A Molecular Signature Response Classifier to Predict Inadequate Response to Tumor Necrosis Factor-α Inhibitors: The NETWORK-004 Prospective Observational Study.
A Molecular Signature Response Classifier to Predict Inadequate Response to Tumor Necrosis Factor-α Inhibitors: The NETWORK-004 Prospective Observational Study.
复制标题
预测肿瘤坏死因子-α抑制剂反应不足的分子标记反应分类器：NETWORK-004前瞻性观察研究。
DOI：
10.1007/s40744-021-00330-y
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发表时间：
2021-09
影响因子：
3.8
通讯作者：
Akmaev VR
中科院分区：
文献类型：
--
作者：
Cohen S;Wells AF;Curtis JR;Dhar R;Mellors T;Zhang L;Withers JB;Jones A;Ghiassian SD;Wang M;Connolly-Strong E;Rapisardo S;Gatalica Z;Pappas DA;Kremer JM;Saleh A;Akmaev VR
及时将患者与有益的靶向治疗相匹配是类风湿性关节炎（RA）中未满足的需求。预测RA患者对肿瘤坏死因子-α抑制剂（TNFi）治疗不太可能应答的分子标记应答分类器（MSRC）将具有广泛的临床实用性。使用对血液患者样品中的类风湿性关节炎病理生理学和基因表达数据特异性的蛋白质-蛋白质相互作用图谱来发现对TNFi疗法无应答的分子特征。在来自CERTAIN队列和一项多中心盲法前瞻性观察性临床研究（NETWORK-004）的391例靶向治疗初治患者和113例TNF-α暴露患者样本的血液样本中验证了不充分的反应预测。主要终点评价了MSRC根据ACR 50在6个月时识别对TNFi治疗反应不充分的患者的能力。其他终点通过ACR 70、DAS 28-CRP和CDAI评估了3个月和6个月时疗效不充分的预测。23特征分子标记考虑了TNFα参与RA病理生理学的上游和下游途径。预测性能在CERTAIN队列和NETWORK-004研究之间是一致的。NETWORK-004研究符合主要和次要终点。在45%的靶向治疗初治患者中检测到无应答的分子特征。MSRC的曲线下面积（AUC）为0.64，根据6个月时的ACR 50，患者不太可能充分响应TNFi治疗，比值比为4.1（95%置信区间2.0-8.3，p值0.0001）。3个月和6个月时其他终点的比值比（3.4-8.8）具有显著性（p值< 0.01），AUC值高达0.74。在TNFi暴露患者中，MSRC的AUC高达0.83，并且与ACR、DAS 28-CRP和CDAI指标的3.3-26.6的显著比值比相关。MSRC根据对TNFi治疗反应不足的可能性对患者进行分层，并提供患者特异性数据，以指导靶向治疗初治和TNFi暴露患者的RA治疗选择。在线版本包含补充材料，可通过10.1007/s40744-021-00330-y获得。基于血液的分子特征响应分类器（MSRC）将下一代RNA测序数据与临床特征相结合，预测类风湿性关节炎患者对TNFi治疗反应不足的可能性。由测试结果指导的治疗选择，可能不充分的反应者适当地重新定向到不同的治疗，可以提高对TNFi治疗的反应率，节省医疗费用，并增加风湿病学家对处方决策和改变治疗选择的信心。本研究中描述的MSRC预测了一项多中心、24周设盲前瞻性临床研究（NETWORK-004）中靶向治疗初治和TNFi暴露患者对TNFi治疗反应不足的可能性。根据ACR 50、ACR 70、CDAI和DAS 28-CRP，与缺乏分子特征的患者相比，具有无应答分子特征的患者对TNFi治疗的充分应答的可能性较小，靶向治疗初治患者的显著比值比为3.4-8.8，TNFi暴露患者的显著比值比为3.3-26.6。这种MSRC提供了一个解决方案，长期需要精确的医学工具来预测类风湿关节炎的药物反应，类风湿关节炎是一种异质性和进行性疾病，有丰富的治疗选择。这些数据验证了MSRC在靶向治疗初治和TNFi治疗暴露患者的设盲前瞻性临床研究中的性能。在线版本包含补充材料，可通过10.1007/s40744-021-00330-y获得。
Timely matching of patients to beneficial targeted therapy is an unmet need in rheumatoid arthritis (RA). A molecular signature response classifier (MSRC) that predicts which patients with RA are unlikely to respond to tumor necrosis factor-α inhibitor (TNFi) therapy would have wide clinical utility. The protein–protein interaction map specific to the rheumatoid arthritis pathophysiology and gene expression data in blood patient samples was used to discover a molecular signature of non-response to TNFi therapy. Inadequate response predictions were validated in blood samples from the CERTAIN cohort and a multicenter blinded prospective observational clinical study (NETWORK-004) among 391 targeted therapy-naïve and 113 TNFi-exposed patient samples. The primary endpoint evaluated the ability of the MSRC to identify patients who inadequately responded to TNFi therapy at 6 months according to ACR50. Additional endpoints evaluated the prediction of inadequate response at 3 and 6 months by ACR70, DAS28-CRP, and CDAI. The 23-feature molecular signature considers pathways upstream and downstream of TNFα involvement in RA pathophysiology. Predictive performance was consistent between the CERTAIN cohort and NETWORK-004 study. The NETWORK-004 study met primary and secondary endpoints. A molecular signature of non-response was detected in 45% of targeted therapy-naïve patients. The MSRC had an area under the curve (AUC) of 0.64 and patients were unlikely to adequately respond to TNFi therapy according to ACR50 at 6 months with an odds ratio of 4.1 (95% confidence interval 2.0–8.3, p value 0.0001). Odds ratios (3.4–8.8) were significant (p value < 0.01) for additional endpoints at 3 and 6 months, with AUC values up to 0.74. Among TNFi-exposed patients, the MSRC had an AUC of up to 0.83 and was associated with significant odds ratios of 3.3–26.6 by ACR, DAS28-CRP, and CDAI metrics. The MSRC stratifies patients according to likelihood of inadequate response to TNFi therapy and provides patient-specific data to guide therapy choice in RA for targeted therapy-naïve and TNFi-exposed patients. The online version contains supplementary material available at 10.1007/s40744-021-00330-y. A blood-based molecular signature response classifier (MSRC) integrating next-generation RNA sequencing data with clinical features predicts the likelihood that a patient with rheumatoid arthritis will have an inadequate response to TNFi therapy. Treatment selection guided by test results, with likely inadequate responders appropriately redirected to a different therapy, could improve response rates to TNFi therapies, generate healthcare cost savings, and increase rheumatologists’ confidence in prescribing decisions and altered treatment choices. The MSRC described in this study predicts the likelihood of inadequate response to TNFi therapies among targeted therapy-naïve and TNFi-exposed patients in a multicenter, 24-week blinded prospective clinical study: NETWORK-004. Patients with a molecular signature of non-response are less likely to have an adequate response to TNFi therapies than those patients lacking the signature according to ACR50, ACR70, CDAI, and DAS28-CRP with significant odds ratios of 3.4–8.8 for targeted therapy-naïve patients and 3.3–26.6 for TNFi-exposed patients. This MSRC provides a solution to the long-standing need for precision medicine tools to predict drug response in rheumatoid arthritis—a heterogeneous and progressive disease with an abundance of therapeutic options. These data validate the performance of the MSRC in a blinded prospective clinical study of targeted therapy-naïve and TNFi therapy-exposed patients. The online version contains supplementary material available at 10.1007/s40744-021-00330-y.
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影响因子：
3.8
作者：
Bergman MJ;Kivitz AJ;Pappas DA;Kremer JM;Zhang L;Jeter A;Withers JB
通讯作者：
Withers JB
影响因子：
1.6
作者：
Conigliaro, Paola;Chimenti, Maria Sole;Perricone, Roberto
通讯作者：
Perricone, Roberto
影响因子：
2.4
作者：
Chastek, Benjamin;Becker, Laura K.;Curtis, Jeffrey R.
通讯作者：
Curtis, Jeffrey R.
影响因子：
4.9
作者：
Jin, Yinzhu;Desai, Rishi J.;Kim, Seoyoung C.
通讯作者：
Kim, Seoyoung C.
影响因子：
4.3
作者：
Ghiassian SD;Menche J;Barabási AL
通讯作者：
Barabási AL