Rheumatoid arthritis (RA) is a systemic inflammatory disorder affecting approximately 1.5 million people in the United States. Although parenchymal lung disease, which encompasses interstitial lung disease (ILD) and emphysema, is a common lungcomplication of RA with increasing prevalence and mortality, no strategies currently exist for early detection or risk stratification of progressive disease. This is an area of unmet need that could lead to improved opportunities for intervention and a decrease in the considerable morbidity and mortality of RA-associated parenchymal lung disease. In this proposal, we aim to fully characterize early parenchymal lung disease in RA and establish risk factors for progressive disease. We hypothesize that clinical and molecular risk factors can predict the development and progression of RA-associated parenchymal lung disease, including preclinical ILD (preILD) and emphysema, and that the molecular profile of progressive RA-preILD will overlap with fibrotic RA-ILD. To test this hypothesis, we will propose the following: In Specific Aim 1, we will determine the prevalence and progression of RA-associated preILD and emphysema using visual and objective radiologic approaches and correlate these measurements with functional capacity, respiratory symptoms, and health-related quality of life assessments. In Specific Aim 2, we will define clinical and molecular determinants that predict the development and progression of RA emphysema and compare the molecular profile of emphysema with preILD to provide mechanistic insight into the divergent patterns of parenchymal lung injury caused by RA. In Specific Aim 3, we will demonstrate that progressive RA-preILD and fibrotic RA-ILD have similar molecular signatures, suggesting phenotypic and mechanistic overlap. To achieve the aims of this proposal, a longitudinal cohort of 200 RA patients without a history of ILD will be followed for up to 6 years with detailed clinical, functional, radiologic, and molecular phenotyping. The successful completion of this research will provide us with a better understanding of the early characteristics and natural history of RA-associated ILD and emphysema and establish novel non-invasive ways to identify those at risk for progressive disease. This will enable closer monitoring and earlier opportunities for intervention, potentially leading to decreased morbidity and mortality in individuals afflicted with RA-associated parenchymal lung disease.