IgA Antibodies Directed Against Citrullinated Protein Antigens Are Elevated in Patients With Idiopathic Pulmonary Fibrosis

Background: The etiology of idiopathic pulmonary fibrosis (IPF) is unknown. Because it shares genetic, histopathologic, and radiographic features with the fibrosing interstitial lung disease seen in rheumatoid arthritis (RA), the goal of this study was to investigate RA-related autoantibodies in IPF. Methods: The study included patients with IPF from two separate cohorts at National Jewish Health and Brigham Women's Hospital (n = 181), general population control subjects (n = 160), and control subjects with disease (n = 86 [40 with RA-usual interstitial pneumonia and 46 with hypersensitivity pneumonitis]). Serum was tested for RA-associated antibodies (including IgG and IgA) to citrullinated protein antigens (ACPA). Lung tissue in 11 patients with IPF was examined for ectopic lymphoid aggregates. Results: An increased prevalence of ACPA positivity was found in two separate IPF cohorts. In particular, positivity for IgA-ACPA was increased in these two IPF cohorts compared with general population control subjects (21.3% and 24.8% vs 5.6%; P < .01). Patients with IPF were more likely to be IgA-ACPA-positive than IgG-ACPA-positive (23.2% vs 8.3%; P < .01), whereas patients with RA were more likely to be IgG-ACPA-positive than IgA-ACPA-positive (72.5% vs 52.5%; P = .04). There was a strong correlation between IgA-ACPA level and the number of ectopic lymphoid aggregates on lung histologic examination in IPF (r = 0.72; P = .01). Conclusions: In this study, IgA-ACPA was elevated in patients with IPF and correlated with lymphoid aggregates in the lung, supporting the theory that IgA-ACPA may play a role in lung disease pathogenesis in a subset of individuals with IPF. Future studies are needed to determine whether this subset of ACPA-positive patients with IPF is distinct from patients with IPF but without antibodies.