Plasma Metabolome Normalization in Rheumatoid Arthritis Following Initiation of Methotrexate and the Identification of Metabolic Biomarkers of Efficacy.
Plasma Metabolome Normalization in Rheumatoid Arthritis Following Initiation of Methotrexate and the Identification of Metabolic Biomarkers of Efficacy.
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甲氨蝶呤启动后类风湿关节炎的血浆代谢组归一化和疗效代谢生物标志物的鉴定。
DOI：
10.3390/metabo11120824
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发表时间：
2021-11-30
期刊：
影响因子：
4.1
通讯作者：
Funk RS
中科院分区：
文献类型：
--
作者：
Medcalf MR;Bhadbhade P;Mikuls TR;O'Dell JR;Gundry RL;Funk RS
甲氨蝶呤(MTX)治疗类风湿性关节炎(RA)的疗效是可变的和不可预测的，因此需要确定生物标志物来指导药物治疗。本研究评价RA患者与MTX反应相关的血浆代谢组的变化，目的是了解MTX疗效的代谢基础，以识别MTX反应的潜在代谢生物标志物。分别于治疗前和治疗16周后采集健康对照组(n=20)和类风湿关节炎患者(n=20)的血浆样本。对样本进行半靶向代谢组学分析，然后进行单变量和多变量分析，以及浓缩分析。MTX反应被定义为28个关节的疾病活动评分(DAS-28)在临床上显著降低超过1.2分；临床缓解的实现，定义为DAS-28<；2.6，也被用作额外的反应测量。在这项研究中，类风湿关节炎与血浆代谢组改变有关，该代谢组在MTX治疗开始后恢复正常。类风湿关节炎患者的代谢产物种类多样，包括甘油三酯(p=1.1×10−16)、脂肪酸(p=8.0×10−12)和神经酰胺(p=9.8×10−13)。根据对MTX的反应进行分层，确定了在应答者和无应答者中受到不同影响的各种代谢物，包括葡萄糖神经酰胺(GlcCer)、磷脂酰胆碱(PC)、神经鞘蛋白(SM)、磷脂酰乙醇胺(PE)、胆碱、肌苷、次黄嘌呤、鸟苷、烟酰胺和衣康酸(p<；0.05)。综上所述，类风湿关节炎与MTX治疗16周后至少部分恢复正常的血浆代谢组的显著改变有关。多种代谢物的变化被发现与MTX的疗效有关，包括与脂肪酸/脂类、核苷酸和能量代谢有关的代谢物。
Methotrexate (MTX) efficacy in the treatment of rheumatoid arthritis (RA) is variable and unpredictable, resulting in a need to identify biomarkers to guide drug therapy. This study evaluates changes in the plasma metabolome associated with response to MTX in RA with the goal of understanding the metabolic basis for MTX efficacy towards the identification of potential metabolic biomarkers of MTX response. Plasma samples were collected from healthy control subjects (n = 20), and RA patients initiating MTX therapy (n = 20, 15 mg/week) before and after 16 weeks of treatment. The samples were analyzed by a semi-targeted metabolomic analysis, and then analyzed by univariate and multivariate methods, as well as an enrichment analysis. An MTX response was defined as a clinically significant reduction in the disease activity score in 28 joints (DAS-28) of greater than 1.2; achievement of clinical remission, defined as a DAS-28 < 2.6, was also utilized as an additional measure of response. In this study, RA is associated with an altered plasma metabolome that is normalized following initiation of MTX therapy. Metabolite classes found to be altered in RA and corrected by MTX therapy were diverse and included triglycerides (p = 1.1 × 10−16), fatty acids (p = 8.0 × 10−12), and ceramides (p = 9.8 × 10−13). Stratification based on responses to MTX identified various metabolites differentially impacted in responders and non-responders including glucosylceramides (GlcCer), phosphatidylcholines (PC), sphingomyelins (SM), phosphatidylethanolamines (PE), choline, inosine, hypoxanthine, guanosine, nicotinamide, and itaconic acid (p < 0.05). In conclusion, RA is associated with significant alterations to the plasma metabolome displaying at least partial normalization following 16 weeks of MTX therapy. Changes in multiple metabolites were found to be associated with MTX efficacy, including metabolites involved in fatty acid/lipid, nucleotide, and energy metabolism.
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DOI：
10.1002/art.40504
发表时间：
2018-07
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
--
作者：
Falconer J;Murphy AN;Young SP;Clark AR;Tiziani S;Guma M;Buckley CD
通讯作者：
Buckley CD
类风湿关节炎的新治疗方法可能来自胆碱能抗炎途径和镇痛途径
影响因子：
--
作者：
Pan XH;Zhang J;Yu X;Qin L;Kang L;Zhang P
通讯作者：
Zhang P
影响因子：
3.9
作者：
Funk, Ryan S.;Singh, Rakesh K.;Becker, Mara L.
通讯作者：
Becker, Mara L.
DOI：
10.1038/nrrheum.2016.178
发表时间：
2017-01
期刊：
Nature reviews. Rheumatology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.2
作者：
Abbenhardt, Clare;Miller, Joshua W.;Ulrich, Cornelia M.
通讯作者：
Ulrich, Cornelia M.