Altered plasma metabolomic profiles in treatment-naïve patients with newly diagnosed rheumatoid arthritis

Rheumatoid arthritis (RA) is characterized by chronic inflammatory polyarthritis. Despite recent advances in treatment, a subset of patients remains refractory, highlighting the need for better biomarkers for diagnosis and disease activity monitoring to determine appropriate interventions. Therefore, this study aimed to characterize the plasma metabolic profiles of RA and identify candidate metabolite markers for the disease. Plasma samples from treatment-naïve patients with newly diagnosed RA (n = 48) and healthy controls (HC; n = 45) were analyzed using liquid chromatography-tandem mass spectrometry. Fifty-five metabolites were included in the analysis; carnosine, glutamic acid, dimethylglycine, and taurine were significantly increased in RA, whereas histidine, methionine sulfoxide, tryptophan, and alanine were significantly decreased. Metabolite set enrichment analysis showed altered histidine metabolism in patients with RA, and the carnosine/histidine ratio showed the highest area under the ROC curve among the metabolites tested. Histidine was also inversely associated with disease activity and anti-citrullinated protein antibody (ACPA) production. In addition, decreased citrulline levels were significantly associated with higher ACPA production. This study identified the carnosine/histidine ratio as a candidate marker for RA and implicates an imbalance between carnosine synthesis and degradation in its pathophysiology, based on an analysis of treatment-naïve patients with covariate adjustments.