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Summary: Background: Gluten‐free diet (GFD) is the only treatment for patients with coeliac disease (CD) and its compliance should be monitored to avoid cumulative damage. Aims: To analyse gluten exposures of coeliac patients on GFD for at least 24 months using different monitoring tools and its impact on duodenal histology at 12‐month follow‐up and evaluate the interval of determination of urinary gluten immunogenic peptides (u‐GIP) for the monitoring of GFD adherence. Methods: Ninety‐four patients with CD on a GFD for at least 24 months were prospectively included. Symptoms, serology, CDAT questionnaire, and u‐GIP (three samples/visit) were analysed at inclusion, 3, 6, and 12 months. Duodenal biopsy was performed at inclusion and 12 months. Results: At inclusion, 25.8% presented duodenal mucosal damage; at 12 months, this percentage reduced by half. This histological improvement was indicated by a reduction in u‐GIP but did not correlate with the remaining tools. The determination of u‐GIP detected a higher number of transgressions than serology, regardless of histological evolution type. The presence of >4 u‐GIP‐positive samples out of 12 collected during 12 months predicted histological lesion with a specificity of 93%. Most patients (94%) with negative u‐GIP in ≥2 follow‐up visits showed the absence of histological lesions (p < 0.05). Conclusion: This study suggests that the frequency of recurrent gluten exposures, according to serial determination of u‐GIP, could be related to the persistence of villous atrophy and that a more regular follow‐up every 6 months, instead of annually, provides more useful data about the adequate adherence to GFD and mucosal healing. [ABSTRACT FROM AUTHOR]

Summary: Background: Primary sclerosing cholangitis (PSC) is a progressive bile duct disease associated with inflammatory bowel disease (PSC‐IBD). Aim: To investigate whether patients with PSC‐IBD benefit from a gluten‐free and amylase trypsin inhibitor (ATI)‐free diet (GFD). Methods: We performed a prospective clinical pilot study administering an eight‐week GFD. The primary outcomes were colonic inflammation assessed by proctosigmoidoscopy, and liver stiffness (surrogate for fibrosis, inflammation and cholestasis) measured by transient elastography before and after GFD. Amongst the secondary (exploratory) outcomes were colonic mucosal and serum cytokine/chemokine changes, the intestinal microbiome and transcriptome dynamics, and shifts in serum markers of hepatic fibrogenesis. Results: Fifteen patients with PSC‐IBD completed the study. The study did not meet its primary outcome: the endoscopic score and liver stiffness remained unchanged. However, the expression of pro‐inflammatory mucosal cytokines and chemokines such as IL6, IL8, CCL2, and TNFα was significantly down‐regulated. Two critical markers of liver fibrosis and matrix remodelling, thrombospondin‐2 and ‐4, decreased significantly. The microbiota composition changed slightly, including a decrease in the pathogen Romboutsia ilealis. The intestinal transcriptome indicated a gut barrier improvement. Pruritus, fatigue, overall well‐being, faecal calprotectin levels, and serum alkaline phosphatase did not change significantly. Conclusions: This study did not demonstrate a clinical improvement with short‐term GFD in patients with PSC‐IBD. However, a gluten/ATI‐free diet may improve biomarkers of intestinal inflammation and barrier function in these patients with associated changes in the enteric microbiota. Further investigation of the therapeutic potential of the GFD in PSC‐IBD is warranted. [ABSTRACT FROM AUTHOR]

Summary: Background: A gluten‐free diet reduces symptoms in some patients with irritable bowel syndrome (IBS) through unclear mechanisms. Aims: To assess the effects of gluten‐free versus gluten‐containing diet on symptoms and the gut microenvironment, and to identify predictors of response to the gluten‐free diet in IBS Methods: Twenty patients with IBS and 18 healthy controls (HC) followed a gluten‐free diet during two 14‐day intervention periods where they sprinkled either gluten (14 g/day) or rice flour powder over their meals. Primary outcomes included effects of the interventions on IBS symptoms (IBS‐SSS) and bowel habits. Secondary outcomes included effects of gluten‐free diet on faecal microbiota and metabolite profile. Results: IBS symptoms improved during the gluten‐free (p = 0.02), but not the gluten‐containing period, with no difference between the interventions. IBS patients reported fewer loose stools during the gluten‐free intervention (p = 0.01). Patients with IBS and HC presented distinct metabolite profiles based on the effects of the gluten‐free diet (p < 0.001). True responders (reduced IBS‐SSS by ≥50 solely after gluten‐free period) and non‐responders were discriminated based on the effects of the gluten‐free diet on the microbiota (p < 0.01) and metabolite profiles (p < 0.001). The response to the gluten‐free diet could be predicted by the metabolite profile before the intervention (p < 0.001). Conclusions: A gluten‐free diet may influence symptoms in a subset of patients with IBS, with a particular effect on bowel habits. A gluten‐free diet seems to impact the gut microenvironment. Responsiveness to the gluten‐free diet may be predicted by the metabolite profile. Clinicaltrials.gov: NCT03869359. [ABSTRACT FROM AUTHOR]

Summary: Background: The best‐known symptoms of coeliac disease are related to the gastrointestinal tract, but the disease may also present with various systemic manifestations outside the intestine. Some of these consequences may remain permanent in undiagnosed individuals or if the diagnostic delay is prolonged. However, for many of the systemic manifestations, the scientific evidence remains scant and contradictory. Aims and Methods: We conducted a narrative review of the most thoroughly studied and clinically relevant systemic consequences of coeliac disease, especially those that could be prevented or alleviated by early diagnosis. The review is intended particularly for physicians encountering these patients in daily clinical practice. Results: The possible systemic consequences of coeliac disease extend to multiple organ systems, the best studied of which are related to skeletal, reproductive, cardiovascular and neurological systems. Furthermore, the disease is associated with an elevated risk of psychiatric comorbidities, non‐Hodgkin lymphomas and intestinal adenocarcinoma. Conclusions: The various systemic consequences of coeliac disease play a significant role in the overall health of patients. Early diagnosis and treatment with a gluten‐free diet appear to be beneficial for most, but not all of these conditions. The possible negative metabolic and psychosocial effects of the diet should be acknowledged during follow‐up. [ABSTRACT FROM AUTHOR]

Summary: As the gluten‐free diet is currently the only treatment for coeliac disease and one that needs to applied in the long term, this review aims to explore the various issues confronting an individual and discuss the importance of ongoing dietary management. The process of dietary counselling has shifted from one that focuses on just foods to avoid to one that evaluates the multiple life factors (social, cultural, environmental, biological) that affect the individual's food choices and dietary behaviour. The nutritional quality of a gluten‐free diet continues to affect vitamin, mineral and weight status of individuals with coeliac disease. There are many barriers to dietary adherence including increased cost and limited availability of gluten‐free products, as well as the negative impact on an individual's social domain of quality of life. Therefore, assessment, education and counselling by a coeliac specialist dietitian should be the cornerstone of dietary management. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: Coeliac 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. [ABSTRACT FROM AUTHOR]

Summary: Background: Coeliac disease (CeD) is an immune‐mediated small bowel enteropathy resulting from dietary gluten exposure. Presently, the only effective treatment is adoption of a gluten‐free diet (GFD), although strict adherence is challenging to maintain, and inadvertent gluten exposures are inevitable for most patients. Hence, there is substantial interest in drug development in CeD and multiple novel therapies are under investigation. Aims: To review existing and upcoming clinical trial programmes for pharmacologic agents for CeD. Methods: A narrative review was performed, informed by a search of MEDLINE, Embase, the Cochrane CENTRAL Library and clinicaltrials.gov. Results: We summarise the pathophysiology of CeD and the specific steps that are potentially amenable to pharmacologic treatment. We evaluate the evidence supporting existing and future drug targets, including trials of peptidases, gluten sequestrants, tight junction regulators, anti‐transglutaminase 2 therapies, immune tolerizing agents, advanced biologics and small molecules, and microbiome‐targeted strategies. We highlight unique considerations for conducting CeD trials, including identifying appropriate study populations, assessing results in the context of a gluten challenge, and interpreting CeD‐specific clinical and histologic outcomes. Understanding these factors is crucial for accurately appraising the evidence. Finally, we outline what the future of CeD therapy may hold with the introduction of pharmacotherapies. Conclusions: There is a need for pharmacologic options for CeD, either used adjunctively with a GFD for accidental or intentional gluten exposures or for refractory disease. Multiple promising agents are in development, and these trials are likely to lead to approvals for the first generation of pharmacologic agents for CeD within the next 5 years. [ABSTRACT FROM AUTHOR]

Background: The popularity of the gluten‐free diet and sales of gluten‐free products have increased immensely. Aims: To investigate whether gluten induces gastrointestinal symptoms, measured by self‐reported questionnaires, as well as mental health symptoms in adolescents from a population‐based cohort. Methods: The eligible participants (n = 273) were recruited from a population‐based cohort of 1266 adolescents and had at least four different gastrointestinal symptoms. Phase one (n = 54) was a run‐in phase where the participants lived gluten‐free for 2 weeks. If they improved they continued to phase 2 (n = 33), a blinded randomised cross‐over trial. Participants were blindly randomised either to start with 7 days of gluten, eating two granola bars containing 10 g of gluten or to 7 days on placebo, eating two granola bars without gluten, followed by the reverse and separated by a 7‐day washout period. The effects of the intervention on gastrointestinal symptoms and mental health symptoms were assessed. Results: In total, 54/273 participants entered the run‐in phase and 35 were eligible for randomization. A total of 33 were randomised and 32 completed the trial. The median age was 20.3 (IQR 19.2–20.9) and 32/33 participants were females. Compared with a placebo, gluten did not induce gastrointestinal symptoms. The difference in the average VAS was −0.01 (95% confidence interval −2.07 to 2.05). Nor did we find a difference in the outcomes measuring mental health. Conclusion: Compared with placebo, adding gluten to the diet did not induce gastrointestinal symptoms or worsened mental health in adolescents recruited from a population‐based cohort. The trial registration number is NCT04639921. [ABSTRACT FROM AUTHOR]

Summary: Background: Seronegative coeliac disease is poorly defined. Aims: To study clinical phenotypes and long‐term outcomes of seronegative coeliac disease in a multicentre cohort over 20 years. Methods: Seronegative coeliac disease was diagnosed in HLA‐DQ2/DQ8‐positive patients with villous atrophy (VA), negative IgA endomysial (EmA), tissue transglutaminase (tTG) and deamidated‐gliadin antibodies (DGP), clinical and histological response to a gluten‐free diet (GFD), and no alternative causes for VA. In patients with IgA deficiency, coeliac disease was diagnosed through VA, positive IgG EmA/tTG/DGP and clinical/histological response to a GFD (coeliac disease+IgAd). Patients with seropositive coeliac disease served as controls. Results: Of 227 patients previously diagnosed with seronegative coeliac disease, true seronegative coeliac disease was confirmed in 84, coeliac disease+IgAd in 48, and excluded in 55. Lack of follow‐up duodenal biopsy precluded diagnosing seronegative coeliac disease in 40 patients. 2084 patients with seropositive coeliac disease served as controls. True seronegative coeliac disease had more severe symptoms at diagnosis and a higher risk of complications (HR 10.87, 95% CI 6.11‐19.33, P < 0.001) and mortality (HR 2.18, 95% CI 1.12‐4.26, P < 0.01) than seropositive coeliac disease. There were no differences between true seronegative coeliac disease and coeliac disease+IgAd. On multivariate analysis, age at diagnosis, lack of clinical response to a GFD, true seronegative coeliac disease, coeliac disease+IgAd, and classical presentation predicted complications. Age at diagnosis, complications and absence of clinical response to a GFD predicted mortality. Conclusions: Seronegative coeliac disease has a more aggressive disease phenotype than seropositive coeliac disease. These data argue against over‐reliance on serology for the diagnosis of coeliac disease and support a strict clinical and histologic follow‐up in seronegative coeliac disease. [ABSTRACT FROM AUTHOR]

Summary: Background: The healing of the mucosal lesion in patients with coeliac disease is slow. Aim: To determine whether concurrent budesonide and gluten‐free diet hasten small bowel healing and symptomatic improvement in patients with newly diagnosed coeliac disease. Methods: In a pilot, randomised, double‐blind trial, effects on Marsh grading and quantitative duodenal morphometry of 10 weeks' effervescent budesonide (initially 9 mg/day) or placebo were assessed after 8 and 52 weeks. Multiple clinical measures and adverse events were assessed. Results: Nineteen patients were randomised to budesonide and 18 to placebo. No differences (all P > 0.32) were observed for the week‐8 mucosal response (Marsh 0 or 1) (budesonide: 37% vs placebo: 28%), week‐8 remission (Marsh 0) (32% vs 17%), week‐52 response (63% vs 44%) and week‐52 remission (42% vs 33%). Likewise, the improvement from baseline in villous‐height : crypt‐depth ratio was not different for the treatment groups. There were no statistically significant differences in clinical measures or adverse events between the treatment groups. No corticosteroid adverse effects were observed. In a post hoc analysis of all patients, Marsh 3C was present at the diagnostic biopsy in 1/9 achieving mucosal remission at 8 weeks versus 18/23 not (P < 0.001) and mean villous‐height : crypt‐depth ratio was 1.06 (SD: 0.73) versus 0.46 (0.38) (P = 0.005). Conclusions: In this pilot trial, induction therapy with budesonide had no significant effect on mucosal healing in patients with coeliac disease concurrently initiated on a gluten‐free diet. Mucosal remission at 8 weeks occurred in approximately one in four patients and was associated with less severe histological lesions at diagnosis. [ABSTRACT FROM AUTHOR]

Summary: Background: A major deficit in understanding and improving treatment in coeliac disease (CD) is the lack of empiric data on real world gluten exposure. Aims: To estimate gluten exposure on a gluten‐free diet (GFD) using immunoassays for gluten immunogenic peptides (GIP) and to examine relationships among GIP detection, symptoms and suspected gluten exposures Methods: Adults with biopsy‐confirmed CD on a GFD for 24 months were recruited from a population‐based inception cohort. Participants kept a diary and collected urine samples for 10 days and stools on days 4‐10. 'Doggie bags' containing ¼ portions of foods consumed were saved during the first 7 days. Gluten in food, stool and urine was quantified using A1/G12 ELISA. Results: Eighteen participants with CD (12 female; age 21‐70 years) and three participants on a gluten‐containing diet enrolled and completed the study. Twelve out of 18 CD participants had a median 2.1 mg gluten per exposure (range 0.2 to >80 mg). Most exposures were asymptomatic and unsuspected. There was high intra‐individual variability in the interval between gluten ingestion and excretion. Participants were generally unable to identify the food. Conclusions: Gluten exposure on a GFD is common, intermittent, and usually silent. Excretion kinetics are highly variable among individuals. The amount of gluten varied widely, but was typically in the milligram range, which was 10‐100 times less than consumed by those on an unrestricted diet. These findings suggest that a strict GFD is difficult to attain, and specific exposures are difficult to detect due to variable time course of excretion. [ABSTRACT FROM AUTHOR]

Summary: Background: In patients with coeliac disease, FODMAPs in gluten‐containing foods, and participant anticipation of a harmful ('nocebo') effect, may contribute to acute symptoms after gluten challenge. Aim: To establish acute gluten‐specific symptoms linked to immune activation in coeliac disease Methods: We included 36 coeliac disease patients on a gluten‐free diet receiving placebo in the RESET CeD trial. Double‐blind, bolus vital wheat gluten (~6‐g gluten protein) and sham challenges low in FODMAPs were consumed 2 weeks apart. Assessments included daily Coeliac Disease Patient Reported Outcome (CeD PRO) symptom scores (0‐10), adverse events and serum interleukin‐2 (baseline and 4 hours). Results: Median CeD PRO score for nausea increased most (sham: 0 vs gluten: 5.5; P <.001). Apart from tiredness (1 vs 4, P =.005) and headache (0 vs 2, P =.002), changes in other symptoms were small or absent. Only nausea increased significantly in occurrence with gluten (11% vs 69%, P <.001). Without nausea, only tiredness and flatulence were common after gluten. Nausea (6% vs 61%, P <.001; median onset: 1:34 hours) and vomiting (0% vs 44%, P <.001; 1:51 hours) were the only adverse events more common with gluten than sham. Interleukin‐2 was always below the level of quantitation (0.5 pg/mL) at baseline, and after sham. Interleukin‐2 was elevated after gluten in 97% of patients (median fold‐change: 20), and correlated with severity of nausea (rs =.49, P =.0025) and occurrence of vomiting (P =.0005). Conclusions: Nausea and vomiting are relatively specific indicators of acute gluten ingestion, and correlate with immune activation. IBS‐like symptoms without nausea are unlikely to indicate recent gluten exposure. [ABSTRACT FROM AUTHOR]

Summary: Background: Coeliac disease patients on a gluten‐free diet experience reactions to gluten, but these are not well characterised or understood. Systemic cytokine release was recently linked to reactivation of gluten immunity in coeliac disease. Aim: To define the nature and time‐course of symptoms and interleukin‐2 changes specific for coeliac disease patients. Methods: 25 coeliac disease patients on a gluten‐free diet and 25 healthy volunteers consumed a standardised 6 gram gluten challenge. Coeliac Disease Patient‐Reported Outcome survey and global digestive symptom assessment were completed hourly up to 6 hours after gluten. Adverse events over 48 hours were recorded. Serum interleukin‐2 was measured at baseline, and 2, 4 and 6 hours. Results: Serum interleukin‐2 was always undetectable in healthy controls, whereas it was undetectable at baseline and elevated >0.5 pg/ml at 4 hours in 92% of coeliac disease patients. All patient‐reported outcome severity scores increased significantly after gluten in coeliac disease patients (P < .001 Wilcoxon signed rank test), but not in controls. Symptoms began after 1 hour, and peaked in the third. Nausea and vomiting characterised severe reactions, but mild reactions were limited to headache and tiredness. Peak interleukin‐2 correlated with symptom severity, particularly for nausea and vomiting. Conclusions: Serum interleukin‐2 elevations correlate with timing and severity of symptoms after gluten in coeliac disease. Standardised bolus gluten food challenge and interleukin‐2 assessment could provide a valuable clinical test to monitor and diagnose coeliac disease in patients established on a gluten‐free diet. [ABSTRACT FROM AUTHOR]

Summary: Background: Treatment for coeliac disease is a lifelong strict gluten‐free diet. Although guidelines recommend regular follow‐up with dietary interviews and coeliac serology, these methods may be inaccurate. Aim: To evaluate the usefulness of faecal gluten immunogenic peptides to support the diagnosis and to determine the adherence to the gluten‐free diet in coeliac children. Methods: Multicentre prospective observational study including 64 coeliac children. Faecal gluten peptides, and tissue transglutaminase and deamidated gliadin peptide antibodies were analyzed at diagnosis, and 6, 12 and 24 months thereafter. Gluten consumption was estimated from gluten peptide levels. Results: Most children (97%) had detectable gluten peptides at diagnosis. On a gluten‐free diet, the rate of gluten peptides increased from 13% at 6 months to 25% at 24 months. Mean estimated gluten exposure dropped from 5543 mg/d at diagnosis to 144 mg/d at 6 months, then increased to 606 mg/d by 24 months. In contrast, deamidated gliadin peptide antibodies normalised and only 20% had elevated tissue transglutaminase antibody by 24 months. The elevation of tissue transglutaminase antibody was more prolonged in patients with detectable gluten peptides (P < 0.05). Nevertheless, absolute levels of tissue transglutaminase antibody had low sensitivity to identify patients with detectable gluten peptides (P > 0.1). Dietitian assessment was only moderately correlated with gluten peptide detection (κ = 0.5). Conclusions: Faecal gluten peptides testing may guide treatment of coeliac disease prior to diagnosis and during the assessment diet adherence. Further studies could determine if early identification of gluten exposure reduces the need for expensive/invasive investigations for non‐responsive coeliac disease. ClinicalTrials.gov Number: NCT02711397. [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to Liwinski et al paper. To view this article, visit https://doi.org/10.1111/apt.17256 [ABSTRACT FROM AUTHOR]

Summary: Background: A better understanding of coeliac disease can be achieved by assessing health‐related quality of life alongside clinical factors. Existing patient‐reported outcome measures (PROMs) evaluating quality of life in coeliac disease have not been developed in accordance with the US Food and Drug Administration guidelines. Aim: To develop a PROM in accordance with best practice guidelines, capturing all aspects of quality of life important to adults with coeliac disease. Methods: Candidate items for the Coeliac Disease Assessment Questionnaire (CDAQ) were refined through item appraisal, expert review, cognitive interviews, and a translatability assessment. A cross‐sectional survey determined further item reduction and the CDAQ's structure. The final CDAQ was administered alongside the Short Form Health Survey Version 2 (SF?36v2) in a second survey to assess construct validity and test‐retest reliability. Results: Pre‐testing the 64 candidate items revealed a range of issues which guided their refinement and reduction, resulting in the final CDAQ with 32 items representing 5 subscales: stigma (eight items), dietary burden (eight items), symptoms (five items), social isolation (five items), and worries and concerns (six items). Cronbach's alpha ranged between 0.82 and 0.88 for all domains. Further results showed CDAQ scores were more strongly correlated with the SF‐36v2's mental health dimensions, as expected. Intraclass correlation coefficients ranged from 0.79 to 0.89. Conclusion: The CDAQ is a reliable and valid coeliac‐specific measure that captures all aspects of quality of life important to adults with coeliac disease. Further work is underway to assess the CDAQ's responsiveness to change. [ABSTRACT FROM AUTHOR]

Summary: Background: A gluten‐free diet treats coeliac disease, but its efficacy depends on strict adherence. A variety of patient factors may influence adherence but have not been well described at a population level. Aim: To comprehensively assess the patient factors that influence gluten‐free diet adherence in patients with coeliac disease. Methods: Patients with coeliac disease completed an online survey comprising the validated Celiac Dietary Adherence Test in addition to data on demographics, details of diagnosis and management and assessment of diet knowledge, quality of life and psychological distress. Survey data were analysed for predictors of adherence and quality of life. Results: Of 7393 responses, 5310 completed the Celiac Dietary Adherence Test and 3230 (61%) were adherent to a gluten‐free diet. Multivariate regression showed older age, being male, symptoms after gluten ingestion, better food knowledge and lower risk of psychological distress were independent predictors of adherence (each P ≤ 0.008). Additionally, dietary adherence was associated with better quality of life (P < 0.001; multiple regression). Respondents who considered themselves to have poor food knowledge were more likely to incorrectly identify gluten‐free foods, but could still recognise gluten‐containing foods, suggesting that poor knowledge may lead to over‐restriction of diet. Conclusions: Poor knowledge of a gluten‐free diet and psychological wellbeing were independent modifiable risk factors for inadequate adherence to a gluten‐free diet in patients with coeliac disease. Involvement of both a dietitian and mental health care professional, in the presence of psychological distress, is likely to be necessary to improve adherence and health outcomes. [ABSTRACT FROM AUTHOR]

Background The frequency of coeliac disease (CD) has been on the rise over the past decades, especially in Western Europe, but current trends are unclear. Aim To research the recent temporal changes in the incidence of adult, biopsy-verified coeliac disease and dermatitis herpetiformis (DH) in Finland, a country with a high frequency of coeliac disease. Methods All coeliac disease and DH cases diagnosed at age 20-79 years during 2005-2014 were retrieved from a nationwide database documenting all applicants for monthly compensation to cover the extra cost of maintaining a gluten-free diet. This benefit is granted on the basis of histology, not socioeconomic status. Temporal trends in the annual incidences were estimated using Poisson regression analyses. Results The total incidence of coeliac disease decreased from 33/100 000 during the years 2005-2006 to 29/100 000 during 2013-2014. The mean annual incidence of coeliac disease was nearly twice as high among women as among men, 42 vs 22 per 100 000, respectively. For middle- and old-aged women, the average rate of decrease in incidence was 4.8% (95% CI 3.9-5.7) per year and for men 3.0% (1.8-4.1) ( P for linear trend <.001, for both). Similarly, the annual incidence of DH declined. For young adults, the rate of change remained low and nonsignificant throughout the period 2005-2014. Conclusions Although the awareness of coeliac disease has increased during the past decades, the incidence of biopsy-verified diagnoses is not increasing, which suggests that exposure to yet unidentified triggering factors for coeliac disease has plateaued among the Finnish adult population. [ABSTRACT FROM AUTHOR]

Background A gluten-free diet is currently the only reliable therapeutic strategy that is approved for coeliac disease ( CD). For many patients, however, compliance remains inadequate. Aim To investigate the immunogenicity of wheat flour that was pre-treated with selected lactobacilli and fungal proteases (hydrolysed wheat gluten) in coeliac patients. Methods The immunogenicity of hydrolysed wheat gluten was evaluated both in vitro in intestinal T cell lines ( TCLs) and in vivo in treated CD patients after a short-term gluten challenge. Twenty treated CD patients were enrolled and equally randomised into two groups. The patients ate bread that was prepared with hydrolysed wheat flour or natural wheat flour (10 g of gluten/d for 3 days). The interferon ( INF)-γ responses to natural gliadin and a 33-mer peptide were assessed by the enzyme-linked immunospot ( ELISPOT) assay on peripheral blood mononuclear cells ( PBMCs) both before and 6 days after the start of the challenge. Results Hydrolysed wheat was not able to activate the TCLs from the coeliac intestinal mucosa. Consistent with the in vitro results, no significant increase in INF-γ secretion was observed in patients who consumed hydrolysed wheat flour. Conversely, the consumption of natural wheat gluten mobilised INF-γ secreting cells in the blood ( P<.05). Conclusions We confirm that fermentation of wheat flour with sourdough lactobacilli and fungal proteases is capable of abolishing the T cell immunogenicity of gluten in coeliac patients. Our data also validate the short-term oral challenge as a useful tool for testing the efficacy of novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background A repeat biopsy is recommended, but often omitted in coeliac disease patients on a gluten-free diet. The effect of performing or not performing repeat biopsies is currently unknown. Aim To identify factors associated with and the significance of lacking biopsy for long-term outcome. Predictors and the importance of incomplete histological recovery after 1 year was investigated in re-biopsied patients. Methods A total of 760 patients participated in a nationwide follow-up study. Medical data were gathered via interviews and patient records, and blood samples were drawn for serology. Current symptoms and well-being were assessed by validated PGWB, SF-36 and GSRS questionnaires. Results Malabsorption was more common among those with a repeat biopsy (46%) than those without repeat biopsy (33%), P < 0.001, as were severe symptoms at diagnosis (24% vs. 16%, P = 0.05) and concomitant gastrointestinal (40% vs. 32%, P = 0.049) or musculoskeletal (35% vs. 27%, P = 0.023) diseases such as arthritis, osteoporosis and back pain. Repeat biopsy was more rare in subjects diagnosed in private care (11% vs. 23%, P < 0.001) or by screening (10% vs. 16%, P = 0.010). The groups were comparable as to current symptoms and dietary adherence, but those without re-biopsy were less confident of their diet (89% vs. 94%, P = 0.002) and more often seropositive on diet (14% vs. 9%, P = 0.012). They reported better SF-36 physical functioning ( P = 0.043) and less pain and indigestion ( P = 0.013 and P = 0.046 respectively) and total GSRS ( P = 0.052) score. Incomplete mucosal recovery was predicted by more advanced histological ( P < 0.001) and serological ( P = 0.001) disease at diagnosis, whereas the groups did not differ in long-term adherence, symptoms, seropositivity, questionnaire scores, frequency of fractures or malignancies. Conclusions Severe disease at diagnosis predicted the record of a repeat biopsy and incomplete mucosal recovery. Neither lacking biopsy nor incomplete recovery in a relative short time span of 1 year was associated with poorer long-term outcome, although survival bias cannot be excluded. [ABSTRACT FROM AUTHOR]

Background Duodenal injury persists in some coeliac disease patients despite gluten-free diet, and is associated with adverse outcomes. Aim To determine the prevalence and clinical risk factors for persistent villus atrophy among symptomatic coeliac disease patients. Methods A nested cross-sectional analysis was performed on coeliac disease patients with self-reported moderate or severe symptoms while following a gluten-free diet, who underwent protocol-mandated duodenal biopsy upon enrolment in the CeliAction clinical trial. Demographic factors, symptom type, medication use, and serology were examined to determine predictors of persistent villus atrophy. Results Of 1345 symptomatic patients, 511 (38%, 95% CI, 35-41%) were found to have active coeliac disease with persistent villus atrophy, defined as average villus height to crypt depth ratio ≤2.0. On multivariable analysis, older age ( OR, 5.1 for ≥70 vs. 18-29 years, 95% CI, 2.5-10.4) was a risk factor while longer duration on gluten-free diet was protective ( OR, 0.37, 95% CI, 0.24-0.55 for 4-5.9 vs. 1-1.9 years). Villus atrophy was associated with use of proton-pump inhibitors ( PPIs; OR, 1.6, 95% CI, 1.1-2.3), non-steroidal anti-inflammatory drugs ( NSAIDs; OR, 1.64, 95% CI, 1.2-2.2), and selective serotonin reuptake inhibitors ( SSRIs; OR, 1.74, 95% CI, 1.2-2.5). Symptoms were not associated with villus atrophy after adjusting for covariates. Conclusions A majority of symptomatic coeliac disease patients did not have active disease on follow-up histology. Symptoms were poorly predictive of persistent mucosal injury. The impact of NSAIDs, PPIs, and SSRIs on mucosal healing in coeliac disease warrants further study. [ABSTRACT FROM AUTHOR]

Background A gluten-free diet is the only recommended treatment for coeliac disease. Aim To determine the prevalence and characteristics of reactions to gluten among persons with coeliac disease on a gluten-free diet. Methods Adults with biopsy proven, newly diagnosed coeliac disease were prospectively enrolled. A survey related to diet adherence and reactions to gluten was completed at study entry and 6 months. The Coeliac Symptom Index, Coeliac Diet Assessment Tool ( CDAT) and Gluten-Free Eating Assessment Tool ( GF- EAT) were used to measure coeliac disease symptoms and gluten-free diet adherence. Results Of the 105 participants, 91% reported gluten exposure <1 per month and median CDAT score was 9 ( IQR 8-11), consistent with adequate adherence. A suspected symptomatic reaction to gluten was reported by 66%. Gluten consumption was unsuspected until a reaction occurred (63%) or resulted from problems ordering in a restaurant (29%). The amount of gluten consumed ranged from cross-contact (30%) to a major ingredient (10%). Median time to symptom onset was 1 h (range 10 min to 48 h), and median symptom duration was 24 h (range 1 h to 8 days). Common symptoms included abdominal pain (80%), diarrhoea (52%), fatigue (33%), headache (30%) and irritability (29%). Conclusions Reactions to suspected gluten exposure are common among patients with coeliac disease on a gluten-free diet. Eating at restaurants and other peoples' homes remain a risk for unintentional gluten exposure. When following individuals with coeliac disease, clinicians should include questions regarding reactions to gluten as part of their assessment of gluten-free diet adherence. [ABSTRACT FROM AUTHOR]

Background New therapeutics are moving into phase 3 clinical trials for the treatment of coeliac disease, a condition with no established therapies other than gluten-free diet. These trials will require a meaningful, validated and fit for purpose patient-reported outcome measure ( PROM) to quantify the symptomatic improvement of patients. Aim To evaluate existing PROMs for suitability in a Food and Drug Administration ( FDA) approval trial for a coeliac disease therapeutic. Method We performed a systematic search in five online databases (MedLine, EmBase, Web of Science, CENTRAL, CINAHL) for studies that enrolled patients with coeliac disease and used PROMs. Studies included in this review had to measure some PROM concept, be patient administered and based upon a previously validated instrument with published measurement properties. Results Our literature search identified 2706 unique records of which 199 ultimately qualified for abstraction. The majority of PROMs used in studies of coeliac disease was generic and did not measure numerous symptoms or concerns of interest to patients. Four PROMs were found to contain appropriate content for use in an FDA trial: the coeliac disease-specific modification of the Gastrointestinal Symptoms Rating Scale (CeD- GSRS), Psychological General Well-Being Index ( PGWB), the Celiac Disease Symptom Diary ( CDSD) and the Celiac Disease Patient Reported Outcome (CeD- PRO). The GSRS and PGWB are most often used together and are two of the most extensively used measures in coeliac disease. The CDSD and CeD- PRO were developed exclusively for trials in coeliac disease but have much less published information on their measurement properties. Conclusions While we did not find PROMs that currently meet the stated expectations of the FDA for regulatory purposes, four PROMs (CeD- GSRS, PGWB, CDSD and CeD- PRO) appear to contain appropriate content and with modest additional validation work could meet scientific standards for valid and sensitive measures of disease and treatment outcome. Specifically, what is needed for these instruments is an understanding of how sensitive they are to real changes in-patient condition, how stable they are over a period of time when health status should not have changed (test-retest reliability) as well as how they correlate with other measures of patient functioning such as intestinal biopsy. All of these objectives could feasibly be accomplished over a short cohort study of patients with biopsy-defined coeliac disease undergoing gluten challenge. [ABSTRACT FROM AUTHOR]

Background A strict gluten-free diet is the cornerstone of treatment for coeliac disease. Studies of gluten-free diet adherence have rarely used validated instruments. There is a paucity of data on long-term adherence to the gluten-free diet in the adult population. Aims To determine the long-term adherence to the gluten-free diet and potential associated factors in a large coeliac disease referral centre population. Methods We performed a mailed survey of adults with clinically, serologically and histologically confirmed coeliac disease diagnosed ≥5 years prior to survey. The previously validated Celiac Disease Adherence Test was used to determine adherence. Demographic, socio-economic and potentially associated factors were analysed with adherence as the outcome. Results The response rate was 50.1% of 709 surveyed, the mean time on a gluten-free diet 9.9 ± 6.4 years. Adequate adherence (celiac disease adherence test score <13) was found in 75.5% of respondents. A higher level of education was associated with adequate adherence ( P = 0.002) even after controlling for household income ( P = 0.0220). Perceptions of cost, effectiveness of the gluten-free diet, knowledge of the gluten-free diet and self-effectiveness at following the gluten-free diet correlated with adherence scores ( P < 0.001). Conclusions Long-term adherence to a gluten-free diet was adequate in >75% of respondents. Perceived cost remains a barrier to adherence. Perceptions of effectiveness of gluten-free diet as well as its knowledge, are potential areas for intervention. [ABSTRACT FROM AUTHOR]

Background Noncoeliac gluten sensitivity ( NCGS) is a controversial emerging disorder. Despite reported symptoms related to the ingestion of gluten, NCGS remains a diagnosis based on the exclusion of coeliac disease, given the absence of reliable biomarkers. Aim To evaluate the prevalence, diagnostic exclusion of coeliac disease and the efficacy of a gluten-free diet ( GFD) for NCGS patients. Methods A PubMed search was performed up to December 2014. According to consensus diagnostic criteria, NCGS was defined as self-reported gluten intolerance, negative coeliac serology and absence of villous atrophy. Studies evaluating the impact of a GFD on patients with irritable bowel syndrome ( IBS) were also included. Results Prevalence rates of NCGS (0.5-13%) differed widely. Seventeen studies, including 1561 patients (26 children), met the inclusion criteria for NCGS. HLA haplotypes could not be linked to histology [normal or lymphocytic enteritis ( LE)] in 1123 NCGS patients. HLADQ2/ DQ8 haplotypes were present in 44% of NCGS patients. After advanced diagnostic techniques in 189 NCGS patients combining LE and HLADQ2/ DQ8 haplotypes, 39 (20%) were reclassified as coeliac disease. There was a higher than expected family history of coeliac disease and autoimmune disorders in NCGS patients. A GFD resulted in variable results for variable, but significantly improved stool frequency in HLADQ2 positive diarrhoea-predominant IBS patients. Conclusions Prevalence rates for NCGS are extremely variable. A subset of NCGS patients might belong in the so-called 'coeliac-lite' disease. The benefit of a GFD for NCGS patients is currently controversial. HLADQ2 positive diarrhoea-type IBS patients might gain symptom improvement from a GFD. [ABSTRACT FROM AUTHOR]

Background Several studies have shown that weight changes are common in patients with coeliac disease after starting a gluten-free diet (GFD), but data on the prevalence of metabolic syndrome in this population are still scarce. Aims To assess the prevalence of metabolic syndrome in patients with CD at diagnosis and 1 year after starting GFD. Methods We enrolled all consecutive patients with newly diagnosed coeliac disease (CD) who were referred to our third-level CD Unit. For all patients we collected: waist circumference, BMI, blood pressure, lipid profile (HDL cholesterol, triglycerides) and levels of blood glucose. Diagnosis of metabolic syndrome was made according to the International Diabetes Federation (IDF) criteria for European countries. The prevalence of metabolic syndrome was re-assessed after 12 months of GFD. Results Ninety-eight patients with CD were assessed, two patients with CD (2%) fulfilled the diagnostic criteria for metabolic syndrome at diagnosis and 29 patients (29.5%) after 12 months of GFD ( P < 0.01; OR: 20). With regard to metabolic syndrome sub-categories 1 year after GFD compared to baseline respectively: 72 vs. 48 patients exceeded waist circumference cut-off ( P < 0.01; OR: 2.8); 18 vs. 4 patients had high blood pressure ( P < 0.01; OR: 5.2); 25 vs. 7 patients exceeded glycemic threshold ( P = 0.01; OR: 4.4); 34 vs. 32 patients with CD had reduced levels of HDL cholesterol ( P = 0.7); and 16 vs. 7 patients had high levels of triglycerides ( P = 0.05). Conclusions Patients with coeliac disease show a high risk of metabolic syndrome 1 year after starting a gluten-free diet. We suggest that an in-depth nutritional assessment is undertaken for all patients with coeliac disease. [ABSTRACT FROM AUTHOR]

Background Adequate gluten-free diet ( GFD) is the only treatment for coeliac disease ( CD). However, no agreement has been reached on either how and when to assess patient adherence to GFD or its effectiveness on villous atrophy. Aim To assess, in a prospective study, patient adherence to and efficacy of GFD on histological recovery after 1-year of GFD. Methods Between 2009 and 2012, we enrolled 65 consecutive newly-diagnosed adult patients (median age 38 years, 18-70) with biopsy-proven atrophic CD. Patients were re-evaluated after 1 year of GFD with duodenal histology, serological assays, symptoms and a dietary interview based on a validated questionnaire. Complete histological recovery was defined as the absence of villous atrophy and ≤30/100 intraepithelial lymphocytes. Results Overall, 81.5% of patients had adequate adherence ( ADA) to GFD, whereas 18.5% had an inadequate adherence ( IADA); 66% of ADA patients and no IADA patients achieved complete histological recovery ( P < 0.00001). Among ADA patients, antibody seroconversion and symptoms were not significantly different between patients who achieved complete histological recovery and those who achieved partial histological recovery with P = 0.309 and P = 0.197, respectively. Multivariate analysis showed that Marsh 3C was a risk factor for incomplete histological recovery in ADA patients ( OR 8.74, 95% CI: 1.87-40.83). Conclusions This study shows that complete histological recovery after 1-year of GFD in adult patients, who are assessed as adherent to the GFD, can be obtained in 66% of patients. Patients with severe histological damage at diagnosis are at risk for incomplete histological recovery 1 year later. [ABSTRACT FROM AUTHOR]

Background The relationship between eosinophilic oesophagitis (EoE) and coeliac disease ( CD) remains controversial, with studies yielding varied results. Aim To systematically review the evidence of a possible association between both diseases. Methods Electronic searches were performed with keywords relating to EoE and CD in the MEDLINE, EMBASE and SCOPUS databases. Summary estimates were calculated. A random-effects model was used depending on heterogeneity ( I2). Publication bias was assessed with the aid of funnel plot analysis, along with the Begg-Mazumdar, Harbord and Egger tests. Results The search yielded 197 references; 30 were included in the quantitative summary, with most of these presenting methodological inconsistencies. Significant publication bias in favour of short studies reporting positive associations between both diseases was documented. The prevalence of EoE in CD ranged from 0% to 10.7% ( I2 = 78.9%). Prevalence of CD in EoE varied between 0.16% and 57.1% ( I2 = 89%). One high-quality, prospective, randomly selected, population-based study documented a 1.1% prevalence of CD, with no patients presenting EoE. Clinical and methodological heterogeneity hindered the performance of quantitative summaries for prevalence data. A gluten-free diet was effective in achieving histological remission of EoE in 32.1% of coeliac patients (95% confidence interval, 14.9-52.2%; I2 = 52.2%), which was similar to that expected for wheat elimination in EoE patients. Conclusions While a lack of valid studies prevents us from completely ruling out a true association between EoE and CD, currently available evidence does not support this hypothesis. Indeed, the only epidemiological study with sufficient validity points to the independence of both diseases. [ABSTRACT FROM AUTHOR]

Background Mild impairments of cognition or 'Brain fog' are often reported by patients with coeliac disease but the nature of these impairments has not been systematically investigated. Aim This longitudinal pilot study investigated relationships between cognitive function and mucosal healing in people with newly diagnosed coeliac disease commencing a gluten-free diet. Methods Eleven patients (8 females, 3 males), mean age 30 (range 22-39) years, were tested with a battery of cognitive tests at weeks 0, 12 and 52. Information processing efficacy, memory, visuospatial ability, motoric function and attention were tested. Small bowel biopsies were collected via routine gastroscopy at weeks 12 and 52 and were compared to baseline Marsh scores. Cognitive performance was compared to serum concentrations of tissue transglutaminase antibodies, biopsy outcomes and other biological markers. Results All patients had excellent adherence to the diet. Marsh scores improved significantly ( P = 0.001, Friedman's test) and tissue transglutaminase antibody concentrations decreased from a mean of 58.4 at baseline to 16.8 U/mL at week 52 ( P = 0.025). Four of the cognitive tests assessing verbal fluency, attention and motoric function showed significant improvement over the 12 months and strongly correlated with the Marsh scores and tissue transglutaminase antibody levels ( r = 0.377-0.735; all P < 0.05). However, no meaningful patterns of correlations were found for nutritional or biochemical markers, or markers of intestinal permeability. Conclusions In newly diagnosed coeliac disease, cognitive performance improves with adherence to the gluten-free diet in parallel to mucosal healing. Suboptimal levels of cognition in untreated coeliac disease may affect the performance of everyday tasks. [ABSTRACT FROM AUTHOR]

Background Faecal short chain fatty acids ( SCFAs) are produced by the gut microflora. We have previously reported high faecal SCFA levels in children with coeliac disease ( CD), indicating alteration in gut microfloral metabolism. Data accumulated over recent decades by us and others suggest that wheat-free oats can safely be included in a gluten-free diet ( GFD). However, concerns have been raised with respect to the safety of oats in a subset of coeliacs. Aim To describe faecal SCFA patterns in children with newly diagnosed CD treated for 1 year with a GFD with or without oats. Methods This report is part of a randomised, double-blind study on the effect of a GFD containing oats ( GFD-oats) vs. a standard GFD ( GFD-std). Faecal samples were received from 34 children in the GFD-oats group and 37 in the GFD-std group at initial diagnosis and/or after 1 year on a GFD. Faecal SCFAs were analysed. Results The GFD-std group had a significantly lower total faecal SCFA concentration at 12 months compared with 0 months ( P < 0.05). In contrast, total SCFA in the GFD-oats group remained high after 1 year on the GFD. The children in the GFD-oats group had significantly higher acetic acid ( P < 0.05), n-butyric acid ( P < 0.05) and total SCFA concentration ( P < 0.01) after 1-year diet treatment compared to the GFD-std group. Conclusions Our results indicate that oats do affect the gut microflora function, and that some coeliac children receiving oats may develop gut mucosal inflammation, that may present a risk for future complications. [ABSTRACT FROM AUTHOR]

Background Histologically nonresponsive coeliac disease ( NRCD) is a potentially serious condition diagnosed during the follow-up of coeliac disease ( CD) when patients have persistent villous atrophy despite following a gluten-free diet ( GFD). Aim As current assessments of recovery are limited to invasive and costly serial duodenal biopsies, we sought to identify antibody biomarkers for CD patients that do not respond to traditional therapy. Methods Bacterial display peptide libraries were screened by flow cytometry to identify epitopes specifically recognised by antibodies from patients with NRCD, but not by antibodies from responsive CD patients. Deamidated gliadin was confirmed to be the antigen mimicked by library peptides using ELISA with sera from NRCD ( n = 15) and responsive CD ( n = 45) patients on a strict GFD for at least 1 year. Results The dominant consensus epitope sequence identified by unbiased library screening QPxx(A/P)FP(E/D) was highly similar to reported deamidated gliadin peptide ( dGP) B-cell epitopes. Measurement of anti- dGP IgG titre by ELISA discriminated between NRCD and responsive CD patients with 87% sensitivity and 89% specificity. Importantly, dGP antibody titre correlated with the severity of mucosal damage indicating that IgG dGP titres may be useful to monitor small intestinal mucosal recovery on a GFD. Conclusions The finding of increased levels of anti- dGP IgG antibodies in CD patients on strict GFDs effectively identifies patients with NRCD. Finally, anti- dGP IgG assays may be useful to monitor mucosal damage and histological improvement in CD patients on a strict GFD. [ABSTRACT FROM AUTHOR]

Background Accelerated progression of atherosclerosis and increased cardiovascular risk have been described in immune-mediated disorders, but few data are available in coeliac disease. Aim To evaluate instrumental and biochemical signs of atherosclerosis risk in 20 adults at first diagnosis of coeliac disease and after 6-8 months of gluten-free diet with mucosal recovery. Methods We analysed total, high-density lipoprotein ( HDL) and low-density lipoprotein ( LDL) cholesterol, triglycerides, homocysteine, C-reactive protein, folate and vitamin B12; ultrasound measurement of carotid intima-media thickness (IMT) and endothelium-dependent dilatation were both carried on at diagnosis and after gluten withdrawal. Twenty-two healthy members of the hospital staff served as matched controls for vascular examinations. Results At baseline, mean total and HDL-cholesterol (HDL-C) were both within normal range, while mean LDL-cholesterol concentration was slightly increased; diet was associated with an increment in total and HDL-C (68.2 ± 17.4 vs. 51.4 ± 18.6 mg/dL; P < 0.001) and a significant improvement in total/ HDL-C ratio (3.05 ± 0.71 vs. 3.77 ± 0.92; P < 0.02). Mean plasma homocysteine was elevated and not influenced by diet. C-reactive protein significantly decreased with diet (1.073 ± 0.51 vs. 1.92 ± 1.38 mg/dL; P < 0.05). At baseline, in coeliacs, IMT was increased (0.082 ± 0.011 vs. 0.058 ± 0.012 cm; P < 0.005), while endothelium-dependent dilatation was decreased (9.3 ± 1.3 vs. 11.2 ± 1.2%; P < 0.05). Both parameters improved after gluten abstinence. Conclusions Adults with coeliac disease seem to be at potentially increased risk of early atherosclerosis as suggested by vascular impairment and unfavourable biochemical risk pattern. Chronic inflammation might play a determining role. Gluten abstinence with mucosal normalisation reverts to normal the observed alterations. [ABSTRACT FROM AUTHOR]

Background Enterocyte damage is the hallmark of coeliac disease ( CD) resulting in malabsorption. Little is known about the recovery of enterocyte damage and its clinical consequences. Serum intestinal fatty acid binding protein (I- FABP) is a sensitive marker to study enterocyte damage. Aims To evaluate the severity of enterocyte damage in adult-onset CD and its course upon a gluten-free diet ( GFD). Furthermore, the correlation among enterocyte damage, CD autoantibodies and histological abnormalities during the course of disease is studied. Methods Serum I- FABP levels were determined in 96 biopsy-proven adult CD patients and in 69 patients repeatedly upon a GFD. A total of 141 individuals with normal antitissue transglutaminase antibody ( IgA- tTG) levels served as controls. I- FABP levels were related to the degree of villous atrophy (Marsh grade) and IgA- tTG. Results I- FABP levels were elevated in untreated CD (median 691 pg/mL) compared with controls (median 178 pg/mL, P < 0.001) and correlated with Marsh grade ( r = 0.265, P < 0.05) and IgA- tTG ( r = 0.403, P < 0.01). Upon a GFD serum levels decreased significantly, however, not within the range observed in controls, despite the common observed normalisation of IgA- tTG levels and Marsh grade. CD patients with elevated I- FABP levels nonresponding to GFD showed persistent histological abnormalities. Conclusions Enterocyte damage assessed by serum I- FABP correlates with the severity of villous atrophy in coeliac disease at the time of diagnosis. Although enterocyte damage improves upon treatment, substantial enterocyte damage persists despite absence of villous atrophy and low IgA- tTG levels in the majority of cases. Elevated I- FABP levels nonresponding to gluten-free diet are indicative of histological abnormalities and warrant further evaluation. [ABSTRACT FROM AUTHOR]

Background Coeliac disease, an autoimmune disorder triggered by gluten ingestion, is managed by a gluten-free diet ( GFD), which is difficult for many patients. Larazotide acetate is a first-in-class oral peptide that prevents tight junction opening, and may reduce gluten uptake and associated sequelae. Aim To evaluate the efficacy and tolerability of larazotide acetate during gluten challenge. Methods This exploratory, double-blind, randomised, placebo-controlled study included 184 patients maintaining a GFD before and during the study. After a GFD run-in, patients were randomised to larazotide acetate (1, 4, or 8 mg three times daily) or placebo and received 2.7 grams of gluten daily for 6 weeks. Outcomes included an experimental biomarker of intestinal permeability, the lactulose-to-mannitol ( LAMA) ratio and clinical symptoms assessed by Gastrointestinal Symptom Rating Scale ( GSRS) and anti-transglutaminase antibody levels. Results No significant differences in LAMA ratios were observed between larazotide acetate and placebo groups. Larazotide acetate 1-mg limited gluten-induced symptoms measured by GSRS ( P = 0.002 vs. placebo). Mean ratio of anti-tissue transglutaminase IgA levels over baseline was 19.0 in the placebo group compared with 5.78 ( P = 0.010), 3.88 ( P = 0.005) and 7.72 ( P = 0.025) in the larazotide acetate 1-, 4-, and 8-mg groups, respectively. Adverse event rates were similar between larazotide acetate and placebo groups. Conclusions Larazotide acetate reduced gluten-induced immune reactivity and symptoms in patients with coeliac disease undergoing gluten challenge and was generally well tolerated; however, no significant difference in LAMA ratios between larazotide acetate and placebo was observed. Results and design of this exploratory study can inform the design of future studies of pharmacological interventions in patients with coeliac disease. [ABSTRACT FROM AUTHOR]

Summary Background Coeliac disease is managed by life-long gluten withdrawal from the diet. However, strict adherence to a gluten-free diet is difficult and is not always effective. Novel therapeutic approaches are needed to supplement or even replace the dietary treatment. Aim To review recent advances in new therapeutic options for coeliac disease. Methods A literature search was performed on MEDLINE, EMBASE, Web of Science, Scopus, and for English articles and abstracts. The search terms used included, but not limited to, 'Celiac disease', 'new', 'novel', 'Advances', 'alternatives' and 'Drug therapy'. The cited articles were selected based on the relevancy to the review objective. Results Several new therapeutic approaches for coeliac disease are currently under development by targeting its underlying pathogenesis. Alternative therapies range from reproduction of harmless wheat strains to immunomodulatory approaches. Some of these therapies such as enzymatic cleavage of gluten and permeability inhibitors have shown promise in clinical studies. Conclusions Gluten-free diet is still the only practical treatment for patients with coeliac disease. Novel strategies provide promise of alternative adjunctive approaches to diet restriction alone for patients with this disorder. [ABSTRACT FROM AUTHOR]

Summary Background Coeliac disease is increasingly diagnosed and weight changes are common after adoption of a gluten-free diet ( GFD), however data on body mass index ( BMI) changes are limited. Aim To assess changes in BMI after diagnosis in a large coeliac population. Methods A total of 1018 patients with biopsy confirmed coeliac disease seen at our centre were studied retrospectively. Initial and follow-up BMIs were recorded, as was GFD adherence as assessed by an expert dietitian. Results A total of 679 patients with at least two recorded BMIs and GFD adherence data were included in the study. Mean follow-up was 39.5 months. Compared to regional population data, the coeliac cohort was significantly less likely to be overweight or obese (32% vs. 59%, P < 0.0001). Mean BMI increased significantly after GFD initiation (24.0 to 24.6; P < 0.001). 21.8% of patients with normal or high BMI at study entry increased their BMI by more than two points. Conclusions Individuals with coeliac disease have lower BMI than the regional population at diagnosis. BMI increases on the GFD, especially in those that adhere closely to the GFD. On the GFD, 15.8% of patients move from a normal or low BMI class into an overweight BMI class, and 22% of patients overweight at diagnosis gain weight. These results indicate that weight maintenance counselling should be an integral part of coeliac dietary education. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 2011; 34: 783-789 Summary Background An association between coeliac disease (CD) and functional gastrointestinal disorders (FGIDs) has at present only been demonstrated in adults. Aims To assess the prevalence of FGIDs at 1 year and the role of psychological aspects on the development of FGIDs in CD children. Methods One-hundred consecutive CD children (36M and 64F) were followed up for 1 year. Fifty-six children (25M and 31F) represented the control group. All children and/or their parents completed validated questionnaires for GI symptoms, depression, and anxiety. GI symptoms at diagnosis and after 1 year of gluten-free diet (GFD) were compared. Results Twenty-three/82 (28%) CD patients followed up prospectively, on GFD from at least 1 year, fulfilled the Rome III criteria for FGIDs compared with 5/56 (8.9%) controls ( P = 0.008; χ2 = 6.8; OR: 3.97; 95% CI: 1.40-11.21). Children complaining with GI symptoms alone [21/52 (40.3%)] more likely fulfilled Rome III criteria for FGIDs after 1 year of GFD than children with extra-intestinal symptoms ( P = 0.045). CD children with FGDIs presented significantly higher anxiety and depression compared to CD children without FGIDs and controls ( P = 0.02). Conclusions This study demonstrates that children with CD on a GFD for a year have a much higher prevalence of functional GI symptoms than do controls. Whether the risk is due to the residua of a chronic inflammatory process, and/or due to psychological factors remains to be further tested. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 2010; 32: 1031-1036 Summary Background Coeliac disease is a chronic disease with a various clinical presentation, including anxiety and depression. Aim To investigate the quality of sleep in coeliac disease. Methods The participants were coeliacs at diagnosis; coeliacs on a gluten-free diet at follow-up and healthy volunteers. Participants completed the Pittsburgh Sleep Quality Index (PSQI), SF36, Zung and Fatigue scales and State-Trait Anxiety Inventory (STAI). Results The PSQI score was higher in coeliacs at diagnosis and in a gluten-free diet than in healthy volunteers ( P < 0.001). A gluten-free diet did not improve the PSQI score ( P = 0.245) in coeliac disease. The other test scores were similar between coeliacs at diagnosis and those on a gluten-free diet, whereas significant differences were found between coeliacs and volunteers. PSQI score was inversely associated with the quality of the physical ( r = −0.327, P = 0.002) and mental ( r = −0.455, P < 0.001) component scores. The sleep quality scores were related to depression ( r = 0.633, P < 0.001), fatigue ( r = 0.377, P < 0.001), state anxiety ( r = 0.484, P < 0.001) and trait anxiety ( r = 0.467, P < 0.001). Conclusions Sleep disorders are common in coeliac disease not only at diagnosis but also during treatment with a gluten-free diet. Sleep disorders are related to depression, anxiety and fatigue, and inversely related to quality of life scale scores. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 2010; 32: 573–581 Background The only therapy for coeliac disease (CD) is a long-term gluten-free diet (GFD). Little is known about the detailed composition of such a diet. Aim To clarify the nutritional composition of a GFD and to compare it with a non-GFD diet in representative non-CD populations. Methods A total of 139 consecutive patients with CD were invited to fill in a prospective validated 5-day food diary, of whom data from 93 were analysed. Results were compared with data from the National Diet and Nutrition Survey of Adults and the UK Women’s Cohort Study (UKWCS). Results Individuals consuming a strict GFD generally had similar intakes of energy and nutrients to those of comparison populations, but a higher proportion of carbohydrate intake was obtained from nonmilk extrinsic sugars and intakes of nonstarch polysaccharides were low. Compared with the UKWCS sample, female patients adhering to a GFD had lower intakes of magnesium, iron, zinc, manganese, selenium and folate. In male patients, intakes of magnesium and selenium were particularly low. Conclusions This study reinforces the need for clinicians to recognize that avoidance of gluten cannot be the sole focus of a gluten-free diet. Maintenance of adequate intakes of essential nutrients and in particular complex carbohydrates must also be the goal for patients. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 31, 901–910 Background Coeliac disease is frequently diagnosed after a long delay resulting in increased morbidity and mortality. Aims To define the parameters which have the highest impact on the cost-effectiveness of mass screening for coeliac disease. Methods A Markov model examined a coeliac disease screening programme of the healthy young-adult general population compared with a no-screening strategy. The main outcome measures were quality adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER). Effects of variables were examined using sensitivity analyses. Results The screening strategy resulted in a gain of 0.0027 QALYs. The ICER of screening vs. no-screening strategy was US$48 960/QALYs. The variables with the largest impact on cost effectiveness were: the time delay from symptom onset to diagnosis, the utility of adherence to a gluten-free diet (GFD) and the prevalence of coeliac disease. Screening would be cost-effective if the time delay to diagnosis is longer than 6 years and utility of GFD adherence is greater than 0.978. Conclusions Our model suggests that mass screening for coeliac disease of the young-adult general population is associated with improved QALYs and is a cost effectiveness strategy. Shortening of the time-delay to diagnosis by heightened awareness of health-care professionals may be a valid alternative to screening. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 31, 666–675 Background Previous studies on coeliac disease (CD)-related quality of life (QOL) have been limited by their use of a ‘generic’ rather than coeliac disease-specific assessment instruments. Aim To develop and psychometrically validate a new coeliac disease-specific instrument, the CD-QOL. Methods Through a series of focus groups, we elicited items from patients that related to the specific nature of their disease and its impact on their basic needs. Through expert review, cognitive debriefing with patients and pilot testing, a scale was developed, refined and administered to 387 patients on a gluten-free diet from both community-based support groups and a tertiary care referral centre. Finally, a formal validation study was conducted to assess the psychometric properties of the CD-QOL. Results The final CD-QOL has 20 items across four clinically relevant subscales (Limitations, Dysphoria, Health Concerns, and Inadequate Treatment). The CD-QOL has high internal consistency, reliability, and psychometric validation indicates both convergent and discriminate validity. Conclusions The CD-QOL is a reliable and valid measure of coeliac disease related QOL. As a new disease-specific instrument, it is likely to be a useful tool for evaluating patients with this disorder. [ABSTRACT FROM AUTHOR]

Background Coeliac disease is increasingly diagnosed in adult patients who present with atypical symptoms or who are asymptomatic and detected by case screening. Its treatment, a gluten-free diet, can have a considerable impact on daily living. Understanding the factors associated with non-adherence is important in terms of supporting patients with their condition. Aim To investigate factors associated with adherence to a gluten-free diet in adults with coeliac disease. Methods A literature search of multiple electronic databases using a pre-determined search string for literature between 1980 and November 2007 identified a possible 611 hits. After checking for relevance, 38 studies were included in this review. Results Rates for strict adherence range from 42% to 91% depending on definition and method of assessment and are the lowest among ethnic minorities and those diagnosed in childhood. Adherence is most strongly associated with cognitive, emotional and socio-cultural influences, membership of an advocacy group and regular dietetic follow-up. Screen and symptom-detected coeliac patients do not differ in their adherence to a gluten-free diet. Conclusions The existing evidence for factors associated with non-adherence to a gluten-free diet is of variable quality. Further and more rigorous research is needed to characterize those individuals most likely to be non-adherent to assist them better with their treatment. [ABSTRACT FROM AUTHOR]

Background Expected benefits of gluten-free diet (GFD) in coeliac patients include healing of small intestinal mucosa, but it remains unclear to what extent this benefit is achieved in adults. Aim To assess factors affecting histological outcome of GFD in a large cohort of adult coeliac patients. Methods We extracted information on 465 consecutive coeliac patients studied before and during GFD. Results Duodenal biopsies at diagnosis were classified as Marsh I in 11, II in 25 and III in 429 cases. After a median 16 months GFD, 38 (8%) patients had histological ‘normalization’, 300 (65%) had ‘remission’ with persistent intraepithelial lymphocytosis, 121(26%) had ‘no change’ and 6 (1%) had ‘deterioration’. Coeliac disease related serology was negative in 83% of patients with Marsh III lesion during GFD. Male gender and adherence to GFD were independently associated with histological ‘normalization’ and ‘remission’. Persistence of intraepithelial lymphocytosis was not associated with human lymphocyte antigen gene dose or with Helicobacter pylori infection. Conclusions Complete normalization of duodenal lesions is exceptionally rare in adult coeliac patients despite adherence to GFD, symptoms disappearance and negative CD related serology. Control biopsies are mandatory to identify lack of response to gluten-free diet. [ABSTRACT FROM AUTHOR]

Background While gluten-free diet is an effective treatment for coeliac disease, the need for and goals of long-term management of patients are poorly defined. Aim To review systematically the complications and associations of coeliac disease, to identify potential risk factors, to define ways of assessing risk factors and to provide a strategy for management. Methods Review of medical literature from 1975. Results There is an increasing list of potential complications and/or conditions associated with coeliac disease, in particular, autoimmune disease, malignancy and bone disease. Risk factors that may predict or influence long-term outcomes include genetic susceptibility, environmental factors predominantly gluten ingestion, persistent small intestinal inflammation/injury and nutritional deficiencies. Genotyping of patients is yet to have an established clinical role in long-term management. Assessment of adherence to the gluten-free diet largely relies upon skilled dietary history, but the ultimate test is duodenal histopathology, which is the only currently established means of assessing healing. Symptoms, serology or other non-invasive means are poor predictors of healing and the likelihood of complications. Conclusion Evidence (albeit limited) that adherence to a gluten-free diet and mucosal healing prevent and/or ameliorate complications indicates that a planned long-term strategy for follow-up is essential. [ABSTRACT FROM AUTHOR]

Background Increasing numbers of individuals are now being diagnosed with coeliac disease. The only accepted treatment for coeliac disease is lifelong adherence to a strict gluten-free diet (GFD). Individuals’ ability to adhere to the GFD varies, but systematic studies guiding the assessment of adherence are currently lacking. Aim We sought to compare the predictive value of self-report and four serologic tests compared to expert nutritionist evaluation. Methods In all, 154 individual adults with biopsy-proven coeliac disease rated their adherence to the GFD on a Likert scale. Serum antibody titres of IgA anti-tissue transglutaminase, and IgA and IgG anti-deamidated gliadin peptides were determined. Using anova and ROC analyses, results were compared to a standardized evaluation by an expert nutritionist blinded to the participants’ self-rated adherence and serology results. Results All serologic measures as well as participant reported adherence were significantly associated with GFD adherence as assessed by expert nutritionist evaluation. However, on ROC analysis no measure performed satisfactorily. The performance of serologic testing, but not self-report, improved with increased time on the GFD. Conclusion Although current serologic tests have very high sensitivities and specificities for the diagnosis of coeliac disease, they cannot replace trained nutritionist evaluation in the assessment of GFD adherence. [ABSTRACT FROM AUTHOR]

Background Lifelong adherence to a strict gluten-free diet is the cornerstone of coeliac disease treatment. Elucidation of disease pathogenesis has created opportunities for novel therapeutic approaches to coeliac disease. AT-1001 is an inhibitor of paracellular permeability whose structure is derived from a protein secreted by Vibrio cholerae. Aim To determine the safety and tolerability of 12 mg doses of AT-1001 in coeliac disease subjects challenged with gluten. Methods An in-patient, double-blind, randomized placebo-controlled safety study utilizing intestinal permeability, measured via fractional excretions of lactulose and mannitol, as an exploratory measure of drug efficacy. Results Compared to placebo, no increase in adverse events occurred in patients exposed to AT-1001. Following acute gluten exposure, a 70% increase in intestinal permeability was detected in the placebo group, while none was seen in the AT-1001 group. Interferon-γ levels increased in four of seven patients (57%) of the placebo group, but only in four of 14 patients (29%) of the AT-1001 group. Gastrointestinal symptoms were more frequently detected in the placebo group when compared to the AT-1001 group ( P = 0.018). Conclusions AT-1001 is well tolerated and appears to reduce intestinal barrier dysfunction, proinflammatory cytokine production, and gastrointestinal symptoms in coeliacs after gluten exposure. [ABSTRACT FROM AUTHOR]

Background Data available on predictors of reduced health-related quality of life in coeliac disease are not consistent. Aim To test predictors of reduced health-related quality of life, described in the literature, by a multivariate approach. Methods 1000 adult coeliacs of the German Coeliac Society completed a medical and a sociodemographic questionnaire, the Short-Form Health Survey (SF-36), the Coeliac Disease Questionnaire and the Hospital Anxiety and Depression Scale within a postal survey. Predictors of reduced health-related quality of life were tested for by logistic regression analysis. Results Physical comorbidities ( β = −0.41; OR = 0.66, P < 0.001) and mental disorder ( β = 0.88; OR = 2.4, P = 0.03) were associated with a reduced physical summary score of the SF-36. Mental disorder ( β = 2.5; OR = 11.9, P < 0.001), physical comorbidities ( β = −0.26; OR = 0.77, P = 0.004) and younger age at diagnosis ( β = −0.10; OR = 0.91, P = 0.05) predicted a reduced mental summary score of the SF-36. Mental disorder ( β = 0.90; OR = 2.5, P = 0.03), non-compliance with gluten-free diet ( β = 0.44; OR = 1.6, P = 0.009), active medical comorbidities ( β = −0.28; OR = 0.76, P = 0.007) and dissatisfaction with doctor–patient communication ( β = 0.55; OR = 1.7, P = 0.03) were associated with reduced Coeliac Disease Questionnaire scores. Conclusions Reduced health-related quality of life in coeliac disease is associated not only with physical and mental comorbidities, but also with non-compliance with gluten-free diet and dissatisfaction with doctor–patient communication. [ABSTRACT FROM AUTHOR]

Background Patients with coeliac disease may have diarrhoea despite being on a gluten-free diet. Aim To assess whether exocrine pancreatic insufficiency causes persisting symptoms compared with controls, we determined whether pancreatic enzyme supplementation provided symptomatic benefit in coeliac patients with chronic diarrhoea. Methods Patients ( n = 259) were subdivided into four groups: (a) new coeliac disease ( n = 57), (b) coeliac disease patients on a gluten-free diet without gastrointestinal symptoms ( n = 86), (c) coeliac disease patients on a gluten-free diet with chronic diarrhoea ( n = 66) and (d) patients with chronic diarrhoea without coeliac disease ( n = 50). Stool frequency and weight, before and after treatment with pancreatic enzyme supplementation were recorded. Results The prevalence of a low faecal elastase-1 within the groups was: group (A) six of 57 (11%), group (B) five of 86 (6%), group (C) 20 of 66 (30%) and group (D) two of 50 (4%). Low faecal elastase-1 was more frequent in coeliac disease patients with chronic diarrhoea vs. other subgroups of coeliac disease ( P ≤ 0.0001) and controls ( P ≤ 0.0003). In 18 of 20 stool frequency reduced following pancreatic enzyme supplementation from four per day to one ( P ≤ 0.001). No weight increase ( P = 0.3) was observed. Conclusions Low faecal elastase is common in patients with coeliac disease and chronic diarrhoea, suggesting exocrine pancreatic insufficiency. In this group of patients, pancreatic enzyme supplementation may provide symptomatic benefit. [ABSTRACT FROM AUTHOR]

LINKED CONTENT This article is linked to Wang et al and Rej et al papers. To view these articles, visit https://doi.org/10.1111/apt.15419 and https://doi.org/10.1111/apt.15517. [ABSTRACT FROM AUTHOR]