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Refractory coeliac disease

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A small proportion of coeliac disease (CD) patients fail to improve after a gluten-free diet (GFD) and may be considered as atypical regarding their outcome (refractory coeliac disease). The aim of this study is to diagnose and manage patients with CD who fail to improve after a GFD. Refractory coeliac disease (RCD) is a malabsorption syndrome defined by persisting villous atrophy with, usually, an increase of intraepithelial lymphocytes (IELs) in the small bowel in spite of a strict GFD and comprises a heterogenous group of diseases. Some of these diseases have to be excluded and can be treated by specific therapies like antibiotics in tropical sprue and giardiasis and immune globulin substitution in common variable immunodeficiency, while other malabsorption syndromes are less well defined and may require immunosuppressive therapy. Standardized treatment, however, has not been evaluated in such patients so far.

In a subgroup of patients with RCD, an abnormal intraepithelial lymphocyte (IEL) population may be observed with the lack of surface expression of usual T-cell markers (CD3–CD8 and/or the T-cell receptor (TCR)) on IELs associated with T-cell clonality pattern suggest the presence of an early enteropathy-associated T-cell lymphoma (EATL) in a subgroup of patients with RCD. This hypothesis has been supported by studies, which revealed progression into overt intestinal T-cell lymphomas in a subgroup of RCD. Steroid treatment has been reported effective even in patients with underlying early EATL. However, long-term results are unsatisfactory in most of these patients with RCD and parenteral nutrition has to be applied in some of these cases. First results with more aggressive chemotherapies and use of cytokines are under way.

Due to the difficulty of diagnostic and therapeutic regimens patients should be referred to tertiary centres for coeliac disease.

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INTRODUCTION

Coeliac disease (CD) is the most common cause of villous atrophy and is related to gluten intolerance in genetically determined subjects.1 A GFD usually induces clinical improvement within days or weeks. Histological recovery in most adult coeliac patients takes several months and may take years in single cases.2, 3 GFD fails to induce clinical and/or histological improvement in 5–30% of CD patients in spite of a strict GFD.4 In a large part of patients without persisting villous atrophy

Reassessment of the initial diagnosis of coeliac disease

In a patient with villous atrophy refractory to a GFD, the first step requires to reassess the initial diagnosis of CD, in order to exclude other diseases such as tropical sprue, common variable immunodeficiency or autoimmune enteropathy (Table 1). The presence of circulating antigliadin, anti-endomysium (EMA) or anti-transglutaminase (tTG) antibodies before the onset of the GFD, an HLA DQ2 or DQ8 status and an initial clinical and histological improvement after a strict GFD are strongly

Refractory coeliac disease without abnormal IEL clonal population (RCD I)

Histology of the small bowel mucosa in most cases is indistinguishable from active untreated CD. Number of IELs may be lower than in RCD II and active CD although this has not been proven in prospective studies.35 The IEL phenotype is normal with the expression of surface CD3 associated with surface CD8 and TCR-β as in classical active CD.7, 35, 36 Number of CD8− and TCR-β positive IELs should exceed 50% of IELs and lower expression seems to be quite sensitive for differentiation from RCD II

Follow-up and overt lymphoma in patients with refractory coeliac disease

RCD I and particularly RCD II is a serious disorder with a 5-year survival less than 50% and the most frequent cause of death is the occurrence of an overt T-cell lymphoma and recurrent infections. The presence of an abnormal clonal IEL population is significantly associated with a poor survival and a high risk of progression to overt lymphoma.43 The same clonal TCR-gene rearrangement initially identified in patients with clonal RCD may be subsequently observed in lymphomatous specimens

Supportive treatment

The first line of treatment should be to correct nutritional status, if necessary through parenteral nutrition. The GFD should be maintained as good as possible and reassessed since a minority of patients may have a long-term benefit of a strict gluten withdrawal.23 Also patients without evidence of CD should be encouraged to keep a GFD for at least one year.

Corticosteroid therapy is often useful to induce clinical remission.7 There exist no prospective or even randomized trials in the use of

Treatment of refractory coeliac disease I

In contrast to patients with features of an EATL, patients without clonality of the TCR-gene and without loss of antigens in IELs, seem to profit from an immunosuppressive treatment.36 According to the data of Goerres et al, azathioprine should be first line therapy after induction of clinical remission with corticosteroids. Dose and duration of treatment with azathioprine are not established, but recommendations from inflammatory bowel disease may be taken. In contrast to RCD II, long-term

Treatment of refractory coeliac disease II

Response to corticosteroid treatment does not exclude underlying EATL, which has been shown in single cases.49 In case of RCD II and clinical symptoms in spite of a corticosteroid treatment, more aggressive therapeutic schemes should be considered.

Some patients may benefit from infliximab infusions in case of steroid-dependence or steroid resistance. Immunosuprressive therapy may induce a high risk of progression to an overt lymphoma.36 We should not recommend this therapeutic approach in

Conclusion

Before diagnosing patients as having RCD, other specific diseases like autoimmune enteropathy or tropical sprue and especially gluten contamination have to be excluded. In recent years molecular, phenotypic and clinical characterization of patients with RCD has found this entity to comprise a heterogeneous group of diseases. Based on immunohistological and TCR-gene rearrangement investigations, mainly two entities RCD I and RCD II have been differentiated. In RCD I IELs show a normal phenotype

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