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Background: Telomeres prevent damage to coding DNA as end-nucleotides are lost during mitosis. Mutations in telomere maintenance genes cause excessive telomere shortening, a condition known as short telomere syndrome (STS). One hepatic manifestation documented in STS is porto-sinusoidal vascular disorder (PSVD)., Methods: As the etiology of many cases of PSVD remains unknown, this study explored the extent to which short telomeres are present in patients with idiopathic PSVD., Results: This monocentric cross-sectional study included patients with histologically defined idiopathic PSVD. Telomere length in 6 peripheral blood leukocyte subpopulations was assessed using fluorescent in situ hybridization and flow cytometry. Variants of telomere-related genes were identified using high-throughput exome sequencing. In total, 22 patients were included, of whom 16 (73%) had short (9/22) or very short (7/22) telomeres according to age-adjusted reference ranges. Fourteen patients (64%) had clinically significant portal hypertension. Shorter telomeres were more frequent in males (p = 0.005) and patients with concomitant interstitial lung disease (p < 0.001), chronic kidney disease (p < 0.001), and erythrocyte macrocytosis (p = 0.007). Portal hypertension (p = 0.021), low serum albumin level (p < 0.001), low platelet count (p = 0.007), and hyperbilirubinemia (p = 0.053) were also associated with shorter telomeres. Variants in known STS-related genes were identified in 4 patients with VSTel and 1 with STel., Conclusions: Short and very short telomeres were highly prevalent in patients with idiopathic PSVD, with 31% presenting with variants in telomere-related genes. Telomere biology may play an important role in vascular liver disease development. Clinicians should consider measuring telomeres in any patient presenting with PSVD., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Introduction: The Swiss Eosinophilic Esophagitis Cohort Study (SEECS) is a national cohort that was established in 2015 with the aim of improving quality of care of affected adults with eosinophilic esophagitis (EoE). Between 2020 and 2022, paper questionnaires were gradually replaced by fully electronic data capture using Research Electronic Data Capture (REDCap ® ) software. We aim to provide an update of the SEECS 8 years after its launch., Methods: The SEECS prospectively includes adults (≥18 years of age) with EoE as well as patients with gastroesophageal reflux disease (GERD) and healthy control subjects (HC). Upon inclusion and follow-up (typically once every 12-18 months), patients and physicians complete REDCap ® questionnaires, which are available in German, French, and English. Patient-reported outcomes (PROs) and biologic findings are assessed on the same day using validated instruments (EEsAI PRO for symptoms; EoE-QoL-A for QoL; EREFS for endoscopic activity; modified EoE-HSS for histologic activity). The SEECS biobank includes biosamples from patients with EoE, GERD, and HC., Results: As of July 2023, the SEECS included 778 patients (716 [92%] with EoE, 29 [3.8%] with GERD, and 33 [4.2%] HC; 559/778 [71.9%] were male). Mean age ± SD (years) at enrollment according to diagnosis was as follows: EoE 41.9 ± 12.9, GERD 53.6 ± 16.4, HC 51.7 ± 17.2. Concomitant GERD was found in 200 patients (27.9%) of the EoE cohort. Concomitant allergic disorders (asthma, rhinoconjunctivitis, eczema) were present in 500 EoE patients (74.4%). At inclusion, 686 (95.8%) of EoE patients were on ongoing treatment (orodispersible budesonide tablet [Jorveza ® ] in 281 patients [41%]; budesonide or fluticasone syrup or swallowed powder in 290 patients [42.3%]; proton-pump inhibitors in 162 patients [23.6%]; elimination diets in 103 patients [15%]; and esophageal dilation at last visit in 166 patients [24.2%]). A total of 8,698 biosamples were collected, of which 1,395 (16%) were used in the framework of translational research projects., Conclusion: SEECS continuously grows and is operational using fully electronic data capture. SEECS offers up-to-date epidemiologic and real-world clinical efficacy data on EoE and promotes clinical and translational research., Competing Interests: Jeanine Wakim has no relevant financial, professional, or personal relationships to disclose. Ekaterina Safroneeva reports (i) consulting fees from Avir Pharma, Inc., Aptalis Pharma, Inc., Celgene Corp., Novartis, AG, and Regeneron Pharmaceuticals Inc.; (ii) being an employee of Tillotts Pharma AG. Catherine Saner has no relevant financial, professional, or personal relationships to disclose. Jean-Benoit Rossel has no relevant financial, professional, or personal relationships to disclose. Sven Trelle has no relevant financial, professional, or personal relationships to disclose. Marcel Zwahlen has no relevant financial, professional, or personal relationships to disclose. Luc Biedermann received consulting fees and/or speaker fees and/or research grants from Adare/Ellodi Pharmaceuticals, Inc., AstraZeneca, AG, Switzerland, Receptos-Celgene-BMS, Dr. Falk Pharma, GmbH, Germany, Glaxo Smith Kline, AG, Nestlé S. A., Switzerland, Novartis, AG, Switzerland, and Regeneron-Sanofi Pharmaceuticals. Andrea Kreienbuehl has no relevant financial, professional, or personal relationships to disclose. Thomas Greuter received consulting fees and/or speaker fees and/or research grants from Adare/Ellodi Pharmaceuticals, Inc., AstraZeneca, AG, Switzerland, Receptos-Celgene-BMS, Dr. Falk Pharma, GmbH, Germany, Glaxo Smith Kline, AG, Nestlé S. A., Switzerland, Novartis, AG, Switzerland, and Regeneron-Sanofi Pharmaceuticals. Philipp Schreiner received consulting fees and/or speaker fees from Dr. Falk Pharma, GmbH, Takeda, Regerenon-Sanofi Pharmaceuticals, AbbVie, Janssen-Cilag, Receptos-Celgene-BMS. Peter Netzer has no relevant financial, professional, or personal relationships to disclose. Annett Franke has no relevant financial, professional, or personal relationships to disclose. Stephan Brand has no relevant financial, professional, or personal relationships to disclose. Chantal Hasler has no relevant financial, professional, or personal relationships to disclose. Patrick Aepli has no relevant financial, professional, or personal relationships to disclose. Emanuel Burri has no relevant financial, professional, or personal relationships to disclose. Achim Weber has no relevant financial, professional, or personal relationships to disclose. Christine Sempoux has no relevant financial, professional, or personal relationships to disclose. Ruggero Biral has no relevant financial, professional, or personal relationships to disclose. Wolfram Jochum has no relevant financial, professional, or personal relationships to disclose. Joachim Diebold has no relevant financial, professional, or personal relationships to disclose. Niels Willi has no relevant financial, professional, or personal relationships to disclose. Alex Straumann received consulting fees and/or speaker fees and/or research grants from Adare/Ellodi Pharmaceuticals, Inc., AstraZeneca, AG, Switzerland, Receptos-Celgene-BMS, Dr. Falk Pharma, GmbH, Germany, Glaxo Smith Kline, AG, Nestlé S. A., Switzerland, Novartis, AG, Switzerland, and Regeneron-Sanofi Pharmaceuticals. Alain Schoepfer received consulting fees and/or speaker fees and/or research grants from Adare/Ellodi Pharmaceuticals, Inc., AstraZeneca, AG, Switzerland, Receptos-Celgene-BMS, Dr. Falk Pharma, GmbH, Germany, Glaxo Smith Kline, AG, Nestlé S. A., Switzerland, Novartis, AG, Switzerland, and Regeneron-Sanofi Pharmaceuticals., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Eosinophilic esophagitis (EoE) variants have been recently characterized as conditions with symptoms of esophageal dysfunction resembling EoE, but absence of significant esophageal eosinophilia. Their disease course and severity have yet to be determined., Methods: Patients from 6 EoE centers with symptoms of esophageal dysfunction, but peak eosinophil counts of <15/hpf in esophageal biopsies and absence of gastroesophageal reflux disease with at least one follow-up visit were included. Clinical, (immuno)histological, and molecular features were determined and compared with EoE and healthy controls., Results: We included 54 patients with EoE variants (EoE-like esophagitis 53.7%; lymphocytic esophagitis 13.0%; and nonspecific esophagitis 33.3%). In 8 EoE-like esophagitis patients, EoE developed after a median of 14 months (interquartile range 3.6-37.6). Such progression increased over time (17.6% year 1, 32.0% year 3, and 62.2% year 6). Sequential RNA sequencing analyses revealed only 7 genes associated with this progression (with TSG6 and ALOX15 among the top 3 upregulated genes) with upregulation of a previously attenuated Th2 pathway. Immunostaining confirmed the involvement of eosinophil-associated proteins (TSG6 and ALOX15) and revealed a significantly increased number of GATA3-positive cells during progression, indicating a Th1/Th2 switch. Transition from one EoE variant (baseline) to another variant (during follow-up) was seen in 35.2% (median observation time of 17.3 months)., Discussion: Transition of EoE variants to EoE suggests the presence of a disease spectrum. Few genes seem to be associated with the progression to EoE with upregulation of a previously attenuated Th2 signal. These genes, including GATA3 as a Th1/Th2 switch regulator, may represent potential therapeutic targets in early disease pathogenesis., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Introduction: Eosinophilic oesophagitis (EoE) was first described as an orphan disease in the 1990s, but its incidence and prevalence has increased dramatically in the last 20 years. EoE is now the most common cause of dysphagia in young adulthood. EoE is diagnosed endoscopically (with biopsies taken from the oesophagus). Treatment options consist of dietary measures and medications. The latter include PPI (as an off-label medication) and the approved drugs Jorveza (budesonide, topical cortisone preparation) and the monoclonal antibody Dupixent (dupilumab, subcutaneous). The response to therapy is high and the long-term outcome, if treated early, is excellent. However, the disease often remains undetected, mostly due to compensation mechanisms on the part of the patients. Much rarer than EoE are the non-EoE eosinophilic gastrointestinal diseases (EGIDs), in which the eosinophilic tissue infiltration is found in gastrointestinal segments distal to the oesophagus. Their clinical presentation is often non-specific. Pathophysiologically, overlaps with EoE are present. Therapies are also analogous to EoE. An increasing prevalence and incidence is to be expected., Competing Interests: Thomas Greuter erhielt Beraterhonorare von Sanofi-Regeneron, Janssen, BMS, Takeda, Abbvie und Dr Falk Pharma GmbH, Reiseunterstützung von Dr Falk Pharma GmbH, Takeda und Vifor, sowie Vortragshonorare von Norgine und Amgen. Catrina Waldegg hat keine Interessenskonflikte., (© 2023 Aerzteverlag medinfo AG.)

The field of gastroenterology and hepatology is evolving constantly. In 2022, numerous landmark studies have been published in all its subspecialities including hepatology, functional diseases, interventional endoscopy, and inflammatory bowel disease. Among the most significant advances are the antiviral treatment for hepatitis D, the new Chicago classification version 4 for esophageal motility disorders, the first biological treatment for eosinophilic esophagitis, a randomized controlled trial about the efficacy of screening colonoscopy, novel endoscopic techniques such as G-POEM or endoscopic sleeve gastrectomy, and emerging IBD therapies such as ozanimod, upadacitinib or anti-IL23 antibodies., Competing Interests: T. Greuter rapporte des contrats avec Sanofi-Regeneron, Janssen, BMS, Takeda, Abbvie et Falk Pharma GmbH. A. Schoepfer rapporte des contrats avec Falk Pharma GmbH, Ellodi Pharmaceuticals Inc, Celgene-Receptos-BMS et Sanofi-Regeneron. Les autres auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Introduction: There is a complex interrelationship between gastroesophageal reflux disease (GERD) and eosinophilic esophagitis (EoE) potentially promoting the occurrence and modulating severity of each other reciprocally. Presence of Barrett's esophagus (BE) is a defining factor for the diagnosis of GERD. While several studies investigated the potential impact of concomitant GERD on the presentation and course of EoE, little was known with regards to BE in EoE patients., Methods: We analyzed prospectively collected clinical, endoscopic, and histological data from patients enrolled in the Swiss Eosinophilic Esophagitis Cohort Study (SEECS) regarding differences between EoE patients with (EoE/BE+) versus without BE (EoE/BE-) and determined the prevalence of BE in EoE patients., Results: Among a total of 509 EoE patients included in our analysis, 24 (4.7%) had concomitant BE with a high male preponderance (EoE/BE+ 83.3% vs. EoE/BE- 74.4%). While there were no differences in dysphagia, odynophagia was significantly (12.5 vs. 3.1%, p = 0.047) more common in EoE/BE+ versus EoE/BE-. General well-being at last follow-up was significantly lower in EoE/BE+. Endoscopically, we observed an increased incidence of fixed rings in the proximal esophagus in EoE/BE+ (70.8 vs. 46.3% in EoE/BE-, p = 0.019) and a higher fraction of patients with a severe fibrosis in the proximal histological specimen (8.7 vs. 1.6% in EoE/BE, p = 0.017)., Conclusion: Our study reveals that BE is twice as frequent in EoE patients compared to general population. Despite many similarities between EoE patients with and without BE, the finding of a more pronounced remodeling in EoE patients with Barrett is noteworthy., (© 2023 S. Karger AG, Basel.)

Background & Aims: Substantial heterogeneity in terminology used for eosinophilic gastrointestinal diseases (EGIDs), particularly the catchall term "eosinophilic gastroenteritis," limits clinical and research advances. We aimed to achieve an international consensus for standardized EGID nomenclature., Methods: This consensus process utilized Delphi methodology. An initial naming framework was proposed and refined in iterative fashion, then assessed in a first round of Delphi voting. Results were discussed in 2 consensus meetings, and the framework was updated and reassessed in a second Delphi vote, with a 70% threshold set for agreement., Results: Of 91 experts participating, 85 (93%) completed the first and 82 (90%) completed the second Delphi surveys. Consensus was reached on all but 2 statements. "EGID" was the preferred umbrella term for disorders of gastrointestinal (GI) tract eosinophilic inflammation in the absence of secondary causes (100% agreement). Involved GI tract segments will be named specifically and use an "Eo" abbreviation convention: eosinophilic gastritis (now abbreviated EoG), eosinophilic enteritis (EoN), and eosinophilic colitis (EoC). The term "eosinophilic gastroenteritis" is no longer preferred as the overall name (96% agreement). When &gt;2 GI tract areas are involved, the name should reflect all of the involved areas., Conclusions: This international process resulted in consensus for updated EGID nomenclature for both clinical and research use. EGID will be the umbrella term, rather than "eosinophilic gastroenteritis," and specific naming conventions by location of GI tract involvement are recommended. As more data are developed, this framework can be updated to reflect best practices and the underlying science., (Copyright © 2022. Published by Elsevier Inc.)

Background & Aims: Liver sinusoidal endothelial cells (LSECs) are ideally situated to sense stiffness and generate angiocrine programs that potentially regulate liver fibrosis and portal hypertension. We explored how specific focal adhesion (FA) proteins parlay LSEC mechanotransduction into stiffness-induced angiocrine signaling in vitro and in vivo., Methods: Primary human and murine LSECs were placed on gels with incremental stiffness (0.2 kPa vs. 32 kPa). Cell response was studied by FA isolation, actin polymerization assay, RNA-sequencing and electron microscopy. Glycolysis was assessed using radioactive tracers. Epigenetic regulation of stiffness-induced genes was analyzed by chromatin-immunoprecipitation (ChIP) analysis of histone activation marks, ChIP sequencing and circularized chromosome conformation capture (4C). Mice with LSEC-selective deletion of glycolytic enzymes (Hk2 fl/fl /Cdh5 cre -ERT2) or treatment with the glycolysis inhibitor 3PO were studied in portal hypertension (partial ligation of the inferior vena cava, pIVCL) and early liver fibrosis (CCl 4 ) models., Results: Glycolytic enzymes, particularly phosphofructokinase 1 isoform P (PFKP), are enriched in isolated FAs from LSECs on gels with incremental stiffness. Stiffness resulted in PFKP recruitment to FAs, which paralleled an increase in glycolysis. Glycolysis was associated with expansion of actin dynamics and was attenuated by inhibition of integrin β1. Inhibition of glycolysis attenuated a stiffness-induced CXCL1-dominant angiocrine program. Mechanistically, glycolysis promoted CXCL1 expression through nuclear pore changes and increases in NF-kB translocation. Biochemically, this CXCL1 expression was mediated through spatial re-organization of nuclear chromatin resulting in formation of super-enhancers, histone acetylation and NF-kB interaction with the CXCL1 promoter. Hk2 fl/fl /Cdh5 cre -ERT2 mice showed attenuated neutrophil infiltration and portal hypertension after pIVCL. 3PO treatment attenuated liver fibrosis in a CCl 4 model., Conclusion: Glycolytic enzymes are involved in stiffness-induced angiocrine signaling in LSECs and represent druggable targets in early liver disease., Lay Summary: Treatment options for liver fibrosis and portal hypertension still represent an unmet need. Herein, we uncovered a novel role for glycolytic enzymes in promoting stiffness-induced angiocrine signaling, which resulted in inflammation, fibrosis and portal hypertension. This work has revealed new targets that could be used in the prevention and treatment of liver fibrosis and portal hypertension., Competing Interests: Conflicts of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Chronic diarrhea is defined by a decrease in stool consistency and a bowel frequency of more than 3 times per day, lasting for at least 4 weeks. Multiple underlying causes may be responsible for chronic diarrhea. There are four main pathomechanisms for chronic diarrhea: osmotic diarrhea, secretory diarrhea, infectious diarrhea and bowel dysmotility. Overlaps between these mechanisms may exist. A stool collection over a 72-hour period frequently allows to classify diarrhea into one of these four entities. Such classification finally helps for the identification of underlying cause(s), thereby allowing rational diagnostic measures. It also limits the costs of diagnostic workup. This article aims to present the main causes of chronic diarrhea, the diagnostic steps to perform and to provide a guideline for clinicians in daily practice., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Since most pharmacological treatments in case of esophageal food impaction (EFI) are unsuccessful, an endoscopy is usually required to resolve EFI. We present the first results of a budesonide orodispersible tablet (BOT) as a medical treatment option before endoscopy. We evaluated all patients with a suspected EFI to receive BOT before emergent endoscopy at a tertiary hospital between March 2019 and June 2020. A total of eight patients received BOT before endoscopy. Mean age was 50.1 years and 87.5% were male. In 38% (3/8) of patients the EFI resolved without endoscopic intervention. No adverse events occurred. After endoscopy, a diagnosis of EoE was established in 75%. This case series demonstrate the potential of BOT as medical rescue therapy in case of EFI., (© 2021. The Author(s).)

Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Here, we report steroid-free efficacy and safety with tofacitinib among patients with UC who received corticosteroids at baseline of the maintenance study (OCTAVE Sustain)., Methods: This analysis included patients with clinical response following OCTAVE Induction 1 and 2 who were re-randomized to receive placebo, or tofacitinib 5 or 10 mg twice daily (b.d.), in OCTAVE Sustain for 52 weeks and were receiving corticosteroids at OCTAVE Sustain baseline. Corticosteroid tapering was mandatory during OCTAVE Sustain. Rates of steroid-free remission, endoscopic improvement, and clinical response were assessed, stratified by baseline characteristics. Adverse events (AEs) were stratified by treatment and steroid-free remission status., Results: Overall, 289/593 patients had corticosteroid use at OCTAVE Sustain baseline. At week 52, steroid-free remission, endoscopic improvement, and clinical response rates were 10.9%, 11.9%, and 17.8% among patients receiving placebo, 27.7%, 29.7%, and 40.6% among patients receiving tofacitinib 5 mg b.d., and 27.6%, 29.9%, and 43.7% among patients receiving tofacitinib 10 mg b.d., respectively (non-responder imputation; all p  < 0.05 tofacitinib 5 or 10 mg b.d. versus placebo). Discontinuations due to AEs were lower among patients with steroid-free remission versus without. AEs of special interest were infrequent., Conclusion: For patients with baseline corticosteroid use in OCTAVE Sustain, the odds of achieving steroid-free efficacy endpoints were significantly higher for tofacitinib versus placebo, irrespective of tofacitinib dose. There were no apparent differences in AEs of special interest by steroid-free remission status.ClinicalTrials.gov: NCT01458574., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: S.R.V. has received consulting fees and unrestricted research grants from Abbott, Falk Pharma GmbH, Ferring Pharmaceuticals, Janssen, MSD, Pfizer Inc, Sanofi-Aventis, Takeda, Tillotts, UCB, and Vifor. T.G. has a consultancy contract with Sanofi-Aventis; has received a travel grant from Falk Pharma GmbH and Vifor; and has an unrestricted research grant from Novartis. B.L.C. has served as an advisory board member for and received consulting fees from AbbVie, Celgene-Bristol-Myers Squibb, Pfizer Inc, Sublimity Therapeutics, and TARGET RWE; fees from the CME companies, Cornerstones, and Vindico; and has received speaker fees from AbbVie. W.R. has received research grants from Abbott, AbbVie, AESCA, Centocor, Dr. Falk Pharma, Immundiagnostik, and MSD; lecture fees from Abbott, AbbVie, AESCA, Aptalis, Celltrion, Centocor, Danone, Dr. Falk Pharma, Elan, Ferring Pharmaceuticals, Immundiagnostik, Mitsubishi Tanabe Pharma, MSD, Otsuka, PDL, Pharmacosmos, Schering-Plough, Shire, Takeda, Therakos, Vifor, and Yakult; and consulting fees from Abbott, AbbVie, AESCA, Amgen, AM Pharma, Astellas, AstraZeneca, Avaxia Biologics, Bioclinica, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Cellerix, Celltrion, Centocor, ChemoCentryx, Covance, Danone, Dr. Falk Pharma, Elan, Ferring Pharmaceuticals, Galapagos, Genentech, Gilead Sciences, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson and Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millennium, Mitsubishi Tanabe Pharma, MSD, Nestlé, Novartis, Ocera, Otsuka, PDL, Pfizer Inc, Pharmacosmos, Procter & Gamble, Prometheus Laboratories, Robarts Clinical Trials, Schering-Plough, Second Genome, SetPoint Medical, Takeda, Therakos, TiGenix, UCB, Vifor, Zyngenia, and 4SC. F.S. has served as an advisory board member for Pfizer Inc and has received consulting and speaker fees from AbbVie, Eurofarma, Ferring Pharmaceuticals, Janssen, Sandoz, Takeda, and UCB. M.F., X.G., and N.L. are employees and shareholders of Pfizer Inc. J.P. is an employee of Syneos Health, which was a paid contractor to Pfizer in connection with the development of this manuscript and related statistical analysis. L.P.-B. has received honoraria from AbbVie, Allergan, Alma, Amgen Biogen, Arena, Boehringer Ingelheim, Celgene, Celltrion, Enterome, Ferring Pharmaceuticals, Genentech, Gilead Sciences, Hikma, Index Pharmaceuticals, Janssen, MSD, Nestlé, Pfizer Inc, Pharmacosmos, Roche, Samsung Bioepis, Sandoz, Sterna, Takeda, and Tillotts; grants from AbbVie, MSD, and Takeda; and is a stockholder of CTMA., (© The Author(s), 2022.)

Background and Aims: No recommendations exist regarding optimal follow-up schedule in patients with eosinophilic esophagitis (EoE) under maintenance treatment., Methods: We retrospectively evaluated a long-term surveillance concept at the Swiss EoE clinic, where clinical, endoscopic and histological disease activity is assessed annually regardless of EoE symptoms. Data on 159 adult patients under maintenance steroid treatment with available follow-up were analyzed. Patients were classified as having close (duration between visits <18 months) or non-close follow-up (≥18 months)., Results: We analyzed a total of 309 follow-up visits of 159 patients (123 males, age at diagnosis 38.9 ± 15.4 years). 157 (51%) visits were within a close follow-up schedule (median duration between visits of 1.0 years (interquartile range (IQR) 0.9-1.2)), while 152 visits (49%) were not (median duration between visits 2.9 years (IQR 2.0-4.1)). There was no difference regarding ongoing clinical, endoscopic, and histological disease activity, and adherence to prescribed steroid treatment between the two groups. However, stricture formation was significantly less frequently observed at visits within a close follow-up schedule (22.9 vs. 33.6%, p = 0.038). Absence of close follow-up was a significant risk factor for stricture development in a multivariate regression model. Patients who achieved histological remission and were followed within a close-follow-up schedule had significantly earlier detection of histological relapse compared to patients not within such close follow-up., Conclusion: Close follow-up is associated with fewer stricture formation and appears to result in earlier detection of histological relapse in patients with eosinophilic esophagitis. We advocate for regular assessment of disease activity (every 12-18 months) in order to detect relapsing disease as early as possible, and therefore potentially minimize the risk for EoE complications., (© 2022 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Given the paucity of data, we aimed to assess the impact of obesity on disease activity, complications, and quality of life (QoL) in pediatric inflammatory bowel disease (IBD) patients., Methods: Prospective analysis of pediatric IBD patients. Patients were categorized into 4 groups according to the World Health Organization (WHO) child growth standards: obese, overweight, normal weight, and underweight., Results: Three hundred twenty-seven pediatric patients were included (146 with Crohn's disease [CD], 181 with ulcerative colitis of whom 13 [4%] were underweight, 272 [83.2%] had normal weight, 22 [6.7%] were overweight, and 20 [6.1%] were obese). Compared with normal weight patients, obese ulcerative colitis had a significantly higher clinical but not biological disease activity nor severity. Compared with normal weight patients, overweight/obese CD patients did not have higher clinical or biological disease activity nor severity. Perianal abscesses and surgery for this purpose were more frequently observed in overweight/obese CD patients compared with normal weight controls. Overweight/obese IBD patients were similarly hospitalized in the last 12 months compared with normal weight controls., Conclusions: Prevalence of overweight/obesity was 12.8% in pediatric IBD patients. Obesity was not associated with a decrease in disease remission rates nor an increase in the risk of complicated disease progression in IBD pediatric patients, except for the occurrence of perianal abscesses and related surgery in CD patients., Competing Interests: The authors report no conflict of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Inflammatory bowel disease (IBD) patients are at high risk for depression, and depression has been shown to affect disease course. We examined interrelations between depression, genetic risk factors for depression, and IBD flares., Method: In 1973 patients (1137 Crohn's disease, 836 ulcerative colitis) of the Swiss IBD Cohort Study (SIBDCS), depressive status (hospital anxiety and depression subscale for depression, HADS-D ≥11) was assessed on a yearly basis. We investigated the impact of depression on IBD-relevant clinical outcomes in Cox proportional hazards models. We used active disease (CDAI ≥150 or MTWAI ≥10) and 2 published composite flare definitions-FNCE (physician-reported flare, nonresponse to therapy, new complication, or extraintestinal manifestation) and AFFSST (active disease, physician-reported flare, fistula, stenosis, and new systemic therapy)-as clinical end points. Additionally, 62 preselected single nucleotide polymorphisms (SNPs) were screened for cross-sectional associations with depression, and if present, their predictive value for future depression and clinical deterioration was assessed., Results: Depression was a strong risk factor for disease-related end points, including active disease (adjusted hazard ratio [aHR], 3.55; P < 0.001), AFFSST (aHR, 1.62; P < 0.001), and FNCE (aHR, 1.35; P = 0.019). The SNP rs2522833 was significantly associated with depression at enrollment (q = 0.059). The TC allele of rs588765 was negatively associated with the presence of depression at enrollment (q = 0.050) and after enrollment (aHR, 0.67; P = 0.035) and with fewer active disease states (aHR, 0.72; P = 0.045) during follow-up., Conclusion: In IBD, depressive symptoms and inflammatory activity are intimately related. Depressive symptoms were a strong predictor of clinical deterioration, and genetic markers may play a role in this relationship., (© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: End points used to determine treatment efficacy in eosinophilic esophagitis (EoE) have evolved over time. With multiple novel therapies in development for EoE, harmonization of outcomes measures will facilitate evidence synthesis and appraisal when comparing different treatments., Objective: We sought to develop a core outcome set (COS) for controlled and observational studies of pharmacologic and diet interventions in adult and pediatric patients with EoE., Methods: Candidate outcomes were generated from systematic literature reviews and patient engagement interviews and surveys. Consensus was established using an iterative Delphi process, with items voted on using a 9-point Likert scale and with feedback from other participants to allow score refinement. Consensus meetings were held to ratify the outcome domains of importance and the core outcome measures. Stakeholders were recruited internationally and included adult and pediatric gastroenterologists, allergists, dieticians, pathologists, psychologists, researchers, and methodologists., Results: The COS consists of 4 outcome domains for controlled and observational studies: histopathology, endoscopy, patient-reported symptoms, and EoE-specific quality of life. A total of 69 stakeholders (response rate 95.8%) prioritized 42 outcomes in a 2-round Delphi process, and the final ratification meeting generated consensus on 33 outcome measures. These included measurement of the peak eosinophil count, Eosinophilic Esophagitis Histology Scoring System, Eosinophilic Esophagitis Endoscopic Reference Score, and patient-reported measures of dysphagia and quality of life., Conclusions: This interdisciplinary collaboration involving global stakeholders has produced a COS that can be applied to adult and pediatric studies of pharmacologic and diet therapies for EoE and will facilitate meaningful treatment comparisons and improve the quality of data synthesis., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Extraintestinal manifestations are reported to occur in up to 45% of inflammatory bowel disease (IBD) patients during the course of disease. It is unknown whether colectomy reduces the rate of de novo extraintestinal manifestations (EIMs) or impacts on severity of EIMs following a parallel versus independent disease course from underlying IBD., Methods: Using data from the Swiss Inflammatory Bowel Disease Cohort Study we aimed to analyse the course of EIMs in ulcerative colitis (UC) and Crohn's disease (CD) patients undergoing colectomy during the cohort's prospective follow-up., Results: One hundred and twenty-one IBD patients (33 CD, 81 UC and seven unclassified) underwent colectomy during prospective follow-up in the Swiss Inflammatory Bowel Disease Cohort Study. Within the 114 patients with UC or CD any EIM was reported in 40 (nine CD and 31 UC) patients. Activity of EIMs ceased entirely after colectomy in 21 patients (52.5%). Complete cessation of EIM after colectomy was higher in patients with UC versus CD with 58.1% versus 33.3%. After colectomy, 29 out of the 114 patients (25.4%) experienced any EIM. Two thirds of these (19 patients) represented persisting EIMs, while in one third (10 patients) EIM represented a de-novo event after colectomy. Overall, 13.5% of IBD patients developed a de-novo EIM after colectomy., Conclusions: In IBD patients undergoing colectomy, EIMs present prior to surgery will persist in about half of patients. Complete cessation of EIM after colectomy may be less common in CD than in UC. In patients who never experienced EIMs prior to colectomy de-novo manifestations thereafter should be expected in up to one in seven patients., (© 2021 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Eosinophilic gastrointestinal disorders (EGIDs) are a collection of disorders characterized by allergy-driven inflammation of the gastrointestinal (GI) tract. Affected patients typically present with nonspecific symptoms of GI dysfunction and are frequently found to have mucosal abnormalities during endoscopy as well as increased eosinophil levels on tissue biopsy that are felt to be responsible for generating the clinical findings. Each of these findings is important in both the diagnosis and management of EGIDs. Understanding the impact of histopathologic and endoscopic changes on clinical signs and symptoms is critical to developing an understanding of the natural history of these disorders as well as to the generation of validated assessment tools and targeted therapies. We explore these relationships in this review., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Inflammatory bowel diseases (IBD) comprise Crohn's disease (CD) and ulcerative colitis (UC). IBD develops in patients with genetic susceptibility due to an aberrant response of the intestinal immune system toward gut microbiota. The prevalence of IBD is on the rise in Switzerland, with currently 1/250 persons affected, which corresponds to approximately 35,000 patients. Given the complexity of IBD, patients should be managed by a multidisciplinary team. This article focuses on IBD diagnosis and long-term follow-up., Competing Interests: Le Pr Alain Schoepfer était dans les deux dernières années consultant pour Abbvie, Alfasigma, Amgen, AstraZeneca, Janssen-Cilag, Dr Falk Pharma, MSD, Mylan, Pfizer, Takeda et Vifor. Les autres auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Several new techniques have recently been introduced in digestive endoscopy. Among these are anti-reflux mucosectomy (ARMS) or mucosal ablation (ARMA) which have demonstrated efficacy in the treatment of patients with refractory gastro-esophageal reflux disease. Both can be considered in the absence of a large hiatal hernia. Comparable to the well-established peroral endoscopic myotomy (POEM) for the treatment of achalasia, gastric POEM (G-POEM), an endoscopic antro-pyloromyotomy, represents an endoscopic technique for the treatment of gastroparesis, including diabetic, post-surgical and idiopathic subtypes. Finally, endoscopic ultrasound-guided radiofrequency ablation (EUSRA) can be considered as alternative to surgery in selected patients with small tumoral lesions of the pancreas., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Background & Aims: Eosinophilic esophagitis (EoE) most often affects young patients of reproductive age, yet little is known about its effects during pregnancy. We examined the course of EoE during pregnancy, outcomes of pregnancies, and patient concerns related to pregnancy and EoE., Methods: We sent a survey that queried demographic and disease-specific characteristics as well as pregnancy-related topics to all 151 female patients treated at 2 EoE centers in Switzerland. We analyzed cross-sectional survey data., Results: Of 72 patients that returned the survey, we identified 20 patients that had at least 1 pregnancy and analyzed the data on 34 pregnancies. During pregnancy, improvement of dysphagia was reported in 56% (19/34) of all pregnancies, whereas deterioration was reported in 20% (7/34) of all pregnancies. After delivery, dysphagia returned to the pre-pregnancy level in 68% (13/19) of all pregnancies for patients with improvement of dysphagia and 57% (4/7) of all pregnancies for patients with deterioration of dysphagia during pregnancy. Esophagogastroduodenoscopy during pregnancy was required in less than 10% (3/34) of all pregnancies. Pregnancy-related complications occurred in 12% of pregnancies (4/34). The leading patient-reported concerns were fear of heritability (40% of patients, 8/20) and concerns of that use of medication would harm the fetus (30% of patients, 6/20)., Conclusions: Pregnancy affects the course of EoE, with improvement of symptoms reported in most patients. Dysphagia returned to the pre-pregnancy level following delivery. EoE has likely no negative effects on outcomes of pregnancies., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Immune-mediated diseases typically show a female preponderance. Looking at all autoimmune diseases combined, 8 of 10 patients are females. Although not as prominent, gender differences in inflammatory bowel disease (IBD) have been reported for epidemiology, disease presentation, disease course and complications, medical and surgical therapies, adherence, psychosocial functioning, and psychiatric co-disorders. While for some factors evidence is rather good, for others data are conflicting. Gastroenterologists dealing with IBD patients in daily clinical practice should be aware of gender-specific issues for the following reasons: (1) misperception of disease presentation potentially delays IBD diagnosis, which has been shown to have deleterious effects, and (2) awareness of gender-specific symptoms and disease severity allows initiation of early and adequately tailored treatment. This might prevent development of complications. And (3) insights into gender-specific differences in terms of treatment and adherence to treatment can improve disease management and foster a more individualized treatment approach. In this review, we summarize current knowledge about gender-specific differences in IBD and highlight the most clinically relevant aspects., (© 2020 S. Karger AG, Basel.)

Background & Aims: Transforming growth factor (TGF-β)-induced activation of quiescent hepatic stellate cells (HSCs) and their transformation to myofibroblasts is a key event in liver fibrosis and portal hypertension. GIPC (also referred to as synectin) is a downstream signal activation molecule of TGF-β and other receptors. In this study, we sought to identify novel genes targeted by TGF-β and GIPC and elucidate if and how they may contribute to liver fibrosis., Methods: We performed sequential messenger RNA sequencing analysis on TGF-β-stimulated HSCs and then on TGF-β-stimulated HSCs in the presence and absence of GIPC also referred to as synectin (GIPC) knockdown. Insulin-like growth factor binding protein-3 (IGFBP-3) transport protein emerged as a top activation target of both TGF-β and GIPC. Quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, targeted chromatin immunoprecipitation, and Western blot analysis were done for further confirmation., Results: IGFBP-3, an insulin growth factor transport protein, emerged as a top activation target of both TGF-β and GIPC, which was confirmed by quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blot analysis. Targeted chromatin immunoprecipitation showed that GIPC increases the histone 3 lysine 27 (H3K27) acetylation activating mark and concurrently decreases the H3K27 inhibitory trimethylation (H3K27m3) mark, providing an epigenetic correlate to the gene regulation changes. In vivo, global knockout of IGFBP-3 mice resulted in attenuation of HSC activation markers and attenuation of portal pressure in response to chronic liver injury models. Analysis of serum levels from cirrhotic patients also showed an IGFBP-3 increase of more than 2-fold compared with healthy controls. Finally, in vitro mechanism studies showed that IGFBP-3 promotes HSC migration through integrin-dependent phosphorylation of protein kinase B., Conclusions: TGF-β up-regulates IGFBP-3 through GIPC, leading to increased HSC migration in vitro and promotes portal hypertension in vivo. These studies support the role of IGFBP-3 as a potential pathophysiologic target or biomarker in chronic liver disease., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder, primarily of, but not restricted to, the gut. Association between IBD and cancer has been clearly established and is uniformly accepted., Summary: IBD patients are at particular risk for intestinal and extraintestinal cancers. There are 2 underlying mechanisms: (1) IBD-related inflammation triggers initiation and progression of tumor formation. This particularly results in the development of colorectal cancer, small bowel adenocarcinoma, intestinal lymphoma, anal cancer, and cholangiocarcinoma. (2) Immunosuppressive drugs exhibit carcinogenic properties such as shown for azathioprine and anti-TNF promoting lymphoproliferative malignancies and melanoma and nonmelanoma skin cancer. However, within the last years, IBD-related cancer incidence and prevalence have been decreasing, which might be attributed to better treatment options and surveillance strategies. Moreover, novel biological drugs have been introduced in clinical practice and have dramatically changed long-term IBD management. Therefore, we sought to summarize up-to-date knowledge about (1) overall cancer risk; (2) risk and protective factors for cancer development; and (3) inflammation- and immunosuppression-related malignancies in the current anti-TNF era of IBD. Key Messages: Recent studies and meta-analyses questioned the excess rates of cancer in IBD patients. However, IBD still is associated with cancer development due to ongoing intestinal inflammation and the use of potential carcinogenic drugs. Patients should be educated about the increased risk of cancer with IBD and IBD drugs. However, they should also be informed that most malignancy subtypes are possibly preventable by controlling intestinal inflammation and by using adequate screening strategies., (© 2020 The Author(s). Published by S. Karger AG, Basel.)

Background: Loss of response is frequently encountered in patients with inflammatory bowel disease (IBD) treated with antitumor necrosis factor (TNF) agents. Therapeutic drug monitoring (TDM) and antidrug antibody measurement are increasingly used in this setting., Methods: To establish a consensus on the use of TDM in the context of loss of response to anti-TNFs, we performed a vote using a Delphi-style process followed by an expert panel discussion among 8 IBD specialists practicing in Switzerland, Europe. Statements were rated on an even Likert-scale ranging from 1 (strong disagreement) to 4 (strong agreement), based on expert opinion and the available literature., Results: The experts agreed on the following statements: (i) loss of response is associated with inadequate drug levels in both Crohn's disease and ulcerative colitis; (ii) best timepoint for measuring drug levels is prior to the next application (= trough levels) with different thresholds for anti-TNF agents (infliximab 5 μg/mL, adalimumab 8 μg/mL, certolizumab pegol 10 μg/mL); (iii) antidrug antibodies are predictive for loss of response; and (iv) antidrug-antibody titers and drug trough levels are key determinants in the treatment algorithm. Data about non-anti-TNF biologics were considered too limited to propose recommendations., Conclusion: A Delphi-style consensus among 8 IBD experts shows that TDM and measurement of antidrug-antibody titers are useful in the context of loss of response to anti-TNF. Optimal cutoff levels depend on the type of anti-TNF. These values are critical in the decision making process. More studies are needed to address the value of such measurements for non-anti-TNF biologics., (© 2019 S. Karger AG, Basel.)

Background & Aims: Transdifferentiation of hepatic stellate cells (HSCs) into myofibroblasts is a key event in the pathogenesis of liver fibrosis. Transforming growth factor β (TGF-β) and platelet-derived growth factor (PDGF) are canonical HSC activators after liver injury. The aim of this study was to analyze the epigenetic modulators that differentially control TGF-β and PDGF signaling pathways., Methods: We performed a transcriptomic comparison of HSCs treated with TGF-β or PDGF-BB using RNA sequencing. Among the targets that distinguish these 2 pathways, we focused on the histone methyltransferase class of epigenetic modulators., Results: Enhancer of zeste homolog 2 (EZH2) was expressed differentially, showing significant up-regulation in HSCs activated with TGF-β but not with PDGF-BB. Indeed, EZH2 inhibition using either a pharmacologic (GSK-503) or a genetic (small interfering RNA) approach caused a significant attenuation of TGF-β-induced fibronectin, collagen 1α1, and α-smooth muscle actin, both at messenger RNA and protein levels. Conversely, adenoviral overexpression of EZH2 in HSCs resulted in a significant stimulation of fibronectin protein and messenger RNA levels in TGF-β-treated cells. Finally, we conducted in vivo experiments with mice chronically treated with carbon tetrachloride or bile duct ligation. Administration of GSK-503 to mice receiving either carbon tetrachloride or bile duct ligation led to attenuated fibrosis as assessed by Trichrome and Sirius red stains, hydroxyproline, and α-smooth muscle actin/collagen protein assays., Conclusions: TGF-β and PDGF share redundant and distinct transcriptomic targets, with the former predominating in HSC activation. The EZH2 histone methyltransferase is preferentially involved in the TGF-β as opposed to the PDGF signaling pathway. Inhibition of EZH2 attenuates fibrogenic gene transcription in TGF-β-treated HSCs and reduces liver fibrosis in vivo. The data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE119606 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE119606)., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Extraintestinal manifestations in chronic inflammatory bowel diseases Abstract. Chronic inflammatory bowel diseases (IBD) are inflammatory gastrointestinal disorders that are not limited to the gastrointestinal tract. Various organ systems may be involved, making IBD a systemic disease. The most common extraintestinal manifestations (EIMs) include musculoskeletal, ophthalmic, dermatological and hepato-biliary disorders. EIMs considerably contribute to the morbidity of patients with IBD and also limit their quality of life. Due to the diversity of the organ systems involved, care should be provided on an interdisciplinary basis by a medical staff trained in the treatment of IBD. Early detection of EIM allows targeted therapy and reduces the overall morbidity of the affected patients. Of importance is the fact that EIM can occur in up to 25 % of all IBD patients before the onset of the first Crohn's episode or ulcerative colitis. Therefore, dermatologists, ophthalmologists and rheumatologists should beware of this possible association in EIM and the simultaneous occurrence of intestinal symptoms.

The scaffold protein synectin plays a critical role in the trafficking and regulation of membrane receptor pathways. As platelet-derived growth factor receptor (PDGFR) is essential for hepatic stellate cell (HSC) activation and liver fibrosis, we sought to determine the role of synectin on the PDGFR pathway and development of liver fibrosis. Mice with deletion of synectin from HSC were found to be protected from liver fibrosis. mRNA sequencing revealed that knockdown of synectin in HSC demonstrated reductions in the fibrosis pathway of genes, including PDGFR-β. Chromatin IP assay of the PDGFR-β promoter upon synectin knockdown revealed a pattern of histone marks associated with decreased transcription, dependent on p300 histone acetyltransferase. Synectin knockdown was found to downregulate PDGFR-α protein levels, as well, but through an alternative mechanism: protection from autophagic degradation. Site-directed mutagenesis revealed that ubiquitination of specific PDGFR-α lysine residues was responsible for its autophagic degradation. Furthermore, functional studies showed decreased PDGF-dependent migration and proliferation of HSC after synectin knockdown. Finally, human cirrhotic livers demonstrated increased synectin protein levels. This work provides insight into differential transcriptional and posttranslational mechanisms of synectin regulation of PDGFRs, which are critical to fibrogenesis.