Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn's disease
Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn's disease
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DOI：
10.1053/gast.2002.30770
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发表时间：
2002-01-01
期刊：
影响因子：
29.4
通讯作者：
Van Deventer, S
中科院分区：
文献类型：
--
作者：
Hommes, D;Van Den Blink, B;Van Deventer, S
背景与目的：我们研究了抑制丝裂原活化蛋白激酶（MAPK）是否对克罗恩病有益。方法：采用体外实验方法，观察CNI-1493对JNK和p38 MAPK激活的抑制作用。12例重度克罗恩病患者（平均基线，CDAI 380）被随机分配接受8或25 mg/m2 CNI-1493，每日1次，持续12天。临床终点包括安全性、克罗恩病活动指数（CDAI）、炎症性肠病问卷和克罗恩病内镜严重程度指数。结果：结肠活检显示JNK和p38 MAPK活化增强。在体外观察到CNI-1493对JNK和p38磷酸化的抑制。治疗导致JNK磷酸化和肿瘤坏死因子产生减少，以及显著的临床获益和内镜下溃疡快速愈合。未发现严重不良事件。观察到CDAI在第4周降低120（P = 0.005），在第8周降低146.5（P = 0.005）。在第4周和第8周分别有67%和58%的患者出现临床反应。在第4周和第8周分别有25%和42%的患者观察到临床缓解。除1例患者外，所有患者的内镜检查均有所改善。6例英夫利西单抗治疗失败的患者中有3例出现缓解，其中2例出现缓解。5例患者中有4例发生瘘管愈合，89%的患者逐渐减少类固醇。结论：炎症性MAPK在克罗恩病的发病机制中起关键作用，抑制它们提供了一种新的治疗策略。
Background & Aims: We investigated if inhibition of mitogen-activated protein kinases (MAPKs) was beneficial in Crohn's disease. Methods: Inhibition of JNK and p38 MAPK activation with CNI-1493, a guanylhydrazone, was tested in vitro. Twelve patients with severe Crohn's disease (mean baseline, CDAI 380) were randomly assigned to receive either 8 or 25 mg/m(2) CNI-1493 daily for 12 days. Clinical endpoints included safety, Crohn's Disease Activity Index (CDAI), Inflammatory Bowel Disease Questionnaire, and the Crohn's Disease Endoscopic Index of Severity. Results: Colonic biopsies displayed enhanced JNK and p38 MAPK activation. CNI-1493 inhibition of both JNK and p38 phosphorylation was observed in vitro. Treatment resulted in diminished JNK phosphorylation and tumor necrosis factor production as well as significant clinical benefit and rapid endoscopic ulcer healing. No serious adverse events were noted. A CDAI decrease of 120 at week 4 (P = 0.005) and 146.5 at week 8 (P = 0.005) was observed. A clinical response was seen in 67% of patients at 4 weeks and 58% at 8 weeks. Clinical remission was observed in 25% of patients at week 4 and 42% at week 8. Endoscopic improvement occurred in all but 1 patient. Response was seen in 3 of 6 infliximab failures, 2 of whom showed remission. Fistulae healing occurred in 4 of 5 patients, and steroids were tapered in 89% of patients. Conclusions: Inflammatory MAPKs are critically involved in the pathogenesis of Crohn's disease and their inhibition provides a novel therapeutic strategy.