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 casesLipid mediatorCrudeAdjustedb5S-HETE2.10 (1.12, 3.92)2.41 (1.43, 4.07)15S-HETE1.61 (0.88, 2.93)1.52 (0.87, 2.65)17-HDHAa1.59 (0.68, 3.74)1.61 (0.72, 3.56)adichotomized as <limit of detection (reference) or detectedbAdjusted for SE, age at baseline and cohortConclusion: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
The association between omega-3 fatty acid biomarkers and inflammatory arthritis in an anti-citrullinated protein antibody positive population