摘要

        背景：甲氨蝶呤(MTX)是治疗类风湿性关节炎的一线药物。在甲氨蝶呤的疗效和安全性存在很大的个体差异，而最常见的不良反应是肝毒性，但肝损伤的主要原因仍然不明。我们以医院为基础的队列研究，分析甲氨蝶呤导致肝酶升高的影响因素。

        方法：研究对象为服用甲氨蝶呤的114名日本RA门诊成年患者。采用实时荧光定量PCR法检测了15种单核苷酸多态性。从电子病历中收集患者信息。在使用MTX治疗过程中肝酶偏离正常参考值定义为MTX诱导的肝酶升高。观察期为MTX开始后1年。用多变量logistic回归模型评估MTX诱导肝酶升高与患者各个临床因素之间的联系。

        结果：32例患者出现MTX引起的肝酶异常升高。在多变量分析中，MTX的剂量、估算的肾小球滤过率、ABCB1 3435C>T和 ATIC 347C>G基因多态性与MTX诱导的肝酶异常升高有关。

        结论：在这个以医院为基础的队列研究中，日本RA患者MTX诱导的肝酶升高不但与MTX剂量和EGFR等非遗传因素有关，而且与ABCB1 3435C>T和 ATIC347C>G遗传因素也相关。

        附原文：

        BACKGROUNDS:Methotrexate (MTX) is used as first-line treatment of rheumatoid arthritis (RA) worldwide. Large interindividual differences in MTX effectiveness and safety occur, and the most frequent adverse reaction is hepatotoxicity, although the main cause remains unknown. We investigated factors associated with MTX-induced hepatic enzymeelevation in a hospital-based cohort study.

        METHODS:Study participants were 114 Japanese adult RA outpatients prescribed MTX. Fifteen types of single-nucleotide polymorphisms were investigated using real-time PCR. Patient characteristics were collected from the electronic medical records. The onset of MTX-induced abnormal hepatic enzyme elevation was defined according to deviation from normal liver enzyme reference values during treatment. The observation periodwas 1 year after beginning MTX. Associations between MTX-induced hepatic enzyme elevation and patient characteristics were evaluated using the multivariate logistic regression model.

        RESULTS:Thirty-two patients experienced MTX-induced abnormal hepatic enzyme elevation. In multivariate analysis, MTX dosage, estimated glomerular filtration rate (eGFR), and genetic polymorphisms of ABCB13435C>T and ATIC 347C>G were associated with abnormal hepatic enzymeelevation.

        CONCLUSIONS:MTX-induced abnormal hepatic enzyme elevation inJapanese RA patients was associated with dosage and eGFR as non-geneticfactors, and with ABCB1 3435C>T and ATIC 347C>G as genetic factors in this hospital-based cohort study.

        引自：HakamataJ, Hashiguchi M, Kaneko Y, et al. Risk factors for abnormal hepatic enzymeelevation by methotrexate treatment in patients with rheumatoid arthritis: ahospital based-cohort study[J]. Modern Rheumatology, 2017:1-27.