Increased levels of plasma nucleotides in patients with rheumatoid arthritis.

Novel biomarkers of rheumatoid arthritis (RA), in addition to antibodies against cyclic citrullinated peptides, are required. Metabolome analysis is a promising approach to identify metabolite biomarkers for clinical diagnosis. We adopted a comprehensive nontargeted metabolomics approach combining capillary electrophoresis time-of-flight mass-spectrometry (TOFMS) and liquid chromatography TOFMS. We constructed metabolomics profiling of 286 plasma samples of the Japanese population. (92 RA patients, 13 systemic lupus erythematosus (SLE) patients, and 181 healthy controls). RA case-control association tests showed that seven metabolites exhibited significantly increased levels in RA samples than in controls [P & 1.0×10 -4; UTP, ethanolamine phosphate, ATP, GDP, ADP, 6-aminohexanoic acid, and taurine], whereas one exhibited a decreased level (xanthine). The plasma levels of these eight metabolites were not significantly different between seropositive and seronegative RA patients (P > 0.05; n = 68 and 24, respectively). The four nucleotide levels (UTP, ATP, GDP, and ADP) were significantly higher in the non-treatment patients in comparison between patients with and without treatment (P & 0.014; n = 57 and 35, respectively). Furthermore, we found that none of the four nucleotides levels showed significant differences in SLE case-control association tests (P > 0.2; 13 patients with SLE and the 181 shared controls) and psoriatic arthritis (PsA) case-control association tests (P > 0.11; 42 patients with PsA and 38 healthy controls), indicating disease specificity in RA. In conclusion, our large-scale metabolome analysis demonstrated the increased plasma nucleotides levels in RA patients, which could be used as potential clinical biomarkers of RA, especially for seronegative RA.