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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


Detlef Schuppan ... 其他 • 2021.07.01

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。

 

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)。

 

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例、39例、38例和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。

 

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)。





作者信息

Detlef Schuppan, M.D., Ph.D., Markku Mäki, M.D., Ph.D., Knut E.A. Lundin, M.D., Ph.D., Jorma Isola, M.D., Ph.D., Tina Friesing-Sosnik, M.D., Juha Taavela, M.D., Ph.D., Alina Popp, M.D., Ph.D., Jari Koskenpato, M.D., Jost Langhorst, M.D., Øistein Hovde, M.D., Ph.D., Marja-Leena Lähdeaho, M.D., Ph.D., Stefano Fusco, M.D., Michael Schumann, M.D., Helga P. Török, M.D., Juozas Kupcinskas, M.D., Yurdagül Zopf, M.D., Ansgar W. Lohse, M.D., Mika Scheinin, M.D., Ph.D., Karin Kull, M.D., Luc Biedermann, M.D., Valerie Byrnes, M.D., Andreas Stallmach, M.D., Jørgen Jahnsen, M.D., Jonas Zeitz, M.D., Ralf Mohrbacher, M.Sc., and Roland Greinwald, Ph.D. for the CEC-3 Trial Group*
From the Institute of Translational Immunology and Celiac Center, Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg University, Mainz (D.S., T.F.-S.), the Department of Internal and Integrative Medicine, Sozialstiftung Bamberg, Bamberg (J.L.), the Department of Integrative Medicine, University of Duisburg-Essen, Duisburg-Essen (J.L.), the Division of Gastroenterology, Hepatology, and Infectious Diseases, Department of Internal Medicine I, University Hospital Tübingen, Tübingen (S.F.), the Department of Gastroenterology, Infectious Diseases, and Rheumatology, Campus Benjamin Franklin, Charité–University Medicine Berlin, Berlin (M. Schumann), the Department of Medicine II, University Hospital, Ludwig Maximilians University, Munich (H.P.T.), the Department of Medicine 1, Hector Center for Nutrition, Exercise, and Sports, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen (Y.Z.), the Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg (A.W.L.), the Department of Internal Medicine IV, University Hospital, Friedrich-Schiller University Jena, Jena (A.S.), and Dr. Falk Pharma, Freiburg (R.M., R.G.) — all in Germany; the Division of Gastroenterology and Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston (D.S.); the Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital (M.M., A.P., M.-L.L.), the Faculty of Medicine and Health Technology, Tampere University (J.I., J.T.), Jilab (J.I.), and the Department of Pediatrics, Tampere University Hospital (M.-L.L.), Tampere, the Department of Internal Medicine, Central Finland Central Hospital, Jyväskylä (J.T.), Lääkärikeskus Aava Helsinki Kamppi, Helsinki (J. Koskenpato), and Clinical Research Services Turku, Turku (M. Scheinin) — all in Finland; Oslo University Hospital, Rikshospitalet, and Stiftelsen K.G. Jebsen Celiac Disease Research Center, University of Oslo, Oslo (K.E.A.L.), the Medical Department, Innlandet Hospital Trust, Gjøvik (O.H.), and Akershus University Hospital, Lørenskog (J.J.) — all in Norway; the University of Medicine and Pharmacy “Carol Davila” and the National Institute for Mother and Child Health “Alessandrescu-Rusescu,” Bucharest, Romania (A.P.); the Gastroenterology Department and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania (J. Kupcinskas); the Department of Gastroenterology, Internal Medicine Clinic, Tartu University Hospital, Tartu, Estonia (K.K.); the Department of Gastroenterology and Hepatology, University Hospital Zurich (L.B., J.Z.), and the Swiss Celiac Center, Center of Gastroenterology, Clinic Hirslanden (J.Z.) — both in Zurich, Switzerland; and University College Hospital Galway, Galway, Ireland (V.B.). Address reprint requests to Dr. Schuppan at the Institute of Translational Immunology and Celiac Center, Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany, or at detlef.schuppan@unimedizin-mainz.de. A complete list of the investigators and contributors in the CEC-3 Trial Group is provided in the Supplementary Appendix, available at NEJM.org.

 

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