Interstitial Lung Disease (ILD) with c-ANCA Positivity

Overview of the Association

c-ANCA positivity is strongly weighted (+5 points) for GPA in the 2022 ACR/EULAR classification criteria; conversely, it scores −1 for MPA, reflecting its lower frequency there.

1. Granulomatosis with Polyangiitis (GPA) — c-ANCA/PR3-ANCA

Pathogenesis

Pulmonary Manifestations

• Classic pattern: bilateral pulmonary nodules (often multiple, variable size) that may cavitate — present in ~70% of patients
• Diffuse alveolar hemorrhage (DAH): from pulmonary capillaritis — presents with hemoptysis, falling hemoglobin, ground-glass opacities on CT
• ILD: less typical for GPA than MPA, but pulmonary fibrosis can develop, particularly after recurrent episodes of inflammation or DAH
• Airway involvement: subglottic stenosis, endobronchial stenosis, tracheal ulceration — relatively specific to GPA
• Sinopulmonary: >80% have abnormal chest imaging; >70–90% have sinus CT abnormalities

CT Chest Patterns in GPA

• Pulmonary nodules (with or without cavitation) — most characteristic
• Consolidation
• Ground-glass opacification (DAH)
• Atelectasis
• Pleural effusion (10–20%)
• Airway stenosis/ulceration

Serologic Features

• c-ANCA (PR3-ANCA) positive in ~80–90% of active generalized GPA
• Sensitivity ~93%, specificity ~94% for GPA (2022 ACR/EULAR classification)
• A small proportion of GPA patients are ANCA-negative (more likely with limited disease)

2. Why c-ANCA + ILD Should Also Prompt Consideration of MPA

• MPA-ILD can occasionally be associated with PR3-ANCA (though MPO is far more common)
• Fibrosis on chest imaging actually scores +3 points for MPA in the ACR/EULAR criteria (vs. nodules +2 for GPA)
• The pattern of UIP (honeycombing, traction bronchiectasis, basal-predominant fibrosis) should raise MPA over GPA
• Published series confirm that MPO-ANCA ILD may be misdiagnosed as IPF before the ANCA is detected

3. Clinical Approach to c-ANCA + ILD

History & Symptoms

• Upper airway: chronic sinusitis, bloody nasal discharge, saddle nose, septal perforation, hoarse voice → GPA
• Pulmonary: dyspnea, cough, hemoptysis (DAH), progressive breathlessness (fibrosis)
• Renal: hematuria, red cell casts, rising creatinine → pauci-immune GN (very common in GPA)
• Systemic: fever, weight loss, arthralgia
• Neurologic: mononeuritis multiplex (GPA/MPA)

Investigations

Bronchoscopic transbronchial biopsy rarely provides diagnostic tissue in GPA — surgical lung biopsy or open biopsy has higher yield if needed.

Differential Diagnosis of c-ANCA + ILD

• GPA with pulmonary involvement (nodules, DAH, fibrosis post-inflammation)
• MPA with UIP/NSIP pattern (check for MPO-ANCA co-positivity)
• Anti-GBM disease (up to 50% may be ANCA co-positive; presents as DAH + RPGN)
• Connective tissue disease-ILD (RA, SSc, SLE) — check for disease-specific antibodies
• Drug-induced ANCA + ILD (hydralazine, propylthiouracil, minocycline)

4. Management

Induction of Remission

Maintenance

• Rituximab (preferred, q6-monthly dosing) or azathioprine / methotrexate
• Target ANCA negativity + clinical/radiologic stability
• Treatment duration: typically ≥24 months

ILD-specific considerations

• If UIP pattern predominates and is attributed to MPA/GPA: treat the underlying vasculitis — fibrosis may stabilize
• Antifibrotic agents (nintedanib, pirfenidone) are used in progressive pulmonary fibrosis associated with CTD/ANCA vasculitis in some centers (off-label)
• Monitor with serial PFTs (FVC, DLCO) and HRCT

Monitoring for Complications

• Infection — the leading cause of mortality (13–48% of deaths in vasculitis); Pneumocystis prophylaxis with TMP-SMX is standard during immunosuppression
• Cyclophosphamide toxicity: haemorrhagic cystitis (12%), myelodysplasia (8%), solid malignancy (5%)
• Venous thromboembolism: GPA patients have the same VTE rate as patients with prior VTE history (7.0 events/100 person-years)
• Hypogammaglobulinemia with rituximab

Key Points Summary

1. c-ANCA/PR3-ANCA + ILD most strongly points to GPA, which characteristically causes nodules and cavitation; true UIP-pattern fibrosis is less typical but can occur
2. MPA (MPO/p-ANCA) is the ANCA disease most associated with progressive ILD/UIP — fibrosis on HRCT scores +3 for MPA in classification criteria
3. Always assess for renal involvement (RPGN) and upper airway disease to classify the AAV type
4. Serology should use PR3-ANCA and MPO-ANCA immunoassays (preferred over IIF alone per 2016 EUVAS/international consensus)
5. Rituximab + glucocorticoids is first-line induction for severe GPA/MPA (2022 EULAR guidelines, PMID 36927642)