抗 TNF 联合低剂量甲氨蝶呤与抗 TNF 单药治疗在儿童克罗恩病中的比较效果：一项实用随机试验。
Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn's Disease: A Pragmatic Randomized Trial.
机构信息
Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Institute of Global Health and Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
出版信息
Gastroenterology. 2023 Jul;165(1):149-161.e7. doi: 10.1053/j.gastro.2023.03.224. Epub 2023 Mar 31.
BACKGROUND & AIMS: Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy.
METHODS
Patients with pediatric Crohn's disease 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 and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected.
RESULTS
Of 297 participants (mean age, 13.9 years, 35% were 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 (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs.
CONCLUSIONS
Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile.
CLINICALTRIALS
gov, Number: NCT02772965.
背景与目的
肿瘤坏死因子抑制剂（如英夫利昔单抗和阿达木单抗）是儿童克罗恩病治疗的主要方法；然而，无应答和应答丧失很常见。由于与甲氨蝶呤联合治疗可能会提高应答率，我们进行了一项多中心、随机、双盲、安慰剂对照的实用试验，以比较肿瘤坏死因子抑制剂联合口服甲氨蝶呤与肿瘤坏死因子抑制剂单药治疗。
方法
接受英夫利昔单抗或阿达木单抗治疗的儿童克罗恩病患者按 1:1 比例随机分配至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和患者报告的疼痛干扰和疲劳结局。收集不良事件（AE）和严重不良事件（SAE）。
结果
在 297 名参与者（平均年龄 13.9 岁，35%为女性）中，156 名被分配至甲氨蝶呤组（英夫利昔单抗起始治疗 110 例，阿达木单抗起始治疗 46 例），141 名被分配至安慰剂组（英夫利昔单抗起始治疗 102 例，阿达木单抗起始治疗 39 例）。在总体人群中，研究臂之间的治疗失败时间无差异（风险比，0.69；95%CI，0.45-1.05）。在英夫利昔单抗起始治疗者中，联合治疗与单药治疗之间无差异（风险比，0.93；95%CI，0.55-1.56）。在阿达木单抗起始治疗者中，联合治疗与治疗失败时间延长相关（风险比，0.40；95%CI，0.19-0.81）。联合治疗组抗药物抗体发生率较低，但无统计学意义（英夫利昔单抗：比值比，0.72；95%CI，0.49-1.07；阿达木单抗：比值比，0.71；95%CI，0.24-2.07）。患者报告结局无差异。联合治疗导致更多的 AE，但更少的 SAE。
结论
在阿达木单抗但不是英夫利昔单抗起始治疗者中，接受甲氨蝶呤联合治疗的儿童克罗恩病患者治疗失败率降低了 2 倍，安全性可接受。
临床试验
gov，编号：NCT02772965。
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