Abstract/Summary Rheumatoid arthritis (RA), a common autoimmune rheumatic condition, has no cure and even with novel treatments, is associated with significant irreversible joint damage, physical disability, and numerous comorbidities. The appearance of serum anti-citrullinated protein antibodies (ACPAs) indicates RA-related autoimmunity and defines the start of the preclinical period of RA, which is the ideal time to identify relevant disease risk biomarkers and approaches for disease prevention. The etiology of RA has a genetic component, which may interact with environment in the development of disease. RA is characterized by excessive chronic inflammation, suggesting a failure in the ability to control/resolve inflammation. Mechanisms for both initiating and resolving inflammation are important for physiological homeostasis. Lipid mediators, products of the metabolism of omega-3 and omega-6 polyunsaturated fatty acids, are involved in both initiation and resolution of inflammation. We have shown that an elevated level of an individual omega-6 lipid mediator (5-HETE) increased risk of progression from RA-related autoimmunity to inflammatory arthritis. However, as lipid mediators share common pathways and enzymes, we propose that individual lipid mediators do not act in isolation and therefore should be analyzed in combination as a profile. We propose to conduct a study in three novel at-risk cohorts: the Targeting Immune Responses for Prevention of Rheumatoid Arthritis (TIP-RA) cohort of 81 ACPA+ individuals, the Studies of the Etiologies of RA (SERA) cohort of 79 ACPA+ individuals, and the StopRA cohort of 144 ACPA+ individuals in the preclinical period of RA that have been followed over time for the development of RA. We will create lipid mediator profiles (a composite score of combinations of highly correlated lipid mediators) indicating the ability to resolve inflammation by performing principal components analysis of the lipid mediators and look at the trajectories of these profiles over time. Aim 1 will determine if the association of these profiles with progression from ACPA+ to RA differs by genetic susceptibility to RA. We will also explore whether the association is mediated by cytokine profiles or trajectories. Aim 2 will explore the underlying mechanism by examining whether the lipid mediator profiles are associated with DNA methylation differences or trajectories. Aim 3 will examine inflammation resolution in the lung by identifying sputum lipid mediator profiles and cytokines associated with progression from RA-related autoimmunity to RA. Results from this work will provide the foundation for designing prevention studies by elucidating which combinations of lipid mediators play a role in inflammation resolution in preclinical RA. The inability to resolve inflammation can lead to chronic inflammation; a common pathogenic element of RA. Elucidating mechanisms as well as the site (ie lung) of inflammation resolution during the precl...