Purpose:Validated patient-reported outcome measures (PROMs) are required for use in clinical trials of celiac disease (CeD) therapies. The Celiac Disease Symptom Diary 2.1© (CDSD 2.1©), which measures the daily severity of core CeD symptoms (abdominal pain, bloating, diarrhea, nausea, tiredness), was developed according to the latest regulatory guidelines for fit-for-purpose PROMs. This study evaluated the psychometric properties of CDSD 2.1. Methods:Psychometric properties of CDSD 2.1 were evaluated using data from a 12-week US observational study, the Virtual Celiac Symptoms Study (NCT05309330), in patients with CeD maintaining a gluten-free diet. Participants completed CDSD 2.1 daily and other PROMs (Patient Global Impression of Severity [PGIS], Gastrointestinal Symptom Rating Scale [GSRS], and Celiac Symptom Index [CSI]) at specified time points to evaluate the reliability, validity, and responsiveness of CDSD 2.1. Results:Overall, 480 participants (338 adults, 142 adolescents) completed the study. Cronbach's alpha (baseline = 0.77 adults/adolescents) indicated high internal consistency reliability of weekly average gastrointestinal (GI; abdominal pain, bloating, nausea, diarrhea) CDSD 2.1 scores. An intraclass correlation coefficient of 0.89 (adults)/0.88 (adolescents) demonstrated high test-retest reliability among stable patients on PGIS. Moderate-to-strong correlations between weekly average GI CDSD 2.1 scores and GSRS domains at baseline and CSI at Week 3 confirmed construct validity (r = 0.44-0.76; p<0.05). Weekly average GI CDSD 2.1 score changes followed expected patterns based on PGIS change groups, demonstrating responsiveness. Conclusion:This evaluation provides evidence to support the use of CDSD 2.1 in clinical trials as a reliable and responsive measure of CeD symptom severity.

OBJECTIVE:Evaluate the validity of a standard dietitian evaluation (SDE) assessment of gluten-free dietary (GFD) adherence for pediatric patients with celiac disease (CeD). METHODS:Exploratory and confirmatory factor analyses were conducted in this cross-sectional, retrospective study to evaluate the factor structure of a clinical SDE. Construct validity analyses were performed to establish if the SDE was associated with the primary outcome measure of a biological measure of adherence (autoantibody serology). Retrospective data were gathered from 367 pediatric patients from a large pediatric tertiary care center. Patients identified had a documented diagnosis of CeD and at least one SDE completed by a gastroenterology dietitian between January 2014 and March 2020. RESULTS:The results of the exploratory and confirmatory factor analyses supported a single SDE factor. Greater reduction in autoantibody serology since diagnosis was correlated with better SDE score (partial Spearman ρ = 0.22 (95% CI: 0.01, 0.41; P = 0.04). CONCLUSIONS AND PRACTICE IMPLICATIONS:This study is the first to evaluate the structural integrity of an SDE for GFD adherence in pediatric CeD. Findings support the SDE's structural integrity and construct validity with serology, highlighting its potential as a reliable clinical tool for evaluating dietary adherence in pediatric CeD.

Celiac disease (CeD) is a gluten-induced immune-mediated enteropathy that preferentially involves the proximal duodenum. Consequently, iron deficiency is common in CeD, impacting at least 10% of newly diagnosed individuals. In this narrative review, we aim to investigate the mechanisms, prevalence, treatment, and monitoring of iron deficiency and the impacts of a gluten-free diet (GFD) on iron deficiency in individuals with CeD. We will also review the role of and approach to iron supplementation in this population. Specifically, we will explore whether mucosal healing on a GFD is sufficient for the management of iron deficiency amongst individuals with CeD.

Celiac disease (CD) has an estimated global prevalence of 1.4%.1 Guidelines support testing symptomatic or high-risk individuals for CD with total immunoglobulin A (IgA) (to exclude deficiency) and tissue transglutaminase autoantibodies (tTG-IgA).2 However, most cases remain undiagnosed due to unrecognizable symptoms or no known family history of CD.3 Since serial testing may be required over a child's lifetime, initial human leukocyte antigen (HLA) determination followed by tTG-IgA testing in those with increased pretest probability could be cost-effective4 by limiting serologic screening to the 40% of the population with HLA risk.5 Although Italy recently passed a law mandating nationwide childhood screening for CD, the United States Preventive Services Task Force concluded that there was insufficient evidence to screen for asymptomatic CD. Although other countries have examined the cost-effectiveness of screening, such data are not yet available in the United States.6This study aimed to estimate the least costly population level screening strategy for CD in American children: HLA-first testing followed by serial tTG-IgA screening in those at risk vs serial tTG-IgA screening alone.For this cost-minimization analysis with decision-tree modeling, 3 screening strategies were considered: (1) HLA-first genetic testing followed by tTG-IgA screening up to 2 times for those at-risk; (2) tTG-IgA screening for all up to 2 times in childhood; (3) tTG-IgA for all up to 3 times in childhood (Figure 1).We calibrated the model using real-world evidence through the Autoimmunity Screening for Kids, the Diabetes Autoimmunity Study in the Young, and the Environmental Determinants of Diabetes in the Young studies (Supplemental Information).3,5,7,8Average paid claims (IQVIA PharMetrics) in 2022 US dollars were used as a proxy for the cost of laboratory tests and biopsies. Outcomes included cost per CD screening and cost per CD case diagnosed. All antibody-positive children undergo esophagogastroduodenoscopy (EGD) for biopsy confirmation. IgA deficiency was followed with deamidated gliadin peptide immunoglobulin G testing.2Serial serologic screening without preceding HLA risk determination was the least costly screening method. For HLA-first testing, the cost per 1000 children screened was $70 000, and the cost per case diagnosed was $2400. Autoantibody screening 2 times in childhood cost $44 000 per 1000 children screened and $1600 per case diagnosed. Screening 3 times cost $53 000 per 1000 children screened and $1900 per case diagnosed.Per 1000 children, over $25 000 would be saved by autoantibody screening up to 2 times in childhood compared to HLA-first testing.Scenario analysis (Table 1) showed that serial tTG-IgA screening can be done over 5 times in childhood and is still less costly than the HLA screening strategy, with a cost per case diagnosed of $2200.Decreasing the cost of HLA testing by 54%, from $48 to $22 per test, would result in a break-even screening cost with serial tTG-IgA screening at 2 time points.For serial tTG-IgA screening without HLA testing, total IgA testing adds 40% of the cost of total screening for CD.There is an increased cost of initial HLA testing at the population level, compared with serial tTG-IgA screening alone. Total IgA determination to pick up 7% missed cases could be reconsidered as part of a mass screening strategy, but secondary serologic testing costs in IgA deficiency are negligible. For total cost per CD case diagnosed, EGD is the most expensive aspect of screening. This model assumes that every positive screen will undergo diagnostic EGD.2 To decrease costs, serologic diagnosis per European guidelines, if validated in North America, could be used.Repeat testing would be needed if screening started at an early age. However, later-age screening, such as at age 10 years with dyslipidemia screening,9 could result in diagnostic delays. Regardless, integrating screening with routine pediatric care could help reduce health care disparities.There are inherent limitations with cost-minimization analysis. Screening will detect more children with slightly elevated antibodies who require additional workup. This will likely underestimate cost-per-case diagnosed, although relative costs for each screening strategy are unchanged. Health-related quality of life and the negative impact on health and health care utilization from a delayed diagnosis are not incorporated into this model.10 Further analysis is needed to incorporate quality-adjusted life years to determine the cost-effectiveness of screening. The incorporated autoimmunity prevalence and incidence is from the Colorado-based data, which may not be generalizable to other states or countries.The authors would like to thank the patients and their families who contributed to these studies.

BACKGROUND AND OBJECTIVES:Recent changes in European diagnostic criteria allow for serologic diagnosis of celiac disease in children. Those guidelines have not been adopted in North America; hence, we aim to assess the positive predictive value (PPV) of tissue transglutaminase (tTG) immunoglobulin A (IgA) assays used in North America in identifying histologic findings of celiac disease. METHODS:Multicenter retrospective cohort study of children (<18 years) with an elevated tTG IgA within 6 months of an esophagogastroduodenoscopy between January 2016 and December 2021. Biopsy-confirmed celiac disease was determined by the presence of intraepithelial lymphocytosis and villous atrophy. The primary outcomes were the PPV of an elevated tTG IgA and tTG IgA greater than or equal to 10 times the upper limit of normal (10× ULN). RESULTS:Overall, 4019 children (63.3% female; 9% type 1 diabetes, 2% Down syndrome) were included. Histologic findings were consistent with celiac disease for 3321 children (PPV = 82.6% [95% CI, 81.4-83.8]). Among the 1739/4019 (43.2%) children with tTG IgA greater than or equal to 10× ULN, 1651 had biopsy-confirmed celiac disease (PPV10× = 94.9% [95% CI, 93.8-95.9]). Five percent (88/1739) of children did not have histologic findings of celiac disease, including 41/1739 (2%) with normal histology. Diagnostic accuracy of tTG IgA varied widely among assays used in North America (PPV range: 71.5%-88.8%; PPV10× range: 89.3%-97.3%). Assays performed worse in children with type 1 diabetes (PPV10× 89% [95% CI, 83.5-92.8]). CONCLUSIONS:Elevated tTG IgA in isolation is insufficient to confidently diagnose celiac disease. As tTG assay performance varied widely, diagnostic confirmation by a specialist prior to dietary changes is essential.

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.

Plain Language SummaryWhat is this summary about?Rett syndrome is a rare condition that affects how the brain develops and functions. Gastrointestinal problems are experienced by nearly everyone with Rett syndrome (most often constipation). The medication trofinetide (DAYBUE™) was studied in clinical trials, where it showed a benefit in reducing some of the neurologic symptoms of Rett syndrome. The most common side effects in the clinical trials with trofinetide were diarrhea and vomiting; aspiration was rarely seen. To help caregivers and healthcare providers support individuals with Rett syndrome, experts created recommendations on how to prevent and manage gastrointestinal problems, either with or without trofinetide treatment.What were the main conclusions reported?Better management of gastrointestinal problems should lead to a better quality of life for those with Rett syndrome and their caregivers. For those taking trofinetide, improved management of gastrointestinal problems would enable them to continue their treatment with trofinetide.How to say (download PDF and double click sound icon to play sound)…DAYBUE™: day-byooGastroparesis: gas-tro-puh-ree-sisTrofinetide: troh-fin-uh-tideConstipation: When a person has 3 or fewer stools per week, and the stools are hard and difficult to pass.Diarrhea: Loose, watery stools.Vomiting: Forcefully emptying stomach contents through the mouth.Aspiration: When food or liquid enters the airway, either from the mouth or from the reflux or vomiting of stomach contents.This is an abstract of the Plain Language Summary of Publication article.View the full Plain Language Summary PDF of this article to read the full-textLink to original article hereThis article is related to:Recommendations for the management of gastrointestinal comorbidities with or without trofinetide use in Rett syndrome AcknowledgementsThank you to the girls and women, their caregivers, and study investigators and staff who took part in the LAVENDER and DAFFODIL trials. The authors also thank the (non-Rett syndrome) patient who reviewed a draft of the manuscript.Author contributionsKathleen J. Motil, Arthur Beisang, Constance Smith-Hicks, Anthony Lembo, and Edwin Liu all critically reviewed and revised the manuscript and approved the final version for publication.Disclosure statementKathleen J. Motil has received research support from the International Rett Syndrome Foundation and is a paid consultant to Acadia Pharmaceuticals Inc. Arthur Beisang is a paid consultant to Acadia Pharmaceuticals Inc. Constance Smith-Hicks serves on the Acadia Advisory Board and receives research support from the Kennedy Krieger Institute, which has an institutional agreement with Acadia. Anthony Lembo has relationships with Acadia Pharmaceuticals Inc., Ardelyx Inc., Atmo, Bristol Myers Squibb, Evoke Pharma, Ironwood Pharmaceuticals, Johnson & Johnson, Salix Pharmaceuticals, Takeda Pharmaceuticals, and Vibrant LTD. Edwin Liu is a consultant to Takeda Pharmaceuticals and is a contributor to UpToDate for the section on celiac disease. The authors are not employed by nor have stock ownership or options with Acadia Pharmaceuticals Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Writing support, funded by Acadia Pharmaceuticals Inc., was provided by Jennifer L. Giel, PhD, on behalf of Envision Pharma Group.Patient reviewers on this PLSP have received honorarium from Future Rare Diseases for their review work but have no other relevant financial relationships to disclose.Additional informationFundingThis manuscript was funded by Acadia Pharmaceuticals Inc.

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 and Objective: Children with a personal and/or family history of celiac disease (CeD) are at increased risk of type 1 diabetes. However, contemporary evidence is needed to inform potential routine screening for islet autoantibodies (IA) in this high-risk population. We sought to determine the prevalence of IA in general population children with CeD or a family history of CeD. Methods: The Autoimmunity Screening for Kids (ASK) study screened for GAD, IA-2, insulin, and ZnT8 autoantibodies in 31,968 children from the general Colorado population. Of those, 344 children reported preexisting CeD and 2,082 children had a family history of CeD. Radiobinding and electrochemiluminescence assays were used for screening and confirmation. Results: Of the 344 children with CeD, 6 (1.8%, 95% CI 0.6-3.8%)) were positive for multiple IA and 7 (2.0%, 95% CI 0.8-4.2%)) were positive for a single IA. Of the 2,082 children with a family history of CeD, 25 children (1.2%, 95% CI 0.8-1.8% ) were positive for multiple IA and 39 children (1.9%, 95% CI 1.3-2.6% ) were positive for a single IA. Multiple IA were more likely among children with CeD (OR 3.3, 95% CI 1.4-7.5, p=0.005) or with a family history of CeD (OR 2.1, 95% CI 1.4-3.1, p= 0.0007) compared to children without these characteristics, adjusting for age and sex. Conclusion: The high prevalence of islet autoimmunity among children with a personal or family history of CeD supports a routine screening in these at-risk groups. More studies are needed to determine the optimal cadence of such a screening and effective follow-up of screen-positive children. M. Stahl: Other Relationship; Pfizer Inc. Advisory Panel; Takeda Pharmaceutical Company. Consultant; UpToDate. K.M. Simmons: Consultant; Sanofi. Research Support; Sanofi. Advisory Panel; Sanofi, Shoreline Biosciences. F. Dong: None. D. Felipe-Morales: None. E. Liu: Consultant; Takeda Pharmaceutical Company. Other Relationship; UpToDate. M. Rewers: Consultant; Sanofi. Research Support; Sanofi. Collaboration between Breakthrough T1D and The Leona M. And Harry B. Helmsley Charitable Trust (3-SRA-2024-1590-M-B)