Improving outcomes of refractory celiac disease - current and emerging treatment strategies

Abstract

Intestinal inflammation and symptoms of celiac disease (CD) usually respond well to gluten withdrawal, but rare cases are refractory to diet. Two types of refractory CD are discriminated on the basis of the presence or absence of an atypical population of mucosal lymphocytes that may progress to enteropathy-associated T-cell lymphoma. Challenges remain in the secure diagnosis of both types of refractory disease, and evidence on which to base treatment recommendations is flawed by the small numbers of reported patients and the use of different diagnostic strategies. Recent advances in our understanding of the mechanisms of the condition in conjunction with the development of immunomodulatory agents for managing other inflammatory diseases are helping to shape future approaches to targeted therapy. Progression will depend on collaboration and recruitment to trials. In the meantime, there is evidence to suggest that earlier diagnosis and better follow-up and management of CD may prevent the development of refractoriness.

Keywords: celiac disease; gluten; lymphocytes; lymphoma; small intestine.

Figure 1

Characteristic flow cytometry of intraepithelial lymphocytes isolated from intestinal biopsies incubated with anti-CD3 antibodies prior to and after permeabilization in order to identify cell sCD3 (y axis) and cyCD3 (x axis) expression. Notes: (A) Normal individual (not celiac): 26% of cells lack surface and intracellular CD3 expression, 13% demonstrate intracytoplasmic but not cell sCD3 expression, and 56% are sCD3 and intracytoplasmic CD3+ in keeping with mature T-cells. Of these, the majority (96%) express the ab TCR. (B) Patient with RCD1 (note that this is indistinguishable from the patient with active CD): 2% of cells lack sCD3 and intracellular CD3 expression, 0.3% demonstrate intracytoplasmic CD3 but lack sCD3 expression, and 95% are sCD3 and intracytoplasmic CD3+, of which roughly equal proportions express the ab and gd TCR. (C) Patient with RCD2: 12% of cells lack intracytoplasmic and sCD3, 76% express the “aberrant phenotype” of intracytoplasmic CD3 without surface expression, and only 4% are mature T-cells expressing both sCD3 and cyCD3. Abbreviations: sCD3, surface CD3; cyCD3, cytoplasmic CD3; TCR, T-cell receptor; RCD, Refractory Celiac Disease.

Figure 2

An endoscopic image of T-cell lymphoma (EATL).

Figure 3

A flow chart showing suggested pathways for diagnosis and management of RCD. Notes: Dotted lines and italics show pathways that remain unclear or controversial. Arrow marked with * indicates that RCD can develop secondarily after initial response to gluten withdrawal. Abbreviations: RCD, refractory celiac disease; CD, celiac disease; IBS, irritable bowel syndrome; PEI, pancreatic exocrine insufficiency; LC, lymphocytic colitis; SIBO, small intestinal bacterial overgrowth; LI, lactose intolerance; IEL, intraepithelial lymphocyte; TCR, T-cell receptor; EATL, enteropathy-associated T-cell lymphoma; TNF-α, tumor necrosis factor-α; Tx, transplantation.