Abstract

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.

中文翻译：

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类风湿关节炎患者血浆核苷酸水平升高

摘要

除了针对环状瓜氨酸肽的抗体外，还需要新的类风湿性关节炎 (RA) 生物标志物。代谢组分析是一种很有前途的方法，可以识别用于临床诊断的代谢物生物标志物。我们采用了一种综合的非靶向代谢组学方法，结合了毛细管电泳飞行时间质谱 (TOFMS) 和液相色谱 TOFMS。我们对日本人群的 286 份血浆样本（92 名 RA 患者、13 名系统性红斑狼疮 (SLE) 患者和 181 名健康对照）进行了代谢组学分析。RA 病例-对照关联测试表明，与对照相比，RA 样本中的七种代谢物水平显着升高（P < 1.0 × 10 ^-4; UTP、乙醇胺磷酸盐、ATP、GDP、ADP、6-氨基己酸和牛磺酸），而一种表现出降低的水平（黄嘌呤）。这八种代谢物的血浆水平在血清反应阳性和阴性 RA 患者之间没有显着差异（P > 0.05；n = 68 和 24，分别）。与接受治疗和未经治疗的患者相比，未经治疗的患者的四种核苷酸水平（UTP、ATP、GDP 和 ADP）显着升高（P < 0.014；n = 57 和 35）。此外，我们发现四种核苷酸水平在 SLE 病例对照关联测试中均未显示出显着差异（P> 0.2; 13 名 SLE 患者和 181 名共享对照）和银屑病关节炎（PsA）病例对照关联测试（P > 0.11；42 名 PsA 患者和 38 名健康对照），表明 RA 的疾病特异性。总之，我们的大规模代谢组分析表明 RA 患者血浆核苷酸水平升高，这可用作 RA 的潜在临床生物标志物，尤其是血清阴性 RA。