Non-Responsive Coeliac Disease: A Compreshensive Review from the NHS England Centre for Refractory Coeliac Disease

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Persisting inflammation in the small intestine in active coeliac disease (CD), as a result of an abnormal immune response to gluten, places individuals at risk of associated complications. A gluten-free diet (GFD) is the mainstay of treatment and helps to reduce the risk of complications. Whilst the majority of patients with CD will experience symptom improvement following initiation of a GFD, symptoms and/or persisting inflammation can persist in upto 30% of individuals. This is classed as non-responsive CD (NRCD).

Defining Non-Responsive Coeliac Disease

This can be defined as persistent symptoms, signs, laboratory abnormalities or histological changes associated with CD, despite 6-12 months of presumed adherence to a GFD. It is important to note that the length of time taken to respond to a GFD is variable and an overview of the clinical picture should be taken. NRCD can be classed as primary, where there is no response to a GFD, or secondary, where there is an initial response to diet but then symptoms recur despite ongoing dietary adherence.

Causes of Non-Responsive Coeliac Disease

An alternative primary diagnosis

The first step is to ensure the diagnosis of CD is accurate. This is especially important in individuals with a historical diagnosis presenting with secondary NRCD. Data suggest around 8% of patients with a presumed NRCD did not have an original diagnosis of CD. A review of serology and histology at the time of diagnosis can be used to confirm the diagnosis taking into account the change in serological tests used in diagnosis over time.

Whilst seronegative CD exists, it only accounts for 30% of serology negative villous atrophy. Other causes include immune-mediated (e.g. autoimmune enteropathy), inflammatory (e.g. eosinophilic gastroenteritis), infectious (e.g. giardiasis), iatrogenic (e.g. NSAIDs), and idiopathic.

If re-examining the primary diagnosis raises any doubt current coeliac serology and duodenal biopsies should be undertaken. It is important to note that these individuals are likely to be on a GFD and so tests should be performed following a gluten challenge of 10g gluten per day for at least 6 weeks. Human leucocyte antigen (HLA) typing can also prove useful as a negative predictive test but cannot be used solely to diagnose CD.

An associated condition

CD is associated with a number of conditions, which are either related (small intestinal bacterial overgrowth (SIBO), lactose/fructose intolerance) or unrelated (inflammatory bowel disease (IBD), microscopi colitis) to mucosal damage in CD. These can present at the time of, or after, diagnosis and, therefore, these conditions should be considered as a cause of persisting symptoms in patients with CD and managed appropriately.

Functional gastrointestinal disorders (FGIDs), such as irritable bowel syndrome (IBS), are more prevalent in individuals with CD and should be considered as a cause of persisting symptoms in those with normal repeat duodenal histology. A low fermentable oligo-, di-, monon-saccharide and polyol (FODMAP) diet may improve symptoms and quality of life in these individuals. In addition, probiotics have been shown to be potentially beneficial in individuals with CD and IBS symptoms, however, further studies are required to evaluate the use of the low FODMAP diet and/or probiotics in NRCD associated with FGIDs.

Dietary indiscretion

Ongoing gluten ingestion (either deliberate or inadvertent) is one of the commonest causes of persisting symptoms and is reported in 35-50% of NRCD cases. Detailed symptom assessment at follow up is important, however, gluten exposure may not result in symptoms as around 20% of individuals are asymptomatic at diagnosis.

A recent meta-analysis considering the diagnostic accuracy of elevated serological markers for predicting persistent villous atrophy concluded that the tests cannot be relied on to confirm or rule out mucosal healing once on a GFD. Therefore, duodenal biopsy is currently the best way to assess mucosal healing and indirectly inform on gluten avoidance. Due to the variability in rate of mucosal recovery it is difficult to predict when to perform this follow-up biopsy with some studies suggesting it might take upto 5 years in some individuals. Therefore, persistent villous atrophy on follow-up biopsy might be due to a slow response rather than gluten exposure.

Future approaches to monitoring gluten exposure may include faecal and urine gluten immunogenic peptides (GIPs). However, there are certain limitations to these tests as they are only able to detect gluten ingestion 1-2 days (urine) and 2-4 days (faecal) prior to testing.

Gluten Super-Sensitivity

Some individuals with CD are sensitive to even small traces of gluten. These individuals may demonstrate an incomplete response to a strict GFD. A suggested dietary option for these patients is the Gluten Contamination Elimination Diet (GCED) has been developed to prevent ingestion of trace amounts of gluten. In the supersensitive subset of patients with NRCD, who are adherent to diet, an improvement in symptoms has been observed using this approach. It is suggested that the GCED may also be useful in distinguishing between ‘supersensitive’ individuals and those with true RCD. This could be useful in preventing unnecessary drug treatment for an incorrect diagnosis of RCD. Other dietary regimes have also shown potential benefits both histologically and clinically, however, there is a lack of large, long-term studies assessing the efficacy and acceptability of these in this patient group.

Refractory Coeliac Disease

Refractory coeliac disease (RCD) is reported to account for 8-23% of NRCD cases. The wide range shows the difficulty in differentiating between NRCD and RCD. Individuals with RCD can be classified as either RCD type 1 (RCD1) or type 2 (RCD2). Patients with RCD1 frequently show a good response to treatment and have an 80-100% survival rate at 5 years, compared with limited treatment options for RCD2 and a prognosis of around 50% at 5 years. 

RCD should be considered in patients with persisting or worsening symptoms and villous atrophy in those adherent to a GFD. Multi-diagnostic modalities used in the evolving diagnosis of RCD is limited to specialist centres and management of RCD is challenging, also requiring input from tertiary centres with expertise in this area.

The aim of management of RCD1 is to improve symptoms and promote histological recovery which is achieved, in the main, by nutritional support and steroid treatment. A follow-up biopsy should be performed after three months of treatment to assess the extent of histological recovery. Repeat duodenal biopsies should be employed to monitor for progression to RCD2.

On diagnosis of RCD2, individuals should  be checked for enteropathy-associated T-cell lymphoma (EATL). The aim of management is improvement of symptoms and reducing the risk of progression to EATL. As RCD2 is rare, the evidence base for treatment is limited, however, it is recommended that corticosteroid treatment be initiated, although unlike RCD1, azathioprine is not recommended due to the increased risk of EATL development in this subset of patients. There are a number of other possible treatments that have been investigated in RCD1 patients, however, these require careful consideration. Novel therapeutic strategies are required to provide realistic treatment options for RCD2 patients to help impact the high mortality rate in this condition.