转谷氨酰胺酶2抑制剂治疗乳糜泻的随机试验

乳糜泻目前唯一的治疗方案是终身坚持严格的无麸质饮食，但只有50%的患者实现黏膜康复，且许多患者自诉有持续症状。短视频中总结了新的研究发现。                         

转谷氨酰胺酶2抑制剂治疗乳糜泻的随机试验

A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease

摘 要

背景

在乳糜泻中，小肠转谷氨酰胺酶2使麸质肽中的谷氨酰胺残基脱酰胺，因而增强了对T细胞的刺激并导致黏膜损伤。抑制转谷氨酰胺酶2是乳糜泻的潜在治疗方法。

Background

In celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which enhances stimulation of T cells and leads to mucosal injury. Inhibition of transglutaminase 2 is a potential treatment for celiac disease.

方法

在一项概念验证试验中，我们在乳糜泻病情受到控制，并且接受每日麸质激发成人患者中评估了与安慰剂相比，三种剂量水平ZED1227（选择性口服转谷氨酰胺酶2抑制剂）治疗6周的疗效和安全性。主要终点是麸质引起的黏膜损伤（通过绒毛高度与隐窝深度的比值测定）减轻。次要终点包括上皮内淋巴细胞密度、乳糜泻症状指数（Celiac Symptom Index）评分和乳糜泻问卷（Celiac Disease Questionnaire）评分（用于评估健康相关生活质量）。

Methods

In a proof-of-concept trial, we assessed the efficacy and safety of a 6-week treatment with ZED1227, a selective oral transglutaminase 2 inhibitor, at three dose levels as compared with placebo, in adults with well-controlled celiac disease who underwent a daily gluten challenge. The primary end point was the attenuation of gluten-induced mucosal damage, as measured by the ratio of villus height to crypt depth. Secondary end points included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score (for assessment of health-related quality of life).

结果

在10 mg ZED1227组41例患者、50 mg组41例患者、100 mg组41例患者和安慰剂组40例患者中，分别有35、39、38和30例患者有评估主要终点所需的足够十二指肠活检样本。全部三种剂量水平的ZED1227均减轻了麸质引起的十二指肠黏膜损伤。在绒毛高度与隐窝深度的平均比值从基线至第6周的变化方面，10 mg组、50 mg组和100 mg组与安慰剂组的估计差异分别为0.44（95%置信区间[CI]，0.15~0.73）（P=0.001）、0.49（95% CI，0.20~0.77）（P<0.001）和0.48（95% CI，0.20~0.77）（P<0.001）。在上皮内淋巴细胞密度的变化方面，10 mg组、50 mg组和100 mg组与安慰剂组的估计差异分别为-2.7个细胞/100个上皮细胞（95% CI，-7.6~2.2）、-4.2个细胞/100个上皮细胞（95% CI，-8.9~0.6）和-9.6个细胞/100个上皮细胞（95% CI，-14.4~-4.8）。100 mg剂量可能改善了症状和生活质量评分。最常见的不良事件（各组发生率相似）包括头痛、恶心、腹泻、呕吐和腹痛。100 mg组40例患者中的3例（8%）出现了皮疹。

Result

Of the 41 patients assigned to the 10-mg ZED1227 group, the 41 assigned to the 50-mg group, the 41 assigned to the 100-mg group, and the 40 assigned to the placebo group, 35, 39, 38, and 30 patients, respectively, had adequate duodenal-biopsy samples for the assessment of the primary end point. Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P=0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P<0.001), and 0.48 (95% CI, 0.20 to 0.77) in the 100-mg group (P<0.001). The estimated differences from placebo in the change in intraepithelial lymphocyte density were −2.7 cells per 100 epithelial cells (95% CI, −7.6 to 2.2) in the 10-mg group, −4.2 cells per 100 epithelial cells (95% CI, −8.9 to 0.6) in the 50-mg group, and −9.6 cells per 100 epithelial cells (95% CI, −14.4 to −4.8) in the 100-mg group. Use of the 100-mg dose may have improved symptom and quality-of-life scores. The most common adverse events, the incidences of which were similar across all groups, were headache, nausea, diarrhea, vomiting, and abdominal pain. Rash developed in 3 of 40 patients (8%) in the 100-mg group.

结论

在这项初步试验中，ZED1227用于乳糜泻患者后减轻了麸质引起的十二指肠黏膜损伤。（由福克制药[Dr. Falk Pharma]资助；CEC-3在EudraCT注册号为2017-002241-30。）

Conclusions

In this preliminary trial, treatment with ZED1227 attenuated gluten-induced duodenal mucosal damage in patients with celiac disease. (Funded by Dr. Falk Pharma; CEC-3 EudraCT number, 2017-002241-30.)

Detlef Schuppan, Markku Mäki, Knut E.A. Lundin, et al. A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease. DOI: 10.1056/NEJMoa2032441