Jolanda M. van de Water

Consumption of gluten with gluten-degrading enzyme by celiac patients: a pilot-study.

AIM To assesses the safety and efficacy of Aspergillus niger prolyl endoprotease (AN-PEP) to mitigate the immunogenic effects of gluten in celiac patients. METHODS Patients with initial diagnosis of celiac disease as confirmed by positive serology with subtotal or total villous atrophy on duodenal biopsies who adhere to a strict gluten-free diet (GFD) resulting in normalised antibodies and mucosal healing classified as Marsh 0 or I were included. In a randomised double-blind placebo-controlled pilot study, patients consumed toast (approximately 7 g/d gluten) with AN-PEP for 2 wk (safety phase). After a 2-wk washout period with adherence of the usual GFD, 14 patients were randomised to gluten intake with either AN-PEP or placebo for 2 wk (efficacy phase). Measurements at baseline included complaints, quality-of-life, serum antibodies, immunophenotyping of T-cells and duodenal mucosa immunohistology. Furthermore, serum and quality of life questionnaires were collected during and after the safety, washout and efficacy phase. Duodenal biopsies were collected after the safety phase and after the efficacy phase. A change in histological evaluation according to the modified Marsh classification was the primary endpoint. RESULTS In total, 16 adults were enrolled in the study. No serious adverse events occurred during the trial and no patients withdrew during the trial. The mean score for the gastrointestinal subcategory of the celiac disease quality (CDQ) was relatively high throughout the study, indicating that AN-PEP was well tolerated. In the efficacy phase, the CDQ scores of patients consuming gluten with placebo or gluten with AN-PEP did not significantly deteriorate and moreover no differences between the groups were observed. During the efficacy phase, neither the placebo nor the AN-PEP group developed significant antibody titers. The IgA-EM concentrations remained negative in both groups. Two patients were excluded from entering the efficacy phase as their mucosa showed an increase of two Marsh steps after the safety phase, yet with undetectable serum antibodies, while 14 patients were considered histologically stable on gluten with AN-PEP. Also after the efficacy phase, no significant deterioration was observed regarding immunohistological and flow cytometric evaluation in the group consuming placebo compared to the group receiving AN-PEP. Furthermore, IgA-tTG deposit staining increased after 2 wk of gluten compared to baseline in four out of seven patients on placebo. In the seven patients receiving AN-PEP, one patient showed increased and one showed decreased IgA-tTG deposits. CONCLUSION AN-PEP appears to be well tolerated. However, the primary endpoint was not met due to lack of clinical deterioration upon placebo, impeding an effect of AN-PEP.

A new and validated clinical prognostic model (EPI) for Enteropathy Associated T-cell Lymphoma

Purpose: Enteropathy-associated T-cell lymphoma (EATL) is a rare intestinal non–Hodgkin lymphoma with a poor, though variable prognosis. The International Prognostic Index (IPI) and the prognostic index for peripheral T-cell lymphoma (PIT) have limited predictive value for outcome of EATL. The purpose of this study was to develop and validate a prognostic model for EATL, which can identify high-risk patients who need more aggressive therapy. Experimental Design: This retrospective multicenter study was based on 92 patients and included 45 patients diagnosed with EATL between 1999 and 2009 from the Netherlands and 47 patients from England and Scotland, diagnosed with EATL between 1994 and 1998. A new EATL prognostic index (EPI) was constructed using the RPART (recursive partitioning and regression trees) procedure. Validation was performed applying the bootstrap method. Results: Three risk groups were distinguished (P < 0.0001): a high-risk group, characterized by the presence of B-symptoms [median overall survival (OS) of 2 months]; an intermediate-risk group, comprising patients without B-symptoms and an IPI score ≥ 2 (7 months); and a low-risk group, representing patients without B-symptoms and an IPI score of 0 to 1 (34 months). Internal validation showed stability of statistical significance and prognostic discrimination. In contrast with the IPI and PIT, the EPI better classified patients in risk groups according to their clinical outcome. Conclusions: Our new, validated, prognostic model EPI accurately predicts survival outcome in EATL and may be used for patient selection for new therapeutic strategies and evaluation of clinical trials. Clin Cancer Res; 21(13); 3013–9. ©2015 AACR.

Celiac disease: Assessment of quality of life

Adolescents with celiac disease who adhere to a gluten-free diet have a better quality of life than those who do not comply with the diet, according to a new study. Adolescents who are diagnosed as having this disease at a young age also have improved quality of life.

Surgery in (pre)malignant celiac disease

AIM To report the outcome of surgery in patients with (pre)malignant conditions of celiac disease (CD) and the impact on survival. METHODS A total of 40 patients with (pre)malignant conditions of CD, ulcerative jejunitis (n = 5) and enteropathy associated T-cell lymphoma (EATL) (n = 35), who underwent surgery between 2002 and 2013 were retrospectively evaluated. Data on indications, operative procedure, post-operative morbidity and mortality, adjuvant therapy and overall survival (OS) were collected. Eleven patients with EATL who underwent chemotherapy without resection were included as a control group for survival analysis. Patients were followed-up every three months during the first year and at 6-mo intervals thereafter. RESULTS Mean age at resection was 62 years. The majority of patients (63%) underwent elective laparotomy. Functional stenosis (n = 13) and perforation (n = 12) were the major indications for surgery. In 70% of patients radical resection was performed. Early postoperative complications, mainly due to leakage or sepsis, occurred in 14/40 (35%) of patients. Eight patients required reoperation. More patients who underwent resection in the acute setting (n = 3, 20%) died compared to patients treated in the elective setting. With a median follow-up of 20 mo, seven patients (18%) required reoperation due to long-term complications. Significantly more patients who underwent acute surgery could not be treated with adjuvant chemotherapy. Patients who first underwent surgical resection showed significantly better OS than patients who received chemotherapy without resection. CONCLUSION Although the complication rate is high, the preferred first step of treatment in (pre)malignant CD consists of local resection as early as possible to improve survival.

M2032 HLA-DQ Typing of Extra-Intestinal T-Cell Lymphomas: Evidence for An Association with Undiagnosed Celiac Disease? a Pilot Study On Anaplastic Large Cell Lymphomas

Introduction: The prevalence of celiac disease (CD) is 0.5-1% in the Western population. As CD is widely underdiagnosed, the majority of CD patients is still untreated and therefore at greater risk of developing complicated CD, including Enteropathy Associated T-cell Lymphoma (EATL). Differentiation between various T-cell lymphomas is difficult because of similar morphology and immunophenotype. The final diagnosis is based on clinical presentation and localisation of the lymphoma. Consequently, T-cell lymphomas in CD patients and T-cell lymphomas in the small bowel are always diagnosed as EATLs. However, 25% of EATLs are located extra-intestinal. The most frequent type of T-cell lymphomas is anaplastic large cell lymphoma (ALCL). ALCLs are either anaplastic lymphoma kinase (ALK) negative or positive. EATLs are always ALK negative. As is the case for most EATLs, ALCLs are CD30 positive. CD and EATL are strongly associated with HLA-DQ2 and/or -DQ8. HLADQ2 and/or -DQ8 expression is found in 98% of CD and EATL patients, compared to 40% in the Western population. Aims and Methods: We investigated whether the frequency of HLA-DQ2 and/or -DQ8 is increased in extra-intestinal ALCLs compared to the general population, in order to determine if extra-intestinal ALCLs might in fact be undiagnosed EATLs. For this purpose, extra-intestinal ALCL samples, ALK-positive and ALK-negative, were collected and DNA was isolated. DQA1 and DQB1 alleles were amplified using PCR. HLA-DQ typing was subsequently performed using a single strand conformation polymorphism / heteroduplex based method (SSCP/HD). Results: So far, 21 anaplastic large-cell lymphomas have been HLA-DQ typed. HLA-DQ2 was present in 10 lymphomas, of which 3 were homozygous. HLA-DQ8 was present in 4 lymphomas, all heterozygous. In total, twelve lymphomas (57%) were HLA-DQ2 and/or -DQ8 positive, indicating only a slightly higher prevalence than in the general population. However, within the subgroup of ALKnegative ALCLs, representing potentially undiagnosed EATLs, 71% was HLA-DQ2 and/or DQ8 positive (p=0.05). Conclusion: The increased prevalence of HLA-DQ2 and/or -DQ8 in ALK-negative ALCLs suggests underdiagnosis of EATL within this group of extra-intestinal T-cell lymphomas.

M2042 Survival in Refractory Coeliac Disease with Aberrant T-Cells After Cladribine Therapy: Evaluation of a Single Center Experience

Background Aims: Approximately 2-5% of adult-onset coeliac disease patients fails to respond to a gluten free diet and develops refractory celiac disease (RCD). Two types of RCD have been recognized: type I with a phenotypically normal and type II with an aberrant intraepithelial Tcell population. In contrast to RCDI, RCDII seems to be unresponsive to common immunosuppressive treatment. Transition into Enteropathy Associated T-cell Lymphoma (EATL) is seen in 50-60%. This study reports on the effect of cladribine (2-CDA), a purine analogue inducing T-cell depletion, regarding clinical, histolopathologic and immunologic parameters. Design and methods: An analysis was performed in a tertiary referral centre for coeliac disease between 2001 and 2008. Overall, 29 patients diagnosed with RCDII (16 men, 13 women) were treated with 2-CDA (0,1mg/kg/day) intravenously for 5 days, in 1-3 courses every 6 months depending on the response. Symptoms of malabsorption, weight, albumin, haemoglobin, Marsh classification and percentage of aberrant intraepithelial T-cells were evaluated during follow-up. Results: At the time of 2-CDA treatment, the mean age of the 29 patients included was 62.6years (SD±7.6). All patients tolerated 2-CDA without serious side effects. The mean follow-up period was 30.6 months (SD±23.6). Sixteen patients (55%) showed a clinical improvement, nineteen (66%) a histopathological improvement, ten (35%) a significant decrease in aberrant T-cells and fourteen (48%) a complete remission (Marsh 0-1) during follow-up. Four patients had a partial small bowel resection due to UJ before 2-CDA treatment, complete remission was seen in three of them. Four non-responders have had bone marrow transplantation (BMT), among them three eventually showed a complete histological remission and one developed an EATL. Sixteen of 29 (55%) RCDII patients presented as ulcerative jejunitis (UJ). Overall, twelve patients (41%) died. Five out of these 12 patients developed an EATL and died within one year after diagnosing EATL. Seven patients died because of progressive refractory state. The 2-, 3-, 4-year survival after 2-CDA therapy was 75%, 62% and 44%, respectively. Conclusion: Although treatment with 2-CDA of patients with RCDII does not prevent EATL development in all RCDII patients, it seems feasible, well tolerated and induces clinical and histological improvement in 50% of the patients, and complete histological remission in 48%. BMT was only an alternative for nonresponders up to 70 years of age.