Low Anti-Tumor Necrosis Factor Levels During Maintenance Phase Are Associated With Treatment Failure in Children With Crohn's Disease.

IF 4.5 3区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Inflammatory Bowel Diseases Pub Date : 2024-10-17 DOI:10.1093/ibd/izae239

Jonathan Moses, Jeremy Adler, Shehzad A Saeed, Ann M Firestine, Joseph A Galanko, Rana F Ammoury, Dorsey M Bass, Julie A Bass, Monique Bastidas, Keith J Benkov, Athos Bousvaros, José M Cabrera, Kelly Y Chun, Jill M Dorsey, Dawn R Ebach, Ajay S Gulati, Hans H Herfarth, Anastasia Ivanova, Traci W Jester, Jess L Kaplan, Mark E Kusek, Ian H Leibowitz, Tiffany M Linville, Peter A Margolis, Phillip Minar, Zarela Molle-Rios, Barbara Joanna Niklinska-Schirtz, Kelly K Olano, Lourdes Osaba, Pablo J Palomo, Dinesh S Pashankar, Lisa Pitch, Charles M Samson, Kelly C Sandberg, Steven J Steiner, Jennifer A Strople, Jillian S Sullivan, Jeanne Tung, Prateek Wali, David A Wohl, Mike Zikry, Brendan M Boyle, Michael D Kappelman

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Abstract

Background: Higher drug levels and combination therapy with low-dose oral methotrexate (LD-MTX) may reduce anti-tumor necrosis factor (TNF) treatment failure in pediatric Crohn's disease. We sought to (1) evaluate whether combination therapy with LD-MTX was associated with higher anti-TNF levels, (2) evaluate associations between anti-TNF levels and subsequent treatment failure, and (3) explore the effect of combination therapy on maintenance of remission among patients with therapeutic drug levels (>5 µg/mL for infliximab and >7.5 µg/mL for adalimumab).

Methods: We conducted a post hoc analysis of the COMBINE trial, which compared anti-TNF monotherapy to combination therapy with LD-MTX. We included participants who entered maintenance therapy and provided a serum sample approximately 4 months from randomization.

Results: Among 112 infliximab and 41 adalimumab initiators, median drug levels were similar between combination therapy and monotherapy (infliximab: 8.8 vs 7.5 μg/mL [P = .49]; adalimumab: 11.1 vs 10.5 μg/mL [P = .11]). Median drug levels were lower in patients experiencing treatment failure (infliximab: 4.2 vs 9.6 μg/mL [P < .01]; adalimumab: 9.1 vs 12.3 μg/mL [P < .01]). Among patients treated with infliximab with therapeutic drug levels, we observed no difference in treatment failure between participants assigned monotherapy or combination therapy. Among patients treated with adalimumab, a trend towards reduced treatment failure in the combination therapy arm was not statistically significant (P = .14).

Conclusions: LD-MTX combination was not associated with higher drug levels, but higher drug levels were associated with reduced risk of treatment failure. Among patients with therapeutic drug levels, we observed no benefit of LD-MTX for patients treated with infliximab. A nonsignificant trend towards reduced treatment failure with the addition of LD-MTX patients treated with adalimumab warrants further investigation.

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维持阶段抗肿瘤坏死因子水平低与克罗恩病儿童治疗失败有关

背景：较高的药物水平和小剂量口服甲氨蝶呤（LD-MTX）联合疗法可减少小儿克罗恩病中抗肿瘤坏死因子（TNF）治疗的失败。我们试图（1）评估LD-MTX联合疗法是否与较高的抗肿瘤坏死因子水平相关；（2）评估抗肿瘤坏死因子水平与后续治疗失败之间的关联；（3）探讨联合疗法对维持药物治疗水平（英夫利昔单抗>5 µg/mL，阿达木单抗>7.5 µg/mL）患者病情缓解的影响：我们对COMBINE试验进行了一项事后分析，该试验比较了抗肿瘤坏死因子单药疗法和LD-MTX联合疗法。我们纳入了接受维持治疗并在随机化后约4个月提供血清样本的参与者：结果：在112名英夫利昔单抗患者和41名阿达木单抗患者中，联合疗法和单一疗法的中位药物水平相似（英夫利昔单抗：8.8 μg vs 7.5 μg）：8.8 vs 7.5 μg/mL [P = .49]；阿达木单抗：11.1 vs 10.5 μg/mL [P = .11]）。治疗失败患者的药物浓度中位数较低（英夫利昔单抗：4.2 μg/mL vs 9.6 μg/mL [P = .11]）：英夫利西单抗：4.2 vs 9.6 μg/mL [P = .11]）：LD-MTX联合用药与药物浓度升高无关，但药物浓度升高与治疗失败风险降低有关。在具有治疗药物水平的患者中，我们观察到 LD-MTX 对接受英夫利西单抗治疗的患者没有益处。接受阿达木单抗治疗的患者加用LD-MTX后治疗失败率降低的趋势并不明显，值得进一步研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Inflammatory Bowel Diseases 医学-胃肠肝病学

CiteScore

9.70

自引率

6.10%

发文量

462

审稿时长

1 months

期刊介绍： Inflammatory Bowel Diseases® supports the mission of the Crohn''s & Colitis Foundation by bringing the most impactful and cutting edge clinical topics and research findings related to inflammatory bowel diseases to clinicians and researchers working in IBD and related fields. The Journal is committed to publishing on innovative topics that influence the future of clinical care, treatment, and research.