Identifying the Optimum Strategy for Identifying Adults and Children With Celiac Disease: A Cost-Effectiveness and Value of Information Analysis.

OBJECTIVES: Celiac disease (CD) is thought to affect around 1% of people in the United Kingdom, but only approximately 30% are diagnosed. The aim of this work was to assess the cost-effectiveness of strategies for identifying adults and children with CD in terms of who to test and which tests to use. METHODS: A decision tree and Markov model were used to describe testing strategies and model long-term consequences of CD. The analysis compared a selection of pre-test probabilities of CD above which patients should be screened, as well as the use of different serological tests, with or without genetic testing. Value of information analysis was used to prioritize parameters for future research. RESULTS: Using serological testing alone in adults, immunoglobulin A (IgA) tissue transglutaminase (tTG) at a 1% pre-test probability (equivalent to population screening) was most cost-effective. If combining serological testing with genetic testing, human leukocyte antigen combined with IgA tTG at a 5% pre-test probability was most cost-effective. In children, the most cost-effective strategy was a 10% pre-test probability with human leukocyte antigen plus IgA tTG. Value of information analysis highlighted the probability of late diagnosis of CD and the accuracy of serological tests as important parameters. The analysis also suggested prioritizing research in adult women over adult men or children. CONCLUSIONS: For adults, these cost-effectiveness results suggest UK National Screening Committee Criteria for population-based screening for CD should be explored. Substantial uncertainty in the results indicate a high value in conducting further research.

Defining the optimum strategy for identifying adults and children with coeliac disease: systematic review and economic modelling.

BACKGROUND: Coeliac disease is an autoimmune disorder triggered by ingesting gluten. It affects approximately 1% of the UK population, but only one in three people is thought to have a diagnosis. Untreated coeliac disease may lead to malnutrition, anaemia, osteoporosis and lymphoma. OBJECTIVES: The objectives were to define at-risk groups and determine the cost-effectiveness of active case-finding strategies in primary care. DESIGN: (1) Systematic review of the accuracy of potential diagnostic indicators for coeliac disease. (2) Routine data analysis to develop prediction models for identification of people who may benefit from testing for coeliac disease. (3) Systematic review of the accuracy of diagnostic tests for coeliac disease. (4) Systematic review of the accuracy of genetic tests for coeliac disease (literature search conducted in April 2021). (5) Online survey to identify diagnostic thresholds for testing, starting treatment and referral for biopsy. (6) Economic modelling to identify the cost-effectiveness of different active case-finding strategies, informed by the findings from previous objectives. DATA SOURCES: For the first systematic review, the following databases were searched from 1997 to April 2021: MEDLINE® (National Library of Medicine, Bethesda, MD, USA), Embase® (Elsevier, Amsterdam, the Netherlands), Cochrane Library, Web of Science™ (Clarivate™, Philadelphia, PA, USA), the World Health Organization International Clinical Trials Registry Platform ( WHO ICTRP ) and the National Institutes of Health Clinical Trials database. For the second systematic review, the following databases were searched from January 1990 to August 2020: MEDLINE, Embase, Cochrane Library, Web of Science, Kleijnen Systematic Reviews ( KSR ) Evidence, WHO ICTRP and the National Institutes of Health Clinical Trials database. For prediction model development, Clinical Practice Research Datalink GOLD, Clinical Practice Research Datalink Aurum and a subcohort of the Avon Longitudinal Study of Parents and Children were used; for estimates for the economic models, Clinical Practice Research Datalink Aurum was used. REVIEW METHODS: For review 1, cohort and case-control studies reporting on a diagnostic indicator in a population with and a population without coeliac disease were eligible. For review 2, diagnostic cohort studies including patients presenting with coeliac disease symptoms who were tested with serological tests for coeliac disease and underwent a duodenal biopsy as reference standard were eligible. In both reviews, risk of bias was assessed using the quality assessment of diagnostic accuracy studies 2 tool. Bivariate random-effects meta-analyses were fitted, in which binomial likelihoods for the numbers of true positives and true negatives were assumed. RESULTS: People with dermatitis herpetiformis, a family history of coeliac disease, migraine, anaemia, type 1 diabetes, osteoporosis or chronic liver disease are 1.5-2 times more likely than the general population to have coeliac disease; individual gastrointestinal symptoms were not useful for identifying coeliac disease. For children, women and men, prediction models included 24, 24 and 21 indicators of coeliac disease, respectively. The models showed good discrimination between patients with and patients without coeliac disease, but performed less well when externally validated. Serological tests were found to have good diagnostic accuracy for coeliac disease. Immunoglobulin A tissue transglutaminase had the highest sensitivity and endomysial antibody the highest specificity. There was little improvement when tests were used in combination. Survey respondents (n = 472) wanted to be 66% certain of the diagnosis from a blood test before starting a gluten-free diet if symptomatic, and 90% certain if asymptomatic. Cost-effectiveness analyses found that, among adults, and using serological testing alone, immunoglobulin A tissue transglutaminase was most cost-effective at a 1% pre-test probability (equivalent to population screening). Strategies using immunoglobulin A endomysial antibody plus human leucocyte antigen or human leucocyte antigen plus immunoglobulin A tissue transglutaminase with any pre-test probability had similar cost-effectiveness results, which were also similar to the cost-effectiveness results of immunoglobulin A tissue transglutaminase at a 1% pre-test probability. The most practical alternative for implementation within the NHS is likely to be a combination of human leucocyte antigen and immunoglobulin A tissue transglutaminase testing among those with a pre-test probability above 1.5%. Among children, the most cost-effective strategy was a 10% pre-test probability with human leucocyte antigen plus immunoglobulin A tissue transglutaminase, but there was uncertainty around the most cost-effective pre-test probability. There was substantial uncertainty in economic model results, which means that there would be great value in conducting further research. LIMITATIONS: The interpretation of meta-analyses was limited by the substantial heterogeneity between the included studies, and most included studies were judged to be at high risk of bias. The main limitations of the prediction models were that we were restricted to diagnostic indicators that were recorded by general practitioners and that, because coeliac disease is underdiagnosed, it is also under-reported in health-care data. The cost-effectiveness model is a simplification of coeliac disease and modelled an average cohort rather than individuals. Evidence was weak on the probability of routine coeliac disease diagnosis, the accuracy of serological and genetic tests and the utility of a gluten-free diet. CONCLUSIONS: Population screening with immunoglobulin A tissue transglutaminase (1% pre-test probability) and of immunoglobulin A endomysial antibody followed by human leucocyte antigen testing or human leucocyte antigen testing followed by immunoglobulin A tissue transglutaminase with any pre-test probability appear to have similar cost-effectiveness results. As decisions to implement population screening cannot be made based on our economic analysis alone, and given the practical challenges of identifying patients with higher pre-test probabilities, we recommend that human leucocyte antigen combined with immunoglobulin A tissue transglutaminase testing should be considered for adults with at least a 1.5% pre-test probability of coeliac disease, equivalent to having at least one predictor. A more targeted strategy of 10% pre-test probability is recommended for children (e.g. children with anaemia). FUTURE WORK: Future work should consider whether or not population-based screening for coeliac disease could meet the UK National Screening Committee criteria and whether or not it necessitates a long-term randomised controlled trial of screening strategies. Large prospective cohort studies in which all participants receive accurate tests for coeliac disease are needed. STUDY REGISTRATION: This study is registered as PROSPERO CRD42019115506 and CRD42020170766. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 44. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Around 1 in 100 people in the UK has coeliac disease. It develops when the immune system attacks the lining of the gut after eating gluten. It is thought that only one in three people with coeliac disease is currently diagnosed. Without treatment, people with coeliac disease are at an increased risk of anaemia, osteoporosis and cancer. Treatment is a lifelong gluten-free diet. Diagnosing coeliac disease is difficult. Some people have minimal or non-specific symptoms, such as pain, indigestion or bloating, so knowing who to test is tricky. WHAT DID WE DO?: We wanted to establish who should be tested for coeliac disease, what tests should be used and whether or not invasive testing (a gut biopsy) is necessary for everyone. We looked at existing studies and data from general practices, and conducted an online survey, and brought everything together in an economic (cost) analysis. WHAT DID WE FIND?: Using individual symptoms is not helpful to identify people who may have coeliac disease. People with coeliac disease are more likely to have a combination of symptoms. People with anaemia, type 1 diabetes, osteoporosis, thyroid disorders, immunoglobulin A deficiency, Down syndrome, Turner syndrome or a family history of coeliac disease are more likely to have coeliac disease and should be offered tests. Common blood tests for coeliac disease are very accurate, particularly when used in combination with genetic testing. Blood tests alone can be used for diagnosis for some people. Others will need a biopsy to confirm the diagnosis. Whether or not this is needed depends on their risk of coeliac disease: whether or not they have symptoms and whether or not they have a condition that puts them at higher risk. Shared decision-making is important for individuals considering an invasive test, depending on how certain they want to be about their diagnosis before starting a gluten-free diet.

Development and external validation of a clinical prediction model to aid coeliac disease diagnosis in primary care: An observational study.

Background: Coeliac disease (CD) affects approximately 1% of the population, although only a fraction of patients are diagnosed. Our objective was to develop diagnostic prediction models to help decide who should be offered testing for CD in primary care. Methods: Logistic regression models were developed in Clinical Practice Research Datalink (CPRD) GOLD (between Sep 9, 1987 and Apr 4, 2021, n=107,075) and externally validated in CPRD Aurum (between Jan 1, 1995 and Jan 15, 2021, n=227,915), two UK primary care databases, using (and controlling for) 1:4 nested case-control designs. Candidate predictors included symptoms and chronic conditions identified in current guidelines and using a systematic review of the literature. We used elastic-net regression to further refine the models. Findings: The prediction model included 24, 24, and 21 predictors for children, women, and men, respectively. For children, the strongest predictors were type 1 diabetes, Turner syndrome, IgA deficiency, or first-degree relatives with CD. For women and men, these were anaemia and first-degree relatives. In the development dataset, the models showed good discrimination with a c-statistic of 0·84 (95% CI 0·83-0·84) in children, 0·77 (0·77-0·78) in women, and 0·81 (0·81-0·82) in men. External validation discrimination was lower, potentially because 'first-degree relative' was not recorded in the dataset used for validation. Model calibration was poor, tending to overestimate CD risk in all three groups in both datasets. Interpretation: These prediction models could help identify individuals with an increased risk of CD in relatively low prevalence populations such as primary care. Offering a serological test to these patients could increase case finding for CD. However, this involves offering tests to more people than is currently done. Further work is needed in prospective cohorts to refine and confirm the models and assess clinical and cost effectiveness. Funding: National Institute for Health Research Health Technology Assessment Programme (grant number NIHR129020).

The accuracy of diagnostic indicators for coeliac disease: A systematic review and meta-analysis.

BACKGROUND: The prevalence of coeliac disease (CD) is around 1%, but diagnosis is challenged by varied presentation and non-specific symptoms and signs. This study aimed to identify diagnostic indicators that may help identify patients at a higher risk of CD in whom further testing is warranted. METHODS: International guidance for systematic review methods were followed and the review was registered at PROSPERO (CRD42020170766). Six databases were searched until April 2021. Studies investigating diagnostic indicators, such as symptoms or risk conditions, in people with and without CD were eligible for inclusion. Risk of bias was assessed using the QUADAS-2 tool. Summary sensitivity, specificity, and positive predictive values were estimated for each diagnostic indicator by fitting bivariate random effects meta-analyses. FINDINGS: 191 studies reporting on 26 diagnostic indicators were included in the meta-analyses. We found large variation in diagnostic accuracy estimates between studies and most studies were at high risk of bias. We found strong evidence that people with dermatitis herpetiformis, migraine, family history of CD, HLA DQ2/8 risk genotype, anaemia, type 1 diabetes, osteoporosis, or chronic liver disease are more likely than the general population to have CD. Symptoms, psoriasis, epilepsy, inflammatory bowel disease, systemic lupus erythematosus, fractures, type 2 diabetes, and multiple sclerosis showed poor diagnostic ability. A sensitivity analysis revealed a 3-fold higher risk of CD in first-degree relatives of CD patients. CONCLUSIONS: Targeted testing of individuals with dermatitis herpetiformis, migraine, family history of CD, HLA DQ2/8 risk genotype, anaemia, type 1 diabetes, osteoporosis, or chronic liver disease could improve case-finding for CD, therefore expediting appropriate treatment and reducing adverse consequences. Migraine and chronic liver disease are not yet included as a risk factor in all CD guidelines, but it may be appropriate for these to be added. Future research should establish the diagnostic value of combining indicators.

Accuracy of potential diagnostic indicators for coeliac disease: a systematic review protocol.

INTRODUCTION: Coeliac disease (CD) is a systemic immune-mediated disorder triggered by gluten in genetically predisposed individuals. CD is diagnosed using a combination of serology tests and endoscopic biopsy of the small intestine. However, because of non-specific symptoms and heterogeneous clinical presentation, diagnosing CD is challenging. Early detection of CD through improved case-finding strategies can improve the response to a gluten-free diet, patients' quality of life and potentially reduce the risk of complications. However, there is a lack of consensus in which groups may benefit from active case-finding. METHODS AND ANALYSIS: We will perform a systematic review to determine the accuracy of diagnostic indicators (such as symptoms and risk factors) for CD in adults and children, and thus can help identify patients who should be offered CD testing. MEDLINE, Embase, Cochrane Library and Web of Science will be searched from 1997 until 2020. Screening will be performed in duplicate. Data extraction will be performed by one and checked by a second reviewer. Disagreements will be resolved through discussion or referral to a third reviewer. We will produce a narrative summary of identified prediction models. Studies, where 2×2 data can be extracted or reconstructed, will be treated as diagnostic accuracy studies, that is, the diagnostic indicators are the index tests and CD serology and/or biopsy is the reference standard. For each diagnostic indicator, we will perform a bivariate random-effects meta-analysis of the sensitivity and specificity. ETHICS AND DISSEMINATION: Results will be reported in peer-reviewed journals, academic and public presentations and social media. We will convene an implementation panel to advise on the optimum strategy for enhanced dissemination. We will discuss findings with Coeliac UK to help with dissemination to patients. Ethical approval is not applicable, as this is a systematic review and no research participants will be involved. PROSPERO REGISTRATION NUMBER: CRD42020170766.

Determining whether coeliac disease case-finding in primary care is better than random testing: a retrospective study.

BACKGROUND: Over 75% of patients (approximately half a million) with coeliac disease in the UK have not been formally diagnosed. AIM: To determine if case-finding of coeliac disease is better than random testing in primary care. DESIGN & SETTING: A pragmatic study looked at all referrals across a 12-month period (December 2013-November 2014) for coeliac serology testing and the indications for testing across 38 GP practices in a well-defined geographical area in North Yorkshire. There was further follow-up for an additional 12 months to determine conversion of positive serology to duodenal biopsy. METHOD: All serology samples sent into York Hospital biochemistry department during the study period were analysed for the indication for testing. Positive results were cross-referenced for duodenal biopsies over the following 12 months on the York Hospital pathology database. RESULTS: Case-finding of coeliac patients in primary care is no better than random testing of the population. Only 71% of patients with positive serology went on to have a duodenal biopsy in the following 12 months. CONCLUSION: More education of the population and of primary care physicians is needed around the indications for checking for coeliac disease. It may be that primary care is not the best place to case-find patients with coeliac disease.

What Do Participants of the Crohn's and Colitis UK (CCUK) Annual York Walk Think of Their Inflammatory Bowel Disease Care? A Short Report on a Survey.

There has been a growing interest in a patient-centered model of care in inflammatory bowel disease; however, no relevant study using a mixed methodology has been conducted to date. Thus, our multidisciplinary group aimed to explore the issue of patient involvement in care among the inflammatory bowel disease community. A mixed-methods anonymous survey was conducted during the Crohn's and Colitis UK annual event. Summary statistics were used to describe the sample, and a simple thematic analysis identified key themes in qualitative responses. There were 64 survey respondents, representing 73% of the total family/friend groups participating (N = 87). Overall, 75% of respondents answered that they had the opportunity to discuss their care with their inflammatory bowel disease practitioner and 81% felt their opinions were taken on board and valued. A clear majority (84%) had at some point been treated by a gastroenterologist. In contrast, less than half (44%) had the opportunity for a dietician consultation and only 28% had the opportunity for a psychologist/counselor consultation. Although satisfaction with inflammatory bowel disease care was high, access to specialty services was concerning. Efforts should be made to provide access to mental health practitioners for those with clinically significant anxiety and/or depression.

Validation of a care pathway for the use of faecal calprotectin in monitoring patients with Crohn's disease.

INTRODUCTION: We have previously published an evidence-based care pathway for the use of faecal calprotectin (FC) to monitor patients with Crohn's disease established on therapy. Patients are treated as low, intermediate or high risk of continuing Crohn's disease activity based on their FC, whatever their phenotype and surgical status are. Low-risk patients (FC <100 µg/g) are offered 12 monthly follow-ups or step down of therapy if asymptomatic or initial expectant symptomatic treatment. Intermediate-risk patients (FC 100-250 µg/g) are reviewed at 6 months with a repeat FC. High-risk patients (two consecutive FCs >250 µg/g) are flagged up to the responsible clinician as likely having an active Crohn's disease. METHODS: To validate this care pathway over a 2-year period, by determining its negative predictive value (NPV) and positive predictive value (PPV). RESULTS: 123 patients were managed by means of the care pathway for a mean of 24.4 months. The NPV and PPV were 0.97 (CI 0.93 to 0.98) and 0.85 (CI 0.80 to 0.94), respectively (sensitivity: 0.92 (0.83 to 0.96) and specificity: 0.95 (0.92 to 0.98)). Importantly 69% of patients with FC >250 µg/g were in clinical remission, the care pathway identifying patients who would benefit from presymptomatic disease modification. CONCLUSIONS: This validation of a pragmatic clinical care pathway demonstrates a safe and effective mechanism by which to use FC to monitor risk of disease activity in patients with Crohn's disease established on therapy. It provides a framework for prioritising follow-up and for identifying patients at risk of continuing disease activity or those in whom therapy could be stepped down.

Advances in coeliac disease.

PURPOSE OF REVIEW: This article critically summarizes the recent scientific and clinical advances in coeliac disease. RECENT FINDINGS: Epidemiological studies have shown that coeliac disease is as common in parts of Asia, Africa and Eastern Europe as in the western world. Genome-wide association studies continue to identify genetic susceptibilities that are both unique to coeliac disease and overlap with other autoimmune diseases. Human leukocyte antigen genotyping offers additional sensitivity in detecting coeliac disease in individuals who have self-prescribed gluten-free diets (GFD) or have atypical presentations. Immunological advances have highlighted the potential proinflammatory pitfalls of vitamin A supplementation in active coeliac disease and have enabled identification of oat and barley subsets that may be safely incorporated into coeliac diets. Large population-based studies have expanded our knowledge of the long-term risks of coeliac disease, in addition to excluding infertility as a cause for concern once a GFD has been established. SUMMARY: The long-term implications of active coeliac disease emphasize the need for early detection and strict adherence to GFD, which remains the cornerstone of management. Technological advances in food modulation and immuno-therapies offer promise, but remain in the translational phases of clinical trials at present.

Advances in celiac disease.

PURPOSE OF REVIEW: To critically summarize recent research in celiac disease. RECENT FINDINGS: There are new serological markers with potential use not only in the diagnosis of celiac disease but also as important follow-up tools. As our understanding of celiac disease increases with further isolation of nonhuman leukocyte antigen genes and clarification of the intracellular pathways that underlie its pathogenesis, there are new modalities which will not only allow improved risk stratification of individuals but also facilitate the development of novel therapeutic agents. SUMMARY: Small bowel biopsy remains the gold standard for both diagnosis and monitoring. A gluten-free diet currently remains the only treatment option, with potential other options being discovered such as glutenases for predigestion of gluten.

Recent advances in coeliac disease.

PURPOSE OF REVIEW: Worldwide awareness of coeliac disease in all ages continues to grow. This article aims to summarize critically the recent research advances in coeliac disease. RECENT FINDINGS: Large multicentre studies have provided further evidence of the role of environmental and nonhuman leucocyte antigen genetic factors in coeliac disease. Siblings of coeliac patients carry a high risk, but those found to have negative coeliac serology are very unlikely to develop the disease. Advances in the efficacy of serological antibody testing potentiate the possibility of future accurate screening programmes in the community. Adherence to a gluten-free diet remains paramount as the recognition of coeliac related complications increases. SUMMARY: Despite the encouraging progress that has taken place in our genetic and immunological knowledge of coeliac disease, early introduction of a gluten-free diet remains the cornerstone of treatment. Alternatives, however, aimed at altering the toxicity of cereal proteins are now looking more promising.

Advances in coeliac disease.

PURPOSE OF REVIEW: The number of people diagnosed with coeliac disease continues to rise, and this article critically summarizes recent research into the condition. RECENT FINDINGS: Much work has been focused on clarifying the molecular pathways involving cytokines in coeliac disease. Such work will yield improved understanding of the complex pathogenesis of coeliac disease and novel therapeutic targets. SUMMARY: The recent literature predominantly focuses on both elucidating the pathogenesis and improving diagnostic strategies for coeliac disease, but further work into the treatment of coeliac disease is needed.

Advances in celiac disease.

PURPOSE OF REVIEW: Increasing numbers of atypical or asymptomatic cases of celiac disease are being diagnosed. This review aims to summarize recent critical research in celiac disease. RECENT FINDINGS: Alternative candidate genes outside of the human leukocyte antigen complex continue to be identified, whilst innate and adaptive immune responses to key gliadin epitopes are now both recognized to be important in celiac disease pathogenesis. SUMMARY: Serological tests and small bowel biopsy remain the cornerstones of diagnosis. Treatment options other than the restrictive gluten-free diet remain limited.

Advances in celiac disease.

PURPOSE OF REVIEW: This article primarily aims to review critically research in all aspects of celiac disease over the last year. As always, there has been a wealth of relevant papers. RECENT FINDINGS: The role of genetics in disease susceptibility is slowly becoming more clearly defined and a more detailed understanding of the disease processes at the molecular level is paving the way towards the development of specific targeted therapies. SUMMARY: Despite recent advances in our understanding of celiac disease, the gluten-free diet remains the only current viable therapy and even with advances in serological tests and markers, the duodenal biopsy remains the gold standard for diagnosis and monitoring of the response to therapy.

Advances in celiac disease.

PURPOSE OF REVIEW: The number of diagnoses of celiac disease, especially "silent" forms continues to rise world-wide. This review aims to summarize critically recent research in celiac disease. RECENT FINDINGS: New proteomic approaches with the development of a possible powerful animal model have potentially furthered the isolation of the epitopes within gliadin, and other related proteins, that are critical for the development of celiac disease. SUMMARY: The number of potential disease-triggering gliadin components remains large. Small bowel biopsies remain the gold-standard for both diagnosis and monitoring of treatment.