---

ANCA-Associated Pulmonary Vasculitis

---

1. DEFINITION AND CLASSIFICATION

---

2. EPIDEMIOLOGY

• GPA: Most common ANCA vasculitis to involve the lung. Annual incidence ~10 per million; prevalence ~150-250 per million. Peak age 40-60 years; slight male predominance.
• MPA: Annual incidence ~3-10 per million.
• EGPA: Rarest; annual incidence ~1-3 per million. Strongly associated with asthma and atopy.
• Population-based studies show increasing recognition (though some increase may be attributable to improved detection).

---

3. ANCA SEROLOGY - TYPES AND SIGNIFICANCE

• c-ANCA (cytoplasmic): Directed against PR3 (proteinase 3). Highly associated with GPA (sensitivity ~90% in active systemic disease, ~60% in limited disease). Specificity ~95% when combined with anti-PR3 ELISA.
• p-ANCA (perinuclear): Directed against MPO (myeloperoxidase). Associated with MPA and EGPA.

• ANCA testing by indirect immunofluorescence should be confirmed by ELISA (anti-PR3 or anti-MPO).
• A positive c-ANCA/PR3-ANCA in the right clinical context has a high positive predictive value.
• ANCA-negative GPA exists in ~10% - usually limited disease without renal involvement.
• Serial ANCA titers can help monitor disease activity, but rising ANCA alone does not mandate treatment; clinical correlation is always required.
• Patients with PR3-ANCA have higher relapse rates and faster renal function loss compared to MPO-ANCA.
• ANCA specificity (PR3 vs MPO) is clinically more informative than phenotypic diagnosis (GPA vs MPA) - supported by GWAS data.

---

4. PATHOPHYSIOLOGY

• GWAS found MHC and non-MHC associations; GPA and MPA are genetically distinct diseases.
• PR3-ANCA: Strong association with HLA-DP, SERPINA1 gene (encodes α1-antitrypsin, major PR3 inhibitor), and PRTN3 gene (encodes PR3 itself).
• MPO-ANCA: Association with HLA-DQ only.

• Epigenetic modifications interfere with normal silencing of PR3/MPO genes in mature neutrophils → inappropriate overexpression of ANCA autoantigens on neutrophil surface.
• Infections or other environmental exposures → loss of tolerance → inflammatory milieu conducive to autoantibody production.

• In the presence of cytokines (TNF-α, IL-8), neutrophils are primed → PR3 and MPO translocate to cell surface.
• ANCA (IgG) binds membrane-expressed PR3/MPO → FcγRIIIb (CD16) and FcγRIIa (CD32) receptor crosslinking → neutrophil activation.
• Activated neutrophils release reactive oxygen species (ROS), proteolytic enzymes, and neutrophil extracellular traps (NETs) → endothelial injury and vascular inflammation.
• NETs expose PR3 and MPO to antigen-presenting cells → perpetuate autoimmune response (NET-ANCA amplification loop).

• Alternative complement pathway activation plays a role, particularly via the C5a/C5aR axis → further neutrophil priming (rationale for avacopan, a C5aR1 inhibitor).

---

5. GRANULOMATOSIS WITH POLYANGIITIS (GPA)

5a. Clinical Presentation

• Nasal congestion, epistaxis, mucosal ulceration
• Chronic sinusitis, serous otitis media
• Nasal septal perforation → saddle nose deformity (ischemia of nasal cartilage)
• Oral: gingival hyperplasia, oropharyngeal ulcerations
• Subglottic stenosis in ~20% - potentially life-threatening; more common in women; associated with PR3-ANCA

• Cough, hemoptysis, dyspnea, pleuritic chest pain
• Tracheobronchial involvement in 15-55%; more common in women; PR3-ANCA predominates
• Pulmonary nodules (most common lung finding) - single or multiple, bilateral, may cavitate
• Diffuse Alveolar Hemorrhage (DAH) - can be the initial manifestation; early mortality 37% when isolated

• Focal segmental necrotizing glomerulonephritis (pauci-immune, RPGN pattern)
• If untreated: rapidly progressive renal failure

• Severe: Life-threatening (alveolar hemorrhage) or organ-threatening (RPGN, scleritis, mononeuritis multiplex)
• Non-severe (previously "limited"): No life or organ threat; predominantly granulomatous inflammation
• The old term "limited GPA" is now discouraged - replaced by non-severe GPA (Fishman, p. 1320)

5b. Imaging

• Chest X-ray: Multiple bilateral nodules, some cavitating, with air-fluid levels (Fig 74-8 in Fishman)
• CT Chest: Multiple nodules with cavitation; bilateral pleural effusions may be present (Fig 74-9 in Fishman)
• Cavitary lesions are the most characteristic finding; may mimic malignancy or infection

5c. Histopathology of GPA Lung

1. Necrotizing granulomatous inflammation: Small necrotizing microabscesses enlarge and coalesce → geographic basophilic necrosis with palisading histiocytes and scattered giant cells. Mixed infiltrate of lymphocytes, plasma cells, giant cells, and eosinophils.
2. Granulomatous vasculitis: When necrotizing inflammation extends into walls of small vessels - a secondary phenomenon of parenchymal inflammation (unlike capillaritis in MPA, which is primary).
3. Pulmonary capillaritis: Present in 31% of surgical biopsies; may cause DAH.

• Note: Well-defined sarcoid-like non-necrotizing granulomas are NOT found in GPA.
• Tracheobronchial biopsies show nonspecific mucosal inflammation/ulceration/fibrosis - rarely classic vasculitis.

5d. Biopsy Yield

• Surgical lung biopsy: Best yield for histopathologic confirmation (~90%)
• Transbronchial biopsy: Supports diagnosis in ~50% with other supportive features; diagnostic alone in only 20%
• CT-guided core needle biopsy: Preferred for peripheral lesions
• Kidney biopsy: Easier access; shows pauci-immune focal segmental necrotizing GN

---

6. MICROSCOPIC POLYANGIITIS (MPA)

• MPA is defined as necrotizing vasculitis without granulomatous inflammation, affecting predominantly capillaries, venules, arterioles.
• MPO-ANCA (p-ANCA) in ~70%; PR3-ANCA in ~20%.
• Rapidly progressive glomerulonephritis is the dominant manifestation.
• Pulmonary involvement is common:
  • Diffuse alveolar hemorrhage (DAH) via pulmonary capillaritis - more common in MPA than GPA
  • ILD (interstitial lung disease), particularly NSIP and UIP patterns, associated with MPO-ANCA

• ILD is now recognized as a significant manifestation, especially with MPO-ANCA.
• Pattern: NSIP most common; UIP can also occur.
• MPO-ANCA with UIP raises question whether this is MPA-ILD or idiopathic pulmonary fibrosis with incidental ANCA positivity.
• Management of ILD and MPA:
  • Active MPA + ILD: Standard remission induction (glucocorticoids + cyclophosphamide or rituximab)
  • MPO-ANCA + NSIP/inflammatory ILD (without overt vasculitis): Trial of glucocorticoids + azathioprine or MMF
  • MPO-ANCA + UIP without vasculitis: Do NOT give immunosuppression (increases mortality) - offer antifibrotic therapy (nintedanib/pirfenidone) (Fishman, p. 3046)

---

7. EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS (EGPA)

Clinical Phases (classic):

1. Prodromal (allergic): Asthma (often severe, adult-onset), allergic rhinitis/sinusitis, nasal polyposis
2. Eosinophilic: Marked peripheral and tissue eosinophilia; eosinophilic pneumonia (Löffler-like), eosinophilic gastroenteritis, myocarditis
3. Vasculitic: Systemic necrotizing vasculitis affecting multiple organs

Key Diagnostic Features:

• Asthma (almost universal - a sine qua non)
• Eosinophilia >10% or >1.5 × 10⁹/L
• Mononeuropathy (multiplex) or polyneuropathy
• Pulmonary infiltrates (non-fixed, migratory)
• Paranasal sinus abnormality
• Extravascular eosinophil infiltration on biopsy

ANCA in EGPA:

• MPO-ANCA positive in ~40% (predominantly in patients with renal involvement/vasculitic phenotype)
• ANCA-negative patients (60%) tend to have predominantly eosinophilic/cardiac/pulmonary phenotype
• ANCA-positive EGPA has different clinical phenotype from ANCA-negative

Pulmonary Features:

• Migratory/transient pulmonary infiltrates (Löffler-like)
• Bilateral patchy consolidations
• DAH (less common than GPA/MPA)
• Pleural effusions (eosinophilic)
• Nodular lesions (less common)

Prognosis:

• Better prognosis than GPA or MPA
• Most deaths are secondary to cardiac involvement (cardiomyopathy, valvulitis, pericarditis) → all patients must be screened
• Five-factor score (FFS) for poor prognosis: Age >65, cardiac symptoms, GI involvement, renal insufficiency, absence of ENT symptoms

Leukotriene receptor antagonists (LTRAs) and EGPA:

• Early reports suggested LTRAs (montelukast) caused EGPA - now understood as unmasking of underlying EGPA when oral steroids are reduced, not a causal relationship (Fishman, p. 2941)

---

8. DIFFUSE ALVEOLAR HEMORRHAGE (DAH) IN AAV

• DAH is the most feared pulmonary complication of AAV.
• Mechanism: Pulmonary capillaritis → neutrophilic inflammation of alveolar capillaries → destruction of capillary walls → blood into alveolar space.
• Clinical triad: Hemoptysis + drop in hemoglobin + bilateral diffuse alveolar opacities on imaging (though hemoptysis may be absent in ~33%).
• BAL: Progressively bloodier returns on sequential aliquots; hemosiderin-laden macrophages suggest recurrent/chronic hemorrhage (more typical of AAV and SLE than non-vasculitic causes).
• Mortality: High - early mortality 37% when DAH is presenting manifestation of GPA; even higher if accompanied by renal failure.
• In GPA, DAH can occur without other classic features (nodules, sinusitis) - in this context, differentiation from MPA requires ANCA pattern (c-ANCA → GPA; p-ANCA → MPA).
• >40 cases of GPA with isolated DAH + pulmonary capillaritis described; 9/10 also had GN (Murray, p. 4977).
• Alveolar hemorrhage is often subclinical and recurrent in both GPA and MPA.

---

9. PULMONARY-RENAL SYNDROME

• GPA and MPA are the two most common causes
• Anti-GBM disease (Goodpasture) must be distinguished - shows linear IgG deposits on kidney/lung basement membrane vs. pauci-immune (no immune deposits) in AAV
• Both can coexist (dual-positive ANCA + anti-GBM disease) - worst prognosis

---

10. DIAGNOSIS

---

11. TREATMENT

Remission Induction (Severe AAV - GPA/MPA)

• Rituximab (375 mg/m² × 4 weekly doses OR 1000 mg × 2 doses) + high-dose glucocorticoids (methylprednisolone 500-1000 mg IV × 3 days in severe disease, then 1 mg/kg/day oral)
• Cyclophosphamide (oral 2 mg/kg/day OR IV 15 mg/kg pulse q2-3 weeks) + high-dose glucocorticoids - alternative; preferred for CNS/peripheral nerve involvement, severe cardiac GI involvement in EGPA

• Historically used for severe renal failure (creatinine >500 μmol/L or dialysis-dependent) or severe DAH
• PEXIVAS trial (2020) showed PLEX did not reduce the composite endpoint of ESKD or death at 28 days → current guidelines have stepped back from routine PLEX
• May still be considered for concurrent anti-GBM disease or refractory DAH

• Complement inhibitor approved as adjunct to remission induction
• Allows faster tapering of glucocorticoids
• Phase III ADVOCATE trial showed non-inferiority to glucocorticoids at 26 weeks + superiority at 52 weeks

Remission Maintenance (GPA/MPA)

• Rituximab (500 mg every 6 months × 2 years) - preferred for PR3-ANCA or relapsing disease
• Azathioprine (2 mg/kg/day) - alternative; IMPROVE trial showed comparable efficacy to rituximab for maintenance
• Methotrexate (25 mg/week) - alternative for non-renal disease
• Mycophenolate mofetil - less effective than azathioprine for prevention of relapses; second-line
• Duration: At least 18-24 months after achieving remission; PR3-ANCA patients may benefit from longer duration

Glucocorticoid Tapering

• Taper over ~3-6 months to ≤5-7.5 mg/day prednisone equivalent
• Avacopan facilitates faster tapering

Treatment of Non-Severe GPA/MPA

• Oral methotrexate + glucocorticoids (for non-severe non-renal GPA)
• Rituximab preferred over cyclophosphamide even for non-severe cases

EGPA Treatment (Fishman, pp. 3051-3068; Murray, Ch. 96)

• Phase III RCT: Mepolizumab vs placebo as add-on in relapsing/refractory EGPA
• Higher proportion achieving remission, longer duration of remission, lower relapse rate, lower average daily corticosteroid dose
• Particularly effective for difficult-to-control asthma component

• Non-severe: Glucocorticoid tapering alone; or add azathioprine/MTX as steroid-sparing if prednisone cannot be tapered below 10 mg/day
• Severe: Azathioprine for 18-24 months after remission; MMF less effective than azathioprine

---

12. PROGNOSIS AND MONITORING

• Relapse risk: PR3-ANCA patients relapse more frequently than MPO-ANCA patients.
• Monitoring: ANCA titer rise suggests possible relapse but must be correlated clinically; treatment must NOT be initiated on rising ANCA alone.
• Infectious complications: Prophylaxis with TMP-SMX (Pneumocystis) during remission induction with cyclophosphamide or rituximab + high-dose steroids.
• Bladder toxicity: Cyclophosphamide → hemorrhagic cystitis → mesna prophylaxis; limit cumulative dose; IV pulse preferred over oral.

---

SUMMARY TABLE: GPA vs MPA vs EGPA

---

• Fishman's Pulmonary Diseases and Disorders, 2-Volume Set (9th ed.), Chapter 74 (Systemic Vasculitis), Chapter 74 (DAH/Pulmonary-Renal), pp. 1319-1350, 3046-3070
• Murray & Nadel's Textbook of Respiratory Medicine, 2-Volume Set, Chapter 94 (DAH and Pulmonary-Renal Syndromes), Chapter 96 (EGPA), pp. 4967-4985, 1770-1815