肽链内切酶
Latiglutenase（以前被称为 ALV003）可以在肠腔内将麸质消化为非抗原性多肽。一项研究未能证明无反应性乳糜泻的总体组织学或症状改善。[154]Murray JA, Kelly CP, Green PHR, et al. No difference between latiglutenase and placebo in reducing villous atrophy or improving symptoms in patients with symptomatic celiac disease. Gastroenterology. 2017 Mar;152(4):787-98.https://www.gastrojournal.org/article/S0016-5085(16)35346-X/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/27864127?tool=bestpractice.com 一项事后亚组分析发现，在采用无麸质饮食的组织转谷氨酰胺酶（tissue transglutaminase, tTG）阳性乳糜泻患者中，症状得到改善。[155]Syage JA, Murray JA, Green PHR, et al. Latiglutenase improves symptoms in seropositive celiac disease patients while on a gluten-free diet. Dig Dis Sci. 2017 Sep;62(9):2428-32.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709215/http://www.ncbi.nlm.nih.gov/pubmed/28755266?tool=bestpractice.com 最近的一项研究表明，在控制良好的乳糜泻患者中，接受 6 周的麸质激发试验可防止组织学损伤和症状的出现。[156]Murray JA, Syage JA, Wu TT, et al. Latiglutenase protects the mucosa and attenuates symptom severity in patients with celiac disease exposed to a gluten challenge. Gastroenterology. 2022 Dec;163(6):1510-21.e6.https://www.gastrojournal.org/article/S0016-5085(22)00901-5/fulltext?referrer=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2Fhttp://www.ncbi.nlm.nih.gov/pubmed/35931103?tool=bestpractice.com已在一项 1 期试验中证实，另一种内肽酶 TAK-062 能快速有效降解健康对照者体内麸质。[157]Pultz IS, Hill M, Vitanza JM, et al. Gluten degradation, pharmacokinetics, safety, and tolerability of TAK-062, an engineered enzyme to treat celiac disease. Gastroenterology. 2021 Jul;161(1):81-93.e3.https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(21)00527-8http://www.ncbi.nlm.nih.gov/pubmed/33741317?tool=bestpractice.com 需要对乳糜泻患者进行进一步研究。
组织型转谷氨酰胺酶（tTG）抑制剂
tTG 抑制剂可防止脱酰胺以及由此导致的醇溶蛋白肽增效作用。[31]Dieterich W, Esslinger B, Schuppan D. Pathomechanisms in celiac disease. Int Arch Allergy Immunol. 2003 Oct;132(2):98-108.http://www.ncbi.nlm.nih.gov/pubmed/14600421?tool=bestpractice.com 一项关于 tTG 抑制剂 ZED1227 的 2a 期疗效/耐受性研究显示，与接受安慰剂的患者相比，接受 ZED1227 的患者在进行麸质激发试验后，麸质引起的十二指肠黏膜损伤更轻。[158]Schuppan D, Mäki M, Lundin KEA, et al. A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease. N Engl J Med. 2021 Jul 1;385(1):35-45.https://www.nejm.org/doi/10.1056/NEJMoa2032441?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmedhttp://www.ncbi.nlm.nih.gov/pubmed/34192430?tool=bestpractice.com 欧洲目前正在进行一项 2 期研究，招募对象为尽管饮食不含麸质但仍有症状的患者。
免疫调节
免疫调节可恢复对麸质的耐受性。[159]Benahmed M, Mention JJ, Matysiak-Budnik T, et al. Celiac disease: a future without gluten-free diet? Gastroenterology. 2003 Oct;125(4):1264-7.http://www.ncbi.nlm.nih.gov/pubmed/14517809?tool=bestpractice.com TAK-101 是一种纳米颗粒治疗药物，正被研究用于治疗乳糜泻。它旨在通过将包被的醇溶蛋白递送至致耐受性免疫细胞来逆转麸质敏感性，并促进免疫耐受。一项 2a 期试验显示，对于接受 14 日麸质激发试验的乳糜泻控制良好的患者，TAK-101 能有效预防免疫激活和组织学恶化。[160]Kelly CP, Murray JA, Leffler DA, et al. TAK-101 nanoparticles induce gluten-specific tolerance in celiac disease: a randomized, double-blind, placebo-controlled study. Gastroenterology. 2021 Jul;161(1):66-80.e8.http://www.ncbi.nlm.nih.gov/pubmed/33722583?tool=bestpractice.com KAN-101 是一种在研药物，该药物将糖基化标记加入脱酰胺肽，从而作用于肝脏中的 T-reg 细胞。在最近的一项 1 期试验表明，该药物可通过产生白介素-2 和干扰素-γ 降低免疫激活，并且在接受麸质激发试验的患者中，肠道归巢的细胞毒性 CD8+T 细胞没有增加。这些是初期结果，2A 期研究仍在进行中。[161]ClinicalTrials.gov. A study of safety, tolerability, pharmacodynamics, and pharmacokinetics of KAN-101 in people with celiac disease. May 2023 [internet publication].https://classic.clinicaltrials.gov/ct2/show/NCT05574010
白细胞介素-15 拮抗剂
经证实，白细胞介素-15 是影响上皮内淋巴细胞存活和黏膜损伤的关键因素。正在研发可阻断该细胞因子的药物，以用于治疗无反应性和难治性乳糜泻。一项使用白细胞介素-15 抑制剂（AMG 714 ）治疗难治性乳糜泻患者的 2a 期试验报告，与安慰剂组相比，治疗组的异常上皮内淋巴细胞比例没有变化。治疗组的患者报告腹泻症状有所减轻。[162]Cellier C, Bouma G, van Gils T, et al. Safety and efficacy of AMG 714 in patients with type 2 refractory coeliac disease: a phase 2a, randomised, double-blind, placebo-controlled, parallel-group study. Lancet Gastroenterol Hepatol. 2019 Dec;4(12):960-70.http://www.ncbi.nlm.nih.gov/pubmed/31494097?tool=bestpractice.com 此外，还在接受麸质激发试验的乳糜泻控制良好患者中检查了抗 IL15 的疗效。在防止组织学恶化方面，AMG 714 和安慰剂的差异无显著统计学意义。[163]Lähdeaho ML, Scheinin M, Vuotikka P, et al. Safety and efficacy of AMG 714 in adults with coeliac disease exposed to gluten challenge: a phase 2a, randomised, double-blind, placebo-controlled study. Lancet Gastroenterol Hepatol. 2019 Dec;4(12):948-59.http://www.ncbi.nlm.nih.gov/pubmed/31494096?tool=bestpractice.com 目前正在研究该药在坚持无麸质饮食但仍有持续症状患者中的疗效。其在治疗 2 型难治性乳糜泻方面也显示出一些令人鼓舞的结果。
益生菌
早期证据表明，某些益生菌菌株可能对麸质免疫原性起作用，有助于肠道愈合，并改善患者的症状。[164]Smecuol E, Hwang HJ, Sugai E, et al. Exploratory, randomized, double-blind, placebo-controlled study on the effects of Bifidobacterium infantis natren life start strain super strain in active celiac disease. J Clin Gastroenterol. 2013 Feb;47(2):139-47.http://www.ncbi.nlm.nih.gov/pubmed/23314670?tool=bestpractice.com[165]Caminero A, Galipeau HJ, McCarville JL, et al. Duodenal bacteria from patients with celiac disease and healthy subjects distinctly affect gluten breakdown and immunogenicity. Gastroenterology. 2016 Oct;151(4):670-83.http://www.ncbi.nlm.nih.gov/pubmed/27373514?tool=bestpractice.com 一项荟萃分析显示，在胃肠道（gastrointestinal, GI）症状评分量表评估下，一些益生菌株可改善胃肠道症状。[166]Seiler CL, Kiflen M, Stefanolo JP, et al. Correction to: Probiotics for celiac disease: a systematic review and meta-analysis of randomized controlled trials. Am J Gastroenterol. 2021 Sep 1;116(9):1968.http://www.ncbi.nlm.nih.gov/pubmed/34240715?tool=bestpractice.com 建议谨慎使用益生菌，因为有些益生菌可能被麸质污染，且目前没有足够证据支持或反对对乳糜泻使用益生菌。[73]Chaudrey KH. ACG guideline: diagnosis and management of celiac disease. Am J Gastroenterol. 2023;118(1):23.http://www.ncbi.nlm.nih.gov/pubmed/36602833?tool=bestpractice.com
改良小麦麸质
正在研究各种方法以改变小麦粉中存在的麸质免疫原性肽，从而降低其免疫原性；这些方法包括微波、γ 辐射、乳酸杆菌和真菌蛋白酶水解或基因测序改变。[167]Sánchez-León S, Gil-Humanes J, Ozuna CV, et al. Low-gluten, nontransgenic wheat engineered with CRISPR/Cas9. Plant Biotechnol J. 2018 Apr;16(4):902-10.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867031/http://www.ncbi.nlm.nih.gov/pubmed/28921815?tool=bestpractice.com[168]Costabile A, Bergillos-Meca T, Landriscina L, et al. An in vitro fermentation study on the effects of Gluten Friendly™ bread on microbiota and short chain fatty acids of fecal samples from healthy and celiac subjects. Front Microbiol. 2017 Sep 7;8:1722.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594085/http://www.ncbi.nlm.nih.gov/pubmed/28936206?tool=bestpractice.com[169]Mandile R, Picascia S, Parrella C, et al. Lack of immunogenicity of hydrolysed wheat flour in patients with coeliac disease after a short-term oral challenge. Aliment Pharmacol Ther. 2017 Aug;46(4):440-6.http://www.ncbi.nlm.nih.gov/pubmed/28627070?tool=bestpractice.com用微生物转谷氨酰胺酶处理小麦粉是另一种正在研究的方法。[170]Marino M, Casale R, Borghini R, et al. The effects of modified versus unmodified wheat gluten administration in patients with celiac disease. Int Immunopharmacol. 2017 Jun;47:1-8.http://www.ncbi.nlm.nih.gov/pubmed/28343108?tool=bestpractice.com
紧密连接调节剂
拉瑞唑来 (Larazotide) 可加强紧密连接并防止麸质渗入黏膜。[171]Leffler DA, Kelly CP, Abdallah HZ, et al. A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge. Am J Gastroenterol. 2012 Oct;107(10):1554-62.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3463856/http://www.ncbi.nlm.nih.gov/pubmed/22825365?tool=bestpractice.com研究发现，症状持续的患者的症状得到改善，尽管患者也在坚持无麸质饮食。[140]Leffler DA, Kelly CP, Green PH, et al. Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial. Gastroenterology. 2015 Jun;148(7):1311-9;e6.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446229/http://www.ncbi.nlm.nih.gov/pubmed/25683116?tool=bestpractice.com[171]Leffler DA, Kelly CP, Abdallah HZ, et al. A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge. Am J Gastroenterol. 2012 Oct;107(10):1554-62.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3463856/http://www.ncbi.nlm.nih.gov/pubmed/22825365?tool=bestpractice.com 一项 3 期试验比较了 larazotide 和安慰剂对无麸质饮食后仍有持续症状的乳糜泻患者的症状缓解效果，由于在期中分析中发现缺乏症状改善，该试验于 2022 年停止。[172]ClinicalTrials.gov. Study to evaluate the efficacy and safety of larazotide acetate for the relief of CeD symptoms. Aug 2021 [internet publication].https://www.clinicaltrials.gov/ct2/show/NCT03569007
