Review Article | Published:

Mechanisms and management of refractory coeliac disease

Nature Reviews Gastroenterology & Hepatology volume 12, pages 572579 (2015) | Download Citation

This article has been updated

Abstract

A small subset of patients with coeliac disease become refractory to a gluten-free diet with persistent malabsorption and intestinal villous atrophy. The most common cause of this condition is inadvertent gluten exposure, but concomitant diseases leading to villous atrophy should also be considered and excluded. After exclusion of these conditions, patients are referred to as having refractory coeliac disease, of which two categories are recognized based on the absence (type I) or presence (type II) of a clonal expansion of premalignant intraepithelial lymphocyte population with a high potential for transformation into an overt enteropathy-associated T-cell lymphoma. Type I disease usually has a benign course that can be controlled by mild immunosuppressive treatment, but type II can be more severe with cladribine with or without autologous stem cell transplantation effective as treatment. Patients who fail to respond to cladribine therapy, however, still have a high risk of malignant transformation. Insights into the immunophenotype of these cells and the recognition that type II disease is a low-grade, no-mass lymphoma opens avenues for new treatment strategies, including chemotherapeutic and immunomodulating strategies. This Review will provide an overview of refractory coeliac disease, discussing mechanisms, diagnosis and management.

Key points

  • The most common cause of persistent villous atrophy is inadvertent gluten exposure, but refractory coeliac disease can occur

  • Autoimmune enteropathy, common variable immune deficiency and olmesartan-related enteropathy should be excluded in instances of persistent villous atrophy

  • Type II refractory coeliac disease is now considered a low-grade, no-mass lymphoma

  • Patients with enteropathy-associated T-cell lymphoma and refractory coeliac disease should be treated in dedicated coeliac and small bowel disease centres

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Change history

  • 16 September 2015

    In the version of this article originally published online, HLA-DQ2 and fludarabine were misspelled in Figure 1. These errors have been corrected for the PDF, HTML and print versions of the article.

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Affiliations

  1. Department of Gastroenterology, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, Netherlands.

    • Tom van Gils
    • , Petula Nijeboer
    • , Roy L. van Wanrooij
    • , Gerd Bouma
    •  & Chris J. J. Mulder

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Contributions

All authors made equal contributions to writing the article. G.B. and C.J.J.M. made substantial contributions to discussion of content and reviewed/edited the manuscript before submission. P.N., R.L.v.W., G.B. and C.J.J.M. researched data for the article.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Chris J. J. Mulder.

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DOI

https://doi.org/10.1038/nrgastro.2015.155

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