Refractory coeliac disease (RCD) is characterized by the persistence or recurrence of symptoms and signs of malabsorption associated with villous atrophy in patients with coeliac disease who have adhered to a strict gluten-free diet (GFD) for more than 12 months.1–3 Serology is usually negative or, in a small percentage of cases, positive at a low titre.4 Splenic hypofunction, a risk factor for RCD, can be indicated by Howell–Jolly bodies and pitted red cells in a peripheral blood smear. A reduced spleen size visible on ultrasound examination also provides direct evidence of hyposplenism.5
RCD is subdivided into two main clinical subsets—primary and secondary. Patients with primary RCD show no improvement on a GFD, whereas those with secondary RCD experience symptom relapse after a variable period of wellbeing.1–3 RCD can be also classified as type 1 and type 2 (table 1). RCD type 1 and 2 have a similar incidence (0.04% to 1.5%) and age at diagnosis (generally after the age of 50 years);6 however, they differ significantly in terms of complications, prognosis and treatment options, making correct diagnosis essential.7–13
The diagnostic approach to RCD includes assessment of dietary adherence to a GFD and revision of the initial coeliac disease diagnosis. Re-evaluation of duodenal histopathology is mandatory, with immunohistochemical characterization aimed at identifying aberrant intraepithelial lymphocytes (IELs) and TCRℽ chain clonality (regarded as pre- or low-grade lymphoma). Videocapsule endoscopy (VCE) is necessary to determine the extent of the lesions, whereas double balloon enteroscopy (DBE) can be useful for obtaining biopsy samples from distal lesions previously identified by imaging (i.e. entero-MR and entero-CT).8,9 A practical algorithm summarizing the diagnostic process for RCD type 1 and 2 is shown in figure 1.
In this article, we discuss the mistakes most frequently made in patients who have suspected RCD, based on the available evidence and our clinical experience in the field.
Figure 1 | Diagnosis of refractory coeliac disease. A practical algorithm that we developed to summarize the diagnostic process for refractory coeliac disease (RCD) type 1 and 2 compared with slow responding coeliac disease, nonresponsive coeliac disease and other nongluten-dependent enteropathies. EGDS, esophagogastroduodenal endoscopy; GFD, gluten-free diet; TCRℽ, T-cell receptor ℽ.