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Introduction: Coeliac disease and dermatitis herpetiformis are immune-mediated diseases triggered by the consumption of gluten in genetically predisposed individuals. These guidelines were developed to provide general practitioners, paediatricians, gastroenterologists, and other clinicians with an overview on the diagnosis, management and follow-up of coeliac patients and those with dermatitis herpetiformis.Methods: Guidelines were developed by the Italian Societies of Gastroenterology. Following a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation methodol-ogy was used to assess the certainty of the evidence. Statements and recommendations were developed by working groups consisting of gastroenterologists and a paediatrician with expertise in this field.Results: These guidelines provide a practical guidance for the diagnosis, management and follow-up of coeliac patients and dermatitis herpetiformis in children and adults, both in primary care and in specialist settings. We developed four sections on diagnosis, gluten-free diet, follow-up and risk of complications in adults, one section focused on diagnosis and follow-up in children and one on the diagnosis and man-agement of dermatitis herpetiformis.Conclusions: These guidelines may support clinicians to improve the diagnosis and management of pa-tients with coeliac disease.(c) 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

The paper is the first attempt to integrate microdata on universities and firms across most European countries in order to disentangle the impact of knowledge spillovers from human capital (graduates) and intellectual capital (codified research output) on the performance of firms. Data cover all Higher Education Institutions (HEIs) registered in the official European Tertiary Education Register (ETER). Data on performance of firms are from ORBIS and refer to change in the 2011–2015 period in turnover, total assets, intangible assets, and employment. Firms are georeferred and the spillovers from all HEIs located at a given distance are summed and integrated. The findings suggest that, among knowledge spillovers, the creation of human capital via education of students has a larger impact than the circulation of research knowledge. Moreover, the two factors seem to be complements rather than substitutes. Spatial proximity is important for embodied knowledge spillovers (i.e. educated people), while for codified and disembodied spillovers (citations to publications) the spatial dimension is less relevant. The findings have important managerial and policy-making consequences.

Data on factors governing long-term adherence to a gluten-free diet (GFD) in celiac disease (CD) are scarce. We aimed to determine trends and clinical predictors of long-term GFD adherence in adult CD.Initial and long-term (3 years) GFD adherence, clinical characteristics at baseline and follow-up were collected retrospectively from celiac patients followed-up over 20 years (2000-2020). Predictors of long-term GFD adherence at diagnosis, and follow-up were evaluated by multivariate logistic regression.248 patients (37 ± 12 years, 186F, median time on a GFD 90 months) were included. Twenty-five (10.1%) had only short-term follow-up (3 years) while 223 (89.9%) had initial and long-term dietary assessment. 187/223 (83.9%) patients were initially adherent and 36/223 (16.1%) were not. 17/36 (47.2%) patients initially not adherent become adherent, while only 4/187 (2.1%) initially adherent patients became not adherent. In the long-term, 200/223 (89.7%) were adherent and 21/223 (9.4%) patients were not. Adherence improved more frequently than worsened (OR, 39.5; 95% CI, 11.4-178.5; P.01). Classical symptoms (diarrhea, weight loss) at diagnosis of CD predicted stricter long-term GFD adherence (OR, 3.27; 95% CI, 1.21-8.81; P = .02), while anemia (OR, 0.31; 95% CI, 0.12-0.82; P = .02) and dermatitis herpetiformis (OR, 0.23; 95% CI, 0.06-0.91; P = .04) predicted poorer long-term adherence. At follow-up, initial GFD adherence (OR, 42.70; 95% CI, 10.70-171.00; P = .04) was the major determinant of long-term GFD adherence.GFD adherence changes over time in10% of patients, generally improving when it does. Major determinants of long-term GFD adherence are classical symptoms at diagnosis and initial adherence to a GFD. Patients with anemia or dermatitis herpetiformis at diagnosis require stricter dietetic input.

Duodenal villous atrophy is due not only to coeliac disease and its complications but also to other rare enteropathies unrelated to gluten consumption, defined as noncoeliac enteropathies. The diagnosis of noncoeliac enteropathies remains challenging, and HLA typing has been widely used to exclude coeliac disease if DQ2 and DQ8 alleles are absent. However, the frequency of the various HLA alleles in noncoeliac enteropathies is still unknown.To describe the HLA genetic profile of patients affected by noncoeliac enteropathies who have been evaluated at our centres between 2000 and 2021, and to investigate the diagnostic role of HLA typing.Genomic DNA was collected from 44 Italian and 19 British adult patients with noncoeliac enteropathies. Patient genotypes were compared with those of healthy Italian and British populations obtained from HLA bone marrow donors' banks. In addition, genotypes were also compared with those of patients with coeliac disease and complicated coeliac disease.Both in the Italian and in the British group, the DQA1*0102 DQB1*0602 haplotype and related alleles occurred significantly more frequently in patients with noncoeliac enteropathies compared to coeliac disease and complicated coeliac disease.Together with negative HLA-DQ2 and DQ8 haplotypes, the DQA1*0102 DQB1*0602 haplotype can be used to guide the differential diagnosis between coeliac disease and noncoeliac enteropathies.

Data are lacking on the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients affected by coeliac disease, Whipple's disease and other noncoeliac enteropathies (NCE), characterised by primary or drug-related immunosuppression. We aimed to assess humoral response to SARS-CoV-2 vaccination in these patients compared to controls.Between December 2021 and January 2022, IgG anti-SARS-CoV-2 spike protein antibodies were measured in serum samples of coeliac disease, Whipple's disease and NCE patients attending our gastroenterology outpatient clinic for follow-up, who had received their first SARS-CoV-2 vaccination dose 3-6-9 (±1) months prior. Humoral response was compared with healthy controls (vaccinated healthcare workers undergoing serological screening), matched for gender, age, and time from first vaccine dose at sample collection.A total of 120 patients [107 coeliac disease; 10 Whipple's disease; 2 common-variable immunodeficiency (CVID); 1 idiopathic villous atrophy; 77 F, 42 ± 16 years] and 240 matched controls (154 F, 43 ± 14 years) were enrolled. At 3, 6 and 9 months, humoral response in coeliac patients was not impaired compared to controls. Inadequate humoral response to vaccination was significantly more common among Whipple's disease patients than controls ( P 0.001). Patients on immunosuppressive therapy had markedly lower IgG anti-SARS-CoV-2 antibody titres (median 14 vs. 520 BAU/mL, P 0.001). As expected, patients with CVID showed no humoral response to vaccination.Humoral immunogenicity of SARS-CoV-2 vaccines was not reduced in coeliac disease patients compared to controls, although it was in Whipple's disease and CVID patients. Post-vaccination humoral response should be monitored in patients with Whipple's disease and chronic enteropathies on immunosuppressive therapy in order to schedule vaccine booster doses.

Non-coeliac gluten sensitivity (NCGS) is still a poorly defined clinical condition. This review aims to describe the clinical features of subjects with a symptomatic response to gluten intake, and to estimate the prevalence of NCGS.Literature search was conducted in accordance with PRISMA recommendations. The PubMed database was searched for original articles until 1We identified 30 relevant articles, including 14 studies that investigated NCGS through a double-blind, placebo-controlled crossover trial (DBPCC), and 16 that examined the role of gluten in causing symptoms without a DBPCC. We found that regardless of the diagnostic work up, gluten-sensitive patients were predominately middle-aged females complaining of abdominal pain, bloating and diarrhea. The pooled prevalence of NCGS after DBPCC was 24% (5-34%). Subjects with irritable bowel syndrome or self-reporting gluten intolerance accounted for the vast majority of the patients who did not start a DBPCC. A symptomatic response to a gluten-free diet (GFD) occurred in between 7% and 93% of patients. No data on long-term outcomes of NCGS individuals were reported.Clinical features of NCGS patients did not differ among all the included studies, whereas prevalence figures are rather heterogeneous. Long-term benefit of a GFD on these patients still needs to be ascertained.

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

Ongoing symptoms in treated celiac disease (CD) are frequent and are commonly thought of as being due to infractions to a gluten-free diet (GFD) or complications.To study the etiology and natural history of clinically relevant events (CREs) throughout follow-up and identify predictors thereof to guide follow-up.CREs (symptoms/signs requiring diagnostic/therapeutic interventions) occurring in celiac patients between January-2000 and May-2021 were retrospectively collected between June and September 2021 and analysed.One-hundred-and-eighty-nine adult patients (133 F, age at diagnosis 36 ± 13 years, median follow-up 103 months, IQR 54-156) were enrolled. CREs were very common (88/189, 47%), but hardly due to poor GFD adherence (4%) or complications (2%). Interestingly, leading etiologies were functional gastrointestinal disorders (30%), reflux disease (18%) and micronutrient deficiencies (10%). Age at diagnosis ≥ 45 years (HR 1.68, 95%CI 1.05-2.69, p = 0.03) and classical pattern of CD (HR 1.63, 95%CI 1.04-2.54, p = 0.03) were predictors of CREs on a multivariable Cox model. At 5 years, 46% of classical patients ≥ 45 years old at diagnosis were event-free, while this was 62% for non-classical/silent ≥ 45 years, 60% for classical 45 years, and 80% for non-classical/silent 45 years.CREs occurred in almost half of CD patients during follow-up, with functional disorders being very common. New follow-up strategies for adult CD may be developed based on age and clinical pattern at diagnosis.

BACKGROUND A standard tool to assess patients' knowledge about gluten and the gluten-free diet (GFD) is lacking. METHODS We aimed to develop and validate a questionnaire to assess GFD knowledge. A 10-point questionnaire (GLU10) covering different aspects of knowledge about gluten content in food/non-food products and the gluten-free living was developed. To validate this questionnaire, it was administered to adult coeliac patients already instructed on gluten and the GFD and non-coeliac controls. Patients were prospectively recruited at our gastroenterology outpatient clinic between August 2020 and February 2021. RESULTS One hundred and six patients (52 coeliac patients and 54 controls) participated in the validation phase. Coeliac patients scored significantly higher than controls on the GLU10 questionnaire (median 6 points vs 2 points,p

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This study provides comparable lower-bound estimates of inequality of opportunity for tertiary education (EIOp) for 31 countries in Europe, by using the two EU-SILC waves for which information on family background is available (2005 and 2011). The results reveal an important degree of heterogeneity, with Northern European countries showing low levels of inequality of opportunity and Mediterranean and Eastern European countries characterized by significant degrees of unfair educational inequalities. Parental education and occupation are the most relevant circumstances in the great majority of the countries considered. This study also exploits the two point-in-time observations available and analyses the relationship between some country-specific characteristics and inequality of opportunity in tertiary education. The analysis documents a negative association between EIOp and real GDP per capita, possibly indicating that higher equality of opportunity in tertiary education and economic growth are complementary objectives. Two results emerge as especially robust: in all the specifications we find a positive association between EIOp and the students/teacher ratio, and a negative one between EIOp and public spending in tertiary education. While we do not claim that such correlations should be interpreted causally, we think that they might indicate a meaningful underlying relationship between equality of opportunity in tertiary education and the availability of financial and non-financial resources.

ObjectiveDifferential diagnosis of villous atrophy (VA) without coeliac antibodies in adults includes seronegative coeliac disease (CD) and chronic enteropathies unrelated to gluten, ie. non-coeliac enteropathies (NCEs). There is currently no international consensus on the nomenclature and diagnostic criteria for these enteropathies. In this work, a Delphi process was conducted to address this diagnostic and clinical uncertainty.DesignAn international task force of 13 gastroenterologists from six countries was recruited at the 16th International Coeliac Disease Symposium, Paris, 2019. Between September 2019 and July 2021, a Delphi process was conducted through mail surveys to reach a consensus on which conditions to consider in the differential diagnosis of VA with negative coeliac serology and the clinical diagnostic approaches required for these conditions. A 70% agreement threshold was adopted.ResultsChronic enteropathies characterised by VA and negative coeliac serology can be attributed to two main clinical scenarios: forms of CD presenting with negative serology, which also include seronegative CD and CD associated with IgA deficiency, and NCEs, with the latter recognising different underlying aetiologies. A consensus was reached on the diagnostic criteria for NCEs assisting clinicians in differentiating NCEs from seronegative CD. Although in adults seronegative CD is the most common aetiology in patients with VA and negative serology, discriminating between seronegative CD and NCEs is key to avoid unnecessary lifelong gluten-free diet, treat disease-specific morbidity and contrast poor long-term outcomes.ConclusionThis paper describes the Paris consensus on the definitions and diagnostic criteria for seronegative CD and chronic NCEs in adults.

ObjectiveThe differential diagnosis and management of seronegative enteropathies is challenging due to the rarity of these conditions, the overlap of clinical and histopathological features and the current lack of an international consensus on their nomenclature.DesignThis is a narrative review providing pragmatic guide on the investigation and clinical management of seronegative enteropathies in adults based on the available literature and our clinical experience.ConclusionsSeronegative coeliac disease is the most frequent cause among the heterogeneous group of seronegative enteropathies and its diagnosis is confirmed by the clinical and histological response to a gluten-free diet after the exclusion of other causes of villous atrophy. Correct identification and targeted management of seronegative enteropathies is mandatory because of the variation in terms of clinical outcomes and prognosis.

Clinical elements differentiating enteropathy due to angiotensin II-receptor-blockers (ARBs-E) from coeliac disease (CD) are poorly defined. The histopathological features on duodenal and gastric biopsies in these patients still need to be investigated.To describe the clinical phenotype of ARBs-E in comparison to CD, and the histological findings of gastric and duodenal biopsies in ARBs-E.Clinical data of patients with ARBs-E and CD diagnosed between 2013 and 2020 were retrospectively reviewed. Baseline presenting symptoms and demographics were compared (Fisher's exact test and t-test). Gastric and duodenal histology in ARBs-E were revised by two independent pathologists.14 ARBs-E and 112 CD patients were enroled. Weight loss (p 0.01), acute onset of diarrhoea (p 0.01), hospitalization (p 0.01), and older age at diagnosis (p 0.01) were more common in ARBs-E. Duodenal histology in ARBs-E showed intraepithelial lymphocytosis in 71%, increased mucosal eosinophilic count in 57%, with preserved neuroendocrine, Paneth and goblet cells in all patients. Gastric histologic lesions at baseline, including lymphocytic gastritis, eosinophilic gastritis, chronic active gastritis, and metaplastic atrophic gastritis patterns were observed in 73% of patients, without Helicobacter pylori infection.ARBs-E showed a severe clinical phenotype, often requiring hospital admission. Gastric involvement at diagnosis is very common, and this could further support this diagnosis.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is an aggressive type of intestinal lymphoma which affects individuals without evidence of enteropathy. In this single-centre case series, we describe the first two cases of MEITL in Caucasian patients suffering from histologically-proven coeliac disease (CD). Original medical records were retrieved and anonymised. All biopsy and surgical MEITL specimens were reviewed by three haematopathologists. Two patients aged 63- and 55-year old at CD diagnosis, subsequently developed a MEITL. MEITL always involved the ileum and was multifocal. Both patients died from complications after surgery, including gastrointestinal bleeding, septic shock and multiorgan failure, with a mean survival since MEITL diagnosis of 15.5 ± 16.3 months. In one case, array-CGH revealed a large deletion on chromosome nine between 9p13.1 and 9p24.1, and a recurrent chromosome gain at 9q33-q34. Our cases indicate that a subset of MEITL may arise in Caucasian patients suffering from CD. The clinical, pathological and molecular features of these cases show a partial overlap with enteropathy-associated T-cell lymphoma.

Objectives Data on SARS-CoV-2 disease (COVID-19) in adult coeliac disease (CD) are lacking. The aim of the present study is to evaluate the epidemiology and clinical features of COVID-19 in adult coeliac patients regularly followed-up at our centre since January 2015. Methods Data about general health status and clinical features of laboratory-confirmed COVID-19 were prospectively collected over the phone. Data about CD were retrospectively collected from clinical notes. Prevalence and incidence of COVID-19 were compared between the coeliac cohort and the figures in the general population of Lombardy, Northern Italy between 20 February to 5 June 2020 provided by the Italian National Institute of Health (Istituto Superiore di Sanita) and the Lombardy regional government. Results Nine out of 324 patients contracted COVID-19, thus resulting in a prevalence of 2.78% [95% confidence interval (CI) 0.98-4.58] and an incidence rate of 8.15/1000 person-month (95% CI 4.24-15.66). Prevalence of COVID-19 ascertained by means of nasal swab was 1.79% (95% CI 0.22-3.35) and the incidence rate 5.26/1000 person-month (95% CI 2.19-12.63), without difference from the general population. Clinical type of CD, age, sex, duration and adherence to a gluten-free diet, and mucosal healing did not differ between coeliac patients with and without COVID-19. None of the 9 patients with COVID-19 required hospitalization. Conclusion Patients with CD do not seem to carry an increased risk of COVID-19 compared to the general population and their disease course is mild.

Background Duodenal dysbiosis has been suggested to possibly influence the clinical manifestations of coeliac disease (CD), both at onset and when symptoms persist despite a gluten-free diet (GFD). AIMS To evaluate the relationship between duodenal microbiota composition and: i) clinical phenotype of untreated CD (UCD); ii) presence and type of persistent symptoms despite a satisfactory serological and histological response to a strict GFD. Methods Duodenal microbiota was analyzed by 16S rRNA sequencing and compared with i) clinical features in 12 adult UCD patients; ii) presence/absence and type of persistent symptoms (diarrhea-predominant vs. non-diarrhea predominant) in 25 adult treated coeliac patients (TCD) on a strict GFD. Results UCD with iron deficiency anemia (IDA) had a pro-inflammatory shift in their duodenal microbiota (reduction of Firmicutes, p = 0.03; increase of beta-Proteobacteria, p = 0.02) than those without IDA. TCD with persistent diarrhea showed a reduction of Actinobacteria (p = 0.03) and Rothia spp (p = 0.046) compared to TCD suffering from other type of persistent symptoms. Conclusion A distinctive duodenal microbiota profile is associated with IDA in UCD, and diarrhea-predominant persistent symptoms in TCD. Clinical interventions may include reconsidering patients presenting with IDA as a specific disease subtype, and dietary rebalancing if diarrhea persists despite histological response to a GFD.

Objective Bile acid diarrhea is a form of chronic diarrhea caused by excessive bile reaching the colon. Conditions involving the terminal ileum and cholecystectomy are predisposing factors but an idiopathic form of bile acid diarrhea has also been described. In this study we aimed to evaluate the prevalence of bile acid diarrhea in patients consecutively evaluated for chronic diarrhea in an Outpatient Gastroenterology Clinic. Methods Medical records of all patients admitted for chronic diarrhea (>4 weeks) between June 2018 and April 2019 were retrospectively reviewed. Bile acid diarrhea was suspected in patients with ileal disease, cholecystectomy or post-prandial diarrhea. Patients' age at diagnosis, sex, presenting symptoms, results of main test and examinations, final diagnoses and date of last follow-up visit were also collected. Exclusion of chronic diarrhea of other causes and a 6-month clinical improvement with cholestyramine treatment confirmed the diagnosis of bile acid diarrhea. Results In total, 139 patients aged 46 ± 20 years (76 women and 63 men) were included. Diarrhea due to an organic cause was diagnosed in 16 patients. A clinical response to cholestyramine persisting for more than 6 months led to a diagnosis of bile acid diarrhea in 39 (aged 52 ± 19 years) out of the remaining 123 patients with functional forms of diarrhea. Therefore, the prevalence of bile acid diarrhea was 28.1% (95% confidence interval 19.9%-38.4%) in patients with chronic diarrhea. Conclusions Bile acid diarrhea is a very common, yet under-recognized cause of chronic functional diarrhea. A therapeutic trial of cholestyramine is a valid diagnostic strategy.

Background: Little is known about long-term morbidity and mortality in Whipple’s disease (WD). Aim: To describe morbidity and mortality in patients with WD on a long-term follow-up. Materials & methods: Comorbidities, mortality and causes of death were retrospectively registered. Results: A total of 35 patients with WD (9F, 54 ± 11 years) were followed-up for a median of 104 months. Nine patients developed ten complications; three patients died. A total of 31 severe comorbidities apparently unrelated to WD were found in 20 patients: preneoplastic/neoplastic disorders in seven, thromboembolic and cardiovascular events in seven, pneumonia in four, candidiasis in ten patients. Conclusion: WD is frequently complicated by potentially life-threatening infectious, neoplastic and thromboembolic disorders, thus highlighting the need for a life-long multidisciplinary follow-up.

Description Our aim was to provide a consensus statement for the best approaches for diagnosis and management of patients with suspected enteropathy, but negative results from serologic tests for celiac disease (seronegative enteropathy). Methods We collected findings from published cohort, case–control, and cross-sectional studies of diagnosis and case series and descriptive studies of management of patients believed to have celiac disease or other enteropathies unrelated to gluten, but negative results from serologic tests. Best Practice Advice 1 Review histologic findings with experienced pathologists who specialize in gastroenterology. Best Practice Advice 2 Serologic tests are essential for an accurate diagnosis of celiac disease. For patients with suspected celiac disease but negative results from serologic tests, total IgA level should be measured; patients should also be tested for anti-tissue transglutaminase, IgA against deamidated gliadin peptide, and endomysial antibody (IgA). Patients with total IgA levels below the lower limit of detection and IgG against tissue transglutaminase or deamidated gliadin peptide, or endomysial antibody, should be considered to have celiac disease with selective IgA deficiency rather than seronegative celiac disease. Best Practice Advice 3 Patients' diets should be carefully reviewed and duodenal biopsies should be collected and analyzed at the time of serologic testing to determine exposure to gluten and accuracy of test results. Best Practice Advice 4 Thorough medication histories should be collected from patients, with attention to angiotensin II receptor blockers, such as olmesartan, along with travel histories to identify potential etiologies of villous atrophy. This will guide additional testing. Best Practice Advice 5 Patients should be analyzed for disease-associated variants in human leukocyte antigen genes; results must be carefully interpreted. Negative results can be used to rule out celiac disease in seronegative patients. Best Practice Advice 6 Patients with suspected celiac disease who are seronegative but have villous atrophy and genetic risk factors for celiac disease must undergo endoscopic evaluation after 1–3 years on a gluten-free diet to evaluate improvements in villous atrophy. A diagnosis of seronegative celiac disease can then be confirmed based on clinical and histologic markers of improvement on the gluten-free diet. Best Practice Advice 7 Seronegative patients with an identified cause for enteropathy should be treated accordingly; a follow-up biopsy might or might not be necessary. Best Practice Advice 8 Patients with persistent signs and symptoms who do not respond to a gluten-free diet, and for whom no etiology of enteropathy is ultimately identified, should be treated with budesonide. Conclusions These best practice guidelines will aid in diagnosis and management of patients with suspected celiac disease, but negative results from serologic tests.

Objective \ud Causes of small-bowel villous atrophy (VA) include coeliac disease (CD), its complications and other rare non-coeliac enteropathies. However, forms of VA of unknown aetiology may also exist. We defined them as idiopathic VA (IVA). To retrospectively classify the largest cohort of IVA patients and compare their natural history with CD.\ud \ud Methods \ud Notes of 76 IVA patients attending two tertiary centres between January 2000 and March 2019 were retrospectively reviewed. CD, its complications and all the known causes of VA were excluded in all of them. Persistence of VA during follow-up and lymphoproliferative features were used to retrospectively classify IVA, as follows. Group 1: IVA with spontaneous histological recovery (50 patients). Group 2: persistent IVA without lymphoproliferative features (14 patients). Group 3: persistent IVA with lymphoproliferative features (12 patients). Survival was compared between IVA groups and 1114 coeliac patients. HLA was compared between IVA patients, coeliac patients and appropriate controls.\ud \ud Results \ud Five-year survival was 96% in IVA group 1, 100% in IVA group 2, 27% in IVA group 3 and 97% in CD. On a multivariate analysis hypoalbuminemia (P = 0.002) and age at diagnosis (P = 0.04) predicted mortality in IVA. Group 2 showed association with HLA DQB1*0301 and DQB1*06.\ud \ud Conclusion \ud IVA consists of three groups of enteropathies with distinct clinical phenotypes and prognoses. Mortality in IVA is higher than in CD and mainly due to lymphoproliferative conditions necessitating more aggressive therapies.

Background: Growing evidence suggests that an altered microbiota composition contributes to the pathogenesis and clinical features in celiac disease (CD). We performed a comparative analysis of the gut microbiota in adulthood CD to evaluate whether: (i) dysbiosis anticipates mucosal lesions, (ii) gluten-free diet restores eubiosis, (iii) refractory CD has a peculiar microbial signature, and (iv) salivary and fecal communities overlap the mucosal one. Methods: This is a cross-sectional study where a total of 52 CD patients, including 13 active CD, 29 treated CD, 4 refractory CD, and 6 potential CD, were enrolled in a tertiary center together with 31 controls. A 16S rRNA-based amplicon metagenomics approach was applied to determine the microbiota structure and composition of salivary, duodenal mucosa, and stool samples, followed by appropriate bioinformatic analyses. Results: A reduction of both &alpha, and &beta, diversity in CD, already evident in the potential form and achieving nadir in refractory CD, was evident. Taxonomically, mucosa displayed a significant abundance of Proteobacteria and an expansion of Neisseria, especially in active patients, while treated celiacs showed an intermediate profile between active disease and controls. The saliva community mirrored the mucosal one better than stool. Conclusion: Expansion of pathobiontic species anticipates villous atrophy and achieves the maximal divergence from controls in refractory CD. Gluten-free diet results in incomplete recovery. The overlapping results between mucosal and salivary samples indicate the use of saliva as a diagnostic fluid.

Follow-up modalities for adult coeliac patients remain controversial. Non-invasive markers to identify coeliac patients on a gluten-free diet (GFD) with persistence of villous atrophy (VA) are still lacking. We aim to develop a score to stratify coeliac patients on a GFD according to their risk of having persistent VA and to tailor follow-up modalities accordingly. The clinical notes of over 700 coeliac patients attending our unit (September 1999–November 2018) were retrospectively examined. A total of 273 patients on a GFD with a histological follow-up performed 12–24 months after diagnosis were selected. We developed a bivariable model based on diet adherence and clinical response evaluated by previously validated methods. A four-level score (0·5, 1·5, 3, 4) was obtained. Patients on a strict GFD and with good clinical conditions (score 4) have a very low risk of persistence of VA (2 (95 % CI 1, 5) %). Conversely, the risk is very high (46 (95 % CI 25, 68) %) in patients with poor adherence to a GFD and unsatisfactory clinical response (score 0·5). A score of 1·5 (poor GFD adherence and persistent well-being) is linked with a high risk (23 (95 % CI 14, 36) %). Risk is intermediate (6 (95 % CI 3, 10) %) in patients scoring 3 (strict GFD and no/partial clinical improvement). Three patients who developed complications belonged to this scenario. Patients at low risk of persistent VA can be followed-up non-invasively, whereas a biopsy should be repeated in those at high/very high risk. Case-by-case evaluation is needed in patients at intermediate risk. Studies on a larger sample size are required to confirm these data.

Objectives Exclusion of organic disorders involving the upper gastrointestinal (UGI) is a mandatory step before considering a biopsy-avoidance diagnostic strategy for adult coeliac disease. We aim to evaluate the prevalence of alarm symptoms and coincidental UGI endoscopic findings at the time of diagnosis of coeliac disease. To develop consensus criteria to identify patients with coeliac disease requiring a gastroscopy and to evaluate whether alarm symptoms prompting gastroscopy were predictive of endoscopic findings. Methods Presenting symptoms and UGI endoscopic findings at diagnosis of coeliac disease were collected retrospectively in 278 adult patients with coeliac disease diagnosed in Pavia between January 1999 and December 2017. A panel of experts developed criteria to evaluate which clinical scenarios warrant gastroscopy, which was then applied retrospectively to patients diagnosed in Pavia. Results At least one alarm symptom was present in 177/278 patients, 121/278 met our criteria for gastroscopy. Major UGI endoscopic findings included 3 cases of autoimmune atrophic gastritis, 19 oesophagitis and 20 Helicobacter pylori infections. No organic disorders were found. Prevalence of major endoscopic findings did not differ between patients who met our criteria and those who did not. Conclusions Despite the high prevalence of alarm symptoms at diagnosis, coincident major UGI endoscopic findings are rare in adult coeliac disease. These results may be relevant for future developments in coeliac disease diagnosis in adults.

The spectrum of gluten-related disorders (GRD) has emerged as a relevant phenomenon possibly impacting on health care procedures and costs worldwide. Current classification of GRD is mainly based on their pathophysiology, and the following categories can be distinguished: immune-mediated disorders that include coeliac disease (CD), dermatitis herpetiformis (DH), and gluten ataxia (GA); allergic reactions such as wheat allergy (WA); and non-coeliac gluten sensitivity (NCGS), a condition characterized by both gastrointestinal and extra-intestinal symptoms subjectively believed to be induced by the ingestion of gluten/wheat that has recently gained popularity. Although CD, DH, and WA are well-defined clinical entities, whose diagnosis is based on specific diagnostic criteria, a diagnosis of NCGS may on the contrary be considered only after the exclusion of other organic disorders. Neither allergic nor autoimmune mechanisms have been found to be involved in NCGS. Mistakes in the diagnosis of GRD are still a relevant clinical problem that may result in overtreatment of patients being unnecessary started on a gluten-free diet and waste of health-care resources. On the basis of our clinical experience and literature, we aim to identify the main pitfalls in the diagnosis of CD and its complications, DH, and WA. We provide a practical methodological approach to guide clinicians on how to recognize and avoid them.

Gluten-sensitive enteropathy of the Irish Setter is an immune-mediated intolerance to gluten, the protein found in wheat, barley, rye, and oats, reminiscent of human celiac disease. Intestinal histological lesions include partial villous atrophy, infiltration of the lamina propria by lymphocytes and plasma cells, and an increased intraepithelial lymphocyte count. Gluten-sensitive enteropathy is transmitted via autosomal recessive inheritance and its pathogenesis appears to involve cell-mediated immunity but not humoral immunity. In comparison to healthy dogs, levels of anti-gliadin antibodies in diseased Irish Setters are lower, although the significance of this finding is unclear. Irish Setters affected by gluten-sensitive enteropathy present with chronic intermittent diarrhea and weight loss. The use of a gluten-free diet is indispensable both for diagnosis of the disease and for therapy. In this review we discuss the similarities between gluten-sensitive enteropathy of the Irish Setter and human celiac disease.

Seronegative coeliac disease is a poorly defined form of coeliac disease that poses an important challenge to clinicians particularly with regards to the differential diagnosis. This is probably because of lack of a consensus on its definition and incorrect use of specific coeliac serology. Seronegative coeliac disease (SCD) is uncommon and epidemiological data are scarce and contrasting. Therefore, the aim of this review is to provide a critical summary of the most recent work on this topic and a definition of SCD.SCD is rare among coeliac patients but conversely SCD remains one of the most common causes of seronegative villous atrophy. The diagnostic workup of seronegative villous atrophy (SNVA) must ensure exclusion of other enteropathies before starting patients on a lifelong gluten-free diet. This is crucial in order to ensure that patients are not given the wrong diagnosis, which in turn can have implications for their inappropriate treatment and long-term morbidity. Finally, there is some data to suggest that seronegative enteropathies have a higher mortality than conventional coeliac disease.Seronegative coeliac disease is a rare condition that accounts for a very small percentage of cases in the large population of coeliac patients. Strict criteria for the diagnosis of this condition need to be fulfilled and prompt identification of these patients is crucial in order to ensure the appropriate intervention on a case-by-case basis.