ANCA-Associated Pulmonary Vasculitis

(15-Mark Answer - From Fishman's Pulmonary Diseases & Disorders and Murray & Nadel's Textbook of Respiratory Medicine)

1. INTRODUCTION AND CLASSIFICATION

2. PATHOPHYSIOLOGY OF AAV

• A genome-wide association study (GWAS) identified both MHC and non-MHC associations. The strongest genetic associations are based on ANCA antigen specificity (PR3-ANCA vs. MPO-ANCA) rather than clinical phenotype (GPA vs. MPA).
• PR3-ANCA patients: strong HLA-DP association; SERPINA1 gene (encodes alpha-1-antitrypsin, the major inhibitor of PR3); PRTN3 gene (encodes PR3).
• MPO-ANCA patients: HLA-DQ association only.

• Epigenetic modifications interfere with normal silencing of genes coding for ANCA autoantigens (PR3 and MPO) in mature neutrophils, leading to inappropriately increased surface expression of these target antigens.

• Environmental triggers (infections, particularly S. aureus) lead to loss of immune tolerance and production of ANCA in genetically predisposed individuals.
• ANCA interact with PR3 or MPO on primed/activated neutrophils.
• Neutrophil activation causes: (1) respiratory burst, (2) degranulation with release of proteolytic enzymes and reactive oxygen species, (3) activation of the coagulation system with thrombin generation - bridging inflammation and coagulation.

• C5a, generated via the alternative complement pathway, is a potent neutrophil attractant and activator.
• C5a + ANCA co-stimulation causes the full inflammatory injury to vessel walls (capillaritis).
• This mechanism is validated by the murine MPO-ANCA model and has been the basis for therapeutic C5a-receptor antagonism (avacopan).

• PR3-ANCA patients: higher relapse rate, more rapid loss of renal function than MPO-ANCA patients.
• MPO-ANCA patients: higher association with ILD and UIP pattern.
• ANCA alone are not sufficient to cause disease - a proinflammatory milieu is required.

3. GRANULOMATOSIS WITH POLYANGIITIS (GPA)

Definition

Histopathology

• Small-vessel vasculitis (capillaries, arterioles, venules)
• Geographic necrosis and hemorrhagic infarcts
• Mixed inflammatory cellular infiltrate
• Granulomatous component - the distinguishing feature from MPA
• Pauci-immune glomerulonephritis on renal biopsy (scant immune deposits)

Clinical Presentation

• Pulmonary nodules (often cavitating), infiltrates
• Diffuse alveolar hemorrhage (DAH) - uncommon (<15-20%), but life-threatening; when present, RPGN coexists in >90%
• Endobronchial disease with tracheobronchial stenosis

Severity Stratification (2021 ACR/Vasculitis Foundation Guidelines)

• Nonsevere (limited) GPA: Predominantly necrotizing granulomatous inflammation; no immediate threat to life or irreversible organ damage.
• Severe GPA: Threatens life (e.g., alveolar hemorrhage) or a vital organ with risk of irreversible damage (e.g., RPGN, scleritis, mononeuritis multiplex).

Serology

• c-ANCA (PR3-ANCA): >90% in active generalized GPA; 40-70% in active regional/limited GPA.

4. MICROSCOPIC POLYANGIITIS (MPA)

Definition and Distinguishing Features

Histopathology

• Necrotizing capillaritis - indistinguishable from GPA histologically
• Focal segmental necrotizing crescentic glomerulonephritis - most consistent feature
• Lung capillaritis in 20-30% of cases

Clinical Presentation

• Fever, weight loss, malaise (constitutional symptoms)
• Pulmonary capillaritis with DAH (10-50%) - often severe and life-threatening
• RPGN (60-90%)
• Cutaneous vasculitis, myalgias, arthralgias
• Gastrointestinal bleeding from mucosal vasculitis
• Peripheral neuropathy
• Sinusitis (occasional, but absent upper airway granulomas)
• Transition to pulmonary fibrosis and restrictive ventilatory impairment after recurrent DAH has been described (Murray & Nadel)

Serology

• p-ANCA (MPO-ANCA): positive in >80%
• Elevated ESR; nonspecific increases of RF and ANA possible
• Circulating immune complexes in 45%, but tissue localization difficult (pauci-immune)
• Anti-DNA antibodies and hypocomplementemia absent (distinguishes from SLE)
• Hepatitis B/C antibodies present in 33%

Prognosis

• 5-year survival ~65% with early therapy
• DAH contributes to early mortality rate of 25% (Murray & Nadel)

5. EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS (EGPA)

Phases

1. Prodromal/allergic phase: Asthma (often severe, late-onset), allergic rhinitis, nasal polyposis
2. Eosinophilic phase: Peripheral blood and tissue eosinophilia; Loeffler-like pulmonary infiltrates
3. Vasculitic phase: Small vessel vasculitis similar to GPA/MPA

Clinical Features

• Upper airway: 50-60% (allergic rhinitis, polyposis - not destructive like GPA)
• Pulmonary parenchymal: 30% (eosinophilic infiltrates, asthma)
• DAH: <3% (much less common than GPA/MPA)
• Renal (GN): 10-25%
• Cardiac involvement: cardiomyopathy, valvulitis, pericarditis - most common cause of death
• Peripheral neuropathy: mononeuritis multiplex
• Skin: palpable purpura, subcutaneous nodules

Special Note - Leukotriene Receptor Antagonists

Serology

• ANCA (usually MPO-ANCA): ~50% - ANCA-positive patients have a different clinical phenotype with more vasculitic features vs. ANCA-negative patients who have more eosinophil-mediated organ damage.

Prognosis

6. DIFFUSE ALVEOLAR HEMORRHAGE IN AAV

• More than two-thirds of pulmonary-renal syndromes are ANCA-mediated (pauci-immune).
• DAH in AAV results from diffuse pulmonary capillaritis - injury to the alveolar-capillary interface.
• Clinical triad: hemoptysis, diffuse radiographic infiltrates, falling hemoglobin.
• BAL: progressively bloodier sequential aliquots (diagnostic of DAH).
• In the context of DAH, differentiating GPA from MPA is often difficult - clinical presentation, lung histology (capillaritis), and serologic findings can be identical (Murray & Nadel). Differentiation only follows development of more typical upper airway/granulomatous features.

7. DIAGNOSIS

• c-ANCA/PR3-ANCA for GPA
• p-ANCA/MPO-ANCA for MPA/EGPA
• Combination of indirect immunofluorescence + ELISA (PR3/MPO) is the current standard

• HRCT chest: nodules (often cavitating), consolidations, ground-glass opacity (DAH), tracheal/subglottic involvement
• CT orbits: retro-orbital pseudotumor in GPA

• Open/VATS lung biopsy: capillaritis, granulomas (GPA), geographic necrosis
• Renal biopsy: pauci-immune crescentic GN
• Nasal/sinus biopsy: granulomatous inflammation (GPA)

• Increased DLCO during active DAH (hemoglobin in alveoli binds CO)
• Serial DLCO monitoring for disease activity

8. TREATMENT

Principles

1. Remission induction as quickly as possible to minimize irreversible organ damage.
2. Remission maintenance with minimum side effects.
3. Treatment stratified by severity (severe vs. nonsevere).

Remission Induction - Nonsevere Disease

• Oral prednisone 0.5-1 mg/kg/day (max 80 mg/day) + Methotrexate (target 20-25 mg/week, oral or SC)
• Supplemented by folic acid 1 mg/day and PCP prophylaxis (trimethoprim-sulfamethoxazole)
• Alternative immunosuppressants: azathioprine or mycophenolate mofetil (MTX intolerance)
• In ANCA-negative indolent localized GPA: TMP-SMX alone may be tried (possible mechanism: antimicrobial against S. aureus, the principal organism colonizing GPA nares)

Remission Induction - Severe Disease

• Rituximab (anti-CD20 monoclonal antibody): 375 mg/m² IV x 4 doses (weekly) OR 1000 mg x 2 doses (2 weeks apart) - now preferred over cyclophosphamide for most patients with severe GPA/MPA, based on RAVE and RITUXVAS trials (Fishman Ch. 74).
• Cyclophosphamide (oral 2 mg/kg/day for 3-6 months, or IV pulse 15 mg/kg every 2-3 weeks) + glucocorticoids: established standard for decades; equally effective to rituximab for induction, but more toxic.
• Plasma exchange (PLEX): For DAH with hypoxemic respiratory failure or renal failure. Note: In the PEXIVAS trial, PLEX was not associated with benefit for renal outcomes; however, it remains a mainstay for ANCA-associated DAH because that trial was not designed to evaluate pulmonary hemorrhage specifically (Murray & Nadel).
• High-dose IV methylprednisolone pulses for severe/life-threatening manifestations (DAH).

Remission Maintenance

• Rituximab (maintenance infusions) is now preferred over azathioprine for maintenance in PR3-ANCA-positive patients given higher relapse risk.
• Azathioprine or methotrexate for 12-24 months minimum.
• Mycophenolate mofetil: alternative maintenance agent.
• Low-dose prednisone taper.

Special Situations

• Tracheobronchial disease in GPA: High-dose inhaled glucocorticoids + systemic therapy; fixed obstructions may require dilation or silastic stent placement; tracheo/bronchomalacia may respond to CPAP; persistent S. aureus or Pseudomonas infections should be treated (potential antigenic drivers of autoimmunity).
• ILD and MPO-ANCA (with/without MPA):
  • Active MPA + any ILD: standard severe MPA induction (glucocorticoids + CYC or rituximab).
  • NSIP/inflammatory ILD + MPO-ANCA without overt vasculitis: glucocorticoids + azathioprine or MMF.
  • UIP pattern + MPO-ANCA but without vasculitis: monitor; do NOT give immunosuppressants (shown to increase mortality in UIP); offer antifibrotic therapy.
• EGPA treatment:
  • Glucocorticoids are primary induction for all patients.
  • Mepolizumab (anti-IL-5 monoclonal): reduces eosinophilia, effective in nonsevere/refractory EGPA as glucocorticoid-sparing agent.
  • Severe EGPA (cardiac, GI, renal, CNS, mononeuritis multiplex, DAH): cyclophosphamide + glucocorticoids.
  • Refractory EGPA: rituximab.

9. MONITORING DISEASE ACTIVITY

• Erythrocyte sedimentation rate (ESR)
• ANCA titers (serial - rise may precede relapse, especially PR3-ANCA)
• Serial DLCO measurements
• Microscopic urinalysis (urine RBC casts = active nephritis)

10. KEY EXAM POINTS (Summary)