A panel incorporating genetic variants of RIN3, NLRC3, and SLX4 shows promise in predicting remission after tofacitinib therapy in rheumatoid arthritis patients.

IF 3.4 4区 医学 Q2 RHEUMATOLOGY
Po-Ku Chen, Yi-Ming Chen, Chia-Fong Cho, Jeremy J J W Chen, Jian-Ching Wu, David Daf, Ning-Rong Gong, Der-Yuan Chen
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引用次数: 0

Abstract

Objectives: To promote a treat-to-target goal of tofacitinib therapy, there are unmet needs to predict therapeutic response before treatment. Utilising whole-exome sequencing (WES) and real-time polymerase chain reaction (RT-PCR) analysis, we aim to identify predictors of achieving remission after tofacitinib therapy in rheumatoid arthritis (RA) patients.

Methods: We enrolled 242 patients who had received 24-week tofacitinib therapy, including 94 patients (Cohort-1) underwent WES analysis in the discovery stage and 148 patients (Cohort-2) were validated with RT-PCR assays or Sanger sequencing in the replication stage. Disease activity was assessed using the 28-joint disease activity score-erythrocyte sedimentation rate (DAS28-ESR), and therapeutic response at week24 was considered remission if DAS28-ESR <2.6.

Results: The WES analysis identified ten variants of RIN3, NLRC3, and SLX4 genes that were predictive of achieving remission after tofacitinib therapy, and its results were completely consistent with those from TaqMan assay or Sanger sequencing. Combined variants of RIN3, NLRC3, and SLX4 genes could predict achieving remission with AUC 0.831, specificity 97.4%, and accuracy 91.5% (Cohort-1). With validation in Cohort-2, a panel incorporating genetic variants of RIN3, NLRC3, and SLX4 showed a high specificity 97.0% and accuracy 86.0%. Using multiplexed one-step RT-PCR assay, this genetic panel still predicts remission with a high specificity 97.0% and accuracy of 88.0%. The significant differences in plasma levels of NLRC3, caspase-1, and IL-6 between the mutant gene and naive gene support the results of the gene ontology analysis.

Conclusions: Combined variants of RIN3, NLRC3, and SLX4 genes have great potential for predicting remission in tofacitinib-treated patients.

一个包含RIN3、NLRC3和SLX4基因变异的小组显示,在预测类风湿关节炎患者接受托法替尼治疗后的缓解方面有希望。
目的:为了促进托法替尼治疗从治疗到靶向的目标,在治疗前预测治疗反应存在未满足的需求。利用全外显子组测序(WES)和实时聚合酶链反应(RT-PCR)分析,我们旨在确定托法替尼治疗类风湿性关节炎(RA)患者后实现缓解的预测因素。方法:纳入242例接受了24周托法替尼治疗的患者,其中94例患者(队列1)在发现阶段进行了WES分析,148例患者(队列2)在复制阶段进行了RT-PCR检测或Sanger测序验证。使用28关节疾病活动性评分-红细胞沉降率(DAS28-ESR)评估疾病活动性,如果DAS28-ESR,则认为第24周的治疗反应缓解。结果:WES分析确定了10个RIN3、NLRC3和SLX4基因变体,这些基因变体可预测托法替尼治疗后达到缓解,其结果与TaqMan试验或Sanger测序的结果完全一致。RIN3、NLRC3和SLX4基因的联合变异可以预测获得缓解,AUC为0.831,特异性为97.4%,准确性为91.5%(队列1)。在队列2中验证,一个包含RIN3、NLRC3和SLX4遗传变异的小组显示出97.0%的高特异性和86.0%的准确性。使用多重一步RT-PCR检测,该基因面板预测缓解的特异性为97.0%,准确性为88.0%。突变基因与naive基因血浆NLRC3、caspase-1、IL-6水平的显著差异支持基因本体分析的结果。结论:RIN3、NLRC3和SLX4基因的联合变异在预测托法替尼治疗患者的缓解方面具有很大的潜力。
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来源期刊
CiteScore
6.10
自引率
18.90%
发文量
377
审稿时长
3-6 weeks
期刊介绍: Clinical and Experimental Rheumatology is a bi-monthly international peer-reviewed journal which has been covering all clinical, experimental and translational aspects of musculoskeletal, arthritic and connective tissue diseases since 1983.
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