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OBJECTIVES: We sought to identify metabolic changes potentially related to rheumatoid arthritis (RA) pathogenesis occurring in the blood prior to its diagnosis.METHODS: In a US military biorepository, serum samples collected at two timepoints prior to a diagnosis of RA were identified. These were matched to controls who did not develop RA by subject age, race and time between sample collections and RA diagnosis time to stored serum samples. Relative abundances of 380 metabolites were measured using liquid chromatography-tandem mass spectrometry. We determined whether pre-RA case versus control status predicted metabolite concentration differences and differences over time (trajectories) using linear mixed models, assessing for interactions between time, pre-RA status and metabolite concentrations. We separately examined pre-RA and pre-seropositive RA cases versus matched controls and adjusted for smoking. Multiple comparison adjustment set the false discovery rate to 0.05.RESULTS: 291 pre-RA cases (80.8% pre seropositive RA) were matched to 292 controls, all with two serum samples (2.7±1.6 years; 1.0±0.9 years before RA/matched date). 52.0% were women; 52.8% were White, 26.8% Black and 20.4% other race. Mean age was 31.2 (±8.1) years at earliest blood draw. Fourteen metabolites had statistically significant trajectory differences among pre-RA subjects versus controls, including sex steroids, amino acid/lipid metabolism and xenobiotics. Results were similar when limited to pre seropositive RA and after adjusting for smoking.CONCLUSIONS: In this military case-control study, metabolite concentration trajectory differences in pre-RA cases versus controls implicated steroidogenesis, lipid/amino acid metabolism and xenobiotics in RA pathogenesis. Metabolites may have potential as biomarkers and/or therapeutic targets preceding RA diagnosis.