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Background Background: The feasibility of anti-TNF discontinuation in inflammatory bowel disease (IBD) must be proven in clinical trials including patients in clinical, endoscopic, and radiologic remission at the time of anti-TNF withdrawal to make recommendations for clinical practice. Aims Primary: to compare the rates of clinical remission at 1 year in patients who discontinue anti-TNF treatment vs. those who continue treatment. Secondary objectives: to know the effect of anti-TNF withdrawal on relapse-free time, mucosal healing and safety; and to identify predictive factors for relapse. Methods Prospective, quadruple-blind, multicentre, randomised, controlled trial. Patients with ulcerative colitis (UC) or Crohn’s disease (CD) in clinical remission for > 6 months were randomised to maintain anti-TNF treatment [maintenance arm (MA)] or to withdraw it [withdrawal arm (WA)]. Patients who were on infliximab (IFX) received IFX 5 mg/kg or an intravenous placebo every 8 weeks, while patients on adalimumab (ADA) received subcutaneous ADA 40 mg or placebo every other week. Patients were followed-up until month 12 or up to the time of clinical relapse, whichever came first. Inclusion and exclusion criteria, trial scheme and definitions are summarized in figures 1a, 1b and 1c. Results were analysed by intention-to-treat (ITT) and by per-protocol (PP). Local investigators were blinded to faecal calprotectin (FC) and IFX and ADA trough levels. On-site monitoring was performed to assess data quality. Results 159 patients were screened, from whom 140 were randomised and comprised the ITT cohort: 70 allocated to the MA and 70 to the WA. Fifteen patients dropped out before the end of follow-up (12 months or relapse), leaving 63 patients in the MA and 62 patients in the WA for the PP analysis. The characteristics of patients in the MA and WA were similar (figure 2). The proportions of patients who maintained clinical remission -59/70 (84%), 95% confidence interval (CI)=74-92% in the MA vs. 53/70 (76%), 95%CI=64-85% in the WA- and who remained without significant endoscopic lesions at the end of follow-up were similar between groups (figures 3a, 3b, 3c). Only the proportion of patients with FC >250 mg/g was higher in the WA at the end of follow-up (figure 3d). Maintenance of clinical remission was no different between groups (figure 4). The same percentage of patients in both groups had at least one adverse event (69%). The proportion of patients with serious adverse events was also similar between groups (4% in MA vs. 7% in WA). Conclusion Anti-TNF withdrawal in selected IBD patients in clinical, endoscopic, and radiologic remission could be feasible without an increase in the risk of clinical relapse. Long-term follow-up of these patients is warranted.

Background There is scarce information about Crohn’s disease (CD) affecting oesophagus, stomach and duodenum. The aim of the study was to describe phenotypic features, disease course and treatment response in these patients. Methods Patients with CD and upper involvement (oesophagus, stomach and/or duodenum) were included (upper CD=UCD). Extensive CD (ECD) was defined as concomitant distal involvement (jejunal, ileal and/or colonic). A multicentric, longitudinal and retrospective study was designed to evaluate disease characteristics at diagnosis and behaviour of UCD in patients >= 18 years between January 2000 and December 2019 with at least 1 year follow-up since diagnosis. All treatments for UCD diagnosis and reason to start them were recorded, as well as 14- and 52-week response. Incidence of malignancy was also evaluated. Descriptive statistics were applied for quantitative and qualitative variables. Exact Fisher test was used for comparison of proportions. Results 197 (0.9%) UCD among 21.670 patients with Crohn’s Disease (CD) from 28 Spanish centres were included with a median of 10.7 years follow-up (min 2.2– max 22.1). Nearly 55% were men: median age at CD diagnosis was 29 years whereas for UCD was 32 years, with a mean of 2 months between CD and UCD diagnosis (SD 0.4). Only 9 patients had isolated UCD, whereas the rest presented ECD. 97% were diagnosed by endoscopy, in 2/3 due to symptoms (epigastric pain and dyspepsia). Inflammatory phenotype was prevalent in UCD with aphthous ulcer as the main endoscopic lesion (42%). Isolated duodenal location was the most frequent, followed by the antrum. Systemic corticosteroids and thiopurines were the most used treatments after UCD diagnosis. Treatment response at 14- and 52-weeks is detailed in Figures 1 and 2. Treatment withdrawal due to UCD activity was seen in 2-11% of patients. Thiopurines was the most durable treatment (median 50 months, min 0–max 210) followed by infliximab and adalimumab. Ten patients presented phenotype change over time (90% from inflammatory to stricturing). 53% of patients underwent endoscopic control (44% due to symptoms). De novo metaplasia was detected in 3 patients, and low-grade visible dysplasia in one. Two patients developed neoplasia: 1 gastric MALT lymphoma and 1 oesophagus carcinoma 5.5 and 20 years after UCD diagnosis, respectively. Conclusion UCD in adult population is infrequent. Upper involvement does not have an impact on immunosuppressive treatment requirements, but extensive disease does, appreciating a similar response to treatments for proximal and distal disease, both in the short and medium term. Although rare, risk of malignancy in UCD exists.

Cow's milk protein is the main food trigger for eosinophilic oesophagitis (EoE) in children and adults and should be continuously avoided once identified as such.To evaluate tolerance of sterilised cow's milk (boiled instead of UHT processing) with regard to maintenance of EoE remission, health-related quality of life (HRQoL), nutritional intake and allergic sensitisation in patients of all ages with milk-triggered EoE METHODS: We prospectively recruited patients in whom cow's milk was demonstrated to trigger EoE after an empirical food elimination diet-based study. They were given 200 ml of sterilised cow's milk twice daily for 8 weeks. Endoscopic assessment, peak eosinophil counts, oesophageal-related symptoms, HRQoL, blood eosinophils, eosinophil cationic protein (ECP), skin prick test and serum total and specific immunoglobulin E (IgE) to major milk proteins were monitored before and after sterilised milk intake.Eighteen patients (13 male) in EoE remission underwent a sterilised milk challenge. Twelve maintained EoE remission (15 eos/hpf) while EoE recurred in the remainder. Endoscopic appearances deteriorated in non-tolerant patients. HRQoL scored well at baseline and was maintained among patients tolerant to sterilised milk, but deteriorated in reactive ones. No significant changes in blood eosinophil count, ECP, tryptase or total and milk-specific IgE serum levels were observed from baseline. However, cow's milk-specific IgE increased slightly in non-tolerant patients. Clinical and histological remission were maintained in patients who regularly consumed sterilised milk for 1 year.Sterilised milk did not trigger EoE in two-thirds of patients with documented milk-induced EoE, in either the short or long term.

Background: A novel budesonide orodispersible tablet (BOT) has been proven effective in adult patients with active eosinophilic oesophagitis (EoE) in a 6-week placebo-controlled trial (EOS-1). Aims: To report the efficacy of an open-label induction treatment with BOT in a large prospective cohort of EoE patients within the EOS-2 study. Methods: Patients with clinico-histological active EoE were treated with BOT 1 mg BID for 6 weeks. The primary endpoint was clinico-histological remission (≤2 points on numerical rating scales [0–10] each for dysphagia and odynophagia, and peak eosinophil count

The prevalence of penetrating complications in Crohn's disease (CD) increases progressively over time, but evidence on the medical treatment in this setting is limited. The aim of this study was to evaluate the effectiveness of biologic agents in CD complicated with internal fistulizing disease.Adult patients with CD-related fistulae who received at least one biologic agent for this condition from the prospectively-maintained ENEIDA registry were included. Exclusion criteria involved those receiving biologics for perianal disease, enterocutaneous, rectovaginal, anastomotic or periostomal fistulae. The primary endpoint was fistula-related surgery. Predictive factors associated with surgery and fistula closure were evaluated by multivariate logistic regression and survival analyses.A total of 760 patients from 53 hospitals (673 receiving anti-TNFs, 69 ustekinumab, and 18 vedolizumab) were included. After a median follow-up of 56 months (IQR, 26-102), 240 patients required surgery, with surgery rates of 32%, 41%, 24% among those under anti-TNF, vedolizumab, or ustekinumab, respectively. Fistula closure was observed in 24% of patients. Older patients, ileocolonic disease, entero-urinary fistulae, or an intestinal stricture distal to the origin of the fistula were associated with a higher risk of surgery, while non-smokers, and combination therapy with an immunomodulator reduced this risk.Biologic therapy is beneficial in approximately three quarters of patients with fistulizing CD, achieving fistula closure in 24%. However, around one third still undergo surgery due to refractory disease. Some patient and lesion-related factors can identify patients who will obtain more benefit from these drugs.

Background Dupilumab, a fully human monoclonal antibody, blocks interleukin-4 and interleukin-13 signaling, which have key roles in eosinophilic esophagitis. Methods We conducted a three-part, phase 3 trial in which patients 12 years of age or older underwent randomization in a 1:1 ratio to receive subcutaneous dupilumab at a weekly dose of 300 mg or placebo (Part A) or in a 1:1:1 ratio to receive 300 mg of dupilumab either weekly or every 2 weeks or weekly placebo (Part B) up to week 24. Eligible patients who completed Part A or Part B continued the trial in Part C, in which those who completed Part A received dupilumab at a weekly dose of 300 mg up to week 52 (the Part A-C group); Part C that included the eligible patients from Part B is ongoing. The two primary end points at week 24 were histologic remission (≤6 eosinophils per high-power field) and the change from baseline in the Dysphagia Symptom Questionnaire (DSQ) score (range, 0 to 84, with higher values indicating more frequent or more severe dysphagia). Results In Part A, histologic remission occurred in 25 of 42 patients (60%) who received weekly dupilumab and in 2 of 39 patients (5%) who received placebo (difference, 55 percentage points; 95% confidence interval [CI], 40 to 71; P

ObjectiveTo evaluate the use, effectiveness and safety ofHelicobacter pyloriempirical rescue therapy in third and subsequent treatment lines in Europe.DesignInternational, prospective, non-interventional registry of the clinical practice of European gastroenterologists. Data were collected and quality reviewed until October 2021 at Asociación Española de Gastroenterología-Research Electronic Data Capture. All cases with three or more empirical eradication attempts were assessed for effectiveness by modified intention-to-treat and per-protocol analysis.ResultsOverall, 2144 treatments were included: 1519, 439, 145 and 41 cases from third, fourth, fifth and sixth treatment lines, respectively. Sixty different therapies were used; the 15 most frequently prescribed encompassed >90% of cases. Overall effectiveness remained ConclusionEmpirical rescue treatment in third and subsequent lines achieved suboptimal effectiveness in most European regions. Only quadruple bismuth-metronidazole-tetracycline (10-day single-capsule or 14-day traditional scheme) and triple amoxicillin-levofloxacin therapies reached acceptable outcomes in some settings. Compliance with empirical therapy optimisation principles is still poor 5 years after clinical practice guidelines update.Trial registration numberNCT02328131.

Background & Aims: There are no studies or recommendations on optimal monitoring strategies for patients with eosinophilic esophagitis (EoE). Our objective was to develop guidance on how to monitor patients with EoE in routine clinical practice, on the basis of available clinical evidence and expert opinion. Methods: A multidisciplinary, international group of EoE experts identified the following important 3 questions during several consensus meetings: why, by what means, and when to monitor patients with EoE. A steering committee was named, and 3 teams were formed to review literature and to formulate statements for each topic. In a Delphi survey, a level of agreement of ?75% was defined as threshold value for acceptance. In a final conference, results were presented, critical points and comments on the statements were discussed, and statements were rephrased/rewritten if necessary. Results: Eighteen EoE experts (14 adult and pediatric gastroenterologists, 2 pathologists and 2 allergists) with a median of 21.7 years in clinical practice, mostly academic or university-based, completed the Delphi survey, which included 11 statements and a proposed algorithm for monitoring patients with EoE. Each statement attained ?75% agreement. Participants discussed and debated mostly about the statement concerning surveillance intervals for EoE patients with stable disease. Conclusions: It was concluded that effective maintenance treatment probably reduces the development of EoE complications, and regular, structured, and, under certain conditions, individualized clinical follow-up is recommended to assess disease activity while opening a window to monitoring side effects, adjusting therapy, and encouraging adherence to treatment. Follow-up should comprise symptom assessment and periodic or repeated endoscopy with histological assessment in specific EoE settings.

Long-standing inflammation leads to esophageal remodeling with stricture formation in patients with eosinophilic esophagitis (EoE). The ability of proton pump inhibitors (PPI) to reverse endoscopic features of fibrosis is still unknown.To investigate the effect of a short course of PPI treatment in reducing endoscopic findings indicative of esophageal fibrosis in EoE patients.Cross-sectional analysis of the EoE CONNECT registry. Patients who received PPI to induce EoE remission were evaluated. Endoscopic features were graded using the EoE Endoscopic Reference Score (EREFS), with rings and strictures indicating fibrosis. Results were compared to those from patients treated with swallowed topic corticosteroids (STC).Clinico-histological remission was achieved in 83/166 adult patients treated with PPI (50%) and in 65/79 (82%) treated with STC; among responders, 60 (36%) and 57 (72%) patients respectively achieved deep histological remission (5 eosinophils/hpf). At baseline, mean±SD EREFS was lower in patients treated with PPI compared to those who received STC (p 0.001). Short term treatment significantly reduced EREFS scores in patients treated either with PPI or STC as well as rings and strictures. Among patients treated with PPI, deep histological remission (5 eosinophils/hpf) provided further reduction in total EREFS score.Effective PPI therapy for EoE significantly reduced endoscopic esophageal fibrosis in the short term.

Endoscopy plays a critical role in caring for and evaluating the patient with eosinophilic esophagitis (EoE). Endoscopy is essential for diagnosis, assessment of response to therapy, treatment of esophageal strictures, and ongoing monitoring of patients in histologic remission. To date, less-invasive testing for identifying or grading EoE severity has not been established, whereas diagnostic endoscopy as integral to both remains the criterion standard. Therapeutic endoscopy in patients with adverse events of EoE may also be required. In particular, dilation may be essential to treat and attenuate progression of the disease in select patients to minimize further fibrosis and stricture formation. Using a modified Delphi consensus process, a group of 20 expert clinicians and investigators in EoE were assembled to provide guidance for the use of endoscopy in EoE. Through an iterative process, the group achieved consensus on 20 statements yielding comprehensive advice on tissue-sampling standards, gross assessment of disease activity, use and performance of endoscopic dilation, and monitoring of disease, despite an absence of high-quality evidence. Key areas of controversy were identified when discussions yielded an inability to reach agreement on the merit of a statement. We expect that with ongoing research, higher-quality evidence will be obtained to enable creation of a guideline for these issues. We further anticipate that forthcoming expert-generated and agreed-on statements will provide valuable practice advice on the role and use of endoscopy in patients with EoE.

Background The safety of ustekinumab in pregnant patients with inflammatory bowel disease (IBD) and in their offspring has been barely studied. Aims Primary: To know the risk of serious adverse events (SAEs) in women exposed to ustekinumab during pregnancy and in their offspring. Secondary: To assess the risk of complications of the mothers and their offspring. To describe the patterns of use of ustekinumab during pregnancy in these patients Methods Patients with IBD exposed to ustekinumab during pregnancy from DUMBO registry of GETECCU were included. DUMBO is a prospective, observational and multicentre registry, which enrols pregnant women with IBD over 5 years in 70 centres in Spain. The registry was kicked off in September 2019. SAE definition was based on “Clinical Safety Data Management: Definitions and Standards for Expedited Reporting by European Medicines Agency”. Study protocol is summarized in figure 1. Results 49 pregnant patients have been exposed to ustekinumab during pregnancy so far (table 1). All pregnancies were singleton. Two patients were lost of follow-up (1st and 2nd trimester) but had uneventful pregnancies up-to last visit. There were 2 miscarriages (4%) at 1st trimester of gestation, 34 newborns and 11 pregnancies that were still on-going at the time of this analysis. All patients were on ustekinumab at conception (57% of them 90 mg/8 weeks). A total of 12 patients (24%) withdrawn ustekinumab during pregnancy: 1 (8%) due to disease flare, 1 (8%) underwent surgery due to intestinal obstruction, 2 (17%) due to patient’s choice (at 1st and 2nd trimester), and 8 (67%) due to clinicians’ decision (1 at 1st, 5 at 2nd and 2 at 3rd trimesters). No patient flared up after ustekinumab discontinuation. 10 (20%) patients had SAEs: 2 miscarriages, 1 intestinal infection, 1 subcorionic hematoma, 3 preterm birth, 1 intestinal obstruction and perforation (underwent surgery), 1 preeclapmsia, and 1 stoma obstruction. A total of 34 women gave birth after a median of 39 weeks gestation [interquartile range (IQR)=38–40], 3 (9%) preterm births, 55% by caesarean section (82% obstetric reasons and 18% perianal fistulae). Of the 34 newborns, 53% were female, median birth weight was 3,110 g (IQR=2,820–3,325), 3 (9%) low-birth weight, and 50% were breastfed exclusively. Median babies’ follow-up was 12 months (IQR=7–16). During follow-up, 3 children (9%) had severe infections (2 urinary infections, and 1 bronchiolitis by respiratory syncytial virus). In addition, 4 (13%) children were hospitalized: 1 cardiorespiratory arrest, 1 prematurity, 1 jaundice, and 1 vesicoureteral reflux Conclusion Ustekinumab seems to be safe during pregnancy in patients with IBD and their offspring.

Background Treatment with thiopurines may be associated with different adverse effects, including acute pancreatitis. Risk factors for developing pancreatitis due to thiopurines in patients with Inflammatory Bowel Disease (IBD) are not clearly identified, with underlying genetic predisposition being a possible cause. Our aim was to evaluate predictive pharmacogenetic risk of pancreatitis in IBD patients treated with thiopurines. Methods IBD patients treated with thiopurines were identified from the prospectively maintained ENEIDA registry of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU). We included as cases those patients who met the Atlanta diagnostic criteria for pancreatitis and had an imaging test that ruled out biliary origin. We included as controls those patients without pancreatitis after at least two years of treatment with thiopurines. Blood samples were collected, and DNA was extracted from leukocytes for all participants and, subsequently, pooled samples were sequenced. Sequencing of a panel of genes (CASR, CEL, CDLN2, CFTR, CPA1, CTRC, PRSS1, and SPINK1) was carried out in the NextSeq500 platform. Variants detected were classified as pathogenic, variants of unknown significance, and benign according to the American College of Medical Genetics and Genomics (ACMGG) guidelines. Results Ninety-five cases and 105 controls were enrolled, 57% were women. Pancreatitis was diagnosed at a median age of 39±13 years old. No patient had previous history of chronic or acute pancreatitis. There were no differences between thiopurine-treated patients with and without pancreatitis in age, sex, and age at IBD onset. We identified 81 benign variants (50 in cases and 67 in controls) and a total of 35 distinct rare pathogenic and unknown significance variants (10 in CEL, 21 in CFTR, 1 in CDLN2, and 3 in CPA1). Of these 35 variants (12 in cases and 18 in controls), 6 were classified as pathogenic (1 in cases and 5 in controls), belonging to the CEL and CFTR genes, and 30 as variants of uncertain significance (21 in cases and 22 in controls). There were no significant differences between the groups of cases and controls, both in totals and by genes. None of the cases or controls carried pancreatitis-predisposing variants within the CASR, CPA1, PRSS1, and SPINK1 genes. None of the analysed samples with pancreatitis carried a pathogenic CFTR mutation. Four different variants of unknown significance were detected in the CDLN and CPA1 genes. One of them was in the CDLN gene in a single patient with pancreatitis, and 3 variants in the CPA1 gene in 5 control individuals. Conclusion In patients with IBD, there is no predisposition to thiopurine-induced pancreatitis associated with genes known to cause pancreatitis.

Background Some patients with Inflammatory Bowel Disease (IBD) who are treated with anti-TNFα therapy develop a drug-induced psoriasis (IP) as an adverse event. There are some therapeutic approaches, being more frequent to change the biologic therapy to ustekinumab, effective and approved for the treatment of both entities. This could be the best option, but available data are lacking and it could increase the risk of IBD relapse. Our aim is to assess the management of anti-TNF IP in IBD, and the subsequent evolution of both diseases in a large nationwide cohort of patients. Methods Retrospective, observational multicenter study from the prospectively maintained Spanish ENEIDA registry. Participants were patients with IBD and anti-TNFα IP. At baseline, psoriasis severity was classified as mild, moderate or severe, and remission was defined as the resolution of skin lesions, clinical response as an improvement without complete resolution, and no response as the absence of improvement. IBD clinical activity was defined based on Harvey-Bradshaw Index and Partial Mayo Score. All items were evaluated when available at baseline and 16, 32 and 54 weeks. Results Anti-TNFα IP was reported in 234 patients (CD: 185, UC: 46, unclassified IBD: 3). SWAP strategy was chosen in 76 patients (32.5%), most of them to ustekinumab (90.8%), 71 (30.3%) patients continued anti-TNF, 49 (20.9%) discontinued it, and in 38 (16.2%) a switch to a second anti-TNF was made. The decision to continue or not anti-TNF was associated to psoriasis severity (p Conclusion Evaluating IBD activity and psoriasis severity is essential before modifying IBD treatment due to IP. Continuing anti-TNF treatment in mild psoriasis cases, and considering SWAP to ustekinumab in moderate-severe ones, could be a suitable strategy.

Background An increased risk of lymphoma has been described in patients with Inflammatory Bowel Disease (IBD). The aims of our study were to determine the clinical presentation of lymphoma, previous exposure to immunosuppressive and biologic therapies, and the management and evolution of lymphomas in patients with IBD. Methods IBD patients with diagnosis of lymphoma from October 2006 to June 2021 were identified from the prospectively maintained ENEIDA registry of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU). Investigators at each participating centre provided additional information on lymphomas. Results We identified 52 patients with lymphoma in 18 centres following 21,740 patients with IBD (2.4 cases of lymphoma/1,000 patients with IBD; 95% CI 1.8-3.1). 35 were men (67%) and 27 (52%) had Ulcerative Colitis. Non-Hodgkin lymphoma was the most common lymphoma (65%). The median age at diagnosis of lymphoma was 59 years old (IQR 48-67). 31 patients (60%) received thiopurines, and 20 (38%) an anti-TNF drug (one of them had not received thiopurines) before lymphoma diagnosis. Age at diagnosis of lymphoma was lower in those patients treated with thiopurines (53 ± 17 years old) and anti-TNF drugs (47 ± 17 years old) than in those patients not treated with thiopurines nor anti-TNF drugs before the diagnosis of lymphoma (63 ± 12 years old; p Conclusion Most IBD patients with lymphoma had been treated with thiopurines and/or anti-TNF agents before lymphoma diagnosis, and these patients were younger at diagnosis of lymphoma than those not treated with these drugs. IBD treatment was usually changed after a diagnosis of lymphoma. Relapse and mortality of lymphoma were not related to the use and duration of thiopurines or biologic therapies.

Purpose of review The aim of this review is to highlight recent advances in dietary therapy for eosinophilic esophagitis (EoE). Recent findings An empiric elimination diet step-up strategy is now well established as the initial approach for dietary treatment. The most common food triggers are by far cow's milk, followed by wheat and egg. Legumes seem to be important solely in Spain and other Mediterranean countries, where they are regularly consumed. Retrospective efficacy data on cow's milk elimination diet in children vary from 25 to 65%. The recently described esophageal prick test did not detect local reaction to the most common food triggers described for EoE. Summary Within the step-up approach, the specific food group or groups to be first eliminated and whether if it will depend on the geographical setting and food consumption habits remain unknown. Prospective studies on cow's milk elimination diet in children and adults are definitely warranted. Better food allergy testing, identifying specific antigens involved in each food group, should be developed for an individualized therapy. As for disease prevention, we undoubtedly need to understand why foods we have been consuming since the Neolithic age have caused EoE just over the past few decades.

BackgroundDirect comparisons of childhood- and adulthood-onset eosinophilic esophagitis (EoE) are scarce.AimTo compare disease characteristics, endoscopic and histological features, allergic concomitances and therapeutic choices across ages.MethodsCross-sectional analysis of the EoE CONNECT registry.ResultsThe adulthood-onset cohort (those diagnosed at ≥18y) comprised 1044 patients and the childhood‐onset cohort (patients diagnosed at ConclusionsChildhood‐onset EoE has differential characteristics compared with adulthood-onset, but similar response to treatment.

Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si lo hubiere, y los autores pertenecientes a la UAM, The growing prevalence of eosinophilic esophagitis (EoE) represents a considerable burden to patients and health care systems. Optimizing cost-effective management and identifying mechanisms for disease onset and progression are required. However, the paucity of large patient cohorts and heterogeneity of practice hinder the defining of optimal management of EoE. Methods: EoE CONNECT is an ongoing, prospective registry study initiated in 2016 and currently managed by EUREOS, the European Consortium for Eosinophilic Diseases of the Gastrointestinal Tract. Patients are managed and treated by their responsible specialists independently. Data recorded using a web-based system include demographic and clinical variables; patient allergies; environmental, intrapartum, and early life exposures; and family background. Symptoms are structurally assessed at every visit; endoscopic features and histological findings are recorded for each examination. Prospective treatment data are registered sequentially, with new sequences created each time a different treatment (active principle, formulation, or dose) is administered to a patient. EoE CONNECT database is actively monitored to ensure the highest data accuracy and the highest scientific and ethical standards. Results: EoE CONNECT is currently being conducted at 39 centers in Europe and enrolls patients of all ages with EoE. In its aim to increase knowledge, to date EoE CONNECT has provided evidence on the effectiveness of first- and second-line therapies for EoE in clinical practice, the ability of proton pump inhibitors to induce disease remission, and factors associated with improved response. Drug effects to reverse fibrous remodeling and endoscopic features of fibrosis in EoE have also been assessed. Conclusion: This prospective registry study will provide important information on the epidemiological and clinical aspects of EoE and evidence as to the real-world and long-term effectiveness and safety of therapy. These data will potentially be a vital benchmark for planning future EoE health care services in Europe, The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The establishment and design of the EoE CONNECT registry was developed with a grant from the United European Gastroenterology through the National Societies Link Award program. The maintenance of the database is financed by EUREOS (European Society of Eosinophilic Oesophagitis). Funding agencies had no role in the study design, in the writing of this manuscript, or the decision to submit for publication

BACKGROUND & AIMS Disease activity and severity of eosinophilic esophagitis (EoE) dictate therapeutic options and management, but the decision-making process for determining severity varies among practitioners. To reduce variability in practice patterns and help clinicians monitor the clinical course of the disease in an office setting, we aimed to create an international consensus severity scoring index for EoE. METHODS A multidisciplinary international group of adult and pediatric EoE researchers and clinicians, as well as non-EoE allergy immunology and gastroenterology experts, formed 3 teams to review the existing literature on histology, endoscopy, and symptoms of EoE in the context of progression and severity. A steering committee convened a 1-day virtual meeting to reach consensus on each team's opinion on salient features of severity across key clinicopathologic domains and distill features that would allow providers to categorize disease severity. RESULTS Symptom features and complications and inflammatory and fibrostenotic features on both endoscopic and histologic examination were collated into a simplified scoring system-the Index of Severity for Eosinophilic Esophagitis (I-SEE)-that can be completed at routine clinic visits to assess disease severity using a point scale of 0-6 for mild, 7-14 for moderate, and ≥15 for severe EoE. CONCLUSIONS A multidisciplinary team of experts iteratively created a clinically usable EoE severity scoring system denominated "I-SEE" to guide practitioners in EoE management by standardizing disease components reflecting disease severity beyond eosinophil counts. I-SEE should be validated and refined using data from future clinical trials and routine clinical practice to increase its utilization and functionality.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder characterized by symptoms of esophageal dysfunction and eosinophil-predominant inflammation. Left untreated, EoE progresses to fibrous remodeling and stricture formation that impairs quality of life. Therefore, EoE requires either repeated treatments or maintenance therapy. Current guidelines recommend swallowed topical corticosteroids (STCs), proton-pump inhibitors (PPIs), or dietary intervention as initial options to induce and maintain long-term disease remission. Impractical exclusive elemental diets and suboptimal allergy testing-directed food avoidance paved the way for empirical elimination diets. These are moderately effective and highly reproducible in inducing EoE remission and allow for identification of specific food triggers. Step-up strategies, including two- and four-food rather than six-food elimination diets, should be considered as initial approaches for dietary treatment in patients of all ages, as they reduce the need for endoscopic procedures, shorten diagnostic processing time, and avoid unnecessary restrictions. Formulations of STC originally designed for asthma therapy are suboptimal for EoE treatment, with new effervescent orodispersible tablets and viscose formulations designed to coat the esophageal mucosa providing increased effectiveness at reduced doses. The anti-inflammatory effects of PPI in EoE are independent from gastric acid secretion inhibition; despite evidence from observational research, PPIs are the most commonly prescribed first-line therapy for EoE due to their accessibility, low cost, and safety profile. Double doses of PPI only induce remission in half of EoE patients, irrespective of the drug used or patients’ age. Inflammatory rather than stricturing EoE phenotype and treatment duration up to 12 weeks increase chances of achieving EoE remission. Most responders effectively maintain long-term remission with standard PPI doses. Finally, endoscopic dilation should be considered in patients with reduced esophageal caliber or persistent dysphagia despite histological remission. This article provides a state-of-the-art review and updated discussion of current therapies and newly developed options for EoE.

Diagnostic delay; Endoscopy; Eosinophilic esophagitis Retraso en el diagnóstico; Endoscopia; Esofagitis eosinofílica Retard diagnòstic; Endoscòpia; Esofagitis eosinofílica Background: Poor adherence to clinical practice guidelines for eosinophilic esophagitis (EoE) has been described and the diagnostic delay of the disease continues to be unacceptable in many settings. Objective: To analyze the impact of improved knowledge provided by the successive international clinical practice guidelines on reducing diagnostic delay and improving the diagnostic process for European patients with EoE. Methods: Cross-sectional analysis of the EoE CONNECT registry based on clinical practice. Time periods defined by the publication dates of four major sets of guidelines over 10 years were considered. Patients were grouped per time period according to date of symptom onset. Results: Data from 1,132 patients was analyzed and median (IQR) diagnostic delay in the whole series was 2.1 (0.7-6.2) years. This gradually decreased over time with subsequent release of new guidelines (p < 0.001), from 12.7 years up to 2007 to 0.7 years after 2017. The proportion of patients with stricturing of mixed phenotypes at the point of EoE diagnosis also decreased over time (41.3% vs. 16%; p < 0.001), as did EREFS scores. The fibrotic sub-score decreased from a median (IQR) of 2 (1-2) to 0 (0-1) when patients whose symptoms started up to 2007 and after 2017 were compared (p < 0.001). In parallel, symptoms measured with the Dysphagia Symptoms Score reduced significantly when patients with symptoms starting before 2007 and after 2012 were compared. A reduction in the number of endoscopies patients underwent before the one that achieved an EoE diagnosis, and the use of allergy testing as part of the diagnostic workout of EoE, also reduced significantly over time (p = 0.010 and p < 0.001, respectively). Conclusion: The diagnostic work-up of EoE patients improved substantially over time at the European sites contributing to EoE CONNECT, with a dramatic reduction in diagnostic delay.

Background Studies to evaluate the use of mycophenolate mofetil (MMF) in inflammatory bowel disease (IBD) are limited after the appearance of biological treatments. Aims Our primary objective was to evaluate the effectiveness and safety of MMF in IBD. Methods IBD patients who had received MMF were retrieved from the ENEIDA registry. Clinical activity as per the Harvey‐Bradshaw Index (HBI), partial Mayo score (pMS), physician global assessment (PGA) and C-reactive protein (CRP) were reviewed at baseline, at 3 and 6 months, and at final follow-up. Adverse events and causes of treatment discontinuation were documented. Results A total of 83 patients were included (66 Crohn's disease, 17 ulcerative colitis), 90% of whom had previously received other immunosuppressants. In 61% of patients systemic steroids were used at initiation of MMF, and in 27.3% biological agents were co-administered with MMF. Overall clinical effectiveness was observed in 64.7% of the population. At the end of treatment, 45.6% and 19.1% of subjects showed remission and clinical response, respectively. MMF treatment was maintained for a median of 28.9 months (IQR: 20.4–37.5). Conclusion Our study suggests, in the largest cohort to date, that MMF may be an effective alternative to thiopurines and methotrexate in IBD.

Background Prospective registries are necessary to evaluate the safety of inflammatory bowel disease (IBD) treatment during pregnancy and in children in the long term. Aims The overall aim of DUMBO registry is to know the risk of serious adverse events (SAEs) during pregnancy and in children up to 4 years of age exposed during pregnancy to drugs for IBD (mainly focused on biologics), compared to unexposed children. In this analysis we aim to evaluate the risk of SAEs during pregnancy and the predictive factors of it (mainly focused on IBD drugs). Methods Prospective, observational and multicentre registry, which enrols pregnant women with IBD (Crohn’s disease, ulcerative colitis, IBD-unclassified) over 5 years in 70 centres in Spain. The registry was kicked off in September 2019. SAE was defined based on “Clinical Safety Data Management: Definitions and Standards for Expedited Reporting by European Medicines Agency”. Study protocol is summarized in figure 1. Results 433 women have been included so far; 241 got pregnant at least 9 months before this interim analysis (table 1). Mean age was 34 years, and 17% of women had active disease at any time during pregnancy. 23% of pregnancies were exposed to immumodulators (thiopurines), 25% to biologics and 10% to combo therapy (biologics and immunomodulators). 85 pregnancies (35%) were exposed to biologics (60 anti-TNF, 17 ustekinumab, and 8 vedolizumab) either in combo or in monotherapy. There were 237 newborns (227 singleton and 5 pair of twins), 9 miscarriages and 1 abortion. 72% of patients had vaginal delivery and 28% C-sections (18% due to perianal CD or active disease). A total of 59 pregnancies (24.5%) reported at least one SAE: 32% in exposed to biologics and 20.5% in non-exposed group (p>0.05) (figure 2). Four out of 17 pregnancies exposed to ustekinumab and 3 out of 8 exposed to vedolizumab had SAEs (non-related with the drug). In the multivariate analysis, adjusted by disease activity, in comparison with no immunosuppressive treatment, neither immunosuppressants [Odds ratio (OR)=1.1, 95% confidence interval (CI)=0.3–4.3] nor biologics in monotherapy or in combo (OR=0.8; 95%CI=0.2–3) were associated with higher risk of SAEs. 40 patients (17%) were hospitalised due to complications during pregnancy or delivery (figure 3). Two patients underwent surgery during pregnancy due to IBD complications Conclusion IBD treatment (either immunomodulators or biologics) does not increase the risk of SAEs during pregnancy. Nevertheless, one-quarter of IBD women suffer SAEs during pregnancy and about 20% need hospitalisation, which should be taken into account when managing IBD during pregnancy.

Background Treatment with thiopurines in patients with Inflammatory Bowel Disease (IBD) may be associated with different adverse effects, including acute pancreatitis. Our aims were to evaluate the clinical presentation, severity and management of acute pancreatitis related to thiopurines in patients with IBD. Methods IBD patients with acute pancreatitis secondary to treatment with thiopurines for IBD were identified from the prospectively maintained ENEIDA registry of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU). We included those patients who met the Atlanta diagnostic criteria and had an imaging test that ruled out biliary origin of pancreatitis. Investigators at each participating centre provided additional information on pancreatitis clinical evolution and management. Results We included 290 patients with pancreatitis in 34 centres; 54% were women, 84% had Crohn’s disease and 56% were smokers. Five (1.7%) had had pancreatitis before, but no patient met criteria for chronic pancreatitis. The median age at pancreatitis was 36 years (IQR 27-50). In 94% of cases, pancreatitis occurred after the first thiopurine drug. Azathioprine was the thiopurine used in 97% of cases (median dose 2.3 mg/kg/day (IQR 2-2.5)), and 6% were treated with mercaptopurine (1.5 mg/kg/day (IQR 1-1.5)). Pancreatitis was diagnosed after a median of 23 days (IQR 14-35) since the start of the treatment with thiopurines. 81% required hospitalization for pancreatitis for a median of 5 days (IQR 4-7). Four (1.4%) were severe pancreatitis, 16 (5.5%) moderate, and the rest mild, according to the Atlanta classification. No epidemiological or treatment factors were associated with the severity of pancreatitis. Thiopurine was withdrawn in all patients upon diagnosis of pancreatitis. After 2 months (IQR 1-28) of pancreatitis, 16 patients (5.5%) received thiopurines again (5 the same, 11 a different thiopurine), suffering a new episode of pancreatitis in 12 (75%) after a median of 12 days (IQR 5-34). Pancreatitis occurred in all smokers that were treated again with thiopurines (n=7), compared to 5 of the 9 (56%) non-smokers or former smokers (p=0.04, RR 1.8; 95% CI 1.1-3.2). Conclusion Acute pancreatitis secondary to treatment with thiopurines is mild in most patients, usually appearing during the first month of treatment. The reintroduction of thiopurines, although feasible in some cases, is not recommended due to the high risk of developing a new pancreatitis, especially in smokers.

Helicobacter pylori infection is very common in the Spanish population and represents the main cause of chronic gastritis, peptic ulcer, and gastric cancer. The last iteration of Spanish consensus guidelines on H. pylori infection was conducted in 2016. Recent changes in therapeutic schemes along with increasing supporting evidence were key for developing the V Spanish Consensus Conference (May 2021). Fourteen experts performed a systematic review of the scientific evidence and developed a series of recommendations that were subjected to an anonymous Delphi process of iterative voting. Scientific evidence and the strength of the recommendation were classified using GRADE guidelines. An eradication therapy, when prescribed empirically, is considered acceptable when it reliably achieves, or preferably surpass, 90% cure rates. Currently, only quadruple therapies (with or without bismuth) and generally lasting 14 days, accomplish this goal in first- and second-line therapies. A non-bismuth quadruple concomitant regimen (proton pump inhibitor, clarithromycin, amoxicillin, and metronidazole) or a quadruple bismuth-based combination (proton pump inhibitor, bismuth, tetracycline, and metronidazole), are recommended as first-line regimens. Rescue therapies after eradication failure and management of H. pylori infection in peptic ulcer disease were also reviewed.

Background & Aims Due to the poor eradication rates of standard triple therapy, the addition of bismuth salts has been proposed for first-line eradication of Helicobacter pylori. We assessed the effectiveness and safety of the combination of bismuth and the standard, clarithromycin-containing triple therapy in eradication of H pylori infection, using data from a large multi-center registry. Methods We performed an interim analysis of data from the European Registry on H pylori Management, a prospective trial registering clinical data and outcomes from infected patients from 27 countries in Europe since 2013. We extracted data on 1141 treatment-naive patients who received first-line treatment with bismuth salts (240 mg) and a proton pump inhibitor (57% received esomeprazole, 18% received omeprazole, 11% received pantoprazole, and 14% received rabeprazole), amoxicillin (1 g), and clarithromycin (500 mg), all taken twice daily. Results Intention to treat and per-protocol rates of eradication were 88% and 94%, respectively. Intention to treat eradication increased to 93% in patients who received 14-day treatments. Adverse events occurred in 36% of patients; 76% of these events were mild, with a mean duration of 6 days. In multivariate analysis, eradication was associated with treatment compliance (odds ratio [OR], 13.0), a double dose (equivalent to 40 mg omeprazole) of proton pump inhibitor (OR, 4.7), and 14-day duration of treatment (OR, 2.0). Conclusions In an analysis of data from a large multi-center registry, we found the addition of bismuth to 14-day standard triple therapy with clarithromycin and amoxicillin to eradicate H pylori infection in more than 90% of patients, based on intention to treat analysis, with an acceptable safety profile and level of adherence. ClinicalTrials.gov no: NCT02328131 .

Background Whereas the exact aetiology of microscopic colitis [MC] remains unknown, a dysregulated immune response to luminal factors or medications is the most accepted pathogenesis hypothesis. Methods We conducted a systematic review of the pathogenesis of MC. We applied the Joanna Briggs Institute methodologies and the PRISMA statement for the reporting of systematic reviews [PROSPERO Trial Identifier: CRD42020145008]. Populations, Exposure of interest, and Outcome [PEO] questions were used to explore the following topics in MC: 1] intestinal luminal factors; 2] autoimmunity; 3] innate immunity; 4] adaptive immunity; 5] extracellular matrix; 6] genetic risk factors; and 7] mechanism of diarrhoea. A search was done in PubMed, Embase, and Web of Science up to February 2020. A narrative description was performed explaining the findings for each aspect of MC aetiopathogenesis. Results Thirty-eight documents provided evidence for PEO1, 100 for PEO2, 72 for PEO3 and 4, 38 for PEO5, 20 for PEO6, and 23 for PEO7. The majority of documents were cohorts, case reports, and case series, with a few case-control and some experimental studies. Consistency among data provided by different studies was considered to support pathogenetic hypotheses. MC is a multifactorial disease believed to involve innate and adaptive immune responses to luminal factors, genetic risk, autoimmunity, and extracellular matrix alterations, all contributing by varied mechanisms to watery diarrhoea. Conclusions This is the first systematic review on the aetiology of MC supporting the notion that MC is a multifactorial disease. However, high-profile studies are lacking, and most evidence derives from small heterogeneous studies.

Background and Aims The disease course of microscopic colitis [MC] is considered chronic but benign. However, this assumption is based on mainly retrospective studies, reporting on incomplete follow-up of selective cohorts. Systematic, prospective and unbiased data to inform patients and healthcare professionals on the expected course of the disease and real-life response to therapy are warranted. Methods A prospective, pan-European, multi-centre, web-based registry was established. Incident cases of MC were included. Data on patient characteristics, symptoms, treatment and quality of life were systematically registered at baseline and during real-time follow-up. Four disease course phenotypes were discriminated and described. Results Among 381 cases with complete 1-year follow-up, 49% had a chronic active or relapsing disease course, 40% achieved sustained remission after treatment and 11% had a quiescent course. In general, symptoms and quality of life improved after 3 months of follow-up. A relapsing or chronic active disease course was associated with significantly more symptoms and impaired quality of life after 1 year. Conclusions A minority of MC patients follow a quiescent disease course with spontaneous clinical improvement, whereas the majority suffer a chronic active or relapsing disease course during the first year after diagnosis, with persisting symptoms accompanied by a significantly impaired quality of life.

Aim To evaluate the effectiveness and safety of tofacitinib in ulcerative colitis [UC] in real life. Methods Patients from the prospectively maintained ENEIDA registry and treated with tofacitinib due to active UC were included. Clinical activity and effectiveness were defined based on Partial Mayo Score [PMS]. Short-term response/remission was assessed at Weeks 4, 8, and 16. Results A total of 113 patients were included. They were exposed to tofacitinib for a median time of 44 weeks. Response and remission at Week 8 were 60% and 31%, respectively. In multivariate analysis, higher PMS at Week 4 (odds ratio [OR] = 0].2; 95% confidence interval [CI] = 0].1–0.4) was the only variable associated with lower likelihood of achieving remission at Week 8. Higher PMS at Week 4 [OR = 0.5; 95% CI = 0.3–0.7] and higher PMS at Week 8 [OR = 0.2; 95% CI = 0.1–0.5] were associated with lower probability of achieving remission at Week 16. A total of 45 patients [40%] discontinued tofacitinib over time. Higher PMS at Week 8 was the only factor associated with higher tofacitinib discontinuation [hazard ratio = 1.5; 95% CI = 1.3–1.6]. A total of 34 patients had remission at Week 8; of these, 65% had relapsed 52 weeks after achieving remission; the dose was increased to 10 mg/12 h in nine patients, and five of them reached remission again. Seventeen patients had adverse events. Conclusions Tofacitinib is effective and safe in UC patients in real practice, even in a highly refractory cohort. A relevant proportion of patients discontinue the drug over time, mainly due to primary failure.

A lifelong gluten-free diet (GFD) is the only current treatment for celiac disease (CD), but strict compliance is complicated. Duodenal biopsies are the &ldquo, gold standard&rdquo, method for diagnosing CD, but they are not generally recommended for disease monitoring. We evaluated the sensitivity and specificity of fecal gluten immunogenic peptides (GIPs) to detect duodenal lesions in CD patients on a GFD and compared them with serum anti-tissue transglutaminase (tTG) IgA antibodies. A prospective study was conducted at two tertiary centers in Spain on a consecutive series of adolescents and adults with CD who maintained a long-lasting GFD. Adherence to a GFD and health-related quality of life were scored with validated questionnaires. Mucosal damage graded according to the Marsh&ndash, Oberh&uuml, ber classification (Marsh 1/2/3) was used as the reference standard. Of the 97 patients included, 27 presented duodenal mucosal damage and 70 had normal biopsies (Marsh 0). The sensitivity (33%) and specificity (81%) of GIPs were similar to those provided by the two assays used to measure anti-tTG antibodies. Scores in questionnaires showed no association with GIP, but an association between GIPs and patients&rsquo, self-reported gluten consumption was found (p = 0.003). GIP displayed low sensitivity but acceptable specificity for the detection of mucosal damage in CD.

© The Author(s) 2021., Eosinophilic esophagitis (EoE) is a chronic, immune-mediated inflammatory esophageal disease triggered by food antigens. Cumulative evidence supports the implication of microbiota and the innate immune system in the pathogenesis of EoE. Changes in the esophageal microbiome were investigated by applying 16S rRNA gene sequencing on esophageal biopsies of adult patients with active EoE at baseline (n = 30), and after achieving remission with either proton pump inhibitors (PPI, n = 10), swallowed topical corticosteroids (STC, n = 10) or food-elimination diets (FED, n = 10). Ten non-EoE biopsies were also characterized as controls. Compared to controls, no differences in alpha (intra-sample) diversity were found in EoE microbiota overall. However, it decreased significantly among patients who underwent FED. As for beta (inter-sample) diversity, non-EoE controls separated from EoE baseline samples. Post-treatment samples from patients treated with PPI and FED had a more similar microbiota composition, while those receiving STC were closer to controls. Differential testing of microbial relative abundance displayed significant changes for Filifactor, Parvimonas and Porphyromonas genera. Analysis of predicted functions indicated alterations in metabolic pathways and abundance of sulphur-cytochrome oxidoreductases. Our findings demonstrate changes in microbiota associated with EoE, as well as a treatment effect on the microbiome., This work was funded by the Oesophagus-Stomach-Duodenum Grant from Spanish Association of Gastroenterology (Asociación Española de Gastroenterología – AEG) (2017 Call). We are grateful to Dr. Gregor Gorkiewicz and his team (Medical University of Graz, Austria) for being the external service to extract, amplify and sequence 16S rRNA gene. EJ Laserna-Mendieta is a recipient of a Juan Rodes grant (JR19/00005) from Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Health, Social Services and Equality, which is partly funded by the European Social Fund (period 2014-2020). Laura Arias González is recipient of a post-doctoral research grant from Fundación Hospital Nacional de Parapléjicos (II-2018/05).

Background and Aims The development programm UNIFI has shown promising results of ustekinumab in ulcerative colitis [UC] treatment which should be confirmed in clinical practice. We aimed to evaluate the durability, effectiveness, and safety of ustekinumab in UC in real life. Methods Patients included in the prospectively maintained ENEIDA registry, who received at least one intravenous dose of ustekinumab due to active UC [Partial Mayo Score [PMS]>2], were included. Clinical activity and effectiveness were defined based on PMS. Short-term response was assessed at Week 16. Results A total of 95 patients were included. At Week 16, 53% of patients had response [including 35% of patients in remission]. In the multivariate analysis, elevated serum C-reactive protein was the only variable significantly associated with lower likelihood of achieving remission. Remission was achieved in 39% and 33% of patients at Weeks 24 and 52, respectively; 36% of patients discontinued the treatment with ustekinumab during a median follow-up of 31 weeks. The probability of maintaining ustekinumab treatment was 87% at Week 16, 63% at Week 56, and 59% at Week 72; primary failure was the main reason for ustekinumab discontinuation. No variable was associated with risk of discontinuation. Three patients reported adverse events; one of them had a fatal severe SARS-CoV-2 infection. Conclusions Ustekinumab is effective in both the short and the long term in real life, even in a highly refractory cohort. Higher inflammatory burden at baseline correlated with lower probability of achieving remission. Safety was consistent with the known profile of ustekinumab.