Past, Present, and Future of Noninvasive Tests to Assess Gluten Exposure, Celiac Disease Activity, and End-Organ Damage.

Although many biomarkers have been proposed, and several are in widespread clinical use, there is no single readout or combination of readouts that correlates tightly with gluten exposure, disease activity, or end-organ damage in treated patients with celiac disease. Challenges to developing and evaluating better biomarkers include significant interindividual variability-related to immune amplification of gluten exposure and how effects of immune activation are manifest. Furthermore, the current "gold standard" for assessment of end-organ damage, small intestinal biopsy, is itself highly imperfect, such that a marker that is a better reflection of the "ground truth" may indeed appear to perform poorly. The goal of this review was to analyze past and present efforts to establish robust noninvasive tools for monitoring treated patients with celiac disease and to highlight emerging tools that may prove to be useful in clinical practice.

Anti-infliximab antibodies and low infliximab levels correlate with drug discontinuation in pediatric inflammatory bowel disease.

BACKGROUND: Infliximab (IFX) use is limited by loss of response often due to the development of anti-IFX antibodies and low drug levels. METHODS: We performed a single center prospective observational cohort study of pediatric and young adult subjects with inflammatory bowel disease (IBD) on IFX with over 3 years of follow-up. Infliximab levels (IFXL) and antibodies to infliximab (ATI) were measured throughout the study. Subjects were followed until IFX was discontinued. RESULTS: We enrolled 219 subjects with IBD (184: Crohn's disease; 33: Ulcerative colitis; and 2 Indeterminant colitis; 84 female, median age 14.4 years, 37% on concomitant immunomodulator). Nine hundred and nineteen serum samples (mean 4.2 ± 2.1 per patient) were tested for IFXL and ATI. During the study, 31 (14%) subjects discontinued IFX. Sixty patients had ATI. Twenty-two of those 60 patients with ATI discontinued IFX; 14 of 31 patients who discontinued IFX had detectable ATI at study onset. The combination of ATI and IFXL < 5 µg/mL at study entry was associated with the highest risk of drug discontinuation (hazard ratios [HR] ATI 4.27 [p < 0.001] and IFXL < 5 µg/mL [HR]: 3.2 p = 0.001). Patients with IFXL 5-10 µg/mL had the lowest rate of discontinuation (6%). IFX dose escalation eliminated ATI in 21 of 60 subjects. CONCLUSIONS: ATI is a strong predictor of needing to stop IFX use and inversely correlates with IFXL. Detection of ATI during therapeutic drug monitoring postinduction but also periodically during maintenance therapy identifies individuals who may benefit from IFX dose escalation and/or the addition of an immunomodulator, as these interventions may reduce or eliminate ATI.

Standardizing Randomized Controlled Trials in Celiac Disease: An International Multidisciplinary Appropriateness Study.

BACKGROUND & AIMS: There is a need to develop safe and effective pharmacologic options for the treatment of celiac disease (CeD); however, consensus on the appropriate design and configuration of randomized controlled trials (RCTs) in this population is lacking. METHODS: A 2-round modified Research and Development/University of California Los Angeles Appropriateness Method study was conducted. Eighteen gastroenterologists (adult and pediatric) and gastrointestinal pathologists voted on statements pertaining to the configuration of CeD RCTs, inclusion and exclusion criteria, gluten challenge, and trial outcomes. Two RCT designs were considered, representing the following distinct clinical scenarios for which pharmacotherapy may be used: trials incorporating a gluten challenge to simulate exposure; and trials evaluating reversal of histologic changes, despite attempted adherence to a gluten-free diet. Each statement was rated as appropriate, uncertain, or inappropriate, using a 9-point Likert scale. RESULTS: For trials evaluating prevention of relapse after gluten challenge, participants adherent to a gluten-free diet for 12 months or more with normal or near-normal-sized villi should be enrolled. Gluten challenge should be FODMAPS (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) free, and efficacy evaluated using histology with a secondary patient-reported outcome measure. For trials evaluating reversal of villus atrophy, the panel voted it appropriate to enroll participants with a baseline villus height to crypt depth ratio ≤2 and measure efficacy using a primary histologic end point. Guidance for measuring histologic, endoscopic, and patient-reported outcomes in adult and pediatric patients with CeD are provided, along with recommendations regarding the merits and limitations of different end points. CONCLUSIONS: We developed standardized recommendations for clinical trial design, eligibility criteria, outcome measures, gluten challenge, and disease evaluations for RCTs in patients with CeD.

A tip-predominant distribution of villous intraepithelial lymphocytes is not specific to celiac disease in children with Marsh I lesions.

OBJECTIVES: To assess if the distribution of villous intraepithelial lymphocytes (IELs) in a pediatric cohort with Marsh I histopathology is specific to celiac disease (CeD). METHODS: Multicenter, retrospective case-control study between January 2001 and December 2019 in children (<18 years) with and without CeD with intraepithelial lymphocytosis and normal villous architecture. Pathology specimens were reviewed by 2 study pathologists who were blinded to the final diagnosis. Morphologic features (villous height to crypt depth ratio [Vh:Cd]) and IELs in the villous tip, top, or bottom half of the villus were quantified. RESULTS: Of the 97 children with Marsh I histopathology identified during the study period, 63 were excluded due to an insufficient number of well-oriented villous-crypt complexes or a Vh:Cd less than 2. Villous IELs were measured in 34 cases (14 CeD, 20 non-CeD controls). There was no difference between the non-CeD and CeD groups in the mean IELs at the villous tip (14.0 ± 7.1 vs 11.7 ± 6.0, P = .31), top (46.4 ± 18.4 vs 38.3 ± 10.8, P = .11), or bottom (29.8 ± 16.8 vs 28.5 ± 12.8, P = .80) half of each villus, respectively. CONCLUSIONS: The distribution of IELs in Marsh I lesions is not specific for CeD.

Comparing Gastrointestinal Endoscopy Findings in Children with Autism, Developmental Delay, or Typical Development.

OBJECTIVE: To compare endoscopic and histologic upper endoscopy (esophagogastroduodenoscopy [EGD]) findings in children with autism spectrum disorders (ASD) to age- and gender-matched controls with developmental delay (DD) or with typical development (TD). METHODS: Retrospective, cross-sectional study of children undergoing EGD, identifying those diagnosed with ASD, and matching on age and gender to children with DD or TD in ratio of 1:1:2. Rates of EGD findings were compared between the 3 groups using χ² or Fisher exact test. Multivariable linear regression was performed to identify predictors of abnormal histology. RESULTS: A total of 2104 patients were included (526 ASD; 526 DD; 1052 TD). Children with ASD had higher rates of abnormal esophageal histology (ASD 38.4%; DD 33.4%; TD 30.4%, P = .008), particularly esophagitis. In multivariable modeling, ASD diagnosis was an independent predictor of abnormal esophageal histology (OR [95% CI] 1.38 [1.09, 1.76]) compared with TD. Stomach findings did not differ among the groups. In the duodenum, histologic abnormalities were observed with lower frequency in ASD (ASD 17.0%; DD 20.1%; TD 24.2%, P = .005). In multivariable analysis, ASD diagnosis was not a significant predictor (OR 0.78 [0.56, 1.09]) of abnormal duodenal histology. CONCLUSIONS: Children with ASD have higher rates of histologic esophagitis compared with age- and gender-matched DD and TD controls. ASD was a significant independent predictor of abnormal esophageal, but not, duodenal, histology. These results underscore the importance of EGD in children with ASD.

A Composite Morphometric Duodenal Biopsy Mucosal Scale for Celiac Disease Encompassing Both Morphology and Inflammation.

BACKGROUND & AIMS: Villus height to crypt depth ratio (Vh:Cd) and intraepithelial lymphocytes (IEL) are key measures of histology of the small intestine in celiac disease. Although the field of celiac disease has advanced, there remains no broadly accepted measure of mucosal injury. We assessed whether a composite Vh:Cd and IEL scale (VCIEL) can improve accuracy and statistical precision for assessing histology, compared with individual measures. METHODS: The formulation of the VCIEL composite histologic scale was based on combining the Vh:Cd and IEL measurements for individual patients with equal weighting, by converting each scale to a fraction of their standard deviation and summing the results. The VCIEL formula was applied to several clinical trials and the results for Vh:Cd and IEL were compared with those for VCIEL with regards to clinical significance (effect size) and statistical significance. RESULTS: For the ALV003-1021 trial, we observed an effect size and P value (analysis of covariance) of 1.37 and 0.038 for ΔVh:Cd, 1.17 and 0.005 for ΔIEL, and 1.86 and 0.004 for ΔVCIEL. For the similar gluten-challenge IMGX003-NCCIH-1721 trial, the corresponding results were 0.76 and 0.057 for ΔVh:Cd, 0.98 and 0.018 for ΔIEL, and 1.14 and 0.007 for ΔVCIEL. Similar improvements with the use of VCIEL over individual Vh:Cd and IEL measures were observed for other studies, including a nontherapeutic gluten challenge study. CONCLUSIONS: The composite VCIEL scale combining Vh:Cd and IEL values seems to improve accuracy and statistical precision compared with either component alone.

A Clinician's Guide to Gluten Challenge.

Gluten challenge is an essential clinical tool that involves reintroducing or increasing the amount of gluten in the diet to facilitate diagnostic testing in celiac disease (CD). Nevertheless, there is no consensus regarding the applications of gluten timing, dosing, and duration in children. This review aims to summarize the current evidence, discuss practical considerations, and proposes a clinical algorithm to help guide testing in pediatric patients. Childhood development, social circumstances, and long-term health concerns must be considered when identifying a candidate for gluten challenge. Based on previous studies, the authors suggest baseline serology followed by a minimum of 3-6 grams of gluten per day for over 12 weeks to optimize diagnostic accuracy for evaluation of CD. A formal provider check-in at 4-6 weeks is essential so the provider and family can adjust dosing or duration as needed. Increasing the dose of gluten further may improve diagnostic yield if tolerated, although in select cases a lower dose and shorter course (6-12 weeks) may be sufficient. There is consensus that mild elevations in celiac serology (<10 times the upper limit of normal) or symptoms, while supportive are not diagnostic for CD. Current North American Society for Pediatric Gastroenterology, Hepatology and Nutrition guidelines recommend histologic findings of intraepithelial lymphocytosis, crypt hyperplasia, and villous atrophy as the accurate and most appropriate endpoint for gluten challenge.

Low Levels of Detectable Urine and Stool GIPs in Children with Celiac Disease on a Gluten-Free Diet.

Objectives: This study examines the prevalence of detectable gluten immunogenic peptides (GIPs) as a proxy for gluten exposure in children with celiac disease on a gluten-free diet in the United States, as estimated by gluten breakdown products excreted in urine and stool. Methods: Urine and stool samples were collected in 3 settings (home, gastroenterology clinic, and endoscopy) for pediatric participants (ages 6-21 years old) across 2 medical centers. Commercial ELISA assays were used to quantify the GIPs in each sample. Results: GIPs were detected in 4 out of 44 (9.1%) of stool samples and 6 out of 125 (4.8%) of urine samples provided by 84 children. These samples were collected across all settings, and most participants (70%) were asymptomatic at the time of sample collection. For the urine samples collected at the time of endoscopy, all subjects found to have persistent enteropathy had no detectable GIPs (0/12). Discussion: GIPs provide an additional method for screening for gluten exposures in individuals with celiac disease on a gluten-free diet, and may be used across multiple settings. We found a low detection rate of GIPs in children. Our finding of undetectable GIPs in individuals with persistent enteropathy may be expected of a single determination under close observation or represent a lack of gluten exposure within the detection window. More research is needed to understand the dynamics of gluten absorption and excretion in the US pediatric population.

The Spectrum of Duodenal Histologic Findings in Patients With Trisomy 21: A Multicenter Study.

OBJECTIVES: Patients with Trisomy 21 (T21) commonly have gastrointestinal symptoms and diseases that prompt evaluation with esophagogastroduodenoscopy (EGD). Our objective is to characterize duodenal histological abnormalities in these patients when undergoing EGD. A secondary aim is to explore associations of histologic findings with different therapies. METHODS: Patients 30 years old or younger with T21 who underwent EGD from 2000 to 2020 at 6 hospitals were included in this retrospective cohort study. Duodenal biopsies were categorized based on reported histopathology findings as normal or abnormal. Abnormal pathology reports were reviewed and categorized into villous atrophy (VA) and duodenitis without VA. The VA group was further categorized based on the presence or absence of celiac disease (CD). RESULTS: We identified 836 patients with T21 who underwent EGD, 419 (50.1%) of whom had duodenal histologic abnormalities. At the time of the first (index) abnormal duodenal biopsy, 290 of 419 had VA and of those, 172 of 290 met CD diagnostic criteria, while 118 of 290 did not meet CD criteria (nonspecific VA). Among the patients with an abnormal biopsy, acid suppression at the time of the index biopsy was less common in patients with VA-CD compared to patients without VA or patients with nonspecific VA (12.2% vs 45.7% vs 44.9%). CONCLUSIONS: Half of the T21 patients in this cohort had abnormal duodenal biopsies including a subgroup with nonspecific VA. In this cohort, acid suppression use was more prevalent in patients with abnormalities other than CD.

Review article: Becoming and being coeliac-special considerations for childhood, adolescence and beyond.

Classically considered a disease of early childhood characterised by malabsorption and failure to thrive, coeliac disease is now recognised to arise in genetically susceptible individuals at any age. Although permissive HLA genotypes are the strongest predictor of coeliac disease, they are not sufficient. Several prospective cohort studies enrolling genetically at-risk infants have investigated the role of potential triggers of coeliac disease autoimmunity, such as timing of gluten introduction, viral infections and dietary patterns. Much less is known about triggers of coeliac disease in adulthood. Better understanding of factors leading to coeliac disease may be helpful in the management of those with potential coeliac disease (elevated serum celiac antibodies without villous atrophy in the small intestine), many of whom initiate a gluten-free diet without demonstration of villous atrophy. There are a range of clinical presentations of celiac disease in childhood and patterns of coeliac serology, including fluctuation and spontaneous reversion on a gluten-containing diet, vary. There is a current debate over best strategies to manage adults and children with potential coeliac disease to avoid over-treatment and under-treatment. Childhood and adolescence carry unique issues pertaining to the diagnosis and management of coeliac disease, and include nutrition and growth, rescreening, repeat biopsy, dietary adherence concerns and transition to adult care. In conclusion, while coeliac disease has similar pathogenesis and general clinical manifestations in paediatric and adult populations, diagnostic and management approaches need to adapt to the developmental stages.

Genotypes of Pain and Analgesia in a Randomized Trial of Irritable Bowel Syndrome.

Background: Irritable bowel syndrome (IBS) is a highly prevalent chronic pain disorder with multiple underlying mechanisms and few treatments that have been demonstrated to be effective in placebo controlled trials. One potential reason may be the use of composite outcomes, such as the IBS Symptom Severity Scale (IBS-SSS) which includes descriptive items related to pain frequency and pain intensity as well as bowel dysfunction and bloating. We investigated if different features of IBS pain have distinct genetic associations and if these may be moderated by sex hormones. Participants and Setting: Adult outpatients with moderately severe IBS (>175 on IBS-SSS) enrolled in a clinical trial reported IBS-SSS at baseline and after 6 weeks of therapy. Methods: Fixed effects modeling was used to test the effect of COMT rs4680 genotype to change in pain severity (rated 0-100) and pain frequency (defined as number of days with pain in the past 10 days) from baseline to week 6 with IBS treatment. Parallel exploratory genome-wide association studies (GWAS) were also performed to identify single nucleotide polymorphisms (SNPs) associated with change in pain severity or pain frequency across all participants. Results: A total of 212 participants (74% female) were included. The COMT rs4680 met allele was associated with decreased pain severity over the course of the trial in gene dosage models [beta(SE) -5.9 (2.6), P = 0.028]. Exploratory GWAS for change in pain frequency identified 5 SNPs in close proximity on chromosome 18 near L3MBTL4 which reached genome-wide significance (all P < 5.0E-8). This effect was not mediated by changing estradiol levels. There was also a region of chromosome 7 with 24 SNPs of genome-wide suggestive significance for change in pain severity (all P < 1.0E-5). Conclusions: Previously reported association between COMT rs4680 genotype and treatment response as measured by IBS-SSS is related to pain severity, but not pain frequency. We also identified new candidate genes associated with changes in IBS pain severity (SNX13) and pain frequency (L3MBTL4) in response to treatment. Further studies are needed to understand these associations and genetic determinants of different components of IBS-SSS. ClinicalTrials.gov, Identifier: NCT0280224.

Survey-Based Study on Food Insecurity During COVID-19 for Households With Children on a Prescribed Gluten-Free Diet.

Gluten-free (GF) foods are generally costlier than their gluten-containing counterparts. We conducted an anonymous electronic survey to assess food insecurity in households with a child on a prescribed GF diet and how this relates to GF diet adherence during the COVID-19 pandemic. The proportion of households who screened positive using the Hunger Vital Sign was similar to national rates (19%-24%). Approximately 5% of families who screened food secure reported GF food insecurity. Parent-reported intentional gluten consumption due to limited GF food availability in the household increased during the pandemic (7.5%). Food insecurity should be considered in the management of celiac disease.

Patient Perspectives on the Long-term Management of Celiac Disease.

GOAL: The aim of this study was to survey adults with celiac disease (CD) on the utility of specific aspects of follow-up and on information needs. BACKGROUND: Currently, the treatment for CD is strict gluten avoidance. Although this places the onus on the patient for disease management, patient perspectives on CD care have not been formally assessed. STUDY: The Manitoba Celiac Disease Cohort prospectively enrolled adults newly diagnosed with CD using serology and histology. At the 24-month study visits, participants rated the utility of aspects of CD care on a 5-point scale anchored by "not at all useful" and "very useful" and the helpfulness of information on CD-related topics on a 6-point scale anchored by "not at all helpful" and "very helpful." RESULTS: The online survey was completed by 149 of 211 cohort members [median age 40 (interquartile range 30 to 56) y; 68% female]. Adherence to a gluten-free diet was good. Most participants (87%) responded that they should be seen regularly for medical follow-up of CD, preferably every 6 (26%) or 12 months (48%). Blood tests were the most highly rated care component (rated scored ≥4/5 by 78% of respondents), followed by the opportunity to ask about vitamins and supplements (50%), symptom review (47%), and information on CD research (44%). Diet review was not considered helpful. CONCLUSIONS: Two years after diagnosis, most individuals with CD find regular specialist follow-up helpful, particularly for biochemical assessment of disease activity and its complications. Furthermore, information on research and long-term complications of CD is also valued.

Pancreatic enzyme supplementation versus placebo for improvement of gastrointestinal symptoms in non-responsive celiac disease: A cross-over randomized controlled trial.

Background: Pancreatic Exocrine Insufficiency (PEI) is a possible cause of recurrent/persistent symptoms in celiac disease. Although pancreatic enzyme supplementation may be used to treat non-responsive celiac disease (NRCD) in clinical practice, clinical outcomes are variable and there is limited and low quality evidence to support this practice. The aim of this study was to assess the efficacy of pancreatic enzyme supplements (PES) for improvement of gastrointestinal symptoms in NRCD. Methods: Prospective, randomized, placebo-controlled, double-blind, cross-over trial in adults with NRCD examining Celiac Disease-Gastrointestinal Symptom Rating Scale (CeD-GSRS) scores on PES (pancrelipase co-administered with omeprazole) versus placebo (omeprazole only) during a 10-day treatment period. The study was registered under the clinical trials registry (https://clinicaltrials.gov/ number, NCT02475369) on 18 Jun 2015. Results: Twelve participants (nine female) were included in the per-protocol analysis; one participant had low fecal elastase-1. Pancrelipase was not associated with significant change in CeD-GSRS compared to placebo (-0.03 versus -0.26; P = 0.366). There was a significant decrease in mean values of total CeD-GSRS scores (3.58 versus 2.90, P = 0.004), abdominal pain (2.92 versus 2.42, P = 0.009), and diarrhea sub-scores (3.44 versus 2.92, P = 0.037) during the run-in period with omeprazole. Conclusion: In this prospective, cross-over randomized, placebo-controlled study, PES did not improve symptoms in patients with NRCD. It is unclear whether this is a trial effect or related to administration of omeprazole.