Synovial Joint Fluid Metabolomic Profiles and Pathways Differentiate Osteoarthritis, Rheumatoid Arthritis and Psoriatic Arthritis

Abstract Background Distinguishing between osteoarthritis (OA), rheumatoid arthritis (RA) and psoriatic arthritis (PsA) remains challenging despite different underlying mechanisms. Synovial fluid reflects metabolic changes within affected joints, yet comprehensive metabolomic comparisons across these conditions are limited. We aimed to identify disease-specific metabolic signatures in synovial fluid that could improve differential diagnosis and reveal therapeutic targets. Methods We collected synovial fluid from 39 patients (20 OA, 5 RA, 14 PsA) during routine knee arthrocentesis between January 2023 and February 2024. Following metabolite extraction, we performed untargeted metabolomic profiling using quadrupole time-of-flight liquid chromatography–mass spectrometry (Q-TOF LC/MS). Data underwent multivariate statistical analysis including Principal component analysis (PCA), partial least squares–discriminant analysis (PLS-DA), to identify discriminatory metabolites. Results While unsupervised analysis showed overlap between groups, supervised PLS-DA achieved clear metabolic separation. RA samples showed elevated itaconic acid indicating inflammatory macrophage activation, and increased O-acetylserine suggesting altered one-carbon metabolism. Hypoxanthine was decreased, which reflected severe metabolic stress. PsA exhibited the unique elevation of 4,4-dimethylcholestane and 2-oxoarginine. These metabolites were previously unreported in this disease. OA demonstrated increased hippuric acid and indoleacetic acid that are both gut microbiota products, supporting the gut-joint axis hypothesis. Conclusions Each arthritis type displayed distinct metabolic fingerprints in synovial fluid. Novel biomarkers including gut-derived metabolites in OA and specific lipid alterations in PsA open new diagnostic and therapeutic avenues. These metabolites can be translated into clinical tests for early diagnosis and targeted therapeutics addressing disease-specific metabolic disruptions.