Refractory Coeliac Disease: What Should We Be Doing Different?

Stefania Chetcuti Zammit; David S. Sanders; Reena Sidhu

Disclosures

Curr Opin Gastroenterol. 2020;36(3):215-222. 

In This Article

Abstract and Introduction

Abstract

Purpose of review: The aim of this review is to provide insight into the diagnosis and management of patients with refractory coeliac disease (RCD) and highlight recent advances in this field.

Recent findings: The diagnosis of RCD can be more accurately confirmed with flow cytometry in addition to immunohistochemistry. Dietary input and excretion of gluten immunogenic peptides can help rule out gluten contamination, and therefore, substantiate a diagnosis of RCD type I. Small bowel capsule endoscopy (SBCE) is important at diagnosis and follow-up in addition to duodenal histology. Apart from ruling out complications, it can give information on extent of disease in the small bowel, and therefore, help assess response to therapy. Those patients with a poor response can have earlier intensification of therapy, which may result in an improved outcome. RCD also occurs in patients with serology negative coeliac disease but with an increased mortality compared with patients with serology-positive coeliac disease.

Summary: Patients with RCD can present with persistent symptoms of malnutrition but can also be completely asymptomatic. Serology is not a reliable marker to detect refractory disease. Immunostaining and flow cytometry are necessary for a diagnosis of RCD. Small bowel endoscopy enables disease extent to be assessed and allows for small bowel biopsies to be taken in case of suspicious lesions. Small bowel radiology can be complementary to small bowel endoscopy.

Introduction

Some patients with coeliac disease do not demonstrate clinical improvement or have recurrent malabsorption, chronic intestinal inflammation, and villous atrophy. They are, therefore, considered to be refractory to treatment with a gluten-free diet (GFD). Refractory coeliac disease (RCD) has a reported prevalence of between 0.3 and 10% in patients with coeliac disease.[1] The proportion of patients diagnosed with RCD is reported to have decreased over the years.[2] This is secondary to the increased awareness on this condition and the emphasis on early treatment.

However, we are still faced with the question of who is more susceptible to develop RCD. Homozygosity for HLA-DQ2 is present in 44–67% of RCD II, 25–40% of RCD I patients, compared with 21% in individuals with uncomplicated coeliac disease.[3,4] RCD occurs more commonly in older individuals (>50 years), those who are older at the time of diagnosis of coeliac disease, female patients and those with seronegativity at the time of diagnosis.[2,3,5,6] Seronegativity might be indicative of a diagnostic delay in RCD patients. It has been shown that in patients with longstanding coeliac disease, antibodies with increasing avidity for intestinal transglutaminase-2 are produced and antibodies are less likely to spill-over into the serum.[7] Older age at diagnosis accounts for a longer exposure to a GFD. Seronegativity on the other hand may account for the older age at diagnosis.

In RCD I, T cells are converted to lymphokine-activated killer-like cells leading to mucosal damage by TCR-independent cytotoxicity.[8] IL-15 can further mediate T-cell activation,[9] possibly leading to impaired tolerance to dietary and microbial antigens and allows the survival of autoreactive T cells. Interleukin 15 is also upregulated in RCD II[10] and activates intraepithelial lymphocytes (IELs).[11]

RCD is challenging to study in view of the low prevalence of this condition amongst patients with coeliac disease and the low survival of patients with RCD II (50% at 5 years) because of the associated malignant conditions.[6,12] In this review, we address the diagnostic challenges of patients with RCD. We also outline the evidence for investigation, management and follow-up of patients with RCD.

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