Nonresponsive Celiac Disease Research Articles

Computer aided villi morphometric quantification in video-capsule enteroscopy: A newly developed software to quantify small bowel atrophy

Background and AimsSmall bowel capsule endoscopy (SBCE) has an established role in patients with non-responsive celiac disease (CeD). A non-invasive method to quantify small bowel atrophy is still lacking. MethodsWe analysed SBCE frames from CeD patients from 2018 to 2020. Histology was the reference standard, with atrophy defined as Marsh-Oberhuber score ≥ 3a. Three regions of interest (ROI) were blindly selected from each frame by an expert gastroenterologist and analysed using a National Institute of Health J image-processing software into a numerical scale. A 3D surface plot macro identified intestinal villi density through isolines plots. ResultsWe acquired 306 ROIs from 57 frames with macroscopic atrophy and 45 with normal mucosa. Frames were classified as atrophic (n = 63) or non-atrophic (n = 39) per Marsh-Oberhuber classification. Median density score significantly differed between atrophic and non-atrophic frames (p < 0.001). The morphometric analysis showed a sensitivity of 77 % and a specificity of 79 % in discriminating between atrophic or non-atrophic mucosa with a 14.10 cut-off (Youden Index) and an overall AUC of 0.805 (CI 95 % 0.712–0.897). ConclusionsOur newly developed SBCE software can effectively quantify villous atrophy. Further studies are needed to validate its applicability in an external cohort.

Refractory Celiac Disease: What the Gastroenterologist Should Know.

Fewer than 1% of patients with celiac disease (CD) will develop refractory CD (RCD). As such, most gastroenterologists might never need to manage patients with RCD. However, all gastroenterologists must be familiarized with the basic concepts of RCD and non-responsive CD (NRCD), since it can present as a severe disease with high mortality, not only due to intestinal failure, but also due to progression to enteropathy-associated T cell lymphoma (EATL) and a higher susceptibility to life-threatening infections. The diagnostic workup and differential diagnosis with other causes of gastrointestinal symptoms and villous atrophy, as well as the differentiation between type I and II RCD, are complex, and may require specialized laboratories and reference hospitals. Immunosuppression is efficient in the milder RCDI; however, the treatment of RCDII falls short, with current options probably only providing transient clinical improvement and delaying EATL development. This review summarizes the current diagnostic and therapeutic approach for patients with RCD that all doctors that manage patients with CD should know.

Role of capsule endoscopy and double-balloon enteroscopy in the management of adult patients with coeliac disease and persisting symptoms

BackgroundSmall bowel capsule endoscopy (CE) and double-balloon enteroscopy (DBE) are recommended for the management of patients with nonresponsive or refractory coeliac disease (CD). However, there is a paucity of data regarding the clinical profiles and outcomes of patients undergoing these investigations. MethodsWe conducted a retrospective analysis of two databases of adult patients with CD who underwent CE and/or DBE between 2017 and 2022 at the National Centre for Refractory CD in England. Patient demographic, clinical and endoscopic data were collected, and clinically relevant outcomes were reported. ResultsA total of 132 patients (median age 53 years, 64.4 % female) underwent 146 CEs and 25 DBEs. The most common symptoms were diarrhoea (51.5 %), abdominal pain (37.8 %), bloating (34.8 %), and weight loss (29.5 %). The overall detection rate of CE and DBE was 87.6 % and 92 %, respectively. Following CE and DBE, 14 patients (10.6 %) were diagnosed with CD-related complications such as ulcerative jejunitis, strictures and malignancy. Seven patients (5.3 %) died during follow-up, with five of these deaths directly attributed to CD. Older age, weight loss and anaemia were associated with poor outcomes. ConclusionsThe sequential approach of CE and DBE identified CD-related complications in almost 1 in 10 patients with nonresponsive or refractory CD. Older patients with persistent villous atrophy, weight loss and anaemia require close monitoring to help with the early diagnosis and management of complications.

Clinical presentation of celiac disease in adult patients: current real-life experience.

The clinical presentation of celiac disease (CD) has changed over time with more patients presenting with non-classical symptoms, extra-intestinal manifestations (EIM) or no symptoms. We aimed to investigate the main symptoms/signs leading to the diagnosis of CD in adult patients. As secondary end-point, we evaluated the outcome of gastrointestinal (GI) symptoms following gluten-free diet (GFD). All consecutive CD adult patients referring to our University Hospital from September 2022 to February 2024 were included. Clinical data were retrospectively evaluated. 134 patients, 104 females/30 males, median age at diagnosis 35years, were included. 79 patients reported GI symptoms (i.e., diarrhea, abdominal bloating, dyspepsia) as the main symptom leading to CD diagnosis. In 40 patients, the leading symptom/sign was an EIM (i.e., iron deficiency anemia, infertility/miscarriages, dermatitis, osteoporosis, elevated transaminase levels). Fifteen patients were asymptomatic, being diagnosed because of a positive family history or concomitant autoimmune hypothyroidism. Of the 79 patients reporting GI symptoms, 20 did not experience complete resolution with the GFD. Among the 17 patients who reported a strict adherence to GFD (vs 1 patient with low-adherence, 2 non-compliant), lactose intolerance and irritable bowel syndrome overlap were diagnosed in 2 and 15 patients, respectively. GI manifestations remain the main symptoms at presentation of CD, however clinicians should be aware of the EIM of CD and the association with other autoimmune disorders. In non-responsive CD patients, an overlap with functional disorders might be considered.

Budesonide Induces Favourable Histologic and Symptomatic Recovery in Patients with Non-responsive and Refractory Coeliac Disease When Given in an Open Capsule Format

IntroductionNon-responsive coeliac disease (NRCD), where symptoms and enteropathy persist despite a prolonged gluten-free diet (GFD), is common. Refractory coeliac disease (RCD), characterised by malabsorption and extensive enteropathy, is rare but serious. In both, treatment options are limited. Topical budesonide may help and an open capsule format promoting proximal small intestinal delivery may be advantageous.AimTo describe the effect of budesonide and its presentation on mucosal healing, symptoms, and tolerability in NRCD and RCD.MethodsA retrospective cohort study of NRCD and RCD patients who received budesonide for enteropathy despite a strict GFD for over 12 months. Primary outcome was improvement in histology. Symptoms and adverse treatment effects were recorded.Results50 patients with NRCD (n = 14; 86% F), RCD type 1 (n = 30; 60% F), and RCD type 2 (n = 6 based on aberrant duodenal T cells; 33% F) were identified. Common RCD symptoms were diarrhoea (68%), fatigue (40%), and weight loss (34%). 16 received closed capsule budesonide (CCB) 9 mg OD and 35 open capsule budesonide (OCB) 3 mg 3 times a day. Complete and partial mucosal healing was significantly higher after OCB compared to CCB (p < 0.001, Mann–Whitney U test). Symptom improvement was also significantly higher after OCB compared to CCB (p = 0.002, Mann–Whitney U test). Side effects were mild and self-limiting and were reported in 25% of both cohorts.ConclusionOCB was well tolerated and associated with improvements in enteropathy (83%) and symptoms (90%) in NRCD and RCD. Our findings support OCB as the preferred 1st-line therapy for NRCD and RCD type 1.

How Future Pharmacologic Therapies for Celiac Disease Will Complement the Gluten-Free Diet

The only proven treatment for celiac disease is adherence to a strict, lifelong, gluten free diet. However, complete dietary gluten avoidance is challenging and a substantial number of patients do not respond fully, clinically or histologically, despite their best efforts. As celiac disease is common and its central pathophysiology is well elucidated, it has become attractive for drug development to address the limitations of dietary treatment. Most efforts address non-responsive celiac disease, defined as continued symptoms and/or signs of disease activity despite a gluten free diet, including the more severe forms of refractory celiac disease type 1 and 2. An increasing spectrum of therapeutic approaches target defined mechanisms in celiac disease pathogenesis, and some currently advance to phase 2-3 clinical studies. We discuss these approaches in terms of potential efficiency, practicability, safety and need as defined by patients, regulatory authorities, health care providers and payors.

Advances in Nonresponsive and Refractory Celiac Disease

Nonresponsive celiac disease (CeD) is relatively common. It is generally attributed to persistent gluten exposure and resolves after correction of diet errors. However, other complications of CeD and disorders clinically mimicking CeD need to be excluded. Novel therapies are being evaluated to facilitate mucosal recovery, which might benefit patients with nonresponsive CeD. Refractory CeD (RCeD) is rare and is divided into 2 types. The etiology of type I RCeD is unclear. A switch to gluten-independent autoimmunity is suspected in some patients. In contrast, type II RCeD represents a low-grade intraepithelial lymphoma. Type I RCeD remains a diagnosis of exclusion, requiring ruling out gluten intake and other nonmalignant causes of villous atrophy. Diagnosis of type II RCeD relies on the demonstration of a clonal population of neoplastic intraepithelial lymphocytes with an atypical immunophenotype. Type I RCeD and type II RCeD generally respond to open-capsule budesonide, but the latter has a dismal prognosis due to severe malnutrition and frequent progression to enteropathy-associated T-cell lymphoma; more efficient therapy is needed.

Flow cytometry for the assessment and monitoring of aberrant intraepithelial lymphocytes in non-responsive celiac disease and non-celiac enteropathies

BackgroundFew data are available on flow cytometry (FC) for monitoring intraepithelial lymphocytes (IELs) in refractory celiac disease (RCD), non-responsive celiac disease (NRCD), and non-celiac enteropathies (NCEs).AIMS.1) To investigate the significance of monitoring IELs immunophenotype with FC in patients with NRCD, RCD and NCEs; 2) to evaluate FC concordance with immunohistochemistry (IHC) and γ-TCR clonality analysis. MethodsPatients investigated between January-2012 and February-2023 were divided into two groups: 1)confirmed RCD or NRCD being investigated for persistent symptoms and suspected complications of celiac disease (CD); 2)NCEs lacking clinical/histological response. Clinical/molecular features and outcomes were retrospectively collected and analysed according to presence/absence of aberrant IELs on FC (cut-off≥20 % CD103+sCD3-CD8-iCD3+ IELs). Results52 patients (18 RCD,21 NRCD,13 NCEs; 38F, 55±13 years; median follow-up 30 months, IQR 2-58) underwent 100 FC IELs determinations. 22/52 had ≥2 FC determinations and IEL phenotype remained unchanged over time in all them (κ=1.00). Aberrant IEL phenotype in CD was associated with increased mortality (HR 4.2, 95 % CI 1.5–11.9, p < 0.01). No patients with NCEs had an aberrant IEL phenotype at FC, although 3/13 developed lymphoma and 4/13 died. Concordance of FC was fair with both IHC (κ=0.40) and γ-TCR clonality analysis (κ=0.22). ConclusionFC is accurate for assessing and monitoring IEL phenotype and providing important prognostic information in celiac patients. Further study is needed on its role in NCEs.

Evaluating the Frequency and Cause of Persistent Symptoms in Pediatric Patients with Celiac Disease Adhering to a Long-Term Gluten-Free Diet

Background: Celiac disease (CD) treatment is based on life-long adherence to a gluten-free diet (GFD). Some patients with CD experience persistent symptoms despite adhering to a GFD. This condition is defined as a nonresponsive CD. Objectives: The present study aimed to investigate the prevalence and cause of persistent symptoms in pediatric patients with CD adhering to a GFD in Sistan and Baluchestan province, southeastern Iran. Methods: This descriptive cross-sectional study was conducted on 112 patients with CD selected from all diagnosed CD patients receiving a GFD for 6 months and newly diagnosed cases studied within one year. Gastrointestinal (GI) and extraintestinal (EI) symptoms were recorded on a questionnaire at the onset and during treatment. Data were analyzed by SPSS16 software, independent t-test, univariate t-test, and analysis of variance (ANOVA). Results: A total of 46.43% of our sample were boys, and 53.57% were girls (mean age = 82 ± 4.43 months). Abdominal pain and constipation symptoms were reported more frequently at the time of diagnosis and following one year of treatment. The most commonly observed EI symptoms at the time of diagnosis and during treatment were weight loss and growth failure, respectively. The percentage of treatment non-response in patients with a positive family history was significantly greater than in those with a negative family history. Conclusions: The results showed that GFD had a significant effect on the reduction of GI and non-GI symptoms, but the effect of this regime on insignificant symptoms, particularly at older ages, is negligible.

S1833 Prevalence and Etiologies of Non-responsive Celiac Disease: A Systematic Review and Meta-Analysis

S1833 Prevalence and Etiologies of Non-responsive Celiac Disease: A Systematic Review and Meta-Analysis

The Gluten-Free Diet for Celiac Disease: Critical Insights to Better Understand Clinical Outcomes.

The gluten-free diet (GFD) remains a complex paradigm in managing celiac disease (CeD) in children and adults, and there are many reasons why GFD adherence should be strict to improve outcomes. However, this is a challenging task for patients, since they need to have access to quality healthcare resources that facilitate optimal GFD adherence. Understanding the strengths and weaknesses of the GFD, tackling coexisting nutritional deficiencies, and dealing with complex situations, such as seronegative CeD or non-responsive CeD, all require the involvement of a multidisciplinary team. The short- and long-term follow-up of CeD patients should preferably be performed by a combined Gastroenterology and Nutrition service with well-defined quality standards and the multidisciplinary involvement of physicians, nurses, dietitians, and psychologists. Nutritional advice and counseling by an experienced dietitian can reduce the costs associated with long-term follow-up of CeD patients. Likewise, psychological interventions may be essential in specific scenarios where implementing and sustaining a lifelong GFD can cause a significant psychological burden for patients. This manuscript aims to provide guidelines to improve clinical practice in the follow-up and monitoring of CeD patients and provide information on the nutritional risks of an ill-advised GFD. Clinicians, biochemists, food technologists, dietitians, and psychologists with a global view of the disease have been involved in its writing.

Exploring novel therapies for coeliac disease: are safe drugs tolerable?

Coeliac disease is the only autoimmune condition where the main environmental trigger, gluten, is known. 1 Catassi C Verdu EF Bai JC Lionetti E Coeliac disease. Lancet. 2022; 399: 2413-2426 Summary Full Text Full Text PDF PubMed Scopus (36) Google Scholar Adherence to a strict gluten-free diet for life is essential for intestinal mucosal recovery, alleviation of symptoms, and to reduce the risk of complications such as anaemia, osteoporotic fractures, and small bowel cancer. 2 Kivelä L Caminero A Leffler DA et al. Current and emerging therapies for coeliac disease. Nat Rev Gastroenterol Hepatol. 2020; 18: 1-15 Google Scholar However, strict long-term compliance with a gluten-free diet can be socially inconvenient and expensive. 3 Pinto-Sanchez MI Verdu EF Gordillo MC et al. Tax-deductible provisions for gluten-free diet in Canada compared with systems for gluten-free diet coverage available in various countries. Can J Gastroenterol Hepatol. 2015; 29: 104-110 Crossref PubMed Scopus (21) Google Scholar Moreover, up to 30% of people with coeliac disease continue to have symptoms despite attempting the strict diet 4 Penny HA Baggus EMR Rej A et al. Non-responsive coeliac disease: a comprehensive review from the NHS England National Centre for Refractory Coeliac Disease. Nutrients. 2020; 12: 216 Crossref PubMed Scopus (43) Google Scholar , and almost 80% indicated a desire for therapy to liberalise their diet. 5 De Leon Morilla D Ventoso M Lebovits J et al. Patients' risk tolerance for non-dietary therapies in celiac disease. Clin Gastroenterol Hepatol. 2022; 20: 2647-2649 Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar Therefore, emerging therapies to support the gluten-free diet, including those targeting induction of tolerogenic mechanisms, are currently being investigated in clinical trials. 6 Pinto-Sanchez MI Silvester JA Lebwohl B et al. Society for the Study of Celiac Disease position statement on gaps and opportunities in coeliac disease. Nat Rev Gastroenterol Hepatol. 2021; 18: 875-884 Crossref PubMed Scopus (13) Google Scholar Safety and tolerability of KAN-101, a liver-targeted immune tolerance therapy, in patients with coeliac disease (ACeD): a phase 1 trialKAN-101 has an acceptable safety profile in patients with coeliac disease with no dose-limiting toxicities and no maximum tolerated dose was observed. Rapid systemic clearance of KAN-101 was observed and no accumulation on repeated dosing. A future study will evaluate the safety and efficacy, including biomarker responses with a gluten challenge, of KAN-101 at doses 0·6 mg/kg and greater in patients with coeliac disease. Full-Text PDF

Transition of Care in Celiac Disease.

Celiac disease (CD) is a gluten related disorder which affects all age-groups and occurs in genetically susceptible population after introduction of gluten in diet. The worldwide prevalence of CD is ~1% and it is higher in certain "at-risk groups". The clinical features are variable, ranging from classical diarrhea to an asymptomatic state. Diagnosis requires serology and duodenal histology although a non-biopsy diagnosis is recommended by European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) for a select group of children. Treatment of CD is with a life-long strict gluten free diet (GFD) along with correction of nutritional deficiencies. Regular follow-up to assess compliance and efficacy of GFD is mandatory. Non-responsive CD needs evaluation by a specialist as it can be due to incorrect diagnosis, poor dietary compliance, coexisting conditions like small bowel bacterial overgrowth, pancreatic insufficiency etc. and lastly, refractory CD. Most patients diagnosed as CD in childhood receive no medical or dietary supervision after transition to adulthood and nearly a third are non-compliant to GFD. No requirement of medications, patient's perception of understanding GFD and absence of symptoms with intermittent non-compliance leads to neglect of care after transition. Poor dietary adherence leads to nutritional deficiencies, osteoporosis, fertility issues and risk of malignancy. It is mandatory that the patients know about CD, need of strict GFD, regular follow-up, disease complications, and are capable of communicating with the health-care personnel before transition. Formulating a phased transition care program with joint pediatric and adult clinics is required for a successful transition and improving the long-term outcome.

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

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. 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. 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. 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.

American College of Gastroenterology Guidelines Update: Diagnosis and Management of Celiac Disease.

This guideline presents an update to the 2013 American College of Gastroenterology Guideline on the Diagnosis and Management of Celiac Disease with updated recommendations for the evaluation and management of patients with celiac disease (CD). CD is defined as a permanent immune-mediated response to gluten present in wheat, barley, and rye. CD has a wide spectrum of clinical manifestations that resemble a multisystemic disorder rather than an isolated intestinal disease, and is characterized by small bowel injury and the presence of specific antibodies. Detection of CD-specific antibodies (e.g., tissue transglutaminase) in the serum is very helpful for the initial screening of patients with suspicion of CD. Intestinal biopsy is required in most patients to confirm the diagnosis. A nonbiopsy strategy for the diagnosis of CD in selected children is suggested and discussed in detail. Current treatment for CD requires strict adherence to a gluten-free diet (GFD) and lifelong medical follow-up. Most patients have excellent clinical response to a GFD. Nonresponsive CD is defined by persistent or recurrent symptoms despite being on a GFD. These patients require a systematic workup to rule out specific conditions that may cause persistent or recurrent symptoms, especially unintentional gluten contamination. Refractory CD is a rare cause of nonresponsive CD often associated with poor prognosis.

Budesonide and the Gluten Containing Elimination Diet as Treatments for Non-responsive Celiac Disease in Children.

Non-responsive celiac disease (NRCD) is defined as patients having persistent symptoms and enteropathy (Marsh 3 histology) suggestive of active celiac disease (CeD), after following a gluten-free diet (GFD) for at least 12 months. NRCD is suggested to affect 15% of children with CeD but data are limited and there is no research to date describing treatment of children with this condition. The aim of this study was to describe our center's approach to identifying and treating NRCD with budesonide and the Gluten Containing Elimination Diet (GCED). We performed a retrospective, single center analysis over a 5-year period of patients with CD less than 18 years of age (inclusive) who underwent treatment for persistent symptoms and enteropathy despite following a GFD. We identified 22 patients with NRCD. Thirteen were treated with the GCED for 3 months with 46% achieving both histological and symptomatic resolution. Nine patients were treated with budesonide (6-9 mg), with 89% achieving both symptomatic and histologic resolution after a median 3-month treatment course. Further, 67% of patients who responded to the GCED and 100% of patients who responded to budesonide remained in remission for at least 6 months following treatment transition back to exclusive GFD. The GCED and budesonide can provide benefit for NRCD. Most patients with NRCD can return to a GFD after 3 months of treatment.

Regulatory and Clinical Expert Perspective of the 2022 FDA Draft Guidance “Celiac Disease: Developing Drugs for Adjunctive Treatment to a Gluten-Free Diet”

Regulatory and Clinical Expert Perspective of the 2022 FDA Draft Guidance “Celiac Disease: Developing Drugs for Adjunctive Treatment to a Gluten-Free Diet”

Non-Responsive and Refractory Coeliac Disease: Experience from the NHS England National Centre.

We characterised the aetiology of non-responsive coeliac disease (NRCD) and provided contemporary mortality data in refractory coeliac disease (RCD) from our centre. We also measured urine gluten immunogenic peptides (GIPs) in patients with established RCD1 to evaluate gluten exposure in these individuals. Methods: This was a longitudinal cohort study conducted in Sheffield, UK. Between 1998 and 2019, we evaluated 285 adult (≥16 years) patients with NRCD or RCD. Patients with established RCD1 and persisting mucosal inflammation and/or ongoing symptoms provided three urine samples for GIP analysis. Results: The most common cause of NRCD across the cohort was gluten exposure (72/285; 25.3%). RCD accounted for 65/285 patients (22.8%), 54/65 patients (83.1%) had RCD1 and 11/65 patients (16.9%) had RCD2. The estimated 5-year survival was 90% for RCD1 and 58% for RCD2 (p = 0.016). A total of 36/54 (66.7%) patients with RCD1 underwent urinary GIP testing and 17/36 (47.2%) had at least one positive urinary GIP test. Conclusion: The contemporary mortality data in RCD2 remains poor; patients with suspected RCD2 should be referred to a recognised national centre for consideration of novel therapies. The high frequency of urinary GIP positivity suggests that gluten exposure may be common in RCD1; further studies with matched controls are warranted to assess this further.

Review article: Follow-up of coeliac disease.

SummaryCoeliac disease is a lifelong immune‐mediated enteropathy with systemic features associated with increased morbidity and modestly increased mortality. Treatment with a strict gluten‐free diet improves symptoms and mucosal damage but is not curative and low‐level gluten intake is common despite strict attempts at adherence. Regular follow‐up after diagnosis is considered best‐practice however this is executed poorly in the community with the problem compounded by the paucity of data informing optimal approaches. The aim of dietary treatment is to resolve symptoms, reduce complication risk and improve quality of life. It follows that the goals of monitoring are to assess dietary adherence, monitor disease activity, assess symptoms and screen for complications. Mucosal disease remission is regarded a key measure of treatment success as healing is associated with positive health outcomes. However, persistent villous atrophy is common, even after many years of a gluten‐free diet. As the clinical significance of asymptomatic enteropathy is uncertain the role for routine follow‐up biopsies remains contentious. Symptomatic non‐responsive coeliac disease is common and with systematic follow‐up a cause is usually found. Effective models of care involving the gastroenterologist, dietitian and primary care doctor will improve the consistency of long‐term management and likely translate into better patient outcomes. Identifying suitable treatment targets linked to long‐term health is an important goal.

S1378 Constipation as a Cause of Non-Responsive Celiac Disease

Introduction: Celiac disease (CD) is an autoimmune enteropathy triggered by gluten ingestion in genetically predisposed individuals. Certain CD patients have persistent symptoms despite strict adherence to a gluten free diet (GFD) for more than 6-12 months, and are designated as non-responsive (NRCD). A fraction of these NRCD patients have refractory CD (RCD), but the remainder may have irritable bowel syndrome (IBS)-type symptoms like abdominal pain and diarrhea. There are no studies to date that examine constipation in the context of NRCD caused by either IBS-constipation predominant (C) or chronic idiopathic constipation (CIC). We have identified a subset of NRCD patients in whom constipation is the main etiology of persistent symptoms and present their characteristics. Methods: We performed retrospective chart review of 35 non-refractory NRCD patients with histological Marsh scoring of 0-1 on biopsy (normal to near-remission) between 2016 and 2020. Patients were defined as having NRCD if they had a biopsy-confirmed diagnosis of CD but had gastrointestinal symptoms despite a strict GFD for over 6 months. This group was separated further into patients with constipation-related NRCD (c-NRCD, 24 patients) and those with non-constipation related NRCD (nc-NRCD, 11 patients) based on Rome IV criteria and/or improved symptomatic response to bowel regimen. Results: 68.5% of patients with non-refractory NRCD had c-NRCD. The median age of the c-NRCD cohort was overall younger as compared to the nc-NRCD cohort. Most patients in both groups had normalized celiac serology (>70%). Constipation and bloating were the predominant symptoms in the c-NRCD group while diarrhea was the predominant symptom in nc-NRCD. Abdominal x-ray was performed in all of the suspected c-NRCD group as compared to nc-NRCD group (36.4%). Most c-NRCD patients had at least a moderate stool burden radiographically (70.8%) as read by the same radiologist whereas most nc-NRCD patients had no stool burden seen. Conclusion: Constipation is a significant driver of persistent symptoms in CD leading to NRCD, in part due to the lower fiber content of a GFD. Clinicians should screen all NRCD patient based on the Rome IV criteria and consider an abdominal x-ray followed by the initiation of a bowel regimen if overlap constipation is suspected. This can improve the health outcomes in these patients and provide cost-effectiveness prior to employing other modalities like breath tests or infectious evaluation.Figure 1.: Flow Chart for Constipation versus Non-constipation related Non-Responsive Celiac Disease (NRCD).Table 1.: Demographic and Clinical Features of Patients with Constipation-related or Non-Constipation-related Non-Refractory Non-Responsive Celiac Disease (NRCD)