Refractory coeliac disease (RCD)

Symptoms include:

• persistent severe diarrhoea
• abdominal pain
• sudden unexplained weight loss.

Prevalence

Although the real prevalence of RCD is unknown, it is probably are (1). Estimates suggest that around two to five per cent of people with coeliac disease may have RCD(2).

A diagnosis of RCD is extremely rare before 30 years of age and in most cases it is diagnosed over the age of 50. It is estimated that RCD affects two to three times as many women as men and this is consistent with the increased prevalence of coeliac disease in women compared to men (1).

Ongoing symptoms

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 (3). However, there are a number of people with coeliac disease who do not respond to the gluten-free diet (4) or who respond initially and then see a recurrence in their symptoms. 

Failure to respond to a gluten-free diet in coeliac disease usually occurs because of ongoing gluten ingestion and it is important that this is ruled out before considering alternative diagnoses.

Other reasons for ongoing symptoms include:

• co-existent inflammatory bowel disease
• microscopic colitis
• pancreatic insufficiency
• small bowel bacterial overgrowth
• lactose intolerance
• functional bowel disorders.

Definition of RCD

RCD can be defined as a Marsh stage 3 biopsy despite following a gluten-free diet and with other causes of villous atrophy having been excluded.  Marsh stage 3 is defined as raised intraepithelial lymphocytes and crypt hyperplasia with progression of the inflammation to villous atrophy (5).

There are 2 types of RCD which require polymerase chain evaluation (PCR)  of small intestinal biopsy material to be diagnosed.

• Type 1 RCD – there is polyclonal expansion of T-cells as shown by polyclonality of the T-cell receptor loci.
• Type 2 RCD – defined as the presence of monoclonality of the gamma T-cell receptor (TCR).

Complications

RCD is associated with a higher risk of complications and mortality, especially Type 2 RCD.

People with Type 2 RCD are at an increased risk of developing malignancy, particularly enteropathy-associated T-cell lymphoma (EATL) (6) and prognosis is poor. Aberrant intraepithelial lymphocytes in Type 2 RCD are considered a premalignant cell population from which enteropathy T-cell lymphoma can evolve. Nutrition will be impaired because of ongoing malabsorption.

Treatment

Due to the rarity of RCD very few adequate clinical trials have been carried out. Treatments are based on case reports, observational reports and expert opinion (1).

When a patient is not responding to a gluten-free diet it is essential that an experienced dietitian performs a dietary evaluation (7). 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.(1).

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 (1). 

Drug treatments may include steroids, immunosuppressive drugs, chemotherapy or a combination of these (8). However these have had varying results and whichever treatment is chosen ongoing review from the healthcare team is essential. 

Type 1 RCD

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 (1).

In a few individuals with Type 1 RCD an elemental diet has been shown to induce long term immunopathologic, histologic and clinical improvement (8). However, more research is required before this can be considered a valid treatment option for Type 1 RCD.

Type 2 RCD

Treatment for Type 2 RCD is more difficult (9) 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 does not prevent the development of EATL (1). Due to the possibility of developing overt lymphoma, there is a need for close monitoring and follow up (9). Large randomised controlled trials which would require collaboration between several specialist centres is needed to provide an evidence base for the treatment of Type 2 RCD.

Further support for your 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 on the general website which may help to explain it more easily to your patients.

References

• Rubio-Tapia A and Murray J A. (2010). Classification and management of refractory coeliac disease. GUT 59: 547 - 557
• Verbeek W H M, Schreurs M W J, Visser O J, Von  Blomberg BME, Al-Toma A, and Mulder CJJ. (2008) Novel approaches in the management of refractory coeliac disease. Expert review of clinical immunology 4: 205 – 219 
• Ciclitira PJ, Dewar DH, McLaughlin SC et al (2010) The management of adults with coeliac disease. London: British Society of Gastroenterology (BSGBritish Society of Gastroenterology - an organisation focused on the promotion of gastroenterology within the United Kingdom, with a membership drawn from physicians, surgeons, pathologists, radiologists, scientists, nurses, dietitians, and others interested in the field. The BSG is a registered charity.).
• Daum S, Cellier C and Mulder CJJ. (2005). Refractory coeliac disease. Best Practice and Research Clinical Gastroenterology 19 (3): 413 - 424
• Cellier C, Delabesse E, Helmer C et al (2000). Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. The Lancet 356: 203-208
• Al-toma A, Verbeek WHM, Hadithi M, von Blomberg BME and Mulder CJJ. (2007) Survival in refractory coeliac disease and enteropathy-associated T-cell lymphoma: restrospective evaluation of single-centre experience. GUT. 56:1373 – 1378
• Hadithi M and Pena AS. (2011). Current methods to diagnose the unresponsive and complicated forms of coeliac disease. European Journal of Internal Medicine 21: 247 - 253
• Olaussen R, Lovik A, Tollefsen S, Andresen P, Vatn M, De Lange T, Bratlie J, Brandtzaeg P, Farstad I N and Lundin K. (2005). Effect of elemental diet on mucosal immunopathology and clinical symptoms in Type 1 Refractory coeliac disease. Clinical Gastroenterology and Hepatology 3: 875 - 885
• Ho-Yen C et al (2009) Recent advances in refractory coeliac disease: a review. Histopathology 54: 783-795