Molecular and Genetic Characteristics of Progressive Rheumatoid Arthritis-associated Interstitial Lung Disease

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PROJECT SUMMARY / ABSTRACT Rheumatoid arthritis (RA) is a systemic inflammatory disorder affecting approximately 1.3 million people in the United States. Interstitial lung disease (ILD) is a common lung complication of RA with increasing prevalence and mortality. Although RA-associated ILD is similar to other types of lung fibrosis, little is known about the molecular and genetic characteristics and natural history of RA-associated ILD, both early and advanced forms of disease. Some studies have suggested that there is a spectrum of RA-associated ILD with approximately 10% of RA patients having advanced disease, and another 30% with early disease, half of whom will progress. It has also been shown that clinical risk factors and peripheral blood molecular markers may enhance the assessment and prognostication of individuals with RA-associated ILD. In this proposal, the applicant hypothesizes that a clinical predictive model composed of risk factors, functional decrements, and molecular and genetic markers can predict the development and progression of both early and advanced forms of disease. Specifically, in her first aim, she will assess the ability of a risk score to identify subclinical and clinically-evident RA-ILD and evaluate if pulmonary auscultation, respiratory symptoms, and/or functional decrements can enhance the performance of this clinical predictive model. In her second aim, she will determine if the risk score correlates with disease progression through fully characterizing progressive subclinical and clinically-evident RA-associated ILD in the BRASS and TRAIL1 populations with respect to clinical findings, respiratory symptoms, functional decrements, and molecular markers. In her third aim, she will identify genetic markers associated with the development and progression of RA-associated ILD to determine if they can improve the ability of the clinical model to identify progressive disease. To achieve the aims of this proposal, a longitudinal cohort of well-characterized RA patients with early and advanced ILD will be developed with detailed molecular and genetic phenotyping, providing an invaluable resource for future longitudinal studies. The successful completion of this research will provide us with novel non-invasive ways to identify those at risk for progressive RA-associated ILD as well as a better understanding of the characteristics and natural history of early disease. This will enable closer monitoring and earlier treatment of affected individuals, potentially leading to decreased morbidity and mortality in individuals afflicted with RA-associated ILD.