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BACKGROUND: Metabolic dysregulations have been reported in multiple sclerosis (MS), but it is unclear whether metabolic profiles at disease onset predict long-term outcomes.OBJECTIVES: We evaluated whether baseline metabolic profiles at MS onset could predict disease activity/progression over 5 years.METHODS: This prospective study included 468 patients enrolled in the BENEFIT trial at first clinical episode who completed 5 years of follow-up. Untargeted metabolomic profiling of 545 metabolites was performed at baseline using liquid chromatography-mass spectrometry. Associations with clinical and radiological outcomes were assessed using regression models, and machine learning was applied to identify metabolic signatures of worse outcomes. Models were adjusted for demographic, clinical, and lifestyle covariates.RESULTS: Distinct metabolomic signatures were associated with worse 5-year outcomes, including relapses, lesion volume, brain atrophy, and disability (Expanded Disability Status Scale (EDSS), multiple sclerosis functional composite (MSFC)). These signatures modestly improved outcome prediction beyond established predictors, with the largest gain for brain volume loss (area under the curve (AUC) = 0.68-0.86). Pathway analysis showed enrichment of nicotinate/nicotinamide, histidine, and arginine metabolism across several outcomes, with unsaturated fatty acid biosynthesis specifically with relapses.CONCLUSION: Metabolic profiles in early MS modestly improve the prediction of 5-year outcomes beyond clinical factors. Consistent enrichment across some pathways suggests potential biological relevance, warranting further investigation of individual metabolites.