Murray, Joseph A.

SummaryBackgroundCoeliac disease (CD), characterised by the presence of villous atrophy (VA) in the small intestine, is associated with increased mortality, but it is unknown if mortality is influenced by mucosal recovery.AimsTo determine whether persistent VA is associated with mortality in CD.MethodsThrough biopsy reports from all pathology departments (n = 28) in Sweden, we identified 7648 individuals with CD (defined as VA) who had undergone a follow‐up biopsy within 5 years following diagnosis. We used Cox regression to examine mortality according to follow‐up biopsy.ResultsThe mean age of CD diagnosis was 28.4; 63% were female; and the median follow‐up after diagnosis was 11.5 years. The overall mortality rate of patients who underwent follow‐up biopsy was lower than that of those who did not undergo follow‐up biopsy (Hazard Ratio 0.88, 95% CI: 0.80–0.96). Of the 7648 patients who underwent follow‐up biopsy, persistent VA was present in 3317 (43%). There were 606 (8%) deaths. Patients with persistent VA were not at increased risk of death compared with those with mucosal healing (HR: 1.01; 95% CI: 0.86–1.19). Mortality was not increased in children with persistent VA (HR: 1.09 95% CI: 0.37–3.16) or adults (HR 1.00 95% CI: 0.85–1.18), including adults older than age 50 years (HR: 0.96 95% CI: 0.80–1.14).ConclusionsPersistent villous atrophy is not associated with increased mortality in coeliac disease. While a follow‐up biopsy will allow detection of refractory disease in symptomatic patients, in the select population of patients who undergo repeat biopsy, persistent villous atrophy is not useful in predicting future mortality.

Summary Background Coeliac disease, an autoimmune disorder triggered by gluten ingestion, is managed by a gluten‐free diet ( GFD ), which is difficult for many patients. Larazotide acetate is a first‐in‐class oral peptide that prevents tight junction opening, and may reduce gluten uptake and associated sequelae. Aim To evaluate the efficacy and tolerability of larazotide acetate during gluten challenge. Methods This exploratory, double‐blind, randomised, placebo‐controlled study included 184 patients maintaining a GFD before and during the study. After a GFD run‐in, patients were randomised to larazotide acetate (1, 4, or 8 mg three times daily) or placebo and received 2.7 grams of gluten daily for 6 weeks. Outcomes included an experimental biomarker of intestinal permeability, the lactulose‐to‐mannitol ( LAMA ) ratio and clinical symptoms assessed by Gastrointestinal Symptom Rating Scale ( GSRS ) and anti‐transglutaminase antibody levels. Results No significant differences in LAMA ratios were observed between larazotide acetate and placebo groups. Larazotide acetate 1‐mg limited gluten‐induced symptoms measured by GSRS ( P = 0.002 vs. placebo). Mean ratio of anti‐tissue transglutaminase IgA levels over baseline was 19.0 in the placebo group compared with 5.78 ( P = 0.010), 3.88 ( P = 0.005) and 7.72 ( P = 0.025) in the larazotide acetate 1‐, 4‐, and 8‐mg groups, respectively. Adverse event rates were similar between larazotide acetate and placebo groups. Conclusions Larazotide acetate reduced gluten‐induced immune reactivity and symptoms in patients with coeliac disease undergoing gluten challenge and was generally well tolerated; however, no significant difference in LAMA ratios between larazotide acetate and placebo was observed. Results and design of this exploratory study can inform the design of future studies of pharmacological interventions in patients with coeliac disease.

Patients with irritable bowel syndrome (IBS) with diarrhea (IBS-D) carrying human leukocyte antigen (HLA)-DQ2/8 genotypes benefit from gluten withdrawal. Our objective was to compare gastrointestinal barrier function, mucosal inflammation, and transit in nonceliac IBS-D patients and assess association with HLA-DQ2/8 status. In 45 IBS-D patients who were naive to prior exclusion of dietary gluten, we measured small bowel (SB) and colonic mucosal permeability by cumulative urinary lactulose and mannitol excretion (0–2 h for SB and 8–24 h for colon), inflammation on duodenal and rectosigmoid mucosal biopsies (obtained in 28 of 45 patients), tight junction (TJ) protein mRNA and protein expression in SB and rectosigmoid mucosa, and gastrointestinal and colonic transit by validated scintigraphy. SB mucosal biopsies were stained with hematoxylin-eosin to assess villi and intraepithelial lymphocytes, and immunohistochemistry was used to assess CD3, CD8, tryptase, and zonula occludens 1 (ZO-1); colonic biopsy intraepithelial lymphocytes were quantitated. Associations of HLA-DQ were assessed using Wilcoxon's rank-sum test. Relative to healthy control data, we observed a significant increase in SB permeability ( P < 0.001), a borderline increase in colonic permeability ( P = 0.10), and a decrease in TJ mRNA expression in rectosigmoid mucosa in IBS-D. In HLA-DQ2/8-positive patients, ZO-1 protein expression in the rectosigmoid mucosa was reduced compared with that in HLA-DQ2/8-negative patients and colonic transit was slower than in HLA-DQ2/8-negative patients. No other associations with HLA genotype were identified. There is abnormal barrier function (increased SB permeability and reduced mRNA expression of TJ proteins) in IBS-D relative to health that may be, in part, related to immunogenotype, given reduced ZO-1 protein expression in rectosigmoid mucosa in HLA-DQ2/8-positive relative to HLA-DQ2/8-negative patients.

SummaryBackgroundCoeliac disease is managed by life‐long gluten withdrawal from the diet. However, strict adherence to a gluten‐free diet is difficult and is not always effective. Novel therapeutic approaches are needed to supplement or even replace the dietary treatment.AimTo review recent advances in new therapeutic options for coeliac disease.MethodsA literature search was performed on MEDLINE, EMBASE, Web of Science, Scopus, DDW.org and ClinicalTrials.gov for English articles and abstracts. The search terms used included, but not limited to, ‘Celiac disease’, ‘new’, ‘novel’, ‘Advances’, ‘alternatives’ and ‘Drug therapy’. The cited articles were selected based on the relevancy to the review objective.ResultsSeveral new therapeutic approaches for coeliac disease are currently under development by targeting its underlying pathogenesis. Alternative therapies range from reproduction of harmless wheat strains to immunomodulatory approaches. Some of these therapies such as enzymatic cleavage of gluten and permeability inhibitors have shown promise in clinical studies.ConclusionsGluten‐free diet is still the only practical treatment for patients with coeliac disease. Novel strategies provide promise of alternative adjunctive approaches to diet restriction alone for patients with this disorder.