The Anti-Cyclic Citrullinated Protein Antibody Repertoire and Lung Involvement in Rheumatoid Arthritis

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PROJECT SUMMARY/ABSTRACT Though pulmonary fibrosis (PF) is a common and morbid complication of rheumatoid arthritis (RA), little is known about who with RA is at risk for its development and what predicts progressive and lethal PF. Anti-cy- clic citrullinated protein antibodies (ACPA) are present in patients before the development of joint disease in RA and are also found in a subset of patients with usual interstitial pneumonia (UIP), the most common form of PF seen in RA and the one that carries a dismal prognosis. Mounting evidence suggests that the lungs play a key role in the formation of these ACPA and may be intimately involved in the pathogenesis of disease in a subset of patients with RA. The hypothesis of this project is that as patients evolve from pre-RA (i.e., serum or sputum autoimmunity without disease) to RA joint disease to progressive RA-UIP, there is an expansion of cit- rullinated protein targets that encompass both lung and joint specific proteins, and this repertoire can predict clinical phenotype. We will test our hypothesis by identifying 4 subgroups of patients: (1) Pre-RA, (2) UIP pre- RA, (3) RA no UIP and (4) RA-UIP. We will look at the differences in this ACPA repertoire between these co- horts, identify lung-specific ACPA targets that can predict the onset of UIP in RA and explore the relationship between these ACPA targets and progressive lung disease. This proposal helps further the mission of the Na- tional Institute of Arthritis and Musculoskeletal and Skin Diseases by proposing patient-relevant clinical re- search that tests a hypothesis on the etiology of a major co-morbidity of rheumatoid arthritis. This proposal will broaden our understanding of the relationship between RA and the lungs, uncover valuable clinically relevant biomarkers and provide caregivers with tools to predict disease onset and behavior in order to personalize treatment decisions. Long-term goals of this proposal include reducing the burden of disease, strengthening our ability to enrich cohorts for upcoming clinical trials and highlighting plausible disease pathways for future research.