Green, P. H. R.

Linked ContentThis article is linked to Mahadev et al and Braude, Newnham papers. To view these articles visit https://doi.org/10.1111/apt.13988 and https://doi.org/10.1111/apt.14055.

SummaryBackgroundDuodenal injury persists in some coeliac disease patients despite gluten‐free diet, and is associated with adverse outcomes.AimTo determine the prevalence and clinical risk factors for persistent villus atrophy among symptomatic coeliac disease patients.MethodsA nested cross‐sectional analysis was performed on coeliac disease patients with self‐reported moderate or severe symptoms while following a gluten‐free diet, who underwent protocol‐mandated duodenal biopsy upon enrolment in the CeliAction clinical trial. Demographic factors, symptom type, medication use, and serology were examined to determine predictors of persistent villus atrophy.ResultsOf 1345 symptomatic patients, 511 (38%, 95% CI, 35–41%) were found to have active coeliac disease with persistent villus atrophy, defined as average villus height to crypt depth ratio ≤2.0. On multivariable analysis, older age (OR, 5.1 for ≥70 vs. 18–29 years, 95% CI, 2.5–10.4) was a risk factor while longer duration on gluten‐free diet was protective (OR, 0.37, 95% CI, 0.24–0.55 for 4–5.9 vs. 1–1.9 years). Villus atrophy was associated with use of proton‐pump inhibitors (PPIs; OR, 1.6, 95% CI, 1.1–2.3), non‐steroidal anti‐inflammatory drugs (NSAIDs; OR, 1.64, 95% CI, 1.2–2.2), and selective serotonin reuptake inhibitors (SSRIs; OR, 1.74, 95% CI, 1.2–2.5). Symptoms were not associated with villus atrophy after adjusting for covariates.ConclusionsA majority of symptomatic coeliac disease patients did not have active disease on follow‐up histology. Symptoms were poorly predictive of persistent mucosal injury. The impact of NSAIDs, PPIs, and SSRIs on mucosal healing in coeliac disease warrants further study.

SummaryBackgroundVillous atrophy (VA) with intraepithelial lymphocytosis is the histological hallmark of coeliac disease (CD), but reported rates of mucosal recovery are variable.AimTo determine the impact of age and other demographic variables on the probability of persistent VA on follow‐up biopsy.MethodsWe identified patients with VA on duodenal histology at all 28 Swedish pathology departments during the years spanning 1969–2008. We examined age, gender, calendar period, duration of disease and educational attainment to determine predictors of persistent VA.ResultsOf 7648 patients with CD who underwent follow‐up biopsy, persistent VA was present in 3317 (43%; 95% CI 42–44%). The effect of age on persistent VA varied according to time period; among those biopsied in the years spanning 2000–2008, the prevalence of persistent VA was 31%, and increasing age was associated with increasing rates of persistent VA (17% among those younger than 2 years compared to 56% among those ≥70 years). In contrast, persistent VA did not vary widely by age in earlier years. On multivariate analysis (restricted to the calendar period 2000–2008, 2–5 years after CD diagnosis), persistent VA was more common among males (OR 1.43; 95% CI 1.07–1.90) and less common among patients with higher educational attainment (OR for college degree vs. <2 years of high school 0.52, 95% CI 0.35–0.78).ConclusionsThe prevalence of persistent villous atrophy has changed over time, with greater rates of healing in recent years. Social differences in persistent villous atrophy suggest that access and/or education regarding the gluten‐free diet impact mucosal healing.

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.