Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA.
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
J Crohns Colitis. 2019 Aug 14;13(8):1036-1043. doi: 10.1093/ecco-jcc/jjz017.
It is important to identify patients with inflammatory bowel disease [IBD] refractory to anti-tumour necrosis factor [TNF] therapy, to avoid potential adverse effects and to adopt different treatment strategies. We aimed to identify and validate clinical and genetic factors to predict anti-TNF response in patients with IBD.
Mayo Clinic and Washington University IBD genetic association study cohorts were used as discovery and replicate datasets, respectively. Clinical factors included sex, age at diagnosis, disease duration and phenotype, disease location, bowel resection, tobacco use, family history of IBD, extraintestinal manifestations, and response to anti-TNF therapy.
Of 474 patients with IBD treated with anti-TNF therapy, 41 [8.7%] were refractory to therapy and 433 [91.3%] had response. Multivariate analysis showed history of immunomodulator use (odds ratio 10.2, p = 8.73E-4) and bowel resection (odds ratio 3.24, p = 4.38E-4) were associated with refractory response to anti-TNF agents. Among genetic loci, two [rs116724455 in TNFSF4/18, rs2228416 in PLIN2] were successfully replicated and another four [rs762787, rs9572250, rs144256942, rs523781] with suggestive evidence were found. An exploratory risk model predictability [area under the curve] increased from 0.72 [clinical predictors] to 0.89 after adding genetic predictors. Through identified clinical and genetic predictors, we constructed a preliminary anti-TNF refractory score to differentiate anti-TNF non-responders (mean [standard deviation] score, 5.49 [0.99]) from responders (2.65 [0.39]; p = 4.33E-23).
Novel and validated genetic loci, including variants in TNFSF, were found associated with anti-TNF response in patients with IBD. Future validation of the exploratory risk model in a large prospective cohort is warranted.
识别出对肿瘤坏死因子（TNF）治疗无反应的炎症性肠病（IBD）患者非常重要，以避免潜在的不良反应并采取不同的治疗策略。本研究旨在确定和验证临床和遗传因素，以预测 IBD 患者对 TNF 拮抗剂的反应。
分别使用 Mayo 诊所和华盛顿大学的 IBD 遗传关联研究队列作为发现和复制数据集。临床因素包括性别、诊断时年龄、疾病持续时间和表型、疾病部位、肠切除术、吸烟史、IBD 家族史、肠外表现和对 TNF 拮抗剂的反应。
在接受 TNF 拮抗剂治疗的 474 例 IBD 患者中，41 例（8.7%）对治疗无反应，433 例（91.3%）有反应。多变量分析显示，免疫调节剂的使用史（比值比 10.2，p=8.73E-4）和肠切除术（比值比 3.24，p=4.38E-4）与对 TNF 拮抗剂的无反应相关。在遗传位点中，两个[rs116724455 在 TNFSF4/18，rs2228416 在 PLIN2]成功复制，另外四个[rs762787，rs9572250，rs144256942，rs523781]有提示性证据。探索性风险模型预测能力[曲线下面积]从添加遗传预测因子前的 0.72（临床预测因子）增加到 0.89。通过确定的临床和遗传预测因子，我们构建了一个初步的 TNF 拮抗剂无反应评分，以区分 TNF 拮抗剂无反应者（平均[标准差]评分，5.49[0.99]）和反应者（2.65[0.39]；p=4.33E-23）。
发现了新的且经过验证的遗传位点，包括 TNF 相关基因中的变异，与 IBD 患者对 TNF 拮抗剂的反应相关。未来需要在大型前瞻性队列中验证探索性风险模型。
