ASSOCIATIONS BETWEEN CIRCULATING LIPID MEDIATORS AND INCIDENT INFLAMMATORY ARTHRITIS IN AN ANTI-CITRULLINATED PROTEIN ANTIBODY POSITIVE POPULATION

Background: Lipid mediators are endogenously derived from the metabolism of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) and have important roles in promoting and resolving inflammation in the body (1). Epidemiological studies have shown higher omega-3 PUFA status to be associated with a lower risk of both autoimmunity and progression to inflammatory arthritis (IA) (2,3). Objectives: To determine the association of lipid mediators with progression from rheumatoid arthritis (RA)-related autoimmunity to inflammatory arthritis (IA). Methods: We conducted a prospective cohort study using data from the Studies of the Etiologies of Rheumatoid Arthritis (SERA). SERA enrolled first-degree relatives (FDRs) of individuals with RA (FDR cohort) and individuals who screened positive for RA-related autoantibodies at health fairs (screened cohort). We followed 133 anti-CCP3.1 positive participants, of which 29 developed IA (22 classified as RA by 2010 ACR/EULAR criteria). We quantified lipid mediators from stored plasma samples via liquid chromatography tandem mass spectrometry methods validated against the collection and storage methods used in the study. A priori, we selected 5S-HETE, 15S-HETE and 17S-HDHA because they are precursors to leukotrienes, Lipoxin A4 and Resolvin D series lipid mediators, respectively. We fit Cox proportional hazard models for each lipid mediator as a time-varying covariate. For lipid mediators significantly associated with progression to IA we then examined IL-1β, IL-6, IL-8 and TNF-α (Bio-Plex Pro™ assay) as potential mediators of this relationship. Results: Higher plasma 5S-HETE levels were associated with an increased risk of incident IA after adjusting for age at baseline, cohort (FDR or screened), and shared epitope (SE) status ( Table 1 ). The models examining 15S-HETE and 17S-HDHA had the same trend but did not reach statistical significance. We did not find evidence that the association between 5S-HETE and IA risk was mediated by the tested pro-inflammatory cytokines, suggesting a direct role for this lipid mediator in conversion to IA. Table 1. Hazard ratios and 95% confidence intervals of lipid mediator concentrations associated with IA, n=29 IA cases Lipid mediator Crude Adjusted 5S-HETE 2.10 (1.12, 3.92) 2.41 (1.43, 4.07) 15S-HETE 1.61 (0.88, 2.93) 1.52 (0.87, 2.65) 17-HDHA 1.59 (0.68, 3.74) 1.61 (0.72, 3.56) dichotomized as <limit of detection (reference) or detected Adjusted for SE, age at baseline and cohort Conclusion: In a prospective cohort of anti-CCP positive individuals, higher circulating levels of 5S-HETE, an important precursor to pro-inflammatory leukotrienes, was associated with subsequent IA. Our findings highlight the potential pathologic and prognostic significance of these PUFA metabolites in inflammatory processes in pre-RA populations. REFERENCES: [1]Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510(7503):92-101. [2]Gan RW, Bemis EA, Demoruelle MK, Striebich CC, Brake S, Feser ML, et al. The association between omega-3 fatty acid biomarkers and inflammatory arthritis in an anti-citrullinated protein antibody positive population. Rheumatology. 2017. [3]Gan RW, Young KA, Zerbe GO, Demoruelle MK, Weisman MH, Buckner JH, et al. Lower omega-3 fatty acids are associated with the presence of anti-cyclic citrullinated peptide autoantibodies in a population at risk for future rheumatoid arthritis: a nested case-control study. Rheumatology. 2016;55(2):367-76. Disclosure of Interests: Kristen Polinski: None declared, Elizabeth Bemis: None declared, Kristen Demoruelle Grant/research support from: Pfizer, Jennifer Seifert: None declared, Tessa Crume: None declared, Fan Yang: None declared, William Robinson: None declared, Michael Clare-Salzler: None declared, Kevin Deane Grant/research support from: Janssen, Consultant of: Inova, ThermoFisher, Janseen, BMS and Microdrop, Michael Holers Shareholder of: AdMIRx, Grant/research support from: AdMIRx, Pfizer, Janssen R&D, Consultant of: AdMIRx, Janssen R&D, Celgene, Bristol-Myers Squibb, Jill Norris Grant/research support from: Janssen R&D, Pfizer, Consultant of: Celgene, BMS Citation: Ann Rheum Dis, volume 79, supplement 1, year 2020, page 1252Session: Epidemiology, risk factors for disease or disease progression (Poster Presentations)