Non responsive and refractory coeliac disease

  • Diagnosis of non-responsive coeliac disease requires dietary assessment for ongoing gluten ingestion, a review of the diagnosis of coeliac disease and exclusion of other conditions which may be causing symptoms
  • The NHS Rare Disease Collaborative Network for non-responsive and refractory coeliac disease can provide clinical support with diagnosis and care of patients with non-responsive and refractory coeliac disease
  • There are two types of refractory coeliac disease which can be distinguished by the presence (RCD type 2) or absence (RCD type 1) of an aberrant population of intraepithelial lymphocytes (IELs)
  • People with RCD type 2 have an increased risk of malignancy, particularly enteropathy-associated T-cell lymphoma (EATL)
  • A publication by the RDCN team provides a clinical overview of management of patients with persisting symptoms
  • We have developed resources to support you and your patients

Rare Disease Collaborative Network for non-responsive and refractory coeliac disease

Rare Disease Collaborative NetworkSpecialist teams led by Prof David Sanders in Sheffield and Dr Jeremy Woodward in Cambridge have been approved by the NHS for a Rare Disease Collaborative Network (RDCN) to provide support with the diagnosis and care of those difficult cases of non-responsive or refractory coeliac disease. 

The RDCN will provide facilities for a national registry for patients with refractory coeliac disease, a reference diagnostic pathway and will share experience to improve understanding and management of this condition.

These two centres will provide clinical support at the level that the referring clinician would wish. This could involve reviewing notes, histological review, telephone consultation (with patient or clinician) or by seeing the patient and assessing small bowel biopsy for monoclonal lymphocyte population, as well as endoscopic intervention (capsule endoscopy or enteroscopy). This ensures a comprehensive assessment which can lead to discussions about therapeutic options. Therapeutic intervention can either be provided by the RDCN or the referring site. The most important issue is to ensure that patients have a standardised care and that the RDCN can support colleagues in a collaborative manner.

The RDCN will also create a National Register to provide prospective data on such patients. This may allow consideration for novel treatments such as Interleukin-15 or stem cell transplantation.

Non responsive coeliac disease

The majority of individuals with coeliac disease report a rapid clinical improvement after starting a gluten free diet and symptoms usually improve within a few weeks. However, there are a number of people with coeliac disease who do not respond to the gluten free diet or who respond initially and then see a recurrence in their symptoms.

The first step is to review the certainty of the original diagnosis through review of histology and serology. HLA typing may be useful to rule out coeliac disease. Repeat gastroscopy with duodenal biopsies should be carried out once the diagnosis of coeliac disease is confirmed. 

Persisting villous atrophy in coeliac disease usually occurs because of ongoing gluten ingestion (inadvertant or purposeful) and it is important that this is ruled out before considering alternative diagnoses.

Other reasons for ongoing symptoms should also be considered including:

  • co existent inflammatory bowel disease
  • microscopic or inflammatory colitis
  • small bowel bacterial overgrowth
  • lactose intolerance
  • functional bowel disorders
  • Giardiasis
  • Slow response to treatment

Refractory coeliac disease

Symptoms of refractory coeliac disease (RCD) include persistent severe diarrhoea, abdominal pain and sudden unexplained weight loss. The true prevalence of RCD is unknown but estimates suggest that around 0.3 to 4.0% of people with coeliac disease may have RCD.

A diagnosis of RCD is extremely rare before 30 years of age and in most cases it is diagnosed over the age of 50. 

There are two types of RCD, type 1 and type 2, which differ in presentation, diagnosis and mortality. Detailed analysis of cell populations in the duodenal mucosa using immunohistochemistry and flow cytometric analysis is required on fresh biopsy samples, services which are offered via the specialist centres in Cambridge and Sheffield.


RCD is diagnosed if the original diagnosis of coeliac disease has been confirmed, and exposure to gluten and any co existing conditions have been excluded as the cause of continuing symptoms. People with RCD should be referred to a specialist centre for further investigation.

There are two types of RCD which can be distinguished by the presence (RCD type 2) or abscence (RCD type 1) of an abberant population of intraepithelial lymphocytes (IELs) that lack the usual expression of CD3 and CD8 on the cell surface but do express intracellular CD3. The phenotype of this IEL subset is present in the healthy population, uncomplicated coeliac disease and RCD type 1, but at lower frequencies to that found in RCD type 2. Therefore, clonality testing alone is not an adequate indicator of RCD type 2, which requires quantification of the aberrant IEL subset within the small intestine.


RCD is associated with a higher risk of complications and mortality, especially with Type 2 RCD. People with Type 2 RCD are at an increased risk of developing malignancy, particularly enteropathy-associated T-cell lymphoma (EATL) and prognosis is poor. Aberrant intraepithelial lymphocytes in Type 2 RCD are considered a premalignant cell population from which EATL can evolve. Nutrition will be impaired because of ongoing malabsorption.


Due to the rarity of RCD limited clinical trials have been carried out. Treatments are based on case reports, observational reports and expert opinion.

When a patient is not responding to a gluten free diet it is essential that a dietitian performs a dietary evaluation. Regular dietetic input is important to assess nutritional adequacy and despite not responding to the diet it is essential that someone with RCD continues to follow a strict gluten free diet as part of their management plan.

Admission to hospital may be needed to monitor adherence to the gluten free diet. Nutritional treatment should include incorporating strategies to address any nutritional deficiencies.

Drug treatments may include steroids, immunosuppressive drugs, chemotherapy or a combination of these. However these have had varying results and whichever treatment is chosen ongoing review from the healthcare team is essential.

  • Type 1 – Prednisolone, budesonide or a combination of prednisolone and azathioprine can be given to induce clinical remission and mucosal recovery in most people with Type 1 RCD. In a few individuals with Type 1 RCD an elemental diet has been shown to induce long term immunopathologic, histologic and clinical improvement. However, more research is required before this can be considered a valid treatment option for Type 1 RCD.
  • Type 2 – Treatment for Type 2 RCD is more difficult and the consensus on treatment can vary. The majority of people with Type 2 RCD respond clinically to steroids however mucosal recovery is less likely and steroid treatment does not appear to prevent the development of EATL. Due to the possibility of developing overt lymphoma, there is a need for close monitoring and follow up. Large randomised controlled trials which would require collaboration between several specialist centres are needed to provide an evidence base for the treatment of Type 2 RCD.

Baggus et al (2019) How to manage adult coeliac disease: perspective from the NHS England Rare Diseases Collaborative Network for Non-Responsive and Refractory Coeliac Disease. BMJ Frontline Gastroenterology;0:1–8. doi:10.1136/flgastro-2019-101191

Rubio-Tapia A and Murray J A. (2010). Classification and management of refractory coeliac disease. Gut 59: 547-557.

Explaining RCD to patients

It can be difficult to explain RCD to your patients and they may find the diagnosis upsetting and worrying. More information about RCD aimed at our Members is available which may help to explain it more easily to your patients.

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