Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Current Gastroenterology Reports
Published in: Current Gastroenterology Reports 4/2020

01-04-2020 | Lymphoma | Small Intestine (A Stein and D Sachar, Section Editors)

Refractory Celiac Disease

Authors: Isabel A. Hujoel, Joseph A. Murray

Published in: Current Gastroenterology Reports | Issue 4/2020

Login to get access

Abstract

Purpose of Review

To review the epidemiology, pathophysiology, diagnosis, management, and prognosis of refractory celiac disease, with a specific emphasis on recent literature.

Recent Findings

While the pathophysiology of type I refractory celiac disease remains unclear, there have been advances in the understanding of the pathophysiology of type II refractory celiac disease. This has included recognition of the significant role of interleukin-15 and somatic mutations in JAK1 or STAT3 in the proliferation of aberrant T cells. This in turn has led to potential novel therapies targeting these factors, one of which has reached the clinical trial stage.

Summary

The morbidity and mortality associated with type II refractory celiac disease remain significant; however, recent advances in the understanding of the pathophysiology of this condition have led to potential therapeutic options that should be investigated.
Literature
1.
Rowinski S, Christensen E. Epidemiologic and therapeutic aspects of refractory coeliac disease - a systematic review. Dan Med J. 2016;63(12):A5307.PubMed
2.
Eigner W, Bashir K, Primas C, Kazemi-Shirazi L, Wrba F, Trauner M, et al. Dynamics of occurrence of refractory coeliac disease and associated complications over 25 years. Aliment Pharmacol Ther. 2017;45(2):364–72.CrossRefPubMed
3.
Verkarre V, Romana S, Cellier C, Asnafi V, Mention J, Barbe U, et al. Recurrent partial trisomy 1q22-q44 in clonal intraepithelial lymphocytes in refractory celiac sprue. Gastroenterology. 2003;125(1):40–6.CrossRefPubMed
4.
5.
Malamut G, Afchain P, Verkarre V, Lecomte T, Amiot A, Damotte D, et al. Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II. Gastroenterology. 2009;136(1):81–90.CrossRefPubMed
6.
Perfetti V, Baldanti F, Lenti M, Vanoli A, Biagi F, Gatti M, et al. Detection of active Epstein-Barr virus infection in duodenal mucosa of patients with refractory celiac disease. Clin Gastroenterol Hepatol. 2016;14(8):1216–20.CrossRefPubMed
7.
Al-Toma A, Goerres M, Meijer J, Pena A, Crusius J, Mulder C. Human leukocyte antigen-DQ2 homozygosity and the development of refractory celiac disease and enteropathy-associated T-cell lymphoma. Clin Gastroenterol Hepatol. 2006;4(3):315–9.CrossRefPubMed
8.
Wolters V, Verbeek W, Zhernakova A, Onland-Moret C, Schreuers M, Monsuur A, et al. The MYO9B gene is a strong risk factor for developing refractory celiac disease. Clin Gastroenterol Hepatol. 2007;5(12):1399–405.CrossRefPubMed
9.
Hrdlickova B, Mulder C, Malamut G, Meresse B, Platteel M, Kamatani Y, et al. A locus at 7p14.3 predisposes to refractory celiac disease progression from celiac disease. Eur J Gastroenterol Hepatol. 2018;30(8):828–37.CrossRefPubMedPubMedCentral
10.
Cheminant M, Bruneau J, Malamut G, Sibon D, Guegan N, van Gils T, et al. NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: a CELAC study. Gut. 2019;68(8):1396–405.CrossRefPubMed
11.
•• Ettersperger J, Montcuquet N, Malamut G, Guegan N, Lopez-Lastra S, Gayraud S, et al. Interleukin-15-dependent T-Cell-like innate intraepithelial lymphocytes develop in the intestine and transform into lymphomas in celiac disease. Immunity. 2016;45(3):610–25 Detailed review of the role of IL-15 in celiac disease. CrossRefPubMed
12.
Di Sabatino A, Giuffrida P, Vanoli A, Luinetti O, Manca R, Biancheri P, et al. Increase in neuroendocrine cells in the duodenal mucosa of patients with refractory celiac disease. Am J Gastroenterol. 2014;109(2):258–69.CrossRefPubMed
13.
Mention J, Ben Ahmed M, Begue B, Barbe U, Verkarre V, Asnafi V, et al. Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology. 2003;125(3):730–45.CrossRefPubMed
14.
Sedda S, De Simone V, Marafini I, Bevivino G, Izzo R, Paoluzi O, et al. High Smad7 sustains inflammatory cytokine response in refractory coeliac disease. Immunology. 2017;150(3):356–63.CrossRefPubMed
15.
Chander U, Leeman-Neill RJ, Bhagat G. Pathogenesis of Enteropathy-Associated T Cell Lymphoma. Current Hematologic Malignancy Reports. 2018;13:308–17.CrossRefPubMed
16.
van Wanrooij R, de Jong D, Langerak A, Yistra B, van Essen H, Heideman D, et al. Novel variant of EATL evolving from mucosal γδ-T-cells in a patient with type I RCD. BMJ Open Gastroenterol. 2015;2(1):e000026.CrossRefPubMedPubMedCentral
17.
Wierdsma N, Nijeboer P, de van der Schueren M, Berkenpas M, van Bodegraven A, Mulder C. Refractory celiac disease and EATL patients show severe malnutrition and malabsorption at diagnosis. Clin Nutr. 2016;35(3):685–91.CrossRefPubMed
18.
• Chetcuti Zammit S, Sanders D, Cross S, Sidhu R. Capsule endoscopy in the management of refractory coeliac disease. J Gastrointestin liver dis. 2019;28(1):15–22 Study investigating the role of a second capsule endoscopy in the management of refractory celiac disease. CrossRefPubMed
19.
Giuffrida P, Aronico N, Rosselli M, Lenti M, Cococcia S, Roccarina D, et al. Defective spleen function in autoimmune gastrointestinal disorders. Intern Emerg Med. 2019.
20.
Rubio-Tapia A, Murray J. Classification and management of refractory celiac disease. Gut. 2010;59(4):547–57.CrossRefPubMed
21.
Al-Toma A, Volta U, Auricchio R, Castillejo G, Sanders D, Cellier C, et al. European Society for the study of coeliac disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United European Gastroenterol J. 2019;7(5):583–613.CrossRefPubMedPubMedCentral
22.
Abdulkarim A, Burgart L, See J, Murray J. Etiology of nonresponsive celiac disease: results of a systematic approach. Am J Gastroenterol. 2002;97(8):2016–21.CrossRefPubMed
23.
Comino I, Fernandez-Banares F, Esteve M, Ortigosa L, Castillejo G, Fambuena B, et al. Fecal gluten peptides reveal limitations of serological tests and food questionnaires for monitoring gluten-free diet in celiac disease patients. Am J Gastroenterol. 2016;111(10):1456–65.CrossRefPubMedPubMedCentral
24.
Moreno M, Cebolla A, Munoz-Suano A, Carrillo-Carrion C, Comino I, Pizarro A, et al. Detection of gluten immunogenic peptides in the urine of patients with coeliac disease reveals transgressions in the gluten-free diet and incomplete mucosal healing. Gut. 2017;66(2):250–7.CrossRefPubMed
25.
Verbeek W, Goerres M, Von Blomberg B, Oudejans J, Scholten P, Scholten P, et al. Flow cytometric determination of aberrant intra-epithelial lymphocytes predicts T-cell lymphoma development more accurately than T-cell clonality analysis in refractory celiac disease. Clin Immunol. 2008;126(1):48–56.CrossRefPubMed
26.
Verkarre V, Asnafi V, Lecomte T, Patey Mariaud-De Serre N, Leborgne M, Grosdidier E, et al. Refractory coeliac sprue is a diffuse gastrointestinal disease. Gut. 2003;52(2):205–11.CrossRefPubMedPubMedCentral
27.
Pastre J, Juvin K, Malamut G, Derrieux C, Cellier C, Israel-Biet D. Phenotypically aberrant clonal T cells in the lungs of patients with type II refractory celiac disease. Blood. 2014;123(23):3674–5.CrossRefPubMed
28.
Derrieux C, Trinquand A, Bruneau J, Verkarre V, Lhermitte L, Alcantara M, et al. A single-tube, EuroClonality-inspired, TRG clonality multiplex PCR aids management of patients with enteropathic diseases, including from formaldehyde-fixed. Paraffin-Embedded Tissues J Mol Diagn. 2019;21(1):111–22.CrossRefPubMed
29.
Celli R, Hui P, Triscott H, Bogardus S, Gibson J, Hwang M, et al. Clinical insignificance of monoclonal T-cell populations and duodenal intraepithelial T-cell phenotypes in celiac and nonceliac patients. Am J Surg Pathol. 2019;43(2):151–60.CrossRefPubMed
30.
•• Hussein S, Gindin T, Lagana S, Arguelles-Grande C, Krishnareddy S, Alobeid B, et al. Clonal T cell receptor gene rearrangements in coeliac disease: implications for diagnosing refractory coeliac disease. J Clin Pathol. 2018;71(9):825–31 Study demonstrating the potential pitfalls in relying on T-cell receptor gene rearrangements for diagnosing refractory celiac disease. CrossRefPubMed
31.
van Wanrooij R, Muller D, Neefjes-Borst E, Meijer J, Koudstaal L, Heideman D, et al. Optimal strategies to identify aberrant intra-epithelial lymphocytes in refractory coeliac disease. J Clin Immunol. 2014;34(7):828–35.CrossRefPubMed
32.
Rouvroye M, Wicaksono A, Bosch S, Savelkoul E, Covington J, Beaumont H, et al. Faecal scent as a novel Nnn-invasive biomarker to discriminate between coeliac disease and refractory coeliac disease: a proof of principle study. Biosensors. 2019;(2):9, E69.
33.
Branchi F, Locatelli M, Tomba C, Conte D, Ferretti F, Elli L. Enteroscopy and radiology for the management of celiac disease complications: time for a pragmatic roadmap. Dig Liver Dis. 2016;48:578–86.CrossRefPubMed
34.
Elli L, Casazza G, Locatelli M, Branchi F, Ferretti F, Conte D, et al. Use of enteroscopy for the detection of malignant and premalignant lesions of the small bowel in complicated celiac disease: a meta-analysis. Gastrointest Endosc. 2017;86(2):264–73.CrossRefPubMed
35.
Radmard A, Hashemi Taheri A, Salehian Nik E, Kooraki S, Kolahdoozan S, Mirminachi B, et al. MR enterography in nonresponsive adult celiac disease: correlation with endoscopic, pathologic, serologic, and genetic features. J Magn Reson Imaging. 2017;46(4):1096–106.CrossRefPubMed
36.
• Al-Bawardy B, Barlow J, Vasconcelos R, Kim S, Bruining D, Hansel S, et al. Cross-sectional imaging in refractory celiac disease. Abdom Radiol. 2017;42(2):389–95 Study illustrating radiographic differences between type II, type I refractory celiac disease, and healed celiac disease. CrossRef
37.
van Gils T, Nijeboer P, van Waesberghe J, Coupe V, Janssen K, Zegers J, et al. Splenic volume differentiates complicated and non-complicated celiac disease. United European Gastroenterol J. 2017;5(3):374–9.CrossRefPubMed
38.
•• Mukewar S, Sharma A, Rubio-Tapia A, Wu T, Jabri B, Murray J. Open-capsule budesonide for refractory celiac disease. Am J Gastroenterol. 2017;112(6):959–67 Study investigating the role of budesonide in type I and type II refractory celiac disease management. CrossRefPubMed
39.
Al-Toma A, Verbeek W, Hadithi M, Von Blomberg B, Mulder C. Survival in refractory coeliac disease and enteropathy-associated T-cell lymphoma: retrospective evaluation of single-centre experience. Gut. 2007;56(10):1373–8.CrossRefPubMedPubMedCentral
40.
Rawal N, Twaddell W, Fasano A, Blanchard S, Safta A. Remission of refractory celiac disease with infliximab in a pediatric patient. ACG Case Rep J. 2015;2(2):121–3.CrossRefPubMedPubMedCentral
41.
•• Al-Toma A, Goerres M, Meijer J, von Blomberg B, Wahab P, Kerckhaert J, et al. Cladribine therapy in refractory celiac disease with aberrant T cells. Clin Gastroenterol Hepatol. 2006;4(11):1322–7 Recently published guidelines on celiac disease that include a detailed discussion of refractory celiac disease. CrossRefPubMed
42.
43.
Maheshwari P, Feeley I, Oleary H, Goulding C. A 37-year-old woman with refractory coeliac disease type II disease treated by stem cell transplantation. BMJ Case Rep. 2015.
44.
Tack G, Verbeek W, Al-Toma A, Kuik D, Schreurs W, Visser O, et al. Evaluation of cladribine treatment in refractory celiac disease type II. World J Gastroenterol. 2011;17(4):506–13.CrossRefPubMedPubMedCentral
45.
Nijeboer P, Van Wanrooij R, Van Gils T, Wierdsma N, Tack G, Witte B, et al. Lymphoma development and survival in refractory coeliac disease type II: histological response as prognostic factor. United European Gastroenterol J. 2017;5(2):208–17.CrossRefPubMed
46.
Tack G, Wondergem M, Al-Toma A, Verbeek W, Schmittel A, Machado M, et al. Auto-SCT in refractory celiac disease type II patients unresponsive to cladribine therapy. Bone Marrow Transplant. 2011;46(6):840–6.CrossRefPubMed
47.
Ciccocioppo R, Gallia A, Avanzini M, Betti E, Picone C, Vanoli A, et al. A refractory celiac patient successfully treated with mesenchymal stem cell infusions. Mayo Clin Proc. 2016;91(6):812–9.CrossRefPubMed
48.
Vicari A, Schoepfer A, Meresse B, Goffin L, Leger O, Josserand S, et al. Discovery and characterization of a novel humanized anti-IL-15 antibody and its relevance for the treatment of refractory celiac disease and eosinophilic esophagitis. MAbs. 2017;9(6):927–44.CrossRefPubMedPubMedCentral
49.
Cellier C, Bouma G, van Gils T, Khater S, Malamut G, Crespo L, et al. 616-AMG 714 (Anti-IL-15 MAB) halts the progression of aberrant intraepithelial lymphocytes in refractory celiac disease type II (RCD-II): a Phase 2A, randomized, double-blind, placebo-controlled study evaluating AMG 714 in adult patients with RCD-II/Pre-EATL. Gastroenterology. 2018;154(6):S-129–S-30.CrossRef
50.
van Beurden Y, van Gils T, van Gils N, Kassam Z, Mulder C, Aparicio-Pages N. Serendipity in refractory celiac disease: full recovery of duodenal villi and clinical symptoms after fecal microbiota transfer. J Gastrointestin Liver Dis. 2016;25(3):385–8.CrossRefPubMed
51.
• Rubio-Tapia A, Malamut G, Verbeek W, van Wanrooij R, Leffler D, Niveloni S, et al. Creation of a model to predict survival in patients with refractory coeliac disease using a multinational registry. Aliment Pharmacol Ther. 2016;44(7):704–14 Model predicting survival in refractory celiac disease. CrossRefPubMedPubMedCentral
Metadata
Title
Refractory Celiac Disease
Authors
Isabel A. Hujoel
Joseph A. Murray
Publication date
01-04-2020
Publisher
Springer US
Published in
Current Gastroenterology Reports / Issue 4/2020
Print ISSN: 1522-8037
Electronic ISSN: 1534-312X
DOI
https://doi.org/10.1007/s11894-020-0756-8

Other articles of this Issue 4/2020

Current Gastroenterology Reports 4/2020 Go to the issue

Neuromuscular Disorders of the Gastrointestinal Tract (S Rao, Section Editor)

Novel Therapies for Gastroesophageal Reflux Disease: Beyond Proton Pump Inhibitors

Inflammatory Bowel Disease (M Regueiro, Section Editor)

Managing Pain and Psychosocial Care in IBD: a Primer for the Practicing Gastroenterologist

GI Oncology (R Bresalier Section Editor)

Gastrointestinal and Hepatic Complications of Immunotherapy: Current Management and Future Perspectives

Small Intestine (D Sachar and AC Stein, Section Editors)

Review Article: Mesenteric Ischemia

Small Intestine (A Stein and D Sachar, Section Editors)

Role of Diet in the Development and Management of Crohn’s Disease
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits