Presentation and progression of MPO-ANCA interstitial lung disease

Abstract

The association between MPO-ANCA-associated vasculitis (AAV) and interstitial lung disease (ILD) has been well established. Pulmonary fibrosis may coexist with, follow, or even precede the diagnosis of AAV, and its presence adversely affects the prognosis. The optimal approach to investigating ANCA in patients with ILD remains a subject of ongoing debate. Here we aim to describe presentation and progression of MPO-ANCA ILD. We conducted a retrospective evaluation of a cohort of individuals diagnosed with MPO-ANCA ILD, with or without accompanying renal impairment, at the Immunology and Cell Therapy Unit, Careggi University Hospital, Florence, Italy, between June 2016 and June 2022. Clinical records, imaging studies, pathologic examinations, and laboratory test results were collected. Among the 14 patients identified with MPO-ANCA ILD, we observed a significant association between MPO-ANCA titers assessed at the time of ILD diagnosis and renal involvement. Renal impairment in these cases often manifested as subclinical or slowly progressive kidney damage. Interestingly, complement C3 deposits were consistently found in all renal biopsy specimens, thereby suggesting the potential for novel therapeutic targets in managing renal complications associated with MPO-ANCA ILD. The presentation of MPO-ANCA vasculitis as ILD can be the first and only clinical manifestation. MPO-ANCA levels at ILD diagnosis could warn on the progression to renal involvement in patients with MPO-ANCA ILD, hence caution is needed because renal disease can be subclinical or smoldering.

Keywords: ANCA-Associated vasculitis; C3 deposits; Glomerulonephritis; Interstitial lung disease; MPO; MPO-ANCA; Pulmonary fibrosis; UIP.

Fig. 1

ANCA indirect immunofluorescence (IIF) pattern. The serum analysis of a 64-year-old woman with interstitial lung disease and new onset kidney disease revealed a peri-nuclear (P)-ANCA pattern on ethanol-fixed granulocytes (A) that shifted into a cytoplasmic pattern on formalin-fixed cells (B). This particular pattern is indicative of positive anti-myeloperoxidase (MPO) antibodies. The patient was found to have elevated anti-MPO antibodies titers. EOH: neutrophils fixation in ethanol; HCOH: neutrophils fixation in formaldehyde.

Fig. 2

Immunofluorescence staining (C3, C4, IgG, IgA, lambda chains) of kidney biopsy samples from two patients with MPO-ANCA ILD. Immune deposits of C3 are observed in both patients, with higher intensity in Patient 1 (upper row) compared to Patient 2 (lower row). Patient 1 (upper row) underwent kidney biopsy concurrently with the onset of renal function deterioration. The images show immune deposits of C3 with a high intensity (+++), along with deposits of IgG (++), IgA (++) and Lambda chains (++), but no C4 deposits. Conversely, Patient 2 (lower row) had a longer history of kidney disease before undergoing the biopsy. In this case, predominant interstitial fibrosis was observed on light microscopy, and the direct immunofluorescence staining showed only C3 deposition.

Fig. 3

Anti-MPO antibodies titers stratified by renal involvement in patients with MPO-ANCA ILD. Anti-MPO antibodies titers (measured in UI/mL by a commercial ELISA) were evaluated at the time of ILD diagnosis in patients with MPO-ANCA ILD with (n = 8, blue circles) and without (n = 6, orange circles) renal involvement. Box plots represent 25th to 75th percentiles. Black line inside the box represents the median. Whiskers represent maximum and minimum values. *p < 0.05; calculated with Mann-Whitney U test.

Fig. 4

Longitudinal evaluation of anti-MPO antibodies titers. Where available, anti-MPO antibodies titers were retrieved up to 48 months after detection at ILD diagnosis in patients with MPO-ANCA ILD with (n = 8, blue circles) and without (n = 6, orange circles) renal involvement.

Fig. 5

Potential pathogenesis and clinical spectrum of patients with MPO-ANCA ILD. Genetic and environmental factors may contribute to susceptibility. Lung damage may result from endothelial inflammation, oxidative stress, and chronic inflammation leading to fibrosis. Autoimmunity arises due to loss of T and B cell tolerance, with B cells producing ANCA targeting neutrophils. This activates neutrophils, causing vessel damage. It is not known whether MPO-ANCA are needed for pulmonary damage. It could be hypothesized that the immune response originates in the lung, then autoantibodies are directly pathogenic in the kidney. Consequently, there is a linear correlation between kidney damage and antibody titer. Clinical spectrum ranges from isolated fibrotic lung disease to AAV-associated ILD with varying degrees of renal involvement. Therapeutic strategies include immunosuppression and anti-fibrotic treatments. (Illustration created with BioRender.com).