Peripheral Blood Biomarkers of RA-associated Interstitial Lung Disease

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DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is the most common systemic autoimmune disease in the United States, affecting 1-2% of the adult population. Although joints and synovium are the primary targets in this disorder, extra-articular manifestations involving the eyes, skin, heart, vasculature, and lungs can lead to significant morbidity as well as excess mortality. Among the various pulmonary complications that occur in RA, interstitial lung disease (ILD) is the most damaging, with effects that range from subclinical inflammation/scarring to end stage pulmonary fibrosis. Because earlier, subclinical forms of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) may represent more treatable precursors of pulmonary fibrosis, non-invasive peripheral biomarkers are needed to identify this pulmonary complication in advance of clinical decompensation. Based on the hypothesis that CXCR3-binding chemokines and various matrix metalloproteinases play a significant role in driving inflammation as well as tissue damage in RA-ILD, Specific Aim 1 employs multiplex ELISA in RA patients with/without various forms of ILD to correlate the peripheral blood/serum levels of these signaling molecules and degradative enzymes with stage of lung disease. Extending the analysis of Specific Aim 1, Specific Aim 2 defines composite biomarker profiles of serum protein expression patterns in a parallel cohort of VA-derived RA patients with varying stages of ILD, validating the use of serum multiplex ELISA and elucidating the contribution of important secondary factors such as smoking. Finally, Specific Aim 3 complements this molecular phenotyping approach, utilizing immunoprecipitation and ELISA-based techniques to delineate serum anti-citrullinated protein autoantibody profiles that correlate with the presence or absence of ILD. Through the development of peripheral blood biomarker signatures associated with RA-ILD, these collective approaches will provide insight regarding the pathogenesis of RA-ILD and other forms of immunologically mediated lung disease. More importantly, defining the molecular phenotype of ILD will identify therapeutic targets facilitating early treatment intervention in this potentially devastating extra-articular complication of RA.