Jocelyn Anne Silvester

Background: Coeliac disease is due to an acquired, lifelong gluten‐specific immune response resulting in a gluten‐dependent chronic immune‐mediated enteropathy associated with gastrointestinal and extraintestinal morbidity. Strictly avoiding dietary gluten is the only available management but has never been subjected to rigorous efficacy assessment now required for a pharmaceutical agent. Gluten‐free diet (GFD) is partially and inconsistently effective, but it places a high burden on patients, families, the food industry, and regulators and is defined inconsistently around the world, highlighting the need for effective and convenient adjunctive pharmacological therapies. Aims: To summarize key patient, scientific, and regulatory considerations for coeliac disease drug development based on a multi‐stakeholder meeting focused on accelerating clinical trials. Methods: A pre‐competitive meeting convened by the Beyond Celiac Coalition (May 2024) included patients with coeliac disease, academic experts, pharmaceutical industry representatives, and participants from the US Food and Drug Administration. Moderated panel addressed patient priorities, symptom and histologic endpoints, biopsy and histology methods, gluten challenge design, clinical trial duration, and regulatory expectations. Themes were synthesized qualitatively with focus on trial design implications and unresolved questions. Results: Participants described high symptom burden and psychosocial impact despite gluten‐free diet adherence underscoring unmet therapeutic need in coeliac disease. Regulatory perspectives emphasized the need for clinically meaningful improvement and evidence of intestinal benefit, framed as symptom and histology co‐primary endpoints in clinical trials. These expectations were discussed as most applicable to trial populations with both clinically meaningful symptoms and active histologic injury at baseline; for other phenotypes, it was emphasized that endpoint strategy, the role of gluten exposure, and trial duration should be tailored case by case to the population and mechanism of action. Practical challenges identified included endpoint selection and definition, discordance between symptoms and histology, selecting fit‐for‐purpose symptom measures; standardizing biopsy acquisition and central histology reads to address patchiness and variability, pre‐specifying definitions of meaningful histologic change given ongoing uncertainty about healing, and trial feasibility. Controlled gluten exposure was discussed as a tool to improve interpretability of efficacy outcomes, with careful consideration of dose, duration, patient burden and safety. Discussion addressed the ideal length of the double‐blind period, including a shorter 24‐week double‐blind study with an open‐label extension versus a 52‐week double‐blind design. Trial duration should balance scientific rigour, patient retention, and the need for longer‐term safety and durability data, with flexibility to tailor the approach to context. Conclusions: Progress in coeliac disease drug development will require patient‐centred, scientifically robust but feasible trial designs with appropriate endpoints, justified use of gluten exposure, consideration of improved biomarkers to reduce patient burden and early regulatory engagement. Continued multi‐stakeholder collaboration, including dedicated consideration of paediatric drug development, is essential to advance effective therapies.

Lay summary: We describe biochemically and functionally validated primary bile acid malabsorption caused by novel biallelic SLC10A2 variants in a child initially diagnosed with Crohn’s disease. Pediatric IBD cohort reanalysis identified PBAM-compatible genotypes, supporting selective testing when clinical features are suggestive.

INTRODUCTION: Treatment of celiac disease (CeD) requires a strict gluten-free diet (GFD). Adherence is difficult to assess and influenced by many factors. Identification of potential gluten exposures is essential, but no validated screening measures exist in pediatrics. The aim of this study was to develop and validate a measure screening for gluten exposure risk in pediatric patients with CeD. METHODS: The Gluten Exposure Risk Assessment (GERA) was developed in 3 phases. First, items were generated and refined by a modified Delphi process. Next, psychometrics, factor structure, and validity were examined in a sample of caregivers of pediatric patients younger than 18 years with CeD at 12 pediatric celiac centers. Finally, the final measure was tested on an independent sample population using confirmatory factor analysis and test-retest data. RESULTS: A total of 134 items were generated representing up to 6 domains, with 36 items selected for initial testing. Based on psychometrics and confirmatory factor analysis data from 484 caregivers, the final measure included a total of a single screening question and 9 validated items representing 2 domains (Home, Outside). Repeat testing on a separate sample (N = 369) confirmed factor structure and validity of the final measure (Comparative Fit Index = 0.96, Tucker–Lewis index = 0.95, root mean square error of approximation = 0.06). DISCUSSION: The GERA is a valid screening measure, completed by caregivers, for assessment of gluten exposure in children and adolescents with CeD following a GFD. GERA is a useful tool for evaluating the potential of risk of gluten exposure and potential need for intervention.

Objectives: Quantitative glycemic metrics are needed to identify undiagnosed celiac disease in type 1 diabetes and reduce delays in celiac diagnosis. Celiac enteropathy drives malabsorption that increases the risk of prandial insulin-glucose mismatch and hypoglycemia. We assessed if children with type 1 diabetes and celiac disease have lower post-prandial glucose levels preceding celiac diagnosis vs. those without celiac disease, leveraging continuous glucose monitoring (CGM) data and a computational meal annotation algorithm. Methods: In this retrospective cohort study, children with type 1 diabetes <12 months duration using CGM, positive celiac serologies and biopsy confirmed celiac disease (n=16) were matched 1-to-4 to those with negative celiac serologies (n=60). Meals were computationally annotated in the 30-day window before serologies. Differences in post-prandial trough glucose and other prandial glycemic outcomes were assessed via mixed models. Results: Undiagnosed celiac disease was associated with a lower glucose rise from meal start to peak vs. no celiac disease (−8.9 %, 95 % CI, −14.9–−2.5 %, p=0.009) and, during the first meal of the day, a lower fall from peak to trough (−9.3 %, 95 % CI, −16.5 %–−1.5 %, p=0.02). There was no significant association between celiac disease and trough glucose, meal hypoglycemia or time hypoglycemic. Conclusions: Computational analysis revealed that blunted prandial glycemic trajectories, not hypoglycemia, are associated with undiagnosed celiac disease in children with type 1 diabetes using CGM. These findings challenge current guidelines, and future studies should validate and integrate these glycemic biomarkers into a CGM-based model for real-time prediction of celiac disease in type 1 diabetes.

INTRODUCTION: Hereditary alpha-tryptasemia (HαT) is caused by the increased copy number of TPSAB1 when encoding for alpha-tryptase, resulting in elevated basal serum tryptase (BST). Many affected individuals report irritable bowel syndrome–like and reflux symptoms. We aimed to assess the prevalence of HαT in celiac disease (CeD) and whether this genetic trait modifies disease course. METHODS: This study included a prospective cohort of subjects with CeD or nonceliac gluten sensitivity (NCGS) either at diagnosis (Dx), with persisting symptoms on a gluten-free diet, or in clinical remission. BST levels were determined by immunoassay, and tryptase genotyping was performed on genomic DNA using digital droplet polymerase chain reaction (PCR) [ddPCR]. Duodenal and gastric biopsies were stained for c-KIT, and mast cell (MC) counts were averaged over 5 high power field (hpf). RESULTS: There were 153 eligible subjects: 13 with NCGS and 140 with CeD (8 patients with new Dx, 66 with persisting symptoms, 66 in remission). HαT was found in 9 subjects, all symptomatic with CeD (6.4%). One was new Dx, and the others had persisting symptoms (12.3% of subgroup). Excluding HαT, BST levels were higher among patients with CeD vs NCGS (median 5.4 vs 3.9 mcg/L P < 0.05). Duodenal MC counts were higher in CeD vs controls ( P < 0.05) and 24% higher in those with HαT (median HαT CeD 27.3/hpf, non-HαT CeD 22.0/hpf, controls 18.4/hpf). MC counts did not differ based on villous atrophy or clinical presentation. DISCUSSION: The prevalence of HαT in CeD is similar to the general population; however, all participants with CeD and HαT had ongoing gastrointestinal (GI) symptoms. Evaluation for HαT should be considered in the management of patients with CeD and persisting symptoms.

INTRODUCTION: Celiac disease (CeD) is an immune-mediated enteropathy driven by gluten ingestion. Gluten challenges (GC) are commonly used to evaluate novel therapeutics and CeD mechanisms, but their associated symptom burden has not been well characterized. We aim to evaluate the proportion of subjects with gastrointestinal and extraintestinal symptoms during an experimental GC. METHODS: Pubmed, Embase, CINAHL, and Cochrane Central were searched through December 2024 for studies reporting symptoms in adult patients with CeD in remission on a gluten-free diet undergoing a GC. Studies of GC for clinical diagnosis were excluded. Eligible studies included randomized (RCT) and non-randomized trials (non-RCT) that reported symptoms. Data were pooled using random-effects meta-analysis, and heterogeneity was assessed. RESULTS: We identified 48 eligible studies with a total of 1,409 participants of which 35 were included in the meta-analysis (6 RCTs, 29 non-RCTs). The most common symptoms were abdominal pain (RCT 0.56, 95% confidence interval [CI] 0.45–0.65; non-RCT 0.40, 95% CI 0.32–0.49), bloating (RCT 0.55, 95% CI 0.38 to 0.71; non-RCT 0.37, 95% CI 0.28–0.47), and nausea (0.41, 95% CI 0.24–0.59; non-RCT 0.34, 95% CI 0.24–0.46). There was significant heterogeneity across studies, with variable GC doses and durations, no systematic reporting of all symptom categories, and missing individual data for some studies. Bloating, fatigue, flatulence, and nausea were significantly more reported in studies administering ≥6 g gluten/d. DISCUSSION: GC commonly induces gastrointestinal symptoms in patients with CeD, with abdominal pain, bloating, and nausea being most frequent. Standardized challenge protocols are needed to advance therapeutic research while minimizing symptom burden.

INTRODUCTION: Determine contemporary rates of early mucosal recovery in children with celiac disease (CeD). METHODS: Multicenter retrospective cohort study in Canada and the United States. Children diagnosed with CeD between 2016 and 2021 who underwent a follow-up biopsy within 15 months of diagnosis were included. RESULTS: Overall, 96 of 130 children (74%) had mucosal recovery, including 48% children (12/25) who were assessed within 3 months. Musculoskeletal symptoms at diagnosis were the only clinical characteristic associated with persistent enteropathy. DISCUSSION: While mucosal recovery can occur within months, more than a quarter of children with CeD had persistent enteropathy within 15 months of treatment.

INTRODUCTION: Lifelong adherence to a gluten-free diet (GFD) is the primary treatment of celiac disease (CeD), a gluten-driven enteropathy. Concerns have been raised about increased exposure to arsenic from a GFD because rice, which naturally bioaccumulates arsenic, is commonly used as a substitute for gluten-containing grains such as wheat. We hypothesize that arsenic exposure increases in newly diagnosed children with CeD after they adopt a GFD. METHODS: This is a single-center prospective longitudinal cohort study of children (age 2–18 years) with elevated celiac serology who underwent a diagnostic endoscopy before initiation of a GFD between January and May 2022. The primary outcome was change in urinary arsenic concentration between endoscopy and after 6 months on a GFD. RESULTS: Of the 67 recruited participants, 50 had a biopsy diagnostic of CeD and were invited to continue the study. Thirty-five participants completed sample collection. Participants were from a middle-class, well-educated population that was predominantly White with presenting symptoms of abdominal pain (51%) and diarrhea (29%). After 6 months on a GFD, there was a significant increase in the median urinary arsenic concentration (3.3 µg/L vs 13.6 µg/L, P = 0.000004). In regression models, family history of CeD and Hispanic ethnicity were associated with having a higher urinary arsenic concentration after 6 months on a GFD. DISCUSSION: Children with newly diagnosed CeD have increased arsenic exposure shortly after transitioning to a GFD. While the arsenic levels were well below acutely toxic concentrations, the clinical impact of chronic exposure to mildly elevated arsenic levels is unknown.

Introduction: We investigated the frequency of personal involvement with celiac disease (CeD) among CeD researchers and their motive to pursue CeD research, compared to researchers in inflammatory bowel disease (IBD) or type 1 diabetes (T1D) research. Methods: An online survey was sent to CeD, IBD and T1D researchers. Results: 42% of CeD researchers had an involvement with their research interest, which was similar to T1D (51%) and significantly higher than the IBD respondents (27%, p<0.02). Discussion: Personal involvement is common among the CeD researchers. Personal involvement with the disease may be beneficial when conducting patient-oriented research.