Randomised clinical trial: adjunctive induction therapy with oral effervescent budesonide in newly diagnosed coeliac disease.

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.

Effect of Gluten Ingestion and FODMAP Restriction on Intestinal Epithelial Integrity in Patients with Irritable Bowel Syndrome and Self-Reported Non-Coeliac Gluten Sensitivity.

SCOPE: Since epithelial barrier dysfunction has been associated with gluten and fermentable oligosaccharide, disaccharide, monosaccharide, and polyols (FODMAPs), the effect of alterations in FODMAP a gluten intake on epithelial barrier function in patients with irritable bowel syndrome (IBS) who self-reported gluten sensitivity. METHODS AND RESULTS: Circulating concentrations of markers of epithelial injury (syndecan-1 and intestinal fatty acid-binding protein) and bacterial translocation (lipopolysaccharide-binding protein and soluble CD14) are measured while consuming habitual gluten-free diet and during blinded challenges with gluten or placebo on a background of low FODMAP intake. In 33 patients, only syndecan-1 concentrations during their habitual diet are elevated (median 43 ng mL-1 ) compared with 23 ng mL-1 in 49 healthy subjects (p < 0.001). On a low FODMAP diet, symptoms are reduced and levels of syndecan-1 (but not other markers) fell by a median 3335% (p < 0.001) irrespective of whether gluten is present or not. CONCLUSION: Gluten ingestion has no specific effect on epithelial integrity or symptoms in this cohort, but reducing FODMAP intake concomitantly reduces symptoms and reverses apparent colonic epithelial injury. These findings highlight the heterogeneity of populations self-reporting gluten sensitivity and implicate FODMAPs in colonic injury in IBS.

Acute medical stabilisation of adults with anorexia nervosa: experience of a defined interdisciplinary model of care.

BACKGROUND: Patients with anorexia nervosa (AN) are vulnerable to physiological decompensation and often require inpatient management by an eating disorders unit. AIMS: Patients admitted to an Australian tertiary medical centre for medical stabilisation of AN were assessed as part of quality assurance. Analysis included: (i) medical complications during acute inpatient stabilisation; (ii) predictors of refeeding syndrome; (iii) predictors governing length of stay (LOS); and (iv) outcomes pre- and post-implementation of multidisciplinary treatment guidelines. METHODS: A retrosepctive analysis of 95 consecutive admissions (60 individual patients) between November 2011 and August 2017 was performed. RESULTS: Patients had a median LOS of 9.6 days (interquartile range 5.8-19.7) and a mean weight gain of 1.4 kg (standard deviation 2.9). Medical complications included the following: hypoglycaemia (11.6%) and refeeding electrolyte derangement (26.3%). Advancing age (odds ratio (OR) 1.06 per year, P = 0.019), nasogastric tube requirement (OR 3.4, P = 0.014) and Code Grey(s) (security calls) (OR 7.1, P = 0.010) were associated with refeeding electrolyte derangement. Parameters associated with increased LOS included the following: lower body mass index (P = 0.029), Code Grey(s) (P = 0.029) and tachycardia (P = 0.013). Following multivariate analysis, the post-guidelines implementation group required less intravenous fluid and electrolyte replacement, though had lower rates of refeeding electrolyte derangement (OR 0.33 (0.11-0.99)). CONCLUSION: Patients with moderate to severe AN are at risk of dangerous medical complications, and older patients may have heightened predisposition to refeeding electrolyte derangement. Early identification of medically high-risk patients is imperative to implement timely, life-saving interventions.

Investigational drug therapies for coeliac disease - where to from here?

INTRODUCTION: Despite decades of research and a detailed knowledge of the immunopathological basis of coeliac disease (CD), adherence to a lifelong gluten-free diet (GFD) remains the single proven and available treatment. The increasing prevalence of CD combined with variable adherence to the GFD in a significant proportion of patients demands new therapeutic strategies. AREAS COVERED: Trial registries, clinicaltrials.gov, pharmaceutical company website searches as well as published data from PubMed and conference proceedings were used to extract the most recent outcomes for CD therapeutics. This article aims to review the available therapies from a pathophysiological approach, and propose future directions in this interesting yet largely unfulfilled area of research. EXPERT OPINION: Increasingly, the GFD is being challenged by its availability, palatability, practicality and now even efficacy in some populations. Whilst the causative antigens have been well described, it is clear that treatment based on the removal of these immunostimulatory peptides from the diet is far more complex than early experience in CD treatment implied. Despite burgeoning interest and research in experimental therapies for CD over the past twenty years, the only therapy showing promise as a true alternative to a GFD is that of the induction of tolerance via a vaccine.

Coeliac disease in the 21st century: paradigm shifts in the modern age.

The epidemiology of coeliac disease (CD) is changing. Presentation of CD with malabsorptive symptoms or malnutrition is now the exception rather than the rule and, it now affects those underweight and overweight equally. In concert with these epidemiological shifts, the incidence of CD is increasing. These changing patterns of disease presentation are challenging traditional management paradigms, and clinicians now need to adapt to these changes and respond to the demands of an increasingly well-informed consumer population. This article aims to provide historical context to the epidemiological changes in CD, which provides context to direct future research. Changing definitions and diagnostic paradigms are complicating the management of CD. The gold standard of diagnosis, treatment goals, guidelines for follow-up, and the role of population screening in CD remain controversial and unresolved. Although the patient population is interested in new treatments for CD and alternatives to a gluten-free diet, most therapies are not yet widely available or sufficiently researched, and our understanding of the natural history of CD is limited despite a number of retrospective and population-based studies. The management of asymptomatic CD has only recently been examined despite up to half of patients now presenting with no or minimal symptoms. There is surprisingly little evidence to resolve many of these issues, and only with robust prospective studies will our understanding of the true natural history of coeliac disease be clarified.

Adherence to the gluten-free diet can achieve the therapeutic goals in almost all patients with coeliac disease: A 5-year longitudinal study from diagnosis.

BACKGROUND: Key aims of treatment of coeliac disease are to heal the intestinal mucosa and correct nutritional abnormalities. AIM: We aim to determine prospectively the degree of success and time course of achieving those goals with a gluten-free diet. METHODS: Ninety-nine patients were enrolled at diagnosis and taught the diet. The first 52 were reassessed at 1 year and 46 at 5 years, 25 being assessed at the three time points regarding dietary compliance (dietitian-assessed), coeliac serology, bone mineral density and body composition analysis by dual energy X-ray absorptiometry, and intestinal histology. RESULTS: Mean age (range) was 40 (18-71) years and 48 (76%) were female. Dietary compliance was very good to excellent in all but one. Tissue transglutaminase IgA was persistently elevated in 44% at 1 year and 30% at 5 years and were poorly predictive of mucosal disease. Rates of mucosal remission (Marsh 0) and response (Marsh 0/1) were 37% and 54%, and 50% and 85% at 1 and 5 years, respectively. Fat mass increased significantly over the first year in those with normal/reduced body mass index. Lean body mass indices more slowly improved irrespective of status at diagnosis with significant improvement at 5 years. Bone mass increased only in those with osteopenia or osteoporosis, mostly in year 1. CONCLUSION: Dietary compliance is associated with a high chance of healing the intestinal lesion and correction of specific body compositional abnormalities. The time course differed with body fat improving within 1 year, and correction of the mucosal lesion and improvement in lean mass and bone mass taking longer.

Other Dietary Confounders: FODMAPS et al.

BACKGROUND: While it is well documented and widely appreciated that ingestion of wheat (and less so rye and barley) is associated with gastrointestinal symptoms such as bloating or abdominal pain, the component of wheat to which such an effect is attributed is less well established. KEY MESSAGES: Wheat is a complex of proteins (80% gluten, 20% metabolic proteins), carbohydrates (starch, non-starch polysaccharides, fructans), lipids and other components. The majority of attention has focused on gluten as the culprit in triggering symptoms, but re-challenge studies have nearly all used wheat flour-related products (such as bread) as the stimulus. When carbohydrate-deplete gluten was used as the challenge agent, gluten-specific feelings of depression and not gut symptoms were observed in those who fulfilled strict criteria of 'non-coeliac gluten sensitivity', thereby underlining the complexity of cereals and of undertaking research in this area. Candidate components other than gluten include poorly absorbed oligosaccharides (mainly fructans), non-gluten wheat proteins such as amylase-trypsin inhibitors or wheat germ agglutinin, and exorphins released during the digestion of gluten. Specific biological and/or clinical effects associated with gluten-free diets or wheat ingestion need to be carefully dissected before attribution to gluten can be claimed. CONCLUSIONS: Currently, coeliac disease is the only common condition that has been unequivocally linked to gluten. Inaccurate attribution will be associated with suboptimal therapeutic advice and at least partly underlies the current gluten-free epidemic gripping the Western world.

Characterization of Adults With a Self-Diagnosis of Nonceliac Gluten Sensitivity.

Background: Nonceliac gluten sensitivity (NCGS), occurring in patients without celiac disease yet whose gastrointestinal symptoms improve on a gluten-free diet (GFD), is largely a self-reported diagnosis and would appear to be very common. The aims of this study were to characterize patients who believe they have NCGS. Materials and Methods: Advertising was directed toward adults who believed they had NCGS and were willing to participate in a clinical trial. Respondents were asked to complete a questionnaire about symptoms, diet, and celiac investigation. Results: Of 248 respondents, 147 completed the survey. Mean age was 43.5 years, and 130 were women. Seventy-two percent did not meet the description of NCGS due to inadequate exclusion of celiac disease (62%), uncontrolled symptoms despite gluten restriction (24%), and not following a GFD (27%), alone or in combination. The GFD was self-initiated in 44% of respondents; in other respondents it was prescribed by alternative health professionals (21%), dietitians (19%), and general practitioners (16%). No celiac investigations had been performed in 15% of respondents. Of 75 respondents who had duodenal biopsies, 29% had no or inadequate gluten intake at the time of endoscopy. Inadequate celiac investigation was common if the GFD was initiated by self (69%), alternative health professionals (70%), general practitioners (46%), or dietitians (43%). In 40 respondents who fulfilled the criteria for NCGS, their knowledge of and adherence to the GFD were excellent, and 65% identified other food intolerances. Conclusions: Just over 1 in 4 respondents self-reporting as NCGS fulfill criteria for its diagnosis. Initiation of a GFD without adequate exclusion of celiac disease is common. In 1 of 4 respondents, symptoms are poorly controlled despite gluten avoidance.

No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates.

BACKGROUND & AIMS: Patients with non-celiac gluten sensitivity (NCGS) do not have celiac disease but their symptoms improve when they are placed on gluten-free diets. We investigated the specific effects of gluten after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates (fermentable, oligo-, di-, monosaccharides, and polyols [FODMAPs]) in subjects believed to have NCGS. METHODS: We performed a double-blind cross-over trial of 37 subjects (aged 24-61 y, 6 men) with NCGS and irritable bowel syndrome (based on Rome III criteria), but not celiac disease. Participants were randomly assigned to groups given a 2-week diet of reduced FODMAPs, and were then placed on high-gluten (16 g gluten/d), low-gluten (2 g gluten/d and 14 g whey protein/d), or control (16 g whey protein/d) diets for 1 week, followed by a washout period of at least 2 weeks. We assessed serum and fecal markers of intestinal inflammation/injury and immune activation, and indices of fatigue. Twenty-two participants then crossed over to groups given gluten (16 g/d), whey (16 g/d), or control (no additional protein) diets for 3 days. Symptoms were evaluated by visual analogue scales. RESULTS: In all participants, gastrointestinal symptoms consistently and significantly improved during reduced FODMAP intake, but significantly worsened to a similar degree when their diets included gluten or whey protein. Gluten-specific effects were observed in only 8% of participants. There were no diet-specific changes in any biomarker. During the 3-day rechallenge, participants' symptoms increased by similar levels among groups. Gluten-specific gastrointestinal effects were not reproduced. An order effect was observed. CONCLUSIONS: In a placebo-controlled, cross-over rechallenge study, we found no evidence of specific or dose-dependent effects of gluten in patients with NCGS placed diets low in FODMAPs.

Does gluten cause gastrointestinal symptoms in subjects without coeliac disease?

AIM: To determine the evidence for the effect of gluten ingestion on gastrointestinal symptoms, intestinal permeability and other indices of small intestinal injury in non-coeliac, gluten intolerant individuals. METHODS: A literature review was performed searching for interventional studies that addressed the issue. RESULTS: One unblinded study that identified symptomatic response to gluten did not effectively exclude patients with coeliac disease, since many had intraepithelial lymphocytosis. A double-blinded, randomised, placebo-controlled rechallenge trial was recently reported in patients in whom coeliac disease had been excluded by either normal duodenal histology on a gluten containing diet, or absence of the HLA DQ2 or DQ8 haplotype (56%). Participants were randomly assigned to receive either 16 g/day carbohydrate-free gluten or placebo for six weeks. Participants were enrolled if they had gastrointestinal symptoms that had improved on a GFD and had been on a gluten free diet for at least 6 weeks prior to enrollment. 19 received gluten and 15 received placebo. Change between baseline and final weeks were greater for patients receiving gluten in overall symptom severity compared with those receiving placebo (p=0.047). and were worse with gluten within one week for pain (p=0.016), bloating (p=0.031), satisfaction with stool consistency (p=0.024), and tiredness (p=0.001). Mechanisms for symptom induction were not identified. CONCLUSIONS: Non-coeliac gluten intolerance does exist. Future studies need to identify issues of the dose of gluten needed and mechanisms of action.

Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial.

OBJECTIVES: Despite increased prescription of a gluten-free diet for gastrointestinal symptoms in individuals who do not have celiac disease, there is minimal evidence that suggests that gluten is a trigger. The aims of this study were to determine whether gluten ingestion can induce symptoms in non-celiac individuals and to examine the mechanism. METHODS: A double-blind, randomized, placebo-controlled rechallenge trial was undertaken in patients with irritable bowel syndrome in whom celiac disease was excluded and who were symptomatically controlled on a gluten-free diet. Participants received either gluten or placebo in the form of two bread slices plus one muffin per day with a gluten-free diet for up to 6 weeks. Symptoms were evaluated using a visual analog scale and markers of intestinal inflammation, injury, and immune activation were monitored. RESULTS: A total of 34 patients (aged 29-59 years, 4 men) completed the study as per protocol. Overall, 56% had human leukocyte antigen (HLA)-DQ2 and/or HLA-DQ8. Adherence to diet and supplements was very high. Of 19 patients (68%) in the gluten group, 13 reported that symptoms were not adequately controlled compared with 6 of 15 (40%) on placebo (P=0.0001; generalized estimating equation). On a visual analog scale, patients were significantly worse with gluten within 1 week for overall symptoms (P=0.047), pain (P=0.016), bloating (P=0.031), satisfaction with stool consistency (P=0.024), and tiredness (P=0.001). Anti-gliadin antibodies were not induced. There were no significant changes in fecal lactoferrin, levels of celiac antibodies, highly sensitive C-reactive protein, or intestinal permeability. There were no differences in any end point in individuals with or without DQ2/DQ8. CONCLUSIONS: "Non-celiac gluten intolerance" may exist, but no clues to the mechanism were elucidated.

Thiopurines, a previously unrecognised cause for fatigue in patients with inflammatory bowel disease.

BACKGROUND: Active inflammatory bowel disease, anaemia, iron deficiency and depression, alone or in combination, are known contributing factors of fatigue in inflammatory bowel disease. However, in some patients, fatigue cannot be attributed to known causes. Thiopurines are not a recognized cause. AIM: To describe the clinical scenario of a series of patients where thiopurines were the likely cause of fatigue. METHOD: The clinical scenario of 5 patients was examined with specific reference to the temporal association of thiopurine therapy with fatigue, the effect of its withdrawal and rechallenge, and drug specificity. RESULTS: The onset of severe fatigue was related to the introduction of azathioprine or 6-mercaptopurine, rapid relief was experienced on its withdrawal in all patients, and fatigue rapidly occurred on rechallenge. The speed of onset was rapid in two patients and in the context of gradual withdrawal of moderate steroid dose, but recurred rapidly on rechallenge when not on steroids. CONCLUSIONS: Marked fatigue is a previously unrecognized adverse effect of thiopurines. It does not appear to be drug-specific. Its onset might be masked by concurrent steroid therapy.