抗TNF联合低剂量甲氨蝶呤与抗TNF单药治疗对于儿童克隆氏症的比较疗效：一项实用性随机试验。
Comparative Effectiveness of Anti-TNF in Combination with Low Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn's Disease: a Pragmatic Randomized Trial.
发表日期：2023 Mar 31
作者：
Michael D Kappelman, David A Wohl, Hans H Herfarth, Ann M Firestine, Jeremy Adler, Rana F Ammoury, Jeanine E Aronow, Dorsey M Bass, Julie A Bass, Keith Benkov, Catalina Berenblum Tobi, Margie E Boccieri, Brendan M Boyle, William B Brinkman, Jose M Cabera, Kelly Chun, Richard B Colletti, Cassandra M Dodds, Jill M Dorsey, Dawn R Ebach, Edurne Entrena, Christopher B Forrest, Joseph A Galanko, John E Grunow, Ajay S Gulati, Anastasia Ivanova, Traci W Jester, Jess L Kaplan, Subra Kugathasan, Mark E Kusek, Ian H Leibowitz, Tiffany M Linville, Ellen A Lipstein, Peter A Margolis, Phillip Minar, Zarela Molle Rios, Jonathan Moses, Kelly K Olano, Lourdes Osaba, Pablo J Palomo, Helen Pappa, K T Park, Dinesh S Pashankar, Lisa Pitch, Michelle Robinson, Charles M Samson, Kelly C Sandberg, Julia R Schuchard, Michael Seid, Kimberly A Shelly, Steven J Steiner, Jennifer A Strople, Jillian S Sullivan, Jeanne Tung, Prateek Wali, Michael Zikry, Morris Weinberger, Shehzad A Saeed, Athos Bousvaros
来源：
GASTROENTEROLOGY
摘要：
肿瘤坏死因子抑制剂（TNFi），包括英夫利昔单抗和阿达利单抗，是儿童克隆氏病的主要治疗方法；然而，非反应和失去反应是常见的。由于联合甲氨蝶呤治疗可能会改善反应，我们进行了一项多中心、随机、双盲、安慰剂对照的实用试验，比较了TNFi与口服甲氨蝶呤的联合治疗与TNFi单独治疗。开始使用英夫利昔单抗或阿达利单抗的克隆氏病患者在1:1的比例下随机分配到甲氨蝶呤或安慰剂组，并随访12-36个月。主要结局是治疗失败的综合指标。次要结局包括抗药物抗体（ADA）和患者报告的疼痛干扰和疲劳。不良事件（AEs）和严重不良事件（SAEs）得以收集。在297名参与者（平均年龄13.9岁，35%女性）中，有156名分配到甲氨蝶呤组（110名英夫利昔单抗开始者和46名阿达利单抗开始者），141名分配到安慰剂组（102名英夫利昔单抗开始者和39名阿达利单抗开始者）。在总体人群中，治疗失败时间在研究组之间没有差异（HR 0.69，95% CI 0.45-1.05）。在英夫利昔单抗开始者中，联合和单独治疗之间没有差异（HR 0.93，95% CI 0.55-1.56）。在阿达利单抗开始者中，联合治疗与治疗失败的时间更长（HR 0.40，95% CI 0.19-0.81）。联合治疗组抗药物抗体开发趋势降低但不显著（英夫利昔单抗OR 0.72（0.49-1.07）；阿达利单抗OR 0.71（0.24-2.07））。未观察到PROs的差异。联合治疗导致更多AEs但更少的SAEs。在阿达利单抗开始者中，但不是在英夫利昔单抗开始者中，PCD患者接受甲氨蝶呤联合治疗，治疗失败的几率降低了2倍，并具有可耐受的安全性。版权所有©2023 AGA Institute。由Elsevier Inc.出版。保留所有权利。
Tumor Necrosis Factor inhibitors (TNFi), including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease (PCD) therapy; however, non-response and loss of response is common. As combination therapy with methotrexate may improve response, we performed a multi-center, randomized, double-blind, placebo-controlled pragmatic trial to compare TNFi with oral methotrexate to TNFi monotherapy.PCD patients initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies (ADA) and patient reported outcomes (PROs) of pain interference and fatigue. Adverse events (AEs) and Serious AEs (SAEs) were collected.Of 297 participants (mean age 13.9 years, 35% female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (HR 0.69, 95% CI 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (HR 0.93, 95% CI 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (HR 0.40, 95% CI 0.19-0.81). A trend towards lower ADA development in the combination therapy arm was not significant. [(infliximab OR 0.72 (0.49-1.07); adalimumab OR 0.71 (0.24-2.07)]. No differences in PROs were observed. Combination therapy resulted in more AEs but fewer SAEs.Among adalimumab but not infliximab initiators, PCD patients treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile.Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.