Transcriptional Profiling of Tofacitinib Treatment in Juvenile Idiopathic Arthritis: Implications for Treatment Response Prediction.

IF 3.7 2区 医学 Q1 RHEUMATOLOGY
Esraa Eloseily, Alex Pickering, Sanjeev Dhakal, Nicolino Ruperto, Hermine I Brunner, Alexi A Grom, Sherry Thornton
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引用次数: 0

Abstract

Objectives: To assess changes in gene expression following tofacitinib treatment and investigate transcription patterns as potential predictors of treatment response in patients with active juvenile idiopathic arthritis (JIA).

Methods: Whole blood samples were collected from JIA patients at baseline and after 18 weeks of open-label tofacitinib treatment (clinical trial NCT02592434). Patients who achieved a JIA-American College of Rheumatology (ACR) response of 70 or above at week 18 were classified as treatment-responders (TR) while those with at most a JIA-ACR30 response were classified as poor-responders (PR). Differential gene expression and gene ontology (GO) over-representation analyses were performed to compare RNA expression between week 18 and baseline samples, as well as between PR and TR samples at baseline.

Results: Samples from 67 patients at baseline and 60 at week 18 were analyzed. Following 18 weeks of tofacitinib treatment across all JIA subjects, 883 genes showed significant differential expression (week 18 - baseline). The most strongly downregulated genes were over-represented within IL-7, type I, and type II interferon pathways, while upregulated genes were enriched in ontologies related to neuronal cell processes and cell signaling. Comparing PR and TR at baseline, 663 genes showed differential expression. Upregulated genes were over-represented within ontologies including activation of MAPK activity (p=9.40x10-5), myeloid cell development (p=8.13 x10-5), activation of GTPase activity (p=0.00015), and organelle transport along microtubules (p=0.00021).

Conclusions: Tofacitinib treatment in JIA downregulated genes in interferon and IL-7 signaling pathways regardless of effectiveness. Furthermore, baseline upregulation of MAPK signaling may predict poor response to tofacitinib treatment in JIA.

托法替尼治疗幼年特发性关节炎的转录谱分析:治疗反应预测的意义。
目的:评估托法替尼治疗后基因表达的变化,研究转录模式作为活动性幼年特发性关节炎(JIA)患者治疗反应的潜在预测因子:评估活动性幼年特发性关节炎(JIA)患者接受托法替尼治疗后基因表达的变化,并研究作为治疗反应潜在预测因子的转录模式:在基线和开放标签托法替尼治疗18周后收集JIA患者的全血样本(临床试验NCT02592434)。第18周时JIA-美国风湿病学会(ACR)反应达到70或以上的患者被归类为治疗反应者(TR),而最多达到JIA-ACR30反应的患者被归类为不良反应者(PR)。通过差异基因表达和基因本体(GO)过度表现分析,比较了第18周样本与基线样本之间以及基线PR样本与TR样本之间的RNA表达:分析了 67 例患者的基线样本和 60 例患者的第 18 周样本。所有JIA受试者在接受18周的托法替尼治疗后,有883个基因的表达出现了显著差异(第18周-基线)。最强烈下调的基因在IL-7、I型和II型干扰素通路中的比例过高,而上调的基因则富集在与神经元细胞过程和细胞信号传导相关的本体中。比较基线时的 PR 和 TR,有 663 个基因表现出不同的表达。上调基因在本体中的比例较高,包括MAPK活性激活(p=9.40x10-5)、髓样细胞发育(p=8.13x10-5)、GTP酶活性激活(p=0.00015)和细胞器沿微管转运(p=0.00021):结论:托法替尼治疗JIA可下调干扰素和IL-7信号通路中的基因,与疗效无关。此外,MAPK信号通路的基线上调可能预示着JIA患者对托法替尼治疗的不良反应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
9.40
自引率
6.40%
发文量
368
审稿时长
3-6 weeks
期刊介绍: Arthritis Care & Research, an official journal of the American College of Rheumatology and the Association of Rheumatology Health Professionals (a division of the College), is a peer-reviewed publication that publishes original research, review articles, and editorials that promote excellence in the clinical practice of rheumatology. Relevant to the care of individuals with rheumatic diseases, major topics are evidence-based practice studies, clinical problems, practice guidelines, educational, social, and public health issues, health economics, health care policy, and future trends in rheumatology practice.
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