Rheumatoid arthritis (RA)-specific autoantibodies in patients with interstitial lung disease and absence of clinically apparent articular RA

Abstract

The purpose of this study was to identify rheumatoid arthritis (RA)-related autoantibodies in subjects with interstitial lung disease (ILD) and no articular findings of RA, supporting the hypothesis that RA-related autoimmunity may be generated in non-articular sites, such as the lung. This was a retrospective chart review utilizing clinic databases of patients with ILD to identify cases with lung disease, RA-related autoantibody positivity, and no clinical evidence of articular RA. Four patients with ILD, RF, and anti-CCP positivity and no articular findings of RA were identified. All four patients were male with a mean age at time of diagnosis of ILD of 70 years old. All had a history of smoking. Three patients died within 2 years of diagnosis of ILD and never developed articular symptoms consistent with RA; the final case met full criteria for articular RA several months after stopping immunosuppressive treatment for ILD. RF and anti-CCP can be present in smokers with ILD without clinical evidence of articular RA and in one case symptomatic ILD and autoantibody positivity preceded the development of articular RA. These findings suggest that RA-specific autoimmunity may be generated due to immunologic interactions in the lung and may be related to environmental factors such as smoking.

Identification of Citrullinated Hsp90 Isoforms as Novel Autoantigens in Rheumatoid Arthritis–Associated Interstitial Lung Disease

“…Although patients possessing these autoantibodies manifested greater levels of RF and higher (mean) anti-CCP-2 concentrations in conjunction with a trend toward shared epitope positivity, other parameters of articular and global disease activity did not differ significantly between these subgroups. Collectively, however, these data not only provided initial validation of our "reverse immunophenotyping" approach as a viable tool in biomarker discovery, but also supported an emerging paradigm featuring the lung as an important site of protein citrullination and immune-mediated injury in RA (19,28,29).…”

Rheumatoid arthritis-associated lung disease

“…Anti-CCP antibodies have also been associated with the development of airway disease [2]. There is growing evidence that rheumatoid arthritis begins in the lungs, a theory supported by a subgroup of patients who are anti-CCP positive with lung disease but have no articular manifestations [22,23]. Additionally, a form of reactive lymphoid tissue known as inducible bronchus-associated lymphoid tissue (BALT) has been found in patients with rheumatoid arthritis-related lung disease and is associated with local production of inflammatory cytokines and anti-CCP antibodies [24].…”

Rheumatoid Arthritis Interstitial Lung Disease

“…In addition, existing evidence suggests that a proportion of patients with positive RA serology may already have HRCT parenchymal lung changes at time of RA diagnosis (Gabbay et al, 1997, Metafratzi et al, 2007, Reynsdottir et al, 2011. In fact, a retrospective study by Gizinski et al (2009) showed that positive RA serology can be found in smokers with ILD without symptoms and signs of RA, but who may later develop RA. Therefore, clinicians assessing patients with positive RA serology but no articular symptoms should nevertheless inquire and be mindful of respiratory symptoms in these patients.…”