Suzuki Yasuo, Matsui Toshiyuki, Ito Hiroaki, Ashida Toshifumi, Nakamura Shiro, Motoya Satoshi, Matsumoto Takayuki, Sato Noriko, Ozaki Kunihiko, Watanabe Mamoru, Hibi Toshifumi
*Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, Japan; †Department of Gastroenterology, Fukuoka University Chikushi Hospital, Chikushino, Japan; ‡Kinshukai Infusion Clinic, Osaka, Japan; §Inflammatory Bowel Disease Center, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan; ||Division of Lower Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan; ¶Inflammatory Bowel Diseases Center, Sapporo-kosei General Hospital, Sapporo, Japan; **Division of Gastroenterology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan; ††Mitsubishi Tanabe Pharma Corporation, Osaka, Japan; ‡‡Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan; and §§Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.
Inflamm Bowel Dis. 2015 Sep;21(9):2114-22. doi: 10.1097/MIB.0000000000000475.
We aimed to clarify the efficacy, safety, and factors associated with remission on dose escalation in patients with Crohn's disease showing loss of response (LOR) to infliximab treatment of 5 mg/kg at 8-week intervals in a clinical trial.
Thirty-nine patients with LOR to 5 mg/kg infliximab therapy started treatment with 10 mg/kg per 8 weeks. LOR was defined as both a Crohn's Disease Activity Index of ≥175 at 8 weeks after infusion of 5 mg/kg infliximab and a Crohn's Disease Activity Index increase of ≥50 from 4 to 8 weeks after infusion.
At week 8 after the first infusion of 10 mg/kg, median (95% confidence interval) reduction in Crohn's Disease Activity Index of 33 patients evaluated was 95.0 (70.0-134.0), meeting the primary endpoint. Remission rate at week 40 was 41% (16 of 39), with correlation noted between remission achievement and serum infliximab level (P = 0.036). Univariate analysis revealed that "infliximab trough level ≥1 µg/mL," "interleukin 6 level ≤2.41 pg/mL," and "albumin level ≥3.8 g/dL" before dose escalation were significantly associated with remission at week 40 (P = 0.017, P = 0.011, and P = 0.019, respectively), and these variables were correlated with each other (all: P < 0.001). The cutoff infliximab level for remission was 0.42 µg/mL in receiver operating characteristic curve analysis. No adverse events related to dose escalation were observed.
Doubling the infliximab dose safely led to remission in patients with Crohn's disease with LOR to 5 mg/kg treatment. Remission was associated with pre-escalation levels of infliximab, interleukin 6, and albumin. Our findings suggest that dose escalation while maintaining a certain level of infliximab is important in achieving remission.
在一项临床试验中，我们旨在阐明对每8周接受5mg/kg英夫利昔单抗治疗出现反应丧失（LOR）的克罗恩病患者进行剂量递增治疗的疗效、安全性以及与缓解相关的因素。
39例对5mg/kg英夫利昔单抗治疗出现LOR的患者开始每8周接受10mg/kg的治疗。LOR的定义为在输注5mg/kg英夫利昔单抗8周后克罗恩病活动指数≥175，且在输注后4至8周克罗恩病活动指数增加≥50。
在首次输注10mg/kg后的第8周，33例接受评估患者的克罗恩病活动指数中位数（95%置信区间）降低为95.0（70.0 - 134.0），达到主要终点。第40周的缓解率为41%（39例中的16例），缓解的实现与血清英夫利昔单抗水平相关（P = 0.036）。单因素分析显示，剂量递增前“英夫利昔单抗谷浓度≥1μg/mL”、“白细胞介素6水平≤2.41pg/mL”以及“白蛋白水平≥3.8g/dL”与第40周的缓解显著相关（分别为P = 0.017、P = 0.011和P = 0.019），且这些变量相互关联（均为：P < 0.001）。在受试者工作特征曲线分析中，缓解的英夫利昔单抗水平临界值为0.42μg/mL。未观察到与剂量递增相关的不良事件。
将英夫利昔单抗剂量加倍可安全地使对5mg/kg治疗出现LOR的克罗恩病患者实现缓解。缓解与剂量递增前英夫利昔单抗、白细胞介素6和白蛋白的水平相关。我们的研究结果表明，在维持一定英夫利昔单抗水平的同时进行剂量递增对实现缓解很重要。
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