 2026: [Rubin EJ, retraction notice; PMID 42377355](https://pubmed.ncbi.nlm.nih.gov/42377355/).

\[3\] **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

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## Related Resources

- RPGN Diagnostic Algorithm
- Glomerular Disease Diagnostic Algorithm
- CKD Comprehensive Management Pathways

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**Last reviewed:** 2026-02-28 \| **Next update due:** 2026-08-28


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