ILD and ANCA: What to do? Save

Several cohort studies conducted in Asia, Europe and the Americas have evaluated the clinical significance of antineutrophil cytoplasmic antibodies (ANCA) when detected in patients with interstitial lung disease (ILD) as well as the types of ILD encountered in patients with microscopic polyangiitis (MPA) and their effect on the prognosis of MPA(1).

ANCA are detected in about 5-10% of patients presenting with ILD.  Patients with ILD and an MPO-ANCA (not PR3-ANCA) are at risk for progression to microscopic polyangiitis (MPA). Therefore, all patients diagnosed with an ILD should be tested for ANCA, whether symptoms suggestive of MPA are present or not. Patients who are initially ANCA-negative should be retested every 1-2 years as MPO-ANCA can develop later during the course of ILD.

When radiographic abnormalities of ILD are detected in patients at the time of an MPA diagnosis, the identified radiographic patterns are most commonly those of usual interstitial pneumonia (UIP), followed by non-specific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP), or more rarely follicular bronchiolitis. These patterns have also been documented when a video-assisted thoracoscopic lung biopsy was performed (1).

Is there a pathogenic link between ILD and MPO-ANCA and MPA? 

First, there is a genetic link. Gene variants portending a risk for ILD/IPF including the MUC5B risk allele rs35705959 (G/T), the TERT risk allele rs2736100AA and the DSP risk allele rs2076295G are shared between ILD and MPO-ANCA positive patients with or without MPA, but not with PR3-ANCA positive patients(1). Second, the formation of neutrophil extracellular traps (NETs) is an innate immunity defense mechanism against bacterial infections. Increased NET formation has been described as a mechanism promoting fibrosis in ILD as well as of ANCA formation in patients with MPA. Thus, in the case of UIP, which precedes the development of MPO-ANCA and MPA, the traction bronchiectases, which are often bacterially colonized, are thought to provide the inflammatory environment in which the immunetolerance to MPO can be broken, allowing for the development and subsequent persistence of MPO-ANCA. The presence of MPO-ANCA then puts the patient at risk for the development of MPA. This is not as clear for  the more inflammatory ILD conditions, like NSIP or OP, which may very well be disease manifestions of MPO-AAV that respond to immunosuppressive therapy (1).

What does all this mean for the management of individual patients?  Patients with ILD who are found to have an MPO-ANCA should be carefully evaluated for the presence of symptoms and laboratory test abnormalities suggesting the presence of active MPA. Such testing should include testing for C-reactive protein, complete blood count with cell differential, complete metabolic panel and urinalysis and microscopy.  If patients are found to have signs and symptoms suggestive of MPA, and this diagnosis is confirmed, treatment should follow guidelines for ANCA associated vasculitis(2). 

In the absence of abnormalities of markers of inflammation, kidney function or microscopic hematuria, the high resolution computed tomography (HRCT) of the chest should be carefully reviewed for the distinction of features of UIP from those of other non-UIP patterns.  Patients with an UIP pattern should be treated according to guidelines for ILD and offered antifibrotic therapy (3). Such patients should also be followed for the future development of microscopic hematuria as early sign of incipient glomerulonephritis.  If glomerulonephritis develops, treatment should follow guidelines for ANCA-associated vasculitis(2).

Patients with non-UIP type changes on HRCT should be divided based on the presence or absence of GGOs.  Patients with GGO’s should be further evaluated for alveolar hemorrhage with bronchoscopy with BAL. If alveolar hemorrhage is detected, the patient has MPA and should be treated for severe MPA according to the guidelines for ANCA-associated vasculitis (2). If the HRCT pattern is not suggestive of UIP, but there are no GGOs, or if alveolar hemorrhage has been excluded in patients with GGOs, the patients should be treated according to the guidelines for ILD  including a trial of glucocorticoids +/- glucocorticoid sparing immunosuppressive agents(3).

Because the prognosis of patients with ILD and MPA is worse than that of either condition alone, these patients should be managed carefully by a multidisciplinary care team comprised of pulmonologists, rheumatologist and nephrologists at centers experiences with both ILD and ANCA-associated vasculitis.

References:

1. Specks, U. et al., Interstitial lung disease, antineutrophil cytoplasmic antibodies and microscopic polyangiitis. Rheumatology, 2025; 64:i42-i47.

2. Hellmich, B., et al., EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update. Ann Rheum Dis, 2024; 83:30-47.

3. Raghu, G., et al., Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med, 2022; 205: e18-e47.