*F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; †Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea; ‡Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; §Department of Gastroenterology and Inflammatory Bowel Disease Center, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; and ‖Department of Pediatrics, Pediatric Inflammatory Bowel Disease Program, Cedars-Sinai Medical Center, Los Angeles, California.
Inflamm Bowel Dis. 2017 Aug;23(8):1382-1393. doi: 10.1097/MIB.0000000000001150.
Although anti-tumor necrosis factor (TNF) agents are effective in patients with inflammatory bowel disease (IBD), many patients either do not respond to anti-TNF treatment or lose response over time. The aim of this study was to determine factors associated with response to anti-TNF therapy in IBD.
Patients with Crohn's disease (CD) or ulcerative colitis who had consented to participate in a genetics registry and been treated with anti-TNF agents were evaluated retrospectively and categorized as primary nonresponders or secondary nonresponders. We evaluated clinical, serological, and genetic characteristics associated with primary nonresponse or time to loss of response to anti-TNF agents.
We included 314 CD (51 [16.2%] primary nonresponders and 179 [57.0%] secondary nonresponders) and 145 subjects with ulcerative colitis (43 [29.7%] primary nonresponders and 74 [51.0%] secondary nonresponders). Colonic involvement (P = 0.017; odds ratio = 8.0) and anti-TNF monotherapy (P = 0.017; odds ratio = 4.9) were associated in a multivariate analysis with primary nonresponse to anti-TNF agents in CD. In addition, higher anti-nuclear cytoplasmic antibody levels (P = 0.019; hazard ratio = 1.01) in CD, anti-nuclear cytoplasmic antibody positivity (P = 0.038; hazard ratio = 1.6) in ulcerative colitis, and a positive family history of IBD (P = 0.044; hazard ratio = 1.3) in all patients with IBD were associated with time to loss of response to anti-TNF agents. Furthermore, various known IBD susceptibility single-nucleotide polymorphisms and additional variants in immune-mediated genes were shown to be associated with primary nonresponse or time to loss of response.
Our results may help to optimize the use of anti-TNF agents in clinical practice and position these therapies appropriately as clinicians strive for a more personalized approach to managing IBD.
尽管抗肿瘤坏死因子（TNF）药物对炎症性肠病（IBD）患者有效，但许多患者要么对 TNF 治疗无反应，要么随着时间的推移失去反应。本研究旨在确定与 IBD 患者对 TNF 治疗反应相关的因素。
回顾性评估了同意参加遗传登记并接受 TNF 拮抗剂治疗的克罗恩病（CD）或溃疡性结肠炎患者，并将其分为原发性无应答者或继发性无应答者。我们评估了与 TNF 拮抗剂原发性无应答或丧失应答时间相关的临床、血清学和遗传特征。
共纳入 314 例 CD（51 例[16.2%]为原发性无应答者，179 例[57.0%]为继发性无应答者）和 145 例溃疡性结肠炎患者（43 例[29.7%]为原发性无应答者，74 例[51.0%]为继发性无应答者）。多变量分析显示，CD 中结肠受累（P=0.017；比值比=8.0）和 TNF 单药治疗（P=0.017；比值比=4.9）与 TNF 拮抗剂原发性无应答相关。此外，CD 中抗核细胞质抗体水平较高（P=0.019；风险比=1.01）、溃疡性结肠炎中抗核细胞质抗体阳性（P=0.038；风险比=1.6）以及所有 IBD 患者阳性家族史（P=0.044；风险比=1.3）与 TNF 拮抗剂丧失应答时间相关。此外，还发现各种已知的 IBD 易感性单核苷酸多态性和免疫介导基因中的其他变异与原发性无应答或丧失应答时间相关。
我们的研究结果可能有助于优化 TNF 拮抗剂在临床实践中的应用，并使这些治疗方法更适合临床医生为实现更个体化的 IBD 管理而努力。
