Pfizer Inc., Cambridge, USA.
Department of Asthma, Allergy & Lung Biology, GSTT Campus, King's College School of Medicine, London, UK.
J Transl Med. 2018 Jan 29;16(1):18. doi: 10.1186/s12967-018-1387-9.
BACKGROUND: There is a pressing need in rheumatoid arthritis (RA) to identify patients who will not respond to first-line disease-modifying anti-rheumatic drugs (DMARD). We explored whether differences in genomic architecture represented by a chromosome conformation signature (CCS) in blood taken from early RA patients before methotrexate (MTX) treatment could assist in identifying non-response to DMARD and, whether there is an association between such a signature and RA specific expression quantitative trait loci (eQTL). METHODS: We looked for the presence of a CCS in blood from early RA patients commencing MTX using chromosome conformation capture by EpiSwitch™. Using blood samples from MTX responders, non-responders and healthy controls, a custom designed biomarker discovery array was refined to a 5-marker CCS that could discriminate between responders and non-responders to MTX. We cross-validated the predictive power of the CCS by generating 150 randomized groups of 59 early RA patients (30 responders and 29 non-responders) before MTX treatment. The CCS was validated using a blinded, independent cohort of 19 early RA patients (9 responders and 10 non-responders). Last, the loci of the CCS markers were mapped to RA-specific eQTL. RESULTS: We identified a 5-marker CCS that could identify, at baseline, responders and non-responders to MTX. The CCS consisted of binary chromosome conformations in the genomic regions of IFNAR1, IL-21R, IL-23, CXCL13 and IL-17A. When tested on a cohort of 59 RA patients, the CCS provided a negative predictive value of 90.0% for MTX response. When tested on a blinded independent validation cohort of 19 early RA patients, the signature demonstrated a true negative response rate of 86 and a 90% sensitivity for detection of non-responders to MTX. Only conformations in responders mapped to RA-specific eQTL. CONCLUSIONS: Here we demonstrate that detection of a CCS in blood in early RA is able to predict inadequate response to MTX with a high degree of accuracy. Our results provide a proof of principle that a priori stratification of response to MTX is possible, offering a mechanism to provide alternative treatments for non-responders to MTX earlier in the course of the disease.
背景：类风湿关节炎（RA）患者需要明确哪些患者对一线疾病修饰抗风湿药物（DMARD）无应答。我们探讨了在接受甲氨蝶呤（MTX）治疗前，取自早期 RA 患者的血液中染色体构象特征（CCS）所代表的基因组结构差异是否有助于识别 DMARD 无应答者，以及这种特征与 RA 特异性表达数量性状基因座（eQTL）之间是否存在关联。
方法：我们使用 EpiSwitch 通过染色体构象捕获技术，在开始接受 MTX 治疗的早期 RA 患者的血液中寻找 CCS 的存在。使用 MTX 应答者、无应答者和健康对照者的血液样本，我们对定制的生物标志物发现阵列进行了改进，以获得能够区分 MTX 应答者和无应答者的 5 个标志物 CCS。在 MTX 治疗前，我们生成了 150 个随机的 59 名早期 RA 患者（30 名应答者和 29 名无应答者）的组，通过这些组交叉验证了 CCS 的预测能力。我们使用 19 名早期 RA 患者（9 名应答者和 10 名无应答者）的盲法、独立队列验证了 CCS。最后，我们将 CCS 标记物的位置映射到 RA 特异性 eQTL。
结果：我们确定了一个 5 个标志物的 CCS，该 CCS 可以在基线时识别 MTX 的应答者和无应答者。CCS 由 IFNAR1、IL-21R、IL-23、CXCL13 和 IL-17A 基因组区域的二进制染色体构象组成。当在 59 名 RA 患者的队列中进行测试时，CCS 对 MTX 反应的阴性预测值为 90.0%。当在一个由 19 名早期 RA 患者组成的盲法独立验证队列中进行测试时，该特征显示出对 MTX 无应答者的真实阴性反应率为 86%，对 MTX 无应答者的敏感性为 90%。只有应答者的构象映射到 RA 特异性 eQTL。
结论：本研究表明，在早期 RA 患者的血液中检测到 CCS 能够以很高的准确度预测 MTX 应答不足。我们的研究结果提供了一个原理验证，即预先分层 MTX 反应是可能的，为疾病早期对 MTX 无应答的患者提供了更早提供替代治疗的机制。
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