Outcome of Referrals for Non-Responsive Celiac Disease in a Tertiary Center: Low Incidence of Refractory Celiac Disease in the Netherlands.

OBJECTIVES: Refractory celiac disease (RCD) is a severe cause of non-responsive celiac disease (CD) due to its association with the enteropathy associated T-cell lymphoma (EATL). Conflicting data exist on the prevalence and the clinical manifestations of RCD type I (RCD I) and type II (RCD II). The aim of the current study was to provide insight in the incidence of RCD and in the distinction with other causes of non-responsive CD. METHODS: A total of 106 CD patients were referred to our tertiary referral center between January 2006 and December 2011 for evaluation of non-responsive CD. In addition, a questionnaire was sent to all 82 gastroenterology departments in the Netherlands to reveal whether a patient with RCD was currently being evaluated or had been treated between 2006 and 2012. RESULTS: During a 6 year period, a total of 31 patients were diagnosed with RCD (19 RCD I and 12 RCD II). The nationwide survey revealed 5 additional patients with RCD I and one patient with RCD II. This leads to an annual incidence of RCD of 0.83/10.000 CD patients. The remaining patients were diagnosed with involuntary gluten ingestion (21.7%), delayed mucosal recovery (11.3%), enteropathy associated T-cell lymphoma (7.5%) and autoimmune enteropathy (1.8%). CONCLUSIONS: This nationwide study reveals a low incidence of RCD in the Netherlands. Nevertheless, RCD is a clinically relevant disease entity in CD patients non-responsive to the gluten-free diet.

Creation of a model to predict survival in patients with refractory coeliac disease using a multinational registry.

BACKGROUND: Refractory coeliac disease is a severe complication of coeliac disease with heterogeneous outcome. AIM: To create a prognostic model to estimate survival of patients with refractory coeliac disease. METHODS: We evaluated predictors of 5-year mortality using Cox proportional hazards regression on subjects from a multinational registry. Bootstrap resampling was used to internally validate the individual factors and overall model performance. The mean of the estimated regression coefficients from 400 bootstrap models was used to derive a risk score for 5-year mortality. RESULTS: The multinational cohort was composed of 232 patients diagnosed with refractory coeliac disease across seven centres (range of 11-63 cases per centre). The median age was 53 years and 150 (64%) were women. A total of 51 subjects died during a 5-year follow-up (cumulative 5-year all-cause mortality = 30%). From a multiple variable Cox proportional hazards model, the following variables were significantly associated with 5-year mortality: age at refractory coeliac disease diagnosis (per 20 year increase, hazard ratio = 2.21; 95% confidence interval, CI: 1.38-3.55), abnormal intraepithelial lymphocytes (hazard ratio = 2.85; 95% CI: 1.22-6.62), and albumin (per 0.5 unit increase, hazard ratio = 0.72; 95% CI: 0.61-0.85). A simple weighted three-factor risk score was created to estimate 5-year survival. CONCLUSIONS: Using data from a multinational registry and previously reported risk factors, we create a prognostic model to predict 5-year mortality among patients with refractory coeliac disease. This new model may help clinicians to guide treatment and follow-up.

Novel variant of EATL evolving from mucosal γδ-T-cells in a patient with type I RCD.

OBJECTIVES: Enteropathy associated T-cell lymphoma (EATL) is a rare non-Hodgkin lymphoma that may complicate coeliac disease and typically occurs in patients with refractoriness to the gluten-free diet. The majority of these patients harbour a clonal expansion of intraepithelial lymphocytes (IELs) with an aberrant phenotype in the small intestine which are thus considered as the 'precursor' lymphoma cells. We describe a 51-year-old female patient with refractory coeliac disease (RCD) who developed an EATL with manifestations in the proximal small intestine and in a mesenteric lymph node that did not evolve from regular type 'aberrant' αß-T-cells but rather from a clonal expansion of γδ-T-cells. METHODS: Duodenal biopsies and lymphoma tissue from a patient with refractory coeliac disease whom developed an EATL were extensively studied by immunophenotypical, T-cell receptor immunogenetic and chromosomal analysis. RESULTS: Flow cytometric analysis of duodenal IELs revealed an unusual large clonal expansion of CD30 negative γδ-T-cells in a patient with RCD. When the patient clinically deteriorated 18 months later, a substantial part (30%) of this cell population did express CD30. In addition, identical immunogenetic aberrancies had developed in a prehepatic lymph node. CONCLUSIONS: We here report on a case of extraintestinal EATL that originated from a clonal γδ-IEL population rather than from aberrant IEL. This EATL displayed a distinctive pattern of immunophenotypical, T-cell receptor immunogenetic and chromosomal aberrancies as compared to classical EATL, defining this lymphoma as a novel variant of EATL.

Optimal strategies to identify aberrant intra-epithelial lymphocytes in refractory coeliac disease.

INTRODUCTION: Different strategies have been developed to identify those refractory celiac disease (RCD) patients who are at risk to develop an enteropathy associated T-cell lymphoma (EATL). Flow cytometric analysis of intra-epithelial lymphocytes (IEL) with an aberrant phenotype is considered the golden standard but is not widely available. Immunohistochemistry (IHC) and T-cell receptor (TCR) rearrangement studies are commonly available but may lack sensitivity and specificity. Here, we compared the three different methods in the workup of patients suspected for RCD. METHODS: Duodenal biopsies from control patient (n = 5), RCD patients with moderately increased aberrant IEL populations (20-50 %: n = 14), and RCD patients with high numbers of aberrant IEL (>50 %: n = 5) as determined by flow cytometry were analysed by IHC and TCR-γ chain rearrangement analysis. Three pathologists scored the slides independently. RESULTS: Sensitivity of IHC and TCR-γ rearrangement analysis in RCD patients with high numbers of aberrant IELs was 100 and 71 %, respectively. RCD patients with aberrant cells between 25 and 50 % however, were missed by IHC and TCR in 50 and 57 % of cases, respectively. In addition, inter-rater reliability analysis of the IHC scoring revealed coder-pair Kappa coefficients between 0.28 and 0.85. CONCLUSION: Immunohistochemistry and to a lesser extent TCR-γ clonality analysis are sensitive in identifying patients with high numbers of aberrant IEL populations, yet miss half of RCD patients with moderately increased numbers. In addition, IHC has a high inter-observer variability. Therefore, patients suspected for RCD should undergo flow cytometric analysis of the duodenum.

Gluten-free diet in gluten-related disorders.

A gluten-free diet (GFD) is recommended for all patients with coeliac disease (CD). The spectrum of gluten-related disorders in the early 1980s was simple: CD and dermatitis herpetiformis. In the last few years, wheat allergy, gluten ataxia and noncoeliac gluten sensitivity have become new gluten-related topics. Adherence to GFDs in CD is limited and factors influencing adherence are poorly understood. Noncoeliac gluten sensitivity has stimulated the GFD food industry not only in Australia but all over the world. This article provides an overview of GFD in daily practice.

Genetic variations in interleukin-12 related genes in immune-mediated diseases.

The interleukin-12 (IL-12) family comprises a group of heterodimeric cytokines and their respective receptors that play key roles in immune responses. A growing number of autoimmune diseases has been found to be associated with genetic variation in these genes. Based on their respective associations with the IL-12 genes, autoimmune diseases appear to cluster in two groups that either show strong associations with the Th1/Th17 pathway (as indicated by genetic association with IL12B and IL23R) or the Th1/IL-35 pathway as the consequence of their association with polymorphisms in the IL12A gene region. The genetic associations are described in relation to what is known of the functionality of these genes in the various diseases. Comparing association data for gene families in different diseases may lead to better insight in the function of the genes in the onset and course of the disease.

Tioguanine in the treatment of refractory coeliac disease--a single centre experience.

BACKGROUND: Refractory coeliac disease type I is a complicated form of coeliac disease characterised by primary or secondary resistance to a gluten-free diet with persisting or reoccurring intestinal villous atrophy and symptoms of malabsorption. Besides corticosteroids, azathioprine has been advocated for the treatment of refractory coeliac disease type I. However, tioguanine (TG) might be better tolerated and more efficacious owing to a simpler metabolism towards bioactivation. AIM: To evaluate tolerability and effectiveness of the nonconventional thiopurine derivative TG in refractory coeliac disease type I. METHODS: Refractory coeliac disease type I patients treated with TG between June 2001 and November 2010 with a follow-up period of at least 1 year were included. Adverse events, laboratory values, 6-thioguanine nucleotide concentrations and rates of both clinical and histological response were evaluated at baseline and during follow-up. RESULTS: Twelve adult refractory coeliac disease type I patients were included. The median TG treatment duration was 14 months. Ten patients tolerated TG treatment on the long term, whereas two patients withdrew treatment due to adverse events. No nodular regenerative hyperplasia of the liver was observed. During follow-up clinical and histological response was observed in 83% and 78%, respectively. Corticosteroid dependency decreased by 50%. CONCLUSION: Tioguanine appears to be a convenient drug for the treatment of refractory coeliac disease type I based on higher histological and similar clinical response rates as compared with historical conventional therapies.

Colonoscopy-controlled intra-individual comparisons to screen relevant neoplasia: faecal immunochemical test vs. guaiac-based faecal occult blood test.

BACKGROUND: Guaiac-based faecal occult blood tests (g-FOBTs) are most commonly used in colorectal cancer (CRC) screening programmes. Faecal immunochemical tests (FITs) are thought to be superior. AIM: To compare performance of a g-FOBT and a quantitative FIT for detection of CRCs and advanced adenomas in a colonoscopy-controlled population. METHODS: We assessed sensitivity and specificity of both FIT (OC-sensor) and g-FOBT (Hemoccult-II) prior to patients' scheduled colonoscopies. RESULTS: Of the 62 invasive cancers detected in 1821 individuals, g-FOBT was positive in 46 and FIT in 54 (74.2% vs. 87.1%, P = 0.02). Among 194 patients with advanced adenomas, g-FOBT was positive in 35 and FIT in 69 (18.0% vs. 35.6%, P < 0.001). Sensitivity for screen relevant tumours (197 advanced adenomas and 28 stage I or II cancers) was 23.0% for g-FOBT and 40.5% for FIT (P < 0.001). Specificity of g-FOBT compared to FIT for the detection of cancer was 95.7% vs. 91.0%, P < 0.001) and for advanced adenomas (97.4% vs. 94.2%, P < 0.001). CONCLUSIONS: Faecal immunochemical test is more sensitive for CRC and advanced adenomas. Sensitivity of FIT for screen relevant tumours, early-stage cancers and advanced adenomas, is significantly higher. Specificity of g-FOBT is higher compared with FIT.