Vuyyuru Sudheer K, Ma Christopher, Nguyen Tran M, Zou Guangyong, Peyrin-Biroulet Laurent, Danese Silvio, Dulai Parambir, Narula Neeraj, Singh Siddharth, Jairath Vipul
Department of Medicine, Division of Gastroenterology, Schulich School of Medicine, Western University, Canada.
Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, AB, Canada.
EClinicalMedicine. 2024 May 4;72:102621. doi: 10.1016/j.eclinm.2024.102621. eCollection 2024 Jun.
Disease extent in Ulcerative Colitis (UC) has prognostic implications for disease course. It is unclear whether the efficacy of medical therapies for moderate to severely active UC vary according to disease extent at enrollment.
We analyzed patient level data from 11 Phase 2 and 3 clinical trials of advanced therapies in patients with moderate-to-severe UC to assess modifications of advanced therapy effects by disease extent. Primary outcome was clinical response and secondary outcomes were clinical remission, endoscopic response/remission and endoscopic improvement, and Mayo clinic subscore for both induction and maintenance studies. Binary and continuous outcomes were analyzed using the modified Poisson regression model and the mixed-effects model, respectively, adjusting for age, sex, disease duration, concomitant steroid use and prior anti-TNF use. Effect modifications with binary outcomes were quantified by ratios of risk ratio for left-sided to that for extensive colitis while effect modifications with the Mayo subscores were quantified by differences of the differences between mean scores of the left-sided and extensive colitis. Results were presented with point estimates and 95% confidence intervals as well as p-values.
Eleven clinical trials enrolling 5450 UC patients (infliximab = 2, adalimumab = 2, golimumab = 2, vedolizumab = 2, tofacitinib = 3) were included. In induction trials, there was evidence to suggest effect modification by disease extent for clinical response with tofacitinib (the ratio of RRs 0.67, 95% CI [0.45, 0.99], p = 0.049) and clinical remission with infliximab (ratio of RRs 0.33, 95% CI [0.13, 0.85], p = 0.020) favoring patients with extensive colitis. There was no evidence to suggest effect modification for endoscopic improvement and clinical outcomes. There was evidence to suggest effect modification by disease extent for clinical remission with tofacitinib (ratio of RRs 0.44, 95% CI [0.22, 0.89], p = 0.020) favoring patients with extensive colitis. For symptom subscores from the Mayo Clinic score, tofacitinib was associated with a greater reduction in both stool frequency (difference of differences 0.37, 95% CI [0.08, 0.65], p = 0.012) and rectal bleeding scores (difference of differences 0.25, 95% CI [0.03, 0.47], p = 0.026) in patients with extensive colitis compared to left sided.
These findings underscore the possibility of differential efficacy of medical therapies according to disease distribution. These results warrant further exploration in forthcoming trials to better inform treatment strategies and consideration of disease distribution as a baseline stratification factor in clinical trials.
This study did not receive any financial support.
溃疡性结肠炎（UC）的疾病范围对病程具有预后意义。目前尚不清楚中度至重度活动性UC的药物治疗疗效是否会因入组时的疾病范围而异。
我们分析了11项针对中度至重度UC患者的2期和3期先进疗法临床试验的患者水平数据，以评估疾病范围对先进疗法效果的影响。主要结局为临床缓解，次要结局为临床缓解、内镜反应/缓解和内镜改善，以及诱导和维持研究的梅奥诊所子评分。分别使用修正泊松回归模型和混合效应模型分析二元和连续结局，并对年龄、性别、病程、同时使用类固醇和既往使用抗TNF药物进行校正。二元结局的效应修饰通过左侧结肠炎与广泛性结肠炎风险比的比值进行量化，而梅奥子评分的效应修饰通过左侧结肠炎和广泛性结肠炎平均评分差值的差值进行量化。结果以点估计值、95%置信区间以及p值呈现。
纳入了11项临床试验，共5450例UC患者（英夫利昔单抗=2项试验，阿达木单抗=2项试验，戈利木单抗=2项试验，维多珠单抗=2项试验，托法替布=3项试验）。在诱导试验中，有证据表明疾病范围对托法替布的临床缓解存在效应修饰（风险比的比值为0.67，95%置信区间[0.45, 0.99]，p = 0.049），对英夫利昔单抗的临床缓解也存在效应修饰（风险比的比值为0.33，95%置信区间[0.13, 0.85]，p = 0.020），有利于广泛性结肠炎患者。没有证据表明内镜改善和临床结局存在效应修饰。有证据表明疾病范围对托法替布的临床缓解存在效应修饰（风险比的比值为0.44，95%置信区间[0.22, 0.89]，p = 0.020），有利于广泛性结肠炎患者。对于梅奥诊所评分中的症状子评分，与左侧结肠炎患者相比，托法替布在广泛性结肠炎患者中使排便次数（差值的差值为0.37，95%置信区间[0.08, 0.65]，p = 0.012）和直肠出血评分（差值的差值为0.25，95%置信区间[0.03, 0.47]，p = 0.026）的降低幅度更大。
这些发现强调了根据疾病分布药物治疗疗效可能存在差异的可能性。这些结果值得在未来的试验中进一步探索，以便更好地为治疗策略提供信息，并在临床试验中将疾病分布作为基线分层因素加以考虑。
本研究未获得任何资金支持。
