Publications by authors named "Giacomo Caio"

70 Publications

Alcohol use disorder in the COVID-19 era: Position paper of the Italian Society on Alcohol (SIA).

Addict Biol 2021 Sep 16:e13090. Epub 2021 Sep 16.

Department of Translational Medicine, University of Ferrara, Ferrara, Italy.

Coronavirus disease 2019 (COVID-19) first emerged in China in November 2019. Most governments have responded to the COVID-19 pandemic by imposing a lockdown. Some evidence suggests that a period of isolation might have led to a spike in alcohol misuse, and in the case of patients with alcohol use disorder (AUD), social isolation can favour lapse and relapse. The aim of our position paper is to provide specialists in the alcohol addiction field, in psychopharmacology, gastroenterology and in internal medicine, with appropriate tools to better manage patients with AUD and COVID-19,considering some important topics: (a) the susceptibility of AUD patients to infection; (b) the pharmacological interaction between medications used to treat AUD and to treat COVID-19; (c) the reorganization of the Centre for Alcohol Addiction Treatment for the management of AUD patients in the COVID-19 era (group activities, telemedicine, outpatients treatment, alcohol-related liver disease and liver transplantation, collecting samples); (d) AUD and SARS-CoV-2 vaccination. Telemedicine/telehealth will undoubtedly be useful/practical tools even though it remains at an elementary level; the contribution of the family and of caregivers in the management of AUD patients will play a significant role; the multidisciplinary intervention involving experts in the treatment of AUD with specialists in the treatment of COVID-19 disease will need implementation. Thus, the COVID-19 pandemic is rapidly leading addiction specialists towards a new governance scenario of AUD, which necessarily needs an in-depth reconsideration, focusing attention on a safe approach in combination with the efficacy of treatment.
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http://dx.doi.org/10.1111/adb.13090DOI Listing
September 2021

Beyond biologics: advanced therapies in inflammatory bowel diseases.

Minerva Gastroenterol (Torino) 2021 Jul 26. Epub 2021 Jul 26.

Department of Translational Medicine, University of Ferrara, Ferrara, Italy -

Inflammatory bowel diseases (IBDs) are conditions characterized by persistent and relapsing inflammation involving the gastrointestinal tract at various levels. Although the etiopathogenesis of IBDs is partially understood, a deregulated activation of intestinal immune cells in genetically susceptible patients is thought to be key for the disease onset and evolution. Artificial Nutrition might affect favorably on inflammation and related cytokine storm. However, the discovery of monoclonal antibodies blocking pro-inflammatory cytokines (e.g., tumor necrosis factor-α - TNF-α) changed radically the management of IBDs. Anti-TNF-α agents represent the prototype molecule of the so-called 'biologics' / 'biologicals'. These compounds have significantly improved the therapeutic management of IBDs refractory to standard medications, achieving clinical remission, mucosal healing and preventing extra-intestinal manifestations. However, about 50% of patients treated with biologicals experienced drawbacks, such as primary failure or loss of response, requiring new effective treatments. Translational studies have identified other pathways, different from the TNF-α blockade, and new molecules, e.g. sphingosine-1-phosphate agonists and the JAK kinase inhibitors, have been proposed as potential therapeutic options for IBDs. These novel therapeutic approaches represent a "new era" of IBD management, especially for patients poorly responsive to biologicals. In this review, we will summarize the new pharmacological strategies to treat IBDs, and discuss their effectiveness and safety, along with future perspectives for IBD treatment.
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http://dx.doi.org/10.23736/S2724-5985.21.02985-5DOI Listing
July 2021

Wheat ATIs: Characteristics and Role in Human Disease.

Front Nutr 2021 28;8:667370. Epub 2021 May 28.

Laboratory of Food Chemistry, Wageningen University and Research, Wageningen, Netherlands.

Amylase/trypsin-inhibitors (ATIs) comprise about 2-4% of the total wheat grain proteins and may contribute to natural defense against pests and pathogens. However, they are currently among the most widely studied wheat components because of their proposed role in adverse reactions to wheat consumption in humans. ATIs have long been known to contribute to IgE-mediated allergy (notably Bakers' asthma), but interest has increased since 2012 when they were shown to be able to trigger the innate immune system, with attention focused on their role in coeliac disease which affects about 1% of the population and, more recently, in non-coeliac wheat sensitivity which may affect up to 10% of the population. This has led to studies of their structure, inhibitory properties, genetics, control of expression, behavior during processing, effects on human adverse reactions to wheat and, most recently, strategies to modify their expression in the plant using gene editing. We therefore present an integrated account of this range of research, identifying inconsistencies, and gaps in our knowledge and identifying future research needs.   This paper is the outcome of an invited international ATI expert meeting held in Amsterdam, February 3-5 2020.
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http://dx.doi.org/10.3389/fnut.2021.667370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192694PMC
May 2021

Nutritional Treatment in Crohn's Disease.

Nutrients 2021 May 12;13(5). Epub 2021 May 12.

Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy.

Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) which can affect any part of the whole gastrointestinal tract (from mouth to anus). Malnutrition affects 65-75% of CD patients, and it is now well acknowledged that diet is of paramount importance in the management of the disease. In this review, we would like to highlight the most recent findings in the field of nutrition for the treatment of CD. Our analysis will cover a wide range of topics, from the well-established diets to the new nutritional theories, along with the recent progress in emerging research fields, such as nutrigenomics.
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http://dx.doi.org/10.3390/nu13051628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151495PMC
May 2021

Diagnostic Value of Persistently Low Positive TGA-IgA Titers in Symptomatic Children With Suspected Celiac Disease.

J Pediatr Gastroenterol Nutr 2021 05;72(5):712-717

Pediatric Gastroenterology and Liver Unit, Maternal and Child Health Department.

Objectives: While the algorithm to diagnose celiac disease (CD) in children with elevated anti-transglutaminase IgA (TGA-IgA) titers (>10 times upper limit of normal, ULN) is well defined, the management of children with low TGA-IgA values represents a clinical challenge. We aimed to identify the diagnostic value of persistently low positive TGA-IgA titers in predicting CD in children.

Methods: We retrospectively analyzed children with symptoms or signs of CD, not eligible for a no-biopsy approach. We included children with at least 2 TGA-IgA measurements, endomysial antibody (EMA) assessment and esophagogastroduodenoscopy with biopsies. TGA-IgA values were provided as multiples of ULN. Patients were classified in groups according to median TGA-IgA values: A (TGA-IgA>1 ≤ 5 × ULN; defined as "low-positive"), B (TGA-IgA > 5 < 10 × ULN; "moderate-positive"), and C (controls).

Results: Data of 281 children were analyzed. Of 162 children in group A, CD was diagnosed in 142 (87.7%), whereas normal duodenal mucosa was found in 20. In group B, all 62 children (100%) received a CD diagnosis. Group C included 57 controls. EMA were undetectable in 31 (15%) of mucosal atrophy cases. On the receiver-operating characteristic curve (area under the curve = 0.910), a mean value of 1.7 ULN showed a sensitivity of 81.4% and specificity of 81.8% to predict mucosal damage.

Conclusions: Repeated low or moderate TGA-IgA values (<5 ULN or <10 ULN) are good predictors of a CD diagnosis. Symptomatic children with persistently low positive TGA-IgA titers should undergo esophagogastroduodenoscopy regardless of their EMA status.
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http://dx.doi.org/10.1097/MPG.0000000000003047DOI Listing
May 2021

Gastrointestinal Involvement in Anderson-Fabry Disease: A Narrative Review.

Int J Environ Res Public Health 2021 03 23;18(6). Epub 2021 Mar 23.

Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy.

Anderson-Fabry disease (FD) is an X-linked lysosomal storage disorder leading to a wide array of clinical manifestations. Among these, gastrointestinal (GI) symptoms such as abdominal pain, bloating, and diarrhea affect about half of the FD adults and more than half of FD children. GI symptoms could be the first manifestation of FD; however, being non-specific, they overlap with the clinical picture of other conditions, such as irritable bowel syndrome and inflammatory bowel disease. This common overlap is the main reason why FD patients are often unrecognized and diagnosis is delayed for many years. The present narrative review is aimed to promote awareness of the GI manifestations of FD amongst general practitioners and specialists and highlight the latest findings of this rare condition including diagnostic tools and therapies. Finally, we will discuss some preliminary data on a patient presenting with GI symptoms who turned to be affected by a variant of uncertain significance of alpha-galactosidase (GLA) gene.
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http://dx.doi.org/10.3390/ijerph18063320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005161PMC
March 2021

Recurrent myocarditis in a patient with active ulcerative colitis: a case report and review of the literature.

BMJ Open Gastroenterol 2021 03;8(1)

Department of Translational Medicine, University of Ferrara, Ferrara, Italy

Inflammatory bowel diseases such as ulcerative colitis (UC) may be complicated by several extraintestinal manifestations. These involve joints, skin, eyes and less commonly lungs and heart. Myocarditis may result from the toxic effect of drugs (ie, mesalazine) commonly used for the treatment of UC or due to infections (eg, Coxsackieviruses, enteroviruses, adenovirus). Here, we report a case of a 26-year old man affected by UC and complicated by two episodes of myocarditis. Both episodes occurred during two severe exacerbations of UC. However, in both cases the aetiology of myocarditis remains uncertain being ascribable to extraintestinal manifestation, drug toxicity or both.
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http://dx.doi.org/10.1136/bmjgast-2020-000587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970288PMC
March 2021

Evidence of enteric angiopathy and neuromuscular hypoxia in patients with mitochondrial neurogastrointestinal encephalomyopathy.

Am J Physiol Gastrointest Liver Physiol 2021 05 3;320(5):G768-G779. Epub 2021 Mar 3.

Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by thymidine phosphorylase (TP) enzyme defect. As gastrointestinal changes do not revert in patients undergone TP replacement therapy, one can postulate that other unexplored mechanisms contribute to MNGIE pathophysiology. Hence, we focused on the local TP angiogenic potential that has never been considered in MNGIE. In this study, we investigated the enteric submucosal microvasculature and the effect of hypoxia on fibrosis and enteric neurons density in jejunal full-thickness biopsies collected from patients with MNGIE. Orcein staining was used to count blood vessels based on their size. Fibrosis was assessed using the Sirius Red and Fast Green method. Hypoxia and neoangiogenesis were determined via hypoxia-inducible-factor-1α (HIF-1α) and vascular endothelial cell growth factor (VEGF) protein expression, respectively. Neuron-specific enolase was used to label enteric neurons. Compared with controls, patients with MNGIE showed a decreased area of vascular tissue, but a twofold increase of submucosal vessels/mm with increased small size and decreased medium and large size vessels. VEGF positive vessels, fibrosis index, and HIF-1α protein expression were increased, whereas there was a diminished thickness of the longitudinal muscle layer with an increased interganglionic distance and reduced number of myenteric neurons. We demonstrated the occurrence of an angiopathy in the GI tract of patients with MNGIE. Neoangiogenetic changes, as detected by the abundance of small size vessels in the jejunal submucosa, along with hypoxia provide a morphological basis to explain neuromuscular alterations, vasculature breakdown, and ischemic abnormalities in MNGIE. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is characterized by a genetically driven defect of thymidine phosphorylase, a multitask enzyme playing a role also in angiogenesis. Indeed, major gastrointestinal bleedings are life-threatening complications of MNGIE. Thus, we focused on jejunal submucosal vasculature and showed intestinal microangiopathy as a novel feature occurring in this disease. Notably, vascular changes were associated with neuromuscular abnormalities, which may explain gut dysfunction and help to develop future therapeutic approaches in MNGIE.
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http://dx.doi.org/10.1152/ajpgi.00047.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202202PMC
May 2021

Levels and Factors Associated with Resilience in Italian Healthcare Professionals during the COVID-19 Pandemic: A Web-Based Survey.

Behav Sci (Basel) 2020 Nov 29;10(12). Epub 2020 Nov 29.

Medicine & Rheumatology Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.

Background: Resilience is defined as the capacity to cope successfully with change or adversity. The aims of our study were to investigate levels of resilience in Italian healthcare professionals (HCPs) during the Coronavirus disease 2019 (COVID-19) pandemic and to identify potential predictors of resilience.

Methods: We performed a web-based survey of HCPs ( 1009) working in Italian hospitals during the COVID-19 pandemic. The survey contained a 14-item resilience scale (RS14) and questionnaires to evaluate depression and anxiety symptoms. Non-HCP individuals ( 375) from the general population were used for comparison.

Results: HCPs showed significantly lower resilience compared to the control group ( = 0.001). No significant differences were observed after stratification for geographical area, work setting, role, or suspected/confirmed diagnosis of COVID-19. In a linear regression analysis, RS14 was inversely correlated with depression (R = 0.227, < 0.001) and anxiety (R = 0.117, < 0.001) and directly correlated with age (R = 0.012, < 0.001) but not with body mass index (BMI, R = 0.002, = 0.213). In male HCPs, higher depression score (odds ratio (OR) 1.147, < 0.001) or BMI (OR 1.136, = 0.011) significantly predicted having low resilience. In female HCPs, higher depression score (OR 1.111, < 0.0001) and working in a COVID-19 free setting (OR 2.308, = 0.002) significantly predicted having low resilience. HCPs satisfied with personal protective equipment had higher levels of resilience ( < 0.010).

Conclusions: Our findings suggest that resilience was lower in Italian HCPs than in the general population after the first COVID-19 wave. Specific factors can be identified, and targeted interventions may have an important role to foster resilience of HCPs.
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http://dx.doi.org/10.3390/bs10120183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760580PMC
November 2020

Coronaviruses and gastrointestinal symptoms: an old liaison for the new SARS-CoV-2.

Gastroenterol Hepatol Bed Bench 2020 ;13(4):341-350

Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

The coronavirus disease (Covid-19) has caused a pandemic with more than 600,000 deaths to date. It is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a member of the beta-coronavirus genus that also includes SARS and the Middle East Respiratory Syndrome Coronavirus (MERS). While the typical presentation is given by respiratory symptoms and fever, some patients also report gastrointestinal symptoms such as diarrhea, nausea, vomiting, and abdominal pain. Several studies have identified the SARS-CoV-2 RNA in stool specimens of infected patients, and its viral receptor angiotensin-converting enzyme 2 (ACE2) is highly expressed in enterocytes. In this short review, we report the frequency of gastrointestinal symptoms in infected patients and suggest possible implications for disease management, transmission, and infection control.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682957PMC
January 2020

Predicting in-hospital mortality for sepsis: a comparison between qSOFA and modified qSOFA in a 2-year single-centre retrospective analysis.

Eur J Clin Microbiol Infect Dis 2021 Apr 28;40(4):825-831. Epub 2020 Oct 28.

Department of Morphology, Surgery and Experimental Medicine, St. Anna University Hospital, University of Ferrara, Via A. Moro, 844124, Cona, Ferrara, Italy.

Sepsis is a life-threating organ dysfunction caused by a dysregulated host response to infection. This study proposed a new tool, i.e. modified qSOFA, for the early prognostic assessment of septic patients. All cases of sepsis/septic shock consecutively observed in 2 years (January 2017-December 2018), at St. Anna University Hospital of Ferrara, Italy, were included. Each patient was evaluated with qSOFA and a modified qSOFA (MqSOFA), i.e. adding a SpO2/FiO2 ratio to qSOFA. Logistic regression and survival analyses were applied to compare the two scores. A total number of 1137 consecutive cases of sepsis and septic shock were considered. Among them 136 were excluded for incomplete report of vital parameters. A total number of 668 patients (66.7%) were discharged, whereas 333 (33.3%) died because of sepsis-related complications. Data analysis showed that MqSOFA (AUC 0.805, 95% C.I. 0.776-0.833) had a greater ability to detect in-hospital mortality than qSOFA (AUC 0.712, 95% C.I. 0.678-0.746) (p < 0.001). Eighty-five patients (8.5%) were reclassified as high-risk (qSOFA< 2 and MqSOFA≥ 2) resulting in an improvement of sensitivity with a minor reduction in specificity. A significant difference of in-hospital mortality was observed between low-risk and reclassified high-risk (p < 0.001) and low-risk vs. high-risk groups (p < 0.001). We demonstrated that MqSOFA provided a better predictive score than qSOFA regarding patient's outcome. Since sepsis is an underhanded and time-dependent disease, physicians may rely upon the herein proposed simple score, i.e. MqSOFA, to establish patients' severity and outcome.
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http://dx.doi.org/10.1007/s10096-020-04086-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979592PMC
April 2021

Autoimmunity Features in Patients With Non-Celiac Wheat Sensitivity.

Am J Gastroenterol 2021 05;116(5):1015-1023

Unit of Internal Medicine, "V. Cervello" Hospital, Ospedali Riuniti "Villa Sofia-Cervello," Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy.

Introduction: Nonceliac wheat sensitivity (NCWS) is characterized by intestinal and extraintestinal manifestations consequent to wheat ingestion in subjects without celiac disease and wheat allergy. Few studies investigated the relationship between NCWS and autoimmunity. The aim of this study is to evaluate the frequency of autoimmune diseases (ADs) and autoantibodies in patients with NCWS.

Methods: Ninety-one patients (13 men and 78 women; mean age of 40.9 years) with NCWS, recruited in a single center, were included. Seventy-six healthy blood donors (HBD) and 55 patients with a diagnosis of irritable bowel syndrome (IBS) unrelated to NCWS served as controls. Autoantibodies levels were measured. Human leukocyte antigen haplotypes were determined, and duodenal histology performed in all patients carrying the DQ2/DQ8 haplotypes. Participants completed a questionnaire, and their medical records were reviewed to identify those with ADs.

Results: Twenty-three patients with NCWS (25.3%) presented with ADs; autoimmune thyroiditis (16 patients, 17.6%) was the most frequent. The frequency of ADs was higher in patients with NCWS than in HBD (P = 0.002) and in patients with IBS (P = 0.05). In the NCWS group, antinuclear antibodies tested positive in 71.4% vs HBD 19.7%, and vs patients with IBS 21.8% (P < 0.0001 for both). The frequency of extractable nuclear antigen antibody (ENA) positivity was significantly higher in patients with NCWS (21.9%) than in HBD (0%) and patients with IBS (3.6%) (P = 0.0001 and P = 0.004, respectively). Among the patients with NCWS, 9.9% tested positive for antithyroglobulin, 16.5% for antithyroid peroxidase, and 14.3% for antiparietal cell antibodies; frequencies were not statistically different from controls. The presence of ADs was related to older age at NCWS diagnosis, female sex, duodenal lymphocytosis, and eosinophil infiltration.

Discussion: One in 4 patients with NCWS suffered from AD, and serum antinuclear antibodies were positive in a very high percentage of cases. These data led us to consider NCWS to be associated to ADs.
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http://dx.doi.org/10.14309/ajg.0000000000000919DOI Listing
May 2021

Probiotics, Prebiotics and Other Dietary Supplements for Gut Microbiota Modulation in Celiac Disease Patients.

Nutrients 2020 Sep 2;12(9). Epub 2020 Sep 2.

Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44124 Ferrara, Italy.

To date, the only available treatment for celiac disease (CD) patients is a life-lasting gluten-free diet (GFD). Lack of adherence to the GFD leads to a significant risk of adverse health consequences. Food cross-contamination, nutritional imbalances, and persistent gastrointestinal symptoms are the main concerns related to GFD. Moreover, despite rigid compliance to GFD, patients struggle in achieving a full restoring of the gut microbiota, which plays a role in the nutritive compounds processing, and absorption. Pivotal studies on the supplementation of GFD with probiotics, such as and , reported a potential to restore gut microbiota composition and to pre-digest gluten in the intestinal lumen, reducing the inflammation associated with gluten intake, the intestinal permeability, and the cytokine and antibody production. These findings could explain an improvement in symptoms and quality of life in patients treated with GFD and probiotics. On the other hand, the inclusion of prebiotics in GFD could also be easy to administer and cost-effective as an adjunctive treatment for CD, having the power to stimulate the growth of potentially health-promoting bacteria strains. However, evidence regarding the use of prebiotics and probiotics in patients with CD is still insufficient to justify their use in clinical practice.
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http://dx.doi.org/10.3390/nu12092674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551848PMC
September 2020

Minimal Lesions of the Small Intestinal Mucosa: More than Morphology.

Dig Dis Sci 2020 10;65(10):2761-2768

Department of Morphology, Surgery and Experimental Medicine, St. Anna University Hospital, University of Ferrara, Ferrara, Italy.

Minimal lesions of the small bowel are mucosal changes characterized by an increased number of intraepithelial lymphocytes (with or without crypt hyperplasia) and normal villous architecture. Such changes are associated with a wide spectrum of conditions, ranging from food intolerances to infections, and from drugs to immune diseases, with different clinical profiles and manifestations, which complicates the formulation of a differential diagnosis. Patient history, symptom evaluation, and histopathology are the diagnostic features needed to establish a correct diagnosis. Physicians should assist pathologists in formulating a precise morphological evaluation by taking well-oriented small intestinal biopsies and collecting informative clinical findings that inform histopathology. In this current clinical controversy, the authors provide the reader with an appraisal of the small intestine minimal lesions through a careful analysis of the major conditions (e.g., celiac disease and other non-celiac disorders) responsible for such changes and their differential diagnosis. Also, we acknowledge that some of the diseases detailed in this article may progress from an early minimal lesion to overt mucosal atrophy. Thus, the timing of the diagnosis is of paramount importance.
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http://dx.doi.org/10.1007/s10620-020-06571-1DOI Listing
October 2020

Prognostic Role of Mismatch Repair Status, Histotype and High-Risk Pathologic Features in Stage II Small Bowel Adenocarcinomas.

Ann Surg Oncol 2021 Feb 5;28(2):1167-1177. Epub 2020 Aug 5.

Unit of Pathology, Cervello Hospital, Palermo, Italy.

Background: Small bowel adenocarcinoma is a relatively rare cancer, often diagnosed in an advanced stage. In localized and resectable disease, surgery alone or in combination with adjuvant chemotherapy is the mainstay of treatment. In the recently published National Comprehensive Cancer Network Clinical Practice guidelines, criteria for selecting patients with stage II small bowel adenocarcinoma to receive adjuvant chemotherapy are provided, and they are mainly extrapolated from studies on colorectal cancer.

Patients And Methods: In the present study, we aimed to verify whether mismatch repair deficiency phenotype, high-risk pathologic features (including T4, positive resection margins and a low number of lymph nodes harvested), as well as tumor histologic subtype, were associated with cancer-specific survival in 66 stage II non-ampullary small bowel adenocarcinoma patients, collected through the Small Bowel Cancer Italian Consortium. A central histopathology review was performed. Mismatch repair deficiency was tested by immunohistochemistry for MLH1, MSH2, MSH6 and PMS2, and confirmed by polymerase chain reaction for microsatellite instability.

Results: We identified mismatch repair deficiency, glandular/medullary histologic subtype, and celiac disease as significant predictors of favorable cancer-specific survival using univariable analysis with retained significance in bivariable models adjusted for pT stage. Among the high-risk features, only T4 showed a significant association with an increased risk of death; however, its prognostic value was not independent of mismatch repair status.

Conclusions: Mismatch repair protein expression, histologic subtype, association with celiac disease, and, in the mismatch repair proficient subset only, T stage, may help identify patients who may benefit from adjuvant chemotherapy.
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http://dx.doi.org/10.1245/s10434-020-08926-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801310PMC
February 2021

Subclass Profile of IgG Antibody Response to Gluten Differentiates Nonceliac Gluten Sensitivity From Celiac Disease.

Gastroenterology 2020 11 21;159(5):1965-1967.e2. Epub 2020 Jul 21.

Department of Medicine, Columbia University Medical Center, New York, New York; Institute of Human Nutrition, Columbia University Medical Center, New York, New York; Celiac Disease Center, Columbia University Medical Center, New York, New York; Department of Medicine, New York Medical College, Valhalla, New York. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2020.07.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680445PMC
November 2020

Effect of Gluten-Free Diet on Gut Microbiota Composition in Patients with Celiac Disease and Non-Celiac Gluten/Wheat Sensitivity.

Nutrients 2020 Jun 19;12(6). Epub 2020 Jun 19.

Department of Morphology, Surgery and Experimental Medicine, St. Anna University Hospital, University of Ferrara, 44124 Cona, Italy.

Celiac disease (CD) and non-celiac gluten/wheat sensitivity (NCG/WS) are the two most frequent conditions belonging to gluten-related disorders (GRDs). Both these diseases are triggered and worsened by gluten proteins ingestion, although other components, such as amylase/trypsin inhibitors (ATI) and fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs), seem to be involved in the NCG/WS onset. Therefore, the only effective treatment to date is the long-life adherence to a strictly gluten-free diet. Recently, increasing attention has been paid to the intestinal barrier, a dynamic system comprising various components, which regulate the delicate crosstalk between metabolic, motor, neuroendocrine and immunological functions. Among the elements characterizing the intestinal barrier, the microbiota plays a key role, modulating the gut integrity maintenance, the immune response and the inflammation process, linked to the CD and NCG/WS outbreak. This narrative review addresses the most recent findings on the gut microbiota modulation induced by the gluten-free diet (GFD) in healthy, CD and NCG/WS patients.
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http://dx.doi.org/10.3390/nu12061832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353361PMC
June 2020

Life-threatening onset of coeliac disease: a case report and literature review.

BMJ Open Gastroenterol 2020 05;7(1)

Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy

Background: Coeliac disease (CD) results from an immune-mediated reaction to gluten in genetically predisposed individuals. In rare cases CD may occur with acute features deferring the diagnosis and exposing these patients to possible life-threatening complications. Herein we present the case of a young woman with a coeliac crisis, that is, a sudden clinical onset characterised by severe electrolyte imbalance due to an unknown (previously unrecognised) CD.

Methods: This is a case report and literature review revealing that coeliac crisis is under-reported, with a total of 48 adult cases so far published. The diagnosis in our case was established by histopathological analysis of multiple duodenal biopsies. The patient's serum was tested by enzyme-linked immunoassay to detect antitransglutaminase IgA antibodies.

Results: In contrast to cases reported in the literature, with male gender predominance and a mean age of 50±17 years, our patient was a young female case of coeliac crisis. However, like in our patient, a higher incidence of coeliac crisis was associated with the human leucocyte antigen (HLA)-DQ2 haplotype, versus HLA-DQ8, and a severe (Marsh-Oberhüber 3c) duodenal mucosa atrophy. Notably, there is no clear correlation between the antitissue transglutaminase 2 IgA antibody titre and coeliac crisis onset/severity, as confirmed by our case report.

Conclusions: The present case highlights that CD may manifest quite abruptly with a severe malabsorption syndrome, that is, electrolyte abnormalities and hypoproteinaemia. Our case should alert physicians, in particular those in the emergency setting, that even a typically chronic disorder, such as CD, may show life-threatening complications requiring urgent management.
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http://dx.doi.org/10.1136/bmjgast-2020-000406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223027PMC
May 2020

PD-L1 in small bowel adenocarcinoma is associated with etiology and tumor-infiltrating lymphocytes, in addition to microsatellite instability.

Mod Pathol 2020 07 17;33(7):1398-1409. Epub 2020 Feb 17.

Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy.

Small bowel adenocarcinomas (SBAs) are often associated with poor prognosis and have limited therapeutic options. Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment in many microsatellite instability-high (MSI-H) solid tumors. We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary SBAs, associated with celiac disease (CeD), Crohn's disease (CrD), or sporadic, recruited through the Small Bowel Cancer Italian Consortium. We assessed PD-L1 and PD-1 by immunohistochemistry in a series of 121 surgically resected SBAs, including 34 CeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1 expression was correlated with several clinico-pathological features, such as the etiology, microsatellite instability status, and tumor-infiltrating lymphocyte (TIL) density. The prevalence of PD-L1 positivity according to combined positive score (CPS) was 26% in the whole cohort of SBAs, with significantly (p = 0.001) higher percentage (35%) in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs (5%). CPS ≥ 1 SBAs were significantly (p = 0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones (18%); however, 15 CPS ≥ 1 microsatellite stable SBAs were also identified. CPS ≥ 1 SBAs showed higher TIL and PD-1 immune cell density, more frequently medullary histotype, as well as a better outcome in comparison with CPS < 1 cases. This study demonstrates an increased proportion of PD-L1 cases in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of PD-L1 microsatellite stable SBAs supports the need to ascertain additional biomarkers of response to immune checkpoint inhibitors along with MSI-H.
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http://dx.doi.org/10.1038/s41379-020-0497-0DOI Listing
July 2020

Serum zonulin and its diagnostic performance in non-coeliac gluten sensitivity.

Gut 2020 11 14;69(11):1966-1974. Epub 2020 Feb 14.

Department of Medical and Surgical Sciences, University of Bologna, Bologna, Emilia-Romagna, Italy

Objective: Non-coeliac gluten sensitivity (NCGS) is characterised by intestinal and extraintestinal symptoms related to the ingestion of gluten-containing foods, in the absence of coeliac disease (CD) and wheat allergy. No biomarkers are available to diagnose NCGS and the gold standard double-blind placebo-controlled gluten challenge is clinically impractical. The aim of our work was to investigate the role of serum zonulin as a diagnostic biomarker of NCGS and to develop a diagnostic algorithm.

Design: In a multicentre study, we enrolled 86 patients with either self-reported or double-blind confirmed NCGS, 59 patients with diarrhoea-predominant IBS (IBS-D), 15 patients with CD and 25 asymptomatic controls (AC). Zonulin serum levels were assessed and the associated diagnostic power calculated. Clinical and symptomatic data were recorded. The effect of diet on zonulin levels was evaluated in a subgroup of patients with NCGS.

Results: Compared with ACs, the NCGS, irrespective of modality of diagnosis, and patients with CD had significantly increased levels of zonulin, as did both NCGS and patients with CD compared with participants with IBS-D. Self-reported NCGS showed increased zonulin levels compared with double-blind confirmed and not-confirmed NCGS. Six-month wheat avoidance significantly reduced zonulin levels only in HLA-DQ2/8-positive participants with NCGS. The diagnostic accuracy of zonulin levels in distinguishing NCGS from IBS-D was 81%. After exclusion of CD, a diagnostic algorithm combining zonulin levels, symptoms and gender improved the accuracy to 89%.

Conclusion: Zonulin can be considered a diagnostic biomarker in NCGS and combined with demographic and clinical data differentiates NCGS from IBS-D with high accuracy. Wheat withdrawal was associated with a reduction in zonulin levels only in NCGS carrying HLA genotype.
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http://dx.doi.org/10.1136/gutjnl-2019-319281DOI Listing
November 2020

Mast cell-nerve interactions correlate with bloating and abdominal pain severity in patients with non-celiac gluten / wheat sensitivity.

Neurogastroenterol Motil 2020 06 5;32(6):e13814. Epub 2020 Feb 5.

Department of Medical Sciences, University of Ferrara, Ferrara, Italy.

Background: Gastrointestinal (GI) and extra-GI symptoms/manifestations represent key clinical features of patients with non-celiac gluten/wheat sensitivity (NCG/WS). This study aimed to investigate neuro-immune (focusing on mast cells, MCs) interactions in the duodenal submucosa of patients with NCG/WS.

Methods: Submucosal whole mounts from duodenal biopsies of 34 patients with self-reported NCG/WS, 28 with celiac disease (CD), 13 with functional dyspepsia (FD), and 24 healthy controls (HC) were analyzed by immunohistochemistry. Quantitative data on neuronal and MCs density and the percentage of MCs in close vicinity to nerves were obtained, and correlations among neurons, MC density and MC-nerve distance (D), and symptoms were assessed in the three groups.

Key Results: The number of submucosal neurons was not different among groups. In NCG/WS, MC density was not different from HC, while it was slightly increased vs. CD (P = .07) and significantly decreased vs. FD (P < .05). The percentage of MCs close to nerves (D < 15 µm) was similarly increased in all three pathological groups vs. HC (P < .001). In NCG/WS, MC infiltration correlated with bloating (P = .001) and abdominal pain severity (P = .03) and the percentage of MCs in proximity to neurons correlated with the number of GI symptoms (D < 5 µm; P = .05), bloating and abdominal pain severity (D < 15um; P = .01).

Conclusions And Inferences: Submucosal MC infiltration and the close (within 15 µm) MC-to-nerve proximity in the duodenum of NCG/WS patients are features providing a histopathological basis to better understand GI symptoms in this condition.
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http://dx.doi.org/10.1111/nmo.13814DOI Listing
June 2020

Therapeutic options for coeliac disease: What else beyond gluten-free diet?

Dig Liver Dis 2020 02 10;52(2):130-137. Epub 2019 Dec 10.

Department of Medical and Surgical Scieces, University of Bologna, Italy.

Coeliac disease is a chronic and systemic autoimmune condition triggered by gluten ingestion in genetically predisposed subjects. Currently, the only effective treatment available is a strict, lifelong gluten-free diet. However, patients perceive gluten withdrawal as an unsustainable burden in their life and some of them can exhibit persistent symptoms despite a strict diet. Thus, gluten-free diet represents a challenge, leading scientists to look for alternative or complementary treatments. This review will focus on non-dietary therapies for coeliac disease highlighting six therapeutic strategies: (1) decreasing gluten immunogenic content before it reaches the intestine; (2) sequestering gluten in the gut lumen before absorption; (3) blocking the passage of gluten through a leaky intestinal barrier; (4) preventing the enhancement of immune response against gliadin; (5) dampening the downstream immune activation; (6) inducing immune tolerance to gluten. Most developing therapies are only in the pre-clinical phase with only a few being tested in phase 2b or 3 trials. Although new approaches raise the hope for coeliacs giving them a chance to come back to gluten, for the time being a cautionary appraisal of new therapies suggests that they may have a complementary role to gluten withdrawal, mainly to prevent inadvertent gluten contamination.
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http://dx.doi.org/10.1016/j.dld.2019.11.010DOI Listing
February 2020

Methods for diagnosing bile acid malabsorption: a systematic review.

BMC Gastroenterol 2019 Nov 14;19(1):185. Epub 2019 Nov 14.

Department of Medical Sciences, University of Ferrara, Ferrara, Italy.

Background: Bile acid malabsorption (BAM) and bile acid-related diarrhea represent an under-recognized cause of chronic diarrhea mainly because of limited guidance on appropriate diagnostic and laboratory tests. We aimed to perform a systematic review of the literature in order to identify and compare the diagnostic accuracy of different diagnostic methods for patients with BAM, despite a proven gold standard test is still lacking.

Methods: A PubMed literature review and a manual search were carried out. Relevant full papers, evaluating the diagnostic accuracy of different methods for BAM, were assessed. Available data were analyzed to estimate the sensitivity and specificity of each published test.

Results: Overall, more than one test was considered in published papers on BAM. The search strategy retrieved 574 articles; of these, only 16 were full papers (with a total of 2.332 patients) included in the final review. Specifically, n = 8 studies used Selenium-homotaurocholic-acid-test (SeHCAT) with a < 10% retention threshold; n = 8 studies evaluated fasting serum 7-α-hydroxy-4-cholesten-3-one (C4); n = 3 studies involved total fecal bile acid (BA) excretion over 48 h; n = 4 studies assessed fibroblast growth factor 19 (FGF19). SeHCAT showed an average sensitivity and specificity of 87.32 and 93.2%, respectively, followed by serum C4 (85.2 and 71.1%) and total fecal BA (66.6 and 79.3%). Fasting serum FGF19 had the lowest sensitivity and specificity (63.8 and 72.3%). All the extracted data were associated with substantial heterogeneity.

Conclusions: Our systematic review indicates that SeHCAT has the highest diagnostic accuracy for BAM, followed by serum C4 assay. The diagnostic yield of fecal BA and FGF19 assays is still under investigation. Our review reinforces the need for novel biomarkers aimed to an objective detection of BAM and therefore improving the management of this condition.
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http://dx.doi.org/10.1186/s12876-019-1102-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854889PMC
November 2019

Celiac disease: a comprehensive current review.

BMC Med 2019 07 23;17(1):142. Epub 2019 Jul 23.

Center for Celiac Research and Treatment, Massachusetts General Hospital, Boston, MA, 02114, USA.

Background: Celiac disease remains a challenging condition because of a steady increase in knowledge tackling its pathophysiology, diagnosis, management, and possible therapeutic options.

Main Body: A major milestone in the history of celiac disease was the identification of tissue transglutaminase as the autoantigen, thereby confirming the autoimmune nature of this disorder. A genetic background (HLA-DQ2/DQ8 positivity and non-HLA genes) is a mandatory determinant of the development of the disease, which occurs with the contribution of environmental factors (e.g., viral infections and dysbiosis of gut microbiota). Its prevalence in the general population is of approximately 1%, with female predominance. The disease can occur at any age, with a variety of symptoms/manifestations. This multifaceted clinical presentation leads to several phenotypes, i.e., gastrointestinal, extraintestinal, subclinical, potential, seronegative, non-responsive, and refractory. Although small intestinal biopsy remains the diagnostic 'gold standard', highly sensitive and specific serological tests, such as tissue transglutaminase, endomysial and deamidated gliadin peptide antibodies, have become gradually more important in the diagnostic work-up of celiac disease. Currently, the only treatment for celiac disease is a life-long, strict gluten-free diet leading to improvement in quality of life, ameliorating symptoms, and preventing the occurrence of refractory celiac disease, ulcerative jejunoileitis, and small intestinal adenocarcinoma and lymphoma.

Conclusions: The present review is timely and provides a thorough appraisal of various aspects characterizing celiac disease. Remaining challenges include obtaining a better understanding of still-unclear phenotypes such as slow-responsive, potential (minimal lesions) and seronegative celiac disease. The identification of alternative or complementary treatments to the gluten-free diet brings hope for patients unavoidably burdened by diet restrictions.
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http://dx.doi.org/10.1186/s12916-019-1380-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647104PMC
July 2019

Gut epithelial and vascular barrier abnormalities in patients with chronic intestinal pseudo-obstruction.

Neurogastroenterol Motil 2019 08 29;31(8):e13652. Epub 2019 May 29.

Department of Medical Sciences, University of Ferrara, Ferrara, Italy.

Background: Chronic intestinal pseudo-obstruction (CIPO) is a rare condition due to severe impairment of gut motility responsible for recurrent subocclusive episodes. Although neuromuscular-glial-ICC abnormalities represent the main pathogenetic mechanism, the pathophysiology of CIPO remains poorly understood. Intestinal epithelial and vascular endothelial barrier (IEVB) abnormalities can contribute to neuroepithelial changes by allowing passage of harmful substances.

Methods: To test retrospectively whether IEVB defects occur in patients with CIPO, we measured the jejunal protein expression of the major tight junction (TJ) components. CIPO patients were subdivided according to gut neuromuscular histopathology: apparently normal (AN); with inflammation (INF); or with degenerative alterations (DEG). The presence of occludin/claudin oligomers (index of TJ assembly), the amount of occludin, claudin-4, and zonula occludens-1 (ZO-1), and the expression of vasoactive intestinal polypeptide (VIP) and glial fibrillary acidic protein (GFAP) immunoreactivities were evaluated on jejunal full-thickness biopsies using Western blot.

Key Results: Oligomers were absent in the 73% of CIPO. Total occludin decreased in CIPO with AN and INF changes. Claudin-4 was upregulated in CIPO with INF and DEG features. ZO-1 and VIP expression decreased selectively in DEG group. GFAP increased in CIPO regardless the histopathological phenotype.

Conclusions & Inferences: The absence of oligomers demonstrated in our study suggests that IEBV is altered in CIPO. The mechanism leading to oligomerization is occludin-dependent in AN and INF, whereas is ZO-1-dependent in DEG. Our study provides support to IEVB abnormalities contributing to CIPO clinical and histopathological features.
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http://dx.doi.org/10.1111/nmo.13652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639131PMC
August 2019

Immunoreactivity of Gluten-Sensitized Sera Toward Wheat, Rice, Corn, and Amaranth Flour Proteins Treated With Microbial Transglutaminase.

Front Microbiol 2019 26;10:470. Epub 2019 Mar 26.

Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy.

The aim of this study was to analyze the effects of microbial transglutaminase (mTG) on the immunoreactivity of wheat and gluten-free cereals flours to the sera of patients with celiac disease (CD) and non-celiac gluten sensitivity (NCGS). Both doughs and sourdoughs, the latter prepared by a two-step fermentation with and , were studied. In order to evaluate the IgG-binding capacity toward the proteins of the studied flours, total protein as well as protein fractions enriched in albumins/globulins, prolamins and glutelins, were analyzed by SDS-PAGE and enzyme-linked immunosorbent assay (ELISA). Results showed that while mTG modified both gluten and gluten-free flour by increasing the amount of cross-linked proteins, it did not affect the serum's immune-recognition. In fact, no significant differences were observed in the immunoreactivity of sera from CD and NCGS patients toward wheat and gluten-free protein extracts after enzyme treatment, nor did this biotechnological treatment affect the immunoreactivity of control samples or the sera of healthy patients. These results suggest that mTG may be used as a tool to create innovative gluten and gluten-free products with improved structural properties, without increasing the immune-reactivity toward proteins present either in doughs or in sourdoughs.
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http://dx.doi.org/10.3389/fmicb.2019.00470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445063PMC
March 2019

Small bowel adenocarcinoma as a complication of celiac disease: clinical and diagnostic features.

BMC Gastroenterol 2019 Mar 27;19(1):45. Epub 2019 Mar 27.

Department of Medical Sciences, University of Ferrara, St. Anna Hospital, Via Aldo Moro, 8, 44124, Ferrara, Cona, Italy.

Background: Small bowel adenocarcinoma (SBA) is a rare neoplasm, which can occur in a sporadic form or can be associated with a number of predisposing conditions such as hereditary syndromes and immune-mediated intestinal disorders, e.g. celiac disease (CD). However, the features of SBA in the context of CD remain only partly understood. This study was aimed to show the main clinical features, diagnostic procedures and management options of SBA cases detected in a large cohort of celiac patients diagnosed in a single tertiary care center.

Methods: We retrospectively reviewed all the SBA cases detected in a cohort of 770 CD patients (599 females; F / M ratio: 3.5:1; median age at diagnosis 36 years, range 18-80 years), diagnosed at the Celiac Disease Referral Center of our University Hospital (Bologna, Italy) from January 1995 to December 2014.

Results: Five (0.65%) out of our 770 CD patients developed SBA. All of them were female with a mean age of 53 years (range 38-72 years). SBA, diagnosed at the same time of the CD diagnosis in three cases, was localized in the jejunum in four cases and in the duodenum in one case. The clinical presentation of SBA was characterized by intestinal sub-occlusion in two cases, while the predominant manifestation of the remaining three cases was iron deficiency anaemia, abdominal pain and acute intestinal obstruction, respectively. All the patients were referred to surgery, and three cases with advanced stage neoplasia were also treated with chemotherapy. The overall survival rate at 5 years was 80%.

Conclusions: Although in a limited series, herein presented CD-related SBA cases were characterized by a younger age of onset, a higher prevalence in female gender and a better overall survival compared to sporadic, Crohn- and hereditary syndrome-related SBA.
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http://dx.doi.org/10.1186/s12876-019-0964-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437995PMC
March 2019

The effect of non-TNF-targeted biologics on vascular dysfunction in rheumatoid arthritis: A systematic literature review.

Autoimmun Rev 2019 May 4;18(5):501-509. Epub 2019 Mar 4.

Internal Medicine Unit, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.

Background: Rheumatoid arthritis (RA) is burdened by a significant increase in cardiovascular disease (CVD) risk. Amongst CVD risk factors, endothelial dysfunction and arterial stiffness represent powerful predictors of atherosclerosis and cardiovascular events in the general population and in RA patients.

Methods: A systematic review of the literature was performed to identify the available data on the effect of non-TNF-targeted biologics licensed for the treatment of RA on endothelial function, arterial stiffness or subclinical atherosclerosis. MedLine (via PubMed), Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science (WOS) databases were searched using a predefined strategy to identify relevant articles.

Results: The search strategy initially retrieved 389 records. After screening titles and abstracts, a total of 362 studies were excluded. Amongst the remaining 27 studies selected for final examination, 16 articles were included in the systematic literature review. Included studies demonstrated a significant effect of abatacept, anakinra, rituximab and tocilizumab in improving endothelial dysfunction associated with RA; the effect on arterial stiffness was less consistent and deserves further investigation. No significant effect of non-TNF-targeted biologics was observed for measures of subclinical atherosclerosis.

Conclusion: Non-TNF-targeted biologics have been associated with favorable effects on endothelial dysfunction as already demonstrated for TNF inhibitors. Future studies are needed to ascertain the impact of this mediations on arterial stiffness in RA patients.
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http://dx.doi.org/10.1016/j.autrev.2019.03.008DOI Listing
May 2019

Nonceliac Wheat Sensitivity: An Immune-Mediated Condition with Systemic Manifestations.

Gastroenterol Clin North Am 2019 03 13;48(1):165-182. Epub 2018 Dec 13.

Department of Medicine, Columbia University Medical Center, 1130 Saint Nicholas Avenue, New York, NY 10032, USA; Celiac Disease Center, Columbia University Medical Center, 180 Fort Washington Avenue, New York, NY 10032, USA; Institute of Human Nutrition, Columbia University Medical Center, 630 West 168(th) Street, New York, NY 10032, USA. Electronic address:

Non-celiac wheat sensitivity (NCWS) is characterized by gastrointestinal and extra-intestinal symptoms following the ingestion of gluten-containing cereals in subjects without celiac disease or wheat allergy. The identity of the molecular triggers in these cereals responsible for the symptoms of NCWS remains to be delineated. Recent research has identified a biological basis for the condition, with the observation of systemic immune activation in response to microbial translocation that appears to be linked to intestinal barrier defects. Ongoing research efforts are aimed at further characterizing the etiology, mechanism, and biomarkers of the condition.
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http://dx.doi.org/10.1016/j.gtc.2018.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364564PMC
March 2019
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