Increased levels of plasma nucleotides in patients with rheumatoid arthritis

Toshihiro Kishikawa, Yuichi Maeda, Takuro Nii, Noriko Arase, Jun Hirata, Ken Suzuki, Kenichi Yamamoto, Tatsuo Masuda, Kotaro Ogawa, Shigeyoshi Tsuji, Masato Matsushita, Hidetoshi Matsuoka, Maiko Yoshimura, Shinichiro Tsunoda, Shiro Ohshima, Masashi Narazaki, Atsushi Ogata, Yukihiko Saeki, Hidenori Inohara, Atsushi KumanogohKiyoshi Takeda, Yukinori Okada

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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 non-targeted metabolomics approach combining capillary electrophoresis time-of-flight mass spectrometry (TOFMS) and liquid chromatography TOFMS. We constructed metabolomics profiling of 286 plasma samples of a 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 compared with 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 nucleotide 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 nucleotide levels in RA patients, which could be used as potential clinical biomarkers of RA, especially for seronegative RA.

Original languageEnglish
Pages (from-to)119-124
Number of pages6
JournalInternational Immunology
Issue number2
StatePublished - 1 Feb 2021
Externally publishedYes


  • biomarker
  • metabolome
  • psoriatic arthritis
  • systemic lupus erythematosus


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