Lee Han Hee, Solitano Virginia, Singh Sujay, Ananthakrishnan Ashwin N, Jairath Vipul, Syal Gaurav, Boland Brigid S, Ghosh Pradipta, Chang John T, Singh Siddharth
Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, California; Division of Gastroenterology, Department of Internal Medicine, Yeouido St. Mary's Hospital College of Medicine, Catholic University of Korea, Seoul, South Korea.
Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada; Division of Gastroenterology and Gastrointestinal Endoscopy, IRCCS Ospedale San Raffaele, Università Vita-Salute San Raffaele, Milan, Italy.
Clin Gastroenterol Hepatol. 2024 Dec 26. doi: 10.1016/j.cgh.2024.12.007.
We sought to ascertain how prior exposure to tumor necrosis factor (TNF) antagonists impacts treatment response with various classes of advanced therapies in patients with ulcerative colitis (UC), through a systematic review and meta-analysis.
Through a systematic review of multiple databases through June 30, 2024, we identified 17 randomized controlled trials in 8871 adults with moderate-severe UC who were treated with different advanced therapies vs placebo, and reported efficacy in induction of clinical remission, stratified by prior exposure to TNF antagonists. We calculated the ratio of odds ratio of achieving remission with active drug vs placebo, in TNF antagonist-naïve vs TNF antagonist-exposed patients. We grouped advanced therapies based on primary mechanism of action: lymphocyte trafficking inhibitors (anti-integrins and sphingosine-1 phosphate [S1P] receptor modulators), anti-interleukins (interleukin-12/23 antagonist and selective interleukin-23 antagonists) and Janus kinase inhibitors.
Lymphocyte trafficking inhibitors were more efficacious in TNF antagonist-naïve vs exposed patients (5 trials; odds ratio [OR], 1.88; 95% confidence interval [CI], 1.02-3.49), whereas JAK inhibitors were less efficacious in TNF antagonist-naïve vs exposed patients (6 trials; ratio of OR, 0.47; 95% CI, 0.22-1.01). No significant difference was observed in efficacy of selective interleukin-23 antagonists vs placebo in TNF antagonist-naïve vs exposed patients (6 trials; ratio of OR, 1.07; 95% CI, 0.64-1.80). There was minimal heterogeneity across analyses.
There is significant heterogeneity of treatment efficacy with different advanced therapies in inducing remission in patients with UC based on prior exposure to TNF antagonists, with plausible potentiation of JAK inhibitors and attenuation of lymphocyte trafficking inhibitors. Future studies on the mechanistic basis for these observations are warranted.
我们试图通过系统评价和荟萃分析，确定既往接触肿瘤坏死因子（TNF）拮抗剂如何影响溃疡性结肠炎（UC）患者对各类晚期疗法的治疗反应。
通过对多个数据库进行系统检索，截至2024年6月30日，我们在8871例中度至重度UC成年患者中识别出17项随机对照试验，这些患者接受了不同的晚期疗法与安慰剂治疗，并报告了诱导临床缓解的疗效，按既往是否接触TNF拮抗剂进行分层。我们计算了未接触TNF拮抗剂与接触过TNF拮抗剂的患者中，使用活性药物与安慰剂达到缓解的比值比（OR）之比。我们根据主要作用机制对晚期疗法进行分组：淋巴细胞迁移抑制剂（抗整合素和鞘氨醇-1磷酸[S1P]受体调节剂）、抗白细胞介素（白细胞介素-12/23拮抗剂和选择性白细胞介素-23拮抗剂）和Janus激酶抑制剂。
淋巴细胞迁移抑制剂在未接触TNF拮抗剂的患者中比接触过的患者更有效（5项试验；OR，1.88；95%置信区间[CI]，1.02-3.49），而JAK抑制剂在未接触TNF拮抗剂的患者中比接触过的患者效果更差（6项试验；OR之比，0.47；95%CI，0.22-1.01）。在未接触TNF拮抗剂与接触过TNF拮抗剂的患者中，选择性白细胞介素-23拮抗剂与安慰剂相比的疗效未观察到显著差异（6项试验；OR之比，1.07；95%CI，0.64-1.80）。各分析间异质性极小。
基于既往接触TNF拮抗剂情况，不同晚期疗法在诱导UC患者缓解方面的治疗疗效存在显著异质性，JAK抑制剂可能有增强作用，而淋巴细胞迁移抑制剂有减弱作用。有必要对这些观察结果的机制基础进行进一步研究。
