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Background: Early surgical resection is an emerging concept for patients with ileocaecal Crohn's disease (CD). The aim of this study was to compare postoperative outcomes after ileocaecal resections between patients with luminal and complicated CD. Methods: A retrospective analysis of patients operated for ileocaecal CD during an 8-year period in ten tertiary referral academic centres from Latin America was performed. Patients were allocated into 2 groups: those operated for early (luminal) disease (Early Crohn's Disease -ECD-) and for complications of CD (Complicated Crohn's disease -CCD-). A comparative analysis was performed regarding short-term outcomes of surgery, considering overall postoperative complications as main outcome. Results: 337 patients were included in the analysis, 60 (17.80%) in the ECD group. Smoking and exposure to perioperative biologic drugs were more prevalent in CCD group. CCD patients had increased requirement of urgent surgery (26.71 vs. 15%, p = 0.056), longer operative time (164.25 vs. 90.53 min, p< 0.01), lower rates of primary anastomosis (90.23 vs. 100%, p = 0.012), increased rate of overall postoperative complications (33.21 vs. 16.67%, p = 0.013), more reoperations (13.36 vs. 3.33%, p = 0.026), and higher rates of major anastomotic fistulas and hospital stay. On multivariable analysis, smoking (p = 0.001,95%CI: 2.59–32.11), operative time (p = 0.022,95%CI:1–1.02), associated procedures (p = 0.036,95%CI:1.09–15.72) and intraoperative complications (p = 0.021,95%CI:1.45–92.31) were independently related to presenting postoperative complications. Conclusion: Early (luminal) ileocaecal resections were associated to lower rates of overall postoperative complications. Proper timing for surgery, avoiding delays in surgical indication can impact postoperative outcomes.

Contains fulltext : 293034.pdf (Publisher’s version ) (Open Access) OBJECTIVE: It is unknown whether ustekinumab (UST) levels can predict clinical outcomes in Crohn's disease (CD) patients. We assessed the exposure-response relationship of UST trough concentrations with biochemical outcomes at week 24 in a prospective, real-world setting. METHODS: We performed a prospective study in patients with CD starting UST in four academic centres in the Netherlands. All patients received a weight-adjusted intravenous (IV) UST induction dose, followed by one subcutaneous (SC) dose of 90 mg UST at 8 weeks. Maintenance therapy consisted of 90 mg subcutaneous UST every 8 or 12 weeks. Individual UST concentration time course during treatment were estimated using a population pharmacokinetic (PK) model. Quartile analysis and logistic regression were performed to analyse if UST concentrations at week 8 were associated with biochemical remission rates at week 24 (C-reactive protein (CRP) ≤ 5 mg/L and / or faecal calprotectin (FC) ≤ 250 mg/kg). RESULTS: In total, 124 patients with CD were included. Patients achieving biochemical remission at week 12 and 24 had significantly higher UST levels at week 8 compared to patients without biochemical remission (6.6 µg/mL versus 3.9 µg/mL, P

Crohn disease (CD) is often complicated by bowel strictures that can lead to obstructive symptoms, resistant inflammation, and penetrating complications. Endoscopic balloon dilatation of CD strictures has emerged as a safe and effective technique for relieving these strictures, which may obviate the need for surgical intervention in the short and medium term. This technique appears to be underutilized in pediatric CD. This position paper of the Endoscopy Special Interest Group of European Society for Pediatric Gastroenterology, Hepatology and Nutrition describes the potential applications, appropriate evaluation, practical technique, and management of complications of this important procedure. The aim being to better integrate this therapeutic strategy in pediatric CD management.

Induction of remission in biologic-experienced individuals with moderate to severe Crohn’s disease (CD) can be a challenge. We hereby present a case of CD with secondary non-response to infliximab. Adding methotrexate and switching to ustekinumab plus methotrexate did not stop the inflammatory process. Therefore, combination therapy with two classes of biologics consisting of ustekinumab and adalimumab plus methotrexate was initiated. He achieved clinical remission in 4 weeks and remained on triple therapy for 6 months which was subsequently tailored to adalimumab/methotrexate combination therapy due to insurance restriction on ustekinumab. He remained in remission for the duration of follow-up, 14 months after initiation of triple therapy and 8 months after switching to methotrexate/adalimumab biologic monotherapy. Triple therapy with anti-TNF, IL-12/23 inhibitor and methotrexate could potentially be an option for induction of remission in biologic-experienced individuals with good initial clinical response to anti-TNF agents.

ObjectiveThe aim of the study was to characterize the drug utilization and switch patterns of biological treatment of ulcerative colitis (UC) and Crohn’s disease (CD).MethodsUsing Danish national registries, this nationwide study included individuals diagnosed with UC or CD, bio-naïve at the initiation of treatment with infliximab, adalimumab, vedolizumab, golimumab, or ustekinumab in 2015–2020. Hazard ratios of discontinuing the first treatment or switching to another biological treatment were explored using Cox regression.ResultsAmong 2995 UC patients and 3028 CD patients, infliximab was used as a first-line biologic treatment in 89% of UC patients and 85% of CD patients, followed by adalimumab with 6%, vedolizumab with 3%, and golimumab with 1% for UC, and adalimumab with 12%, vedolizumab with 2%, and ustekinumab with 0.4% for CD.When comparing adalimumab as the first treatment series to infliximab, there was a higher risk of treatment discontinuation (excluding switch) among UC patients (hazard ratio: 2.02 [95% confidence interval: 1.57; 2.60]) and CD patients (1.85 [1.52; 2.24]). When comparing vedolizumab to infliximab, there was a lower risk of discontinuation for UC patients (0.51 [0.29–0.89]), and for CD patients, although not significantly (0.58 [0.32–1.03]). We observed no significant difference in the risk of switching to another biologic treatment for any of the biologics.ConclusionMore than 85% of UC and CD patients initiating biologic therapy had infliximab as their first-line biologic treatment, in accordance with official treatment guidelines. Future studies should explore the higher incidence of treatment discontinuation of adalimumab as the first treatment series. Objective: The aim of the study was to characterize the drug utilization and switch patterns of biological treatment of ulcerative colitis (UC) and Crohn’s disease (CD). Methods: Using Danish national registries, this nationwide study included individuals diagnosed with UC or CD, bio-naïve at the initiation of treatment with infliximab, adalimumab, vedolizumab, golimumab, or ustekinumab in 2015–2020. Hazard ratios of discontinuing the first treatment or switching to another biological treatment were explored using Cox regression. Results: Among 2995 UC patients and 3028 CD patients, infliximab was used as a first-line biologic treatment in 89% of UC patients and 85% of CD patients, followed by adalimumab with 6%, vedolizumab with 3%, and golimumab with 1% for UC, and adalimumab with 12%, vedolizumab with 2%, and ustekinumab with 0.4% for CD. When comparing adalimumab as the first treatment series to infliximab, there was a higher risk of treatment discontinuation (excluding switch) among UC patients (hazard ratio: 2.02 [95% confidence interval: 1.57; 2.60]) and CD patients (1.85 [1.52; 2.24]). When comparing vedolizumab to infliximab, there was a lower risk of discontinuation for UC patients (0.51 [0.29–0.89]), and for CD patients, although not significantly (0.58 [0.32–1.03]). We observed no significant difference in the risk of switching to another biologic treatment for any of the biologics. Conclusion: More than 85% of UC and CD patients initiating biologic therapy had infliximab as their first-line biologic treatment, in accordance with official treatment guidelines. Future studies should explore the higher incidence of treatment discontinuation of adalimumab as the first treatment series.Key summary Several biologic therapies are available in the treatment of ulcerative colitis and Crohn’s disease. Clinical guidelines stipulate that infliximab should be the first-line biologic therapy. Drug utilization studies comparing biologic therapies head-to-head are sparse. In Denmark, during 2015–2020 infliximab remained the most widely used biologic treatment, with adalimumab being second. One in four patients experienced more than one biologic during the study period. The risk of discontinuation of biologic treatment (and not starting a new biologic) was higher for initiators of adalimumab. Clinical and social background factors available from the registers could not account for the observed risk difference in discontinuation.

Bushra Abdallah, Mariah Arif, Maryam Al-Malki, Razan Hourani, Tamader Al-Maadeed, Nidal Khodr, Ghaith Al-Kuwari, Mashael Al-Siddiqi, Tanya Kane, Tawanda Chivese Department of Population Medicine, College of Medicine, QU Health, Qatar University, Doha, QatarCorrespondence: Tawanda Chivese, Department of Population Medicine, College of Medicine, QU Health, Qatar University, P O BOX 2713, Doha, Qatar, Tel +974 4403 7831, Email tchivese@qu.edu.qaObjective: This research investigated the association between childhood and adulthood tobacco smoking exposure with ulcerative colitis (UC) and Crohn’s disease (CD) in Qatar.Study Design and Setting: In this case-control study, CD and UC cases were matched to controls of the same age and sex. The associations between UC and CD and childhood passive smoking and adulthood active smoking were assessed using conditional multivariable logistic regression.Results: A total of 89 CD cases, median age of 37 years (IQR 29– 47), and 362 UC cases, median age of 35 years (IQR 28– 44), and equal numbers of controls were included. After multivariable logistic regression, CD was associated with higher odds of being a current smoker (OR 2.51, 95% CI 0.85– 7.37, p=0.095), with weak evidence against the null hypothesis. This association was more pronounced in women, where CD was associated with both adulthood current smoking (OR 42.71, 95% CI, 1.17– 1559.57, p=0.041), and childhood smoking exposure (OR 8.23, 95% CI, 1.36– 49.66, p=0.021). In males, no associations were observed between CD and the smoking exposures. No associations were observed between UC and both smoking variables.Conclusion: In Qatar, adulthood tobacco smoking appears to increase the odds of CD. Further, our findings suggest that both childhood and adulthood cigarette smoke exposure may possibly have a detrimental effect on the odds of CD in females but not in males, although further research is needed.Keywords: Crohn’s disease, ulcerative colitis, inflammatory bowel disease, smoking, childhood passive smoking, Middle East and North Africa

Crohn's Disease (CD), which usually leads to anal fistulas among patients, is the most important inflammatory bowel disease that causes morbidity in many people around the world. This review article proposes using MSCs as a hopeful therapeutic strategy for CD and anal fistula treatment in both preclinical and clinical conditions. Finally, darvadstrocel, a cell-based medication to treat complex anal fistulas in adults, as the only European Medicines Agency (EMA)-approved product for the treatment of anal fistulas in CD is addressed. Although several common therapies, such as surgery and anti-tumor necrosis factor-alpha (TNF-α) drugs as well as a combination of these methods is used to improve this disease, however, due to the low effectiveness of these treatments, the use of new strategies with higher efficiency is still recommended. Cell therapy is among the new emerging therapeutic strategies that have attracted great attention from clinicians due to its unique capabilities. One of the most widely used cell sources administrated in cell therapy is mesenchymal stem cell (MSC). This review article will discuss preclinical and clinical studies about MSCs as a potent and promising therapeutic option in the treatment of CD and anal fistula.

ObjectiveTo estimate the proportion of cases of Crohn’s disease (CD) and ulcerative colitis (UC) that could be prevented by modifiable lifestyle factors.DesignIn a prospective cohort study of US adults from the Nurses’ Health Study (NHS; n=72 290), NHSII (n=93 909) and Health Professionals Follow-up Study (HPFS; n=41 871), we created modifiable risk scores (MRS; 0–6) for CD and UC based on established lifestyle risk factors, and healthy lifestyle scores (HLS; 0–9) derived from American healthy lifestyle recommendations. We calculated the population attributable risk by comparing the incidence of CD and UC between low-risk (CD-MRS≤1, UC-MRS≤2, HLS≥7) and high-risk groups. We externally validated our findings in three European cohorts: the Swedish Mammography Cohort (n=37 275), Cohort of Swedish Men (n=40 810) and European Prospective Investigation into Cancer and Nutrition (n=404 144).ResultsOver 5 117 021 person-years of follow-up (NHS, HPFS: 1986–2016; NHSII: 1991–2017), we documented 346 CD and 456 UC cases. Adherence to a low MRS could have prevented 42.9% (95% CI 12.2% to 66.1%) of CD and 44.4% (95% CI 9.0% to 69.8%) of UC cases. Similarly, adherence to a healthy lifestyle could have prevented 61.1% (95% CI 16.8% to 84.9%) of CD and 42.2% (95% CI 1.7% to 70.9%) of UC cases. In our validation cohorts, adherence to a low MRS and healthy lifestyle could have, respectively, prevented 43.9%–51.2% and 48.8%–60.4% of CD cases and 20.6%–27.8% and 46.8%–56.3% of UC cases.ConclusionsAcross six US and European cohorts, a substantial burden of inflammatory bowel diseases risk may be preventable through lifestyle modification.

Purpose Comprehensive description of surgical techniques for revision of complications of continent ileostomy (CI). Methods By analyzing 133 revision procedures performed over 30 years, a systematically classified approach to the appropriate techniques for CI revision surgery has been derived. Based on the anatomic site and severity of the respective complication, four classes of revision surgeries have been defined: class 1 refers to the nipple valve, class 2 to the pouch, class 3 to the stoma, and class 4 to the afferent loop. The severity of the complication or the complexity of the revision procedure is indicated by a subdivision from a to d. Results The surgical variants (class 1a–d, class 2a–c, class 3a–b, and class 4a–b) are shown in schematic illustrations with accompanying descriptions of technical details, the respective fields of application, and the special indications. Conclusion Based on these classes of revision surgeries, the specialized surgeon may find differentiated techniques at their disposal to save the CI and avoid unnecessary sacrifice of the artificial continence organ.

Introduction: Biologic therapy is widely used for inflammatory bowel disease (IBD) and may decrease surgery rates. However, it remains uncertain if there is unwarranted geographic variation in access to biologic therapy. The aim of the study was to explore if all patients had equal access to biologic therapy in the North Denmark Region.Methods: A cross-sectional register-based study of use of biologics, hospital contacts and surgery among all IBD patients having a hospital contact in the geographically well-defined North Denmark Region during 2016-2018. ICD-10 diagnosis codes, hospital contacts and procedure codes were retrieved from the region's hospital registry. The population is served by an Academic Hospital and two Non-Academic Hospitals constituting three referral areas (according to postal codes).Results: In total, 2371 patients with ulcerative colitis (UC) and 1383 patients with Crohn's disease (CD) had a hospital contact in the region during 2016-2018. Compared to patients from the Academic Hospital, patients from the Non-Academic Hospitals experienced a lower incidence of biologic therapy for UC IRR 0.786 (0.621: 0.994), as well as for CD IRR 0.912 (0.781: 1.065). The incidence of bowel related hospital contacts were higher in patients from Non-Academic hospitals for both UC IRR 1.318 (1.207: 1.438) and CD IRR 1.165 (0.915: 1.483).Conclusions: Patients with IBD living in a referral area to a Non-Academic Hospital in the North Denmark Region are less likely to receive biologics. This was associated with an increased prevalence of IBD related surgical procedures. Introduction: Biologic therapy is widely used for inflammatory bowel disease (IBD) and may decrease surgery rates. However, it remains uncertain if there is unwarranted geographic variation in access to biologic therapy. The aim of the study was to explore if all patients had equal access to biologic therapy in the North Denmark Region.Methods: A cross-sectional register-based study of use of biologics, hospital contacts and surgery among all IBD patients having a hospital contact in the geographically well-defined North Denmark Region during 2016-2018. ICD-10 diagnosis codes, hospital contacts and procedure codes were retrieved from the region's hospital registry. The population is served by an Academic Hospital and two Non-Academic Hospitals constituting three referral areas (according to postal codes).Results: In total, 2371 patients with ulcerative colitis (UC) and 1383 patients with Crohn's disease (CD) had a hospital contact in the region during 2016-2018. Compared to patients from the Academic Hospital, patients from the Non-Academic Hospitals experienced a lower incidence of biologic therapy for UC IRR 0.786 (0.621: 0.994), as well as for CD IRR 0.912 (0.781: 1.065). The incidence of bowel related hospital contacts were higher in patients from Non-Academic hospitals for both UC IRR 1.318 (1.207: 1.438) and CD IRR 1.165 (0.915: 1.483).Conclusions: Patients with IBD living in a referral area to a Non-Academic Hospital in the North Denmark Region are less likely to receive biologics. This was associated with an increased prevalence of IBD related surgical procedures.

Background and Aims Paediatric-onset IBD [pIBD] is associated with an increased risk of cancer and mortality in adulthood. The aims of this study were to measure the incidence of cancer and mortality in patients with pIBD and identify factors associated with mortality and cancer. Methods All patients diagnosed with Crohn’s disease [CD] or ulcerative colitis [UC] before the age of 17 years between 1988 and 2011 in the EPIMAD registry were retrospectively followed until 2013 for cancer and 2015 for mortality. Standardized incidence [SIR] and mortality ratios [SMR] were estimated compared to the general population. Cox regression was used to compare the effect of exposures on cancer and mortality among IBD patients. Results We included 1344 patients [52% males, 75% CD], totalling 12 957 patient-years for cancer incidence and 18 817 patient-years for mortality. There were 14 cases of cancer [median age 27.8 years] and 15 deaths [median age 28.8 years]. The incidence of cancer and of mortality were increased compared to the general population: all-cancer SIR = 2.7 (95% confidence interval [CI]: 1.5–4.8), SMR = 1.7 [95% CI: 1.0–2.8]. Colorectal cancer had the highest SIR and SMR: SIR = 41.2 [95% CI: 17.2–99.0], SMR = 70.4 [95% CI 22.7–218.2]. Cancer was associated with (hazard ratio [HR], 95% CI): active smoking at diagnosis [5.5, 1.8–16.5], p = 0.002; any exposure to anti-tumour necrosis factor [6.1, 1.7–22.3], p = 0.0065; and exposure to combination therapy [7.4, 1.8–29.7], p = 0.0047. Mortality was associated with extraintestinal manifestations (HR 4.9 [95% CI: 1.7–13.8], p = 0.003). Conclusions In this large population-based cohort, patients with pIBD had an increased risk of both cancer [2.7-fold] and mortality [1.7-fold], particularly for colorectal cancer.

Background and Aims The utility of real-world data is dependent on the quality and homogeneity of reporting. We aimed to develop a core outcome set for real-world studies in adult patients with inflammatory bowel disease [IBD]. Methods Candidate outcomes and outcome measures were identified and categorised in a systematic review. An international panel including patients, dietitians, epidemiologists, gastroenterologists, nurses, pathologists, radiologists, and surgeons participated in a modified Delphi consensus process. A consensus meeting was held to ratify the final core outcome set. Results A total of 26 panellists from 13 countries participated in the consensus process. A total of 271 items [130 outcomes, 141 outcome measures] in nine study domains were included in the first-round survey. Panellists agreed that real-world studies on disease activity should report clinical, endoscopic, and biomarker disease activity. A disease-specific clinical index [Harvey–Bradshaw Index, Partial Mayo Score, Simple Clinical Colitis Activity Index] should be used, rather than physician global assessment. In ulcerative colitis [UC], either the UC Endoscopic Index of Severity or the Mayo Endoscopic Score can be used, but there was no consensus on an endoscopic index for Crohn’s disease, nor was there consensus on the use of the presence of ulcers. There was consensus on using faecal calprotectin and C-reactive protein. There was no consensus on the use of histology in real-world studies. Conclusions A core outcome set for real-world studies in IBD has been developed based on international multidisciplinary consensus. Its adoption will facilitate synthesis in the generation of real-world evidence.

Background Intestinal fibrosis and subsequent stricture formation represent frequent complications of Crohn’s disease (CD). In many organs, fibrosis develops as a result of epithelial to mesenchymal transition (EMT). Recent studies suggested that EMT could be involved in intestinal fibrosis as a result of chronic inflammation. Here, we investigated whether EMT might be involved in stricture formation in CD patients. Methods Human colonic tissue specimens from fibrotic areas of 18 CD and 10 non-IBD control patients were studied. Immunohistochemical staining of CD68 (marker for monocytes/macrophages), transforming growth factor-β1 (TGFβ1), β-catenin, SLUG, E-.cadherin, α-smooth muscle actin and fibroblast activation protein (FAP) were performed using standard techniques. Results In fibrotic areas in the intestine of CD patients, a large number of CD68-positive mononuclear cells was detectable suggesting an inflammatory character of the fibrosis. We found stronger expression of TGFβ1, the most powerful driving force for EMT, in and around the fibrotic lesions of CD patients than in non-IBD control patients. In CD patients membrane staining of β-catenin was generally weaker than in control patients and more cells featured nuclear staining indicating transcriptionally active β-catenin, in fibrotic areas. In these regions we also detected nuclear localisation of the transcription factor, SLUG, which has also been implicated in EMT pathogenesis. Adjacent to the fibrotic tissue regions, we observed high levels of FAP, a marker of reactive fibroblasts. Conclusions We demonstrate the presence of EMT-associated molecules in fibrotic lesions of CD patients. These findings support the hypothesis that EMT might play a role for the development of CD-associated intestinal fibrosis. Electronic supplementary material The online version of this article (doi:10.1186/s40169-015-0046-5) contains supplementary material, which is available to authorized users.

Background Infliximab (IFX) has been shown to be effective rescue therapy for hospitalized ulcerative colitis patients failing intravenous (IV) corticosteroids (CS). There is little evidence, however, describing its use in similar hospitalized Crohn's Disease (CD) patients. Study question To determine if IFX is an effective rescue therapy for IV CS resistant CD patients. Study design A retrospective study of inpatients with CD who received IFX as rescue therapy at 2 tertiary care hospitals from January 1, 2006, to December 31, 2016. Records were reviewed for demographics, disease activity, preadmission and inpatient treatment, surgical rates, and 30- and 90-day readmission rates. Measures and Outcomes: Efficacy of IFX as rescue therapy was defined by discharge without surgery and readmission rates. Only patients failing IV CS before IFX were included in the final analysis. Results Forty patients received IFX, of which 17 had failed IV CS. Four patients were receiving outpatient IFX therapy, but still received IV CS during hospitalization before IFX. The mean duration of IV CS therapy before IFX was 6.9 days. Of the 15 patients (88%) who responded to rescue IFX, the median hospital stay following IFX was 3 days (range 3-18 days). Readmission rates were 29% and 47% at 30 and 90 days respectively, without further surgeries noted. Conclusions In our series of hospitalized CD patients failing IV CS, those treated with IFX had low rates of urgent surgery and a generally rapid response to treatment, supporting IFX as an effective rescue therapy. By only including those with prior failure of IV CS, we have likely excluded patients for whom IFX was given in the hospital for reasons other than severe disease. Our results suggest that individuals with severe acute CD flare can be treated with early introduction of IFX, avoiding prolonged CS use, and hospitalization.

Patients with postoperative Crohn's disease are difficult to manage because of their risk of experiencing a more severe course, multiple symptom confounders, and poor sensitivity of symptomatic remission to rule out intestinal inflammation. In this group, data are lacking on biologic therapeutic efficacy, and recommendations are lacking for those with multiple medication failures. Novel noninvasive testing can simultaneously exclude alternate causes of symptoms (serum C4, fecal fat, small intestinal bowel overgrowth breath testing) and assess intestinal inflammation (fecal calprotectin, endoscopic healing index). In addition, endoscopy-based disease activity assessment and management are required. Endoscopy should be performed within 6 months of surgery, and aggressive disease activity monitoring can be considered with colonoscopy every 1-2 years subsequently to ensure late recurrence is detected. Patients with multiple resections should be screened for short bowel syndrome. Predictive biomarkers are needed to guide medication selection in this high-risk population. Postoperative prophylactic biologic therapy is prudent for patients with preoperative biologic failure. However, there are no high-quality data to guide which agent should be selected. Selecting biologics with an alternative mechanism of action in those who had failed a biologic with adequate drug concentrations and selection of different agents in those with previous intolerance are reasonable. Significantly more study is required to assess the efficacy of therapies in this setting.

Anemia is a common complication of gastrointestinal (GI) disorders, with a prevalence up to 60% in celiac disease (CeD) and inflammatory bowel disease (IBD). Iron deficiency anemia (IDA) is the most prevalent form of anemia in these conditions, but chronic inflammation and vitamin B12 deficiency represent other common contributing mechanisms, especially in IBD.We discuss the pathogenesis of anemia in various medical GI disorders, the sometime problematic distinction between IDA, anemia of inflammation (AI) and the association of the two, and therapeutic and preventive measures that can be useful for the management of anemia in GI disorders. Unfortunately, with the exception of IDA and AI in IBD, large RCT concerning the treatment of anemia in GI disorders are lacking.Anemia management strategies in GI disorders are outlined, with a focus on the main prevention, diagnostic, and therapeutic measures. Specific problems and situations such as the role of gluten-free diet for IDA treatment in CeD, the choice between oral and parenteral supplementation of iron or vitamin B12 in carential anemias, the use of endoscopic procedures to stop bleeding in intestinal angiodysplasia and preventive/treatment strategies for NSAID-associated GI bleeding are discussed.

Background: Crohn’s and Ulcerative Colitis Questionnaire-32 (CUCQ-32) is a validated questionnaire to measure the quality of life (QoL) in Inflammatory Bowel Disease (IBD). However, it does not have stoma-specific questions and can be lengthy. This study aimed to validate a subset of the CUCQ-32 that would be suitable for patients with a stoma. Methods: Baseline data were collected from a cohort of patients with acute ulcerative colitis who were participating in the CONSTRUCT multicentre clinical trial. A subset of the CUCQ-32 questions was selected by stepwise regression. Further validation was examined using data from the UK IBD biological therapies audit. Construct validity was carried out using the EuroQol 5 dimensions (EQ5D) questionnaire, Simple Clinical Colitis Activity Index (SCCAI), and the Harvey–Bradshaw Index (HBI). Results: Using the data from 124 patients, a short-version questionnaire (CUCQ-12) was developed. Data from 484 patients with IBD (382 patients with Crohn’s disease, 76 patients with ulcerative colitis, and 26 patients with IBD-Unclassified) and 61 patients with stoma provided further validation of the CUCQ-12. A literature review and an expert focus group identified supplementary stoma-specific questions for the CUCQ-12+. The CUCQ-12+ demonstrated excellent internal consistency (Cronbach’s α = 0.86); established effective reproducibility (intra-class correlation coefficient = 0.74); correlated well with the EQ5D (r= −0.48), HBI (r = 0.45), and SCCAI (r = 0.43); and represented good responsiveness statistics (>0.5). Conclusions: CUCQ-12+ is a valid and reliable QoL measure used for all patients with IBD in clinical practice, including patients with a stoma.

FAMIN is a purine nucleoside enzyme that was first identified in genome-wide association studies (GWAS) as increasing risk for Crohn’s disease (CD). Defects in the enzyme that result in loss of catalytic activity are the only known monogenic cause of Still’s disease, a severe autoinflammatory condition that predisposes for the risk of developing macrophage activation syndrome (MAS). MAS can be triggered by common viral infections and result in hyperactivation of T lymphocytes. The work presented in this thesis builds on the discovery that FAMIN-sufficient mice are protected against influenza A infection, with dendritic cell (DC)- dependent excessive activation of CD8+ T cell responses in their FAMIN-deficient counterparts. Loss of FAMIN activity in DCs was shown to result in increased priming of both CD4+ and CD8+ T cells both in vitro and in vivo, resulting in enhanced antigen-specific cytotoxicity, IFNg secretion, and T cell expansion. Here, we discovered that FAMIN controls the pace of membrane trafficking and DC antigen processing to restrain T cell priming via a cytosolic NADH/ NAD+-dependent mechanism. We describe wide-reaching metabolic defects resulting from loss of FAMIN activity, including in the core pathways of glycolysis and TCA cycle activity, as well as upstream changes in glucose, fatty acid and amino acid metabolism. Notably, depressed rates of glycolysis and oxidative phosphorylation DCs lacking FAMIN function were not responsible for increased T cell priming capacity. Instead, we find that FAMIN balances flux through adenine-guanine nucleotide interconversion cycles to maintain the cytosolic NADH/ NAD+ ratio. We found that FAMIN additionally regulates T cell priming by DCs directly through the enzyme’s purine nucleoside phosphorylase (PNP) activity, converting exogenous hypoxanthine to inosine that acts on the T cell adenosine 2A receptor (A2AR). In summary, FAMIN is a multifunctional purine nucleoside enzyme enabling flux through purine interconversion pathways highly integrated with cytoplasmic and mitochondrial metabolism. In DCs, FAMIN acts as a biochemical checkpoint to restrain T cell priming and prevent autoimmunity and autoinflammation.

International audience; Background: In recent years, an increasing prevalence of obesity in inflammatory bowel disease (IBD) has been observed. However, only a few studies have focused on the impact of overweight and obesity on IBD-related disability.Aims: To identify the factors associated with obese and overweight patients with IBD, including IBD-related disability.Patients and methods: In this cross-sectional study, we included 1704 consecutive patients with IBD in 42 centres affiliated with the Groupe d'Etude Therapeutique des Affections Inflammatoires du tube Digestif (GETAID) using a 4-page questionnaire. Factors associated with obesity and overweight were assessed using univariate and multivariate analyses (odds ratios (ORs) are provided with 95% confidence intervals).Results: The prevalence rates of overweight and obesity were 24.1% and 12.2%, respectively. Multivariable analyses were stratified by age, sex, type of IBD, clinical remission and age at diagnosis of IBD. Overweight was significantly associated with male sex (OR = 0.52, 95% CI [0.39-0.68], p < 0.001), age (OR = 1.02, 95% CI [1.01-1.03], p < 0.001) and body image subscore (OR = 1.15, 95% CI [1.10-1.20], p < 0.001) (Table 2). Obesity was significantly associated with age (OR = 1.03, 95% CI [1.02-1.04], p < 0.001), joint pain subscore (OR = 1.08, 95% CI [1.02-1.14], p < 0.001) and body image subscore (OR = 1.25, 95% CI [1.19-1.32], p < 0.001) (Table 3).Conclusion: The increasing prevalence of overweight and obesity in patients with IBD is associated with age and poorer body image. A holistic approach to IBD patient care should be encouraged to improve IBD-related disability and to prevent rheumatological and cardiovascular complications.

IntroductionCrohn's disease (CD) is a major subtype of inflammatory bowel disease (IBD), a spectrum of chronic intestinal disorders caused by dysregulated immune responses to gut microbiota. Although transcriptional and functional changes in a number of immune cell types have been implicated in the pathogenesis of IBD, the cellular interactions and signals that drive these changes have been less well-studied.MethodsWe performed Cellular Indexing of Transcriptomes and Epitopes by sequencing on peripheral blood, colon, and ileal immune cells derived from healthy subjects and patients with CD. We applied a previously published computational approach, NicheNet, to predict immune cell types interacting with CD8 + T-cell subsets, revealing putative ligand-receptor pairs and key transcriptional changes downstream of these cell-cell communications.ResultsAs a number of recent studies have revealed a potential role for CD8 + T-cell subsets in the pathogenesis of IBD, we focused our analyses on identifying the interactions of CD8 + T-cell subsets with other immune cells in the intestinal tissue microenvironment. We identified ligands and signaling pathways that have implicated in IBD, such as interleukin-1β, supporting the validity of the approach, along with unexpected ligands, such as granzyme B, which may play previously unappreciated roles in IBD.DiscussionOverall, these findings suggest that future efforts focused on elucidating cell-cell communications among immune and nonimmune cell types may further our understanding of IBD pathogenesis.

INTRODUCTION: Dose escalation is one of the treatment approaches studied and suggested in advanced therapies for Crohn's disease (CD) and ulcerative colitis (UC). This study aimed to identify and characterize the dosing escalation patterns of advanced therapies in CD and UC. METHODS: Two systematic literature reviews (SLRs) were conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE®, Embase®, and Cochrane Library were searched for articles published between January 2011 and October 2021 and limited to non-interventional studies in English language. Congress and bibliographic searches were also conducted. Articles were screened by two independent researchers. Dose escalation patterns were described and summarized considering the regional regulatory label recommendation (in North America [NA] or outside of North America [ONA]). RESULTS: Among 3190 CD and 2116 UC articles identified in the Ovid searches, 100 CD and 54 UC studies were included in the SLR, with more studies conducted ONA. Most studies reported an initial maintenance dose pattern aligned with the lower starting dose per local regulatory label; however, several ONA studies (n = 13 out of 14) reported ustekinumab every 8 weeks as starting maintenance pattern in CD. In ONA studies, the median within-guideline escalation rates in CD and UC were 43% in ustekinumab (CD only), 33% and 32% for vedolizumab; 29% and 39% for adalimumab; and 14% and 10% for infliximab. Evidence regarding dose escalation patterns for tofacitinib, certolizumab pegol, and golimumab was limited. Some dose escalation patterns outside of label recommendations were observed including ustekinumab every 8 weeks to every 4 weeks and vedolizumab every 8 weeks to every 6 weeks. CONCLUSION: Dose escalation strategies are widely documented in the literature. The reported dose escalation patterns and escalation rates vary by region and by CD and UC. Most escalation patterns reported were aligned with regulatory recommendations while some reported more diverse or aggressive dose escalation. PROSPERO REGISTRATION: CRD42021289251.

Aim: Patients with Crohn's disease (CD) often suffer from perianal fistulizing disease. Their risk of anorectal cancer remains uncertain. We aimed to examine the long-term risk of anorectal cancer in a population-based cohort of CD patients with anorectal fistula.Method: Our study population covered all individuals (n = 7 987 520) aged 15+ years living in Denmark from 1978 to 2018. We identified all patients with CD and anorectal fistula in the Danish National Patient Register (NPR) and 50 matched noninflammatory bowel disease (IBD) individuals from the general population. Using Cox regression analyses, we examined the risk of anorectal cancer in CD fistula patients versus non-IBD individuals. All patients with CD were identified using codes from the International Classification of Diseases and their data extracted from the NPR. The main outcome measure was cases of anorectal cancer.Results: A total of 2786 CD patients with anorectal fistula and 139 300 non-IBD individuals were followed for 1 553 917 person-years. During follow-up, anorectal cancer was observed in 19 CD patients (0.68%) and 340 non-IBD individuals (0.24%), corresponding to a 2.9-fold increased hazard ratio (HR) of anorectal cancer in CD fistula patients (95% CI 1.80-4.53), with a particularly high risk of anal cancer (HR 15.13, 95% CI 6.88-33.31) and a mean time from CD fistula diagnosis to anorectal cancer of 6.7 (SD 6.5) years. The risk was slightly higher in women than men and had no apparent relation to treatment with tumour necrosis factor-α inhibitors. Sensitivity analyses using CD nonfistula patients for comparison revealed similar results. Individual data on smoking and infection with human papilloma virus were not available.Conclusion: Patients with CD and anorectal fistula have a three-fold increased risk of anorectal cancer compared with the general population. The number needed to surveil to detect one case of anorectal cancer in this patient population was 2160 patients per year in patients with long-standing fistula (>6 years). Aim: Patients with Crohn's disease (CD) often suffer from perianal fistulizing disease. Their risk of anorectal cancer remains uncertain. We aimed to examine the long-term risk of anorectal cancer in a population-based cohort of CD patients with anorectal fistula.Method: Our study population covered all individuals (n = 7 987 520) aged 15+ years living in Denmark from 1978 to 2018. We identified all patients with CD and anorectal fistula in the Danish National Patient Register (NPR) and 50 matched noninflammatory bowel disease (IBD) individuals from the general population. Using Cox regression analyses, we examined the risk of anorectal cancer in CD fistula patients versus non-IBD individuals. All patients with CD were identified using codes from the International Classification of Diseases and their data extracted from the NPR. The main outcome measure was cases of anorectal cancer.Results: A total of 2786 CD patients with anorectal fistula and 139 300 non-IBD individuals were followed for 1 553 917 person-years. During follow-up, anorectal cancer was observed in 19 CD patients (0.68%) and 340 non-IBD individuals (0.24%), corresponding to a 2.9-fold increased hazard ratio (HR) of anorectal cancer in CD fistula patients (95% CI 1.80-4.53), with a particularly high risk of anal cancer (HR 15.13, 95% CI 6.88-33.31) and a mean time from CD fistula diagnosis to anorectal cancer of 6.7 (SD 6.5) years. The risk was slightly higher in women than men and had no apparent relation to treatment with tumour necrosis factor-α inhibitors. Sensitivity analyses using CD nonfistula patients for comparison revealed similar results. Individual data on smoking and infection with human papilloma virus were not available.Conclusion: Patients with CD and anorectal fistula have a three-fold increased risk of anorectal cancer compared with the general population. The number needed to surveil to detect one case of anorectal cancer in this patient population was 2160 patients per year in patients with long-standing fistula (>6 years).

Crohn's disease is a chronic inflammatory bowel disease that affects the gastrointestinal tract, causing a range of symptoms such as abdominal pain, diarrhea, and weight loss. It is estimated to affect around 3 million people worldwide, with a higher incidence in developed countries. This abstract describes the clinical case of a 27-year-old patient diagnosed with Crohn's disease in 2014, who was treated with conventional immunosuppressive drugs such as mesalazine, azathioprine, and mercaptopurine from 2015 to 2022. During this time, the patient experienced several intestinal complications, requiring two partial intestinal resections and recurring anal fistulas. Despite regular antibiotic use, the patient's diet was not addressed by the attending physicians. In 2022, the patient learned about high-dose vitamin D therapy and an anti-inflammatory diet as an alternative solutionfor his condition. He began taking 50,000 IU of D3 a day and after one month into the protocol, he felt 90% better with less bloating, better appetite, better sleep, and overall improved health. The patient has been on the protocol for a whole year, and all of his inflammatory biomarkers have improved, and he is currently in remission. This case highlights the potential benefits of a personalized approach to Crohn's disease treatment, including diet and high-dose vitamin D therapy, when compared to conventional treatments.

Patients with inflammatory bowel disease often experience ongoing pain even after achieving mucosal healing (i.e., post-inflammatory pain). Factors related to the brain-gut axis, such as peripheral and central sensitization, altered sympatho-vagal balance, hypothalamic-pituitary-adrenal axis activation, and psychosocial factors, play a significant role in the development of post-inflammatory pain. A comprehensive study investigating the interaction between multiple predisposing factors, including clinical psycho-physiological phenotypes, molecular mechanisms, and multi-omics data, is still needed to fully understand the complex mechanism of post-inflammatory pain. Furthermore, current treatment options are limited and new treatments consistent with the underlying pathophysiology are needed to improve clinical outcomes.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in Wuhan, China, in late 2019. Responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic, SARS-CoV-2 is one of three structurally similar beta-coronaviruses that can cause a strong upregulation of cytokines referred to as cytokine release syndrome (CRS). Unresolved CRS leads to respiratory symptoms, including pneumonia, and in more severe cases, acute respiratory distress syndrome (ARDS). Although COVID-19 is widely known for these hallmark respiratory symptoms, it also impacts the gut, causing gastrointestinal (GI) tract inflammation and diarrhea. COVID-19’s GI symptoms may be due to the high intestinal expression of angiotensin converting enzyme-2 receptors, which are for the binding of SARS-CoV-2 viral particles. Reports have shown that SARS-CoV-2 can be passed through fecal matter, with one study finding that 48.1% of COVID-19 patients expressed viral SARS-CoV-2 mRNA in their stool. Given that the GI tract is a target tissue affected by COVID-19, this causes concern for those with underlying GI pathologies, such as inflammatory bowel disease (IBD). Regrettably, there have been only limited studies on the impact of COVID-19 on gut health, and the impact of COVID-19 on intestinal inflammation among IBD patients remains unclear. In particular, questions regarding susceptibility to SARS-CoV-2 infection, clinical impact of COVID-19 on IBD, and the potential influence of age, sex, and immunosuppressant medications are still poorly understood. An improved understanding of these issues is needed to address the unique risks of COVID-19 among IBD patients, as well as the potential impact of SARS-CoV-2 on the host intestinal microbiota.

Background and Aims Onset of inflammatory bowel disease (IBD) in men is most common during childbearing age, but little is known about the impact on fertility. Previous studies of fertility in men were small, which justifies this large nation-based registry study. Methods Fertility was assessed in a national cohort of men with IBD aged 15-44 years in 1964-2014, identified from the Swedish National Patient Register, and in a reference cohort matched for age and place of residence (ratio 1:5). Information about childbirths was found in the Swedish Multi-Generation Register. Patients with indeterminate colitis or inconsistent IBD coding were classified as IBD-unclassified (IBD-U). Results The cohorts included 29,104 men with IBD and 140,901 matched individuals. IBD patients had a lower fertility rate (number of births per 1000 person years) compared with the matched individuals; 1.28 (SD 1.27) versus 1.35 (SD 1.31; p < 0.001). Fertility was somewhat impaired in all IBD subtypes compared with the matched cohort; ulcerative colitis (UC) (hazard ratio [HR] 0.93, 95% CI 0.91-0.96), Crohns disease (CD) (HR 0.95, 95% CI 0.92-0.98) and IBD-U 0.92, 95% CI 0.89-0.95. The cumulated total parity and the parity progression were also decreased for all IBD subtypes. Within the IBD cohort disease severity, intensity of medical treatment (CD) and bowel surgery (IBD-U) were further associated with impaired fertility. Conclusions This nationwide cohort study shows only slightly impaired fertility in men with IBD. Funding Agencies|FORSS-Medical Research Council of Southeast Sweden [FORSS-570791]; Futurum-Academy for Health and Care, Region Jonkoping County, Sweden [FUTURUM-937626]

Background: PYRAMID was an international post-marketing registry that aimed to collect data on the long-term safety and effectiveness of adalimumab treatment per local standard of care in patients with moderately to severely active Crohn's disease (CD). Here, we present post hoc analyses of observational data from patients who became pregnant while participating in this registry and receiving adalimumab. Methods: From the subpopulation of patients receiving adalimumab who became pregnant while taking part in PYRAMID, data on patient characteristics, pregnancy outcomes, and complications of pregnancy were analysed retrospectively. Results: Across the PYRAMID registry, 293 pregnancies occurred in patients who had gestational adalimumab exposure (average disease duration at last menstrual period: 8.6 years), resulting in 300 pregnancy outcomes. A total of 197 pregnancies (67.2%) were exposed to adalimumab in all trimesters per physician's decision. Of the known reported outcomes (96.3%), 81.7% (236/289) were live births, 10.4% (30/289) were spontaneous abortions, 4.8% (14/289) elective terminations, 2.8% (8/289) ectopic pregnancies, and 0.3% (1/289) was a stillbirth. Congenital malformations (pulmonary valve stenosis and tricuspid valve incompetence) were reported in one infant. In addition to the pregnancy outcomes described above, 23 complications of pregnancy were reported in 20 patients. Conclusions: This analysis showed that adalimumab treatment in patients with CD, who became pregnant whilst participating in the PYRAMID registry, contributed no additional adverse effects during the pregnancy course or on pregnancy outcomes.

Patients with primary sclerosing cholangitis (PSC) commonly undergo ileal pouch-anal anastomosis (IPAA) for medically-refractory ulcerative colitis (UC) or colorectal dysplasia. Pouchitis develops more frequently in patients with PSC, potentially leading to increased morbidity. We aimed to assess clinical characteristics and treatment outcomes for pouchitis in patients with PSC compared to a matched, non-PSC cohort.All patients with PSC who underwent IPAA and were diagnosed with pouchitis (PSC-pouchitis) were identified. A matched cohort composed of non-PSC patients who underwent IPAA for UC and subsequently developed pouchitis (UC-pouchitis) was developed. Relevant demographic, clinical, endoscopic, histologic, and treatment data were collected and compared between groups.Of those with PSC-pouchitis (n=182), 53.9% and 46.1% underwent IPAA for medically-refractory disease and dysplasia, respectively, compared to 88.7% and 11.3% in the UC-pouchitis group (P.001). Patients with PSC-pouchitis were more likely to develop chronic pouchitis (68.1% vs 34.1%; P.001), have moderate-to-severe pouch inflammation (54.9% vs 32.4%; P.001), and prepouch ileitis (34.1% vs 11.5%; P.001) compared to UC-pouchitis. Of those with PSC-pouchitis, 50.6% and 17.6% developed chronic antibiotic-dependent or antibiotic-refractory pouchitis, respectively, compared to 25.8% and 7.7% with UC-pouchitis. There was no difference in treatment response between the two groups with use of thiopurines, anti-tumor necrosis factor agents, and newer biologics.PSC-associated pouchitis presents with a unique clinical phenotype, characterized by increased risk of chronic pouchitis, moderate-to-severe pouch inflammation, prepouch ileitis, and less response to conventional antimicrobial therapy.

50% to 80% Crohn's disease (CD) and 10% to 30% ulcerative colitis (UC) patients require surgery over their lifetime. Biologic therapies may alter this natural history, but data on the effect of biologics on surgery rates in this patient population are mixed. We sought to investigate the influence of biologics on surgery prevalence in CD and UC.We used a commercial database (Explorys Inc, Cleveland, OH), which includes electronic health record data from 26 major integrated US healthcare systems. We identified all patients who were diagnosed with CD or UC that were treated with any biologics between 2015 and 2020. The primary outcome was to examine the association between biologics therapy and the prevalence of bowel resection. Also, we identified the factors associated with surgery in IBD patients on biologics.Of 32,904,480 patients in the database, we identified 140,540 patients with CD and 115,260 patients with UC, of whom 25,840 (18%) and 9,050 (7.8%) patients received biologics, respectively. The prevalence of intestinal resection was significantly lower in biologics-treated CD patients (9.3%) compared to those who did not receive biologics (12.1%) (p.001). Similarly, biologic-treated UC patients were significantly less likely to undergo colectomy (7.3%) compared to UC patients who did not receive biologic therapy (11.0%) (p.001). Tobacco use, Clostridium difficile infection, and perianal disease were associated with intestinal resection in CD. Colon neoplasm and Clostridium difficile infection were associated with colectomy in UC.In this study of a large healthcare administrative database, inflammatory bowel disease (IBD) patients treated with biologics were significantly less likely to undergo bowel resection when compared to those who never received biologics. This data suggests that biologics may impact surgical rates in IBD.

Background and aimsPost-colonoscopy colorectal cancers (PCCRCs) account for up to 50% of colorectal cancers (CRCs) in patients with inflammatory bowel disease (IBD). We investigated characteristics of IBD patients with PCCRC and their survival.MethodsWe identified IBD patients (ulcerative colitis [UC] and Crohn’s Disease [CD]) diagnosed with CRC from 1995 to 2015. We defined PCCRC as diagnosed between 6 and 36 months, and detected CRC (dCRC) as diagnosed within 6 months after colonoscopy. We computed prevalence ratios (PRs) comparing PCCRC vs. dCRC and followed patients from the diagnosis of PCCRC/dCRC until death, emigration, or study end. Mortality was compared using Cox proportional hazards regression models adjusted for sex, age, year of CRC diagnosis, and stage. The main analyses focused on patients with UC.ResultsAmong 23,738 UC patients undergoing colonoscopy, we identified 352 patients with CRC, of whom 103 (29%) had PCCRC. Compared with dCRC, PCCRC was associated with higher prevalence of metastatic cancer (33% vs. 20%; PR: 1.64, 95% confidence interval [CI]: 1.13-2.38), cancers exhibiting mismatch repair deficiency (79% vs. 56%; PR: 1.40, 95% CI: 1.13-1.72), and proximally located cancers (54% vs. 40%; PR: 1.34, 95% CI: 1.06-1.69). The one- and five -year adjusted hazard ratios (HRs) of death for PCCRC vs. dCRC among UC patients were 1.29 (95% CI: 0.77-2.18) and 1.24 [95% CI: 0.86-1.79), respectively.ConclusionThe characteristics of UC-related PCCRC suggest tumor biology as an important factor in the progression to cancer. However, the prognosis of PCCRC appears similar to that of dCRC.

Biologic treatment options for Crohn's disease (CD) are increasing and providers will need enhanced support in integrating these therapies into routine practice. Using phase 3 clinical trial programs in CD, we have previously built and validated clinical decision support tools for achieving clinical remission (CREM) with vedolizumab and ustekinumab in CD.1-4 We now aim to develop a clinical decision support tool for infliximab in CD.

Active lesions in the small bowel (SB) have been independently associated with poorer prognoses in patients with Crohn's disease (CD)1; however, there has been a lack of accurate and convenient screening methods. Past studies have found that serum levels of the glycoprotein leucine-rich α2 glycoprotein (LRG) correlates with endoscopic activity in ulcerative colitis,2,3 and this is now available for routine clinical use as a biomarker in patients with inflammatory bowel disease in Japan. LRG has not yet been thoroughly verified in CD, and we investigated whether it can be used as a serum biomarker for detecting SB mucosal activity in patients with CD.

Background The best management after ileocolonic resection is still unknown in Crohn’s disease (CD). We compared step-up and top-down approaches to prevent short and long-term postoperative recurrences in CD patients. Methods From a comprehensive database, consecutive CD patients who underwent intestinal resection (2014-2021) were included. Top-down (biologics started within the first month after surgery) or step-up strategies (no biologic between surgery and colonoscopy at 6 months) were performed with systematic colonoscopy at 6 months and therapeutic escalation if Rutgeerts index was ≥i2a (endoscopic postoperative recurrence). Propensity score analysis was applied for each comparison. Results Among 115 CD patients, top-down was the most effective strategy to prevent endoscopic postoperative recurrence (46.8% vs 65.9%, P = .042) and to achieve complete endoscopic remission (Rutgeerts index = i0; 45.3% vs 19.3%; P = .004) at 6 months. We did not observe any significant difference between the 2 groups regarding clinical postoperative recurrence (hazard ratio [HR], .86 [0.44-1.66], P = .66) and progression of bowel damage (HR, 0.81 [0.63-1.06], P = .12). Endoscopic postoperative recurrence at 6 months was associated with increased risk of clinical postoperative recurrence (HR, 1.97 [1.07-3.64], P 0.029) and progression of bowel damage (HR, 3.33 [1.23-9.02], P = .018). Among the subgroup without endoscopic postoperative recurrence at 6 months, the risks of clinical postoperative recurrence and progression of bowel damage were significantly improved in the top-down group (HR, 0.59 [0.37-0.94], P = .025; and HR, 0.73 [0.63-0.83], P < .001, respectively). Conclusions Top-down strategy should be the preferred management to prevent short and long-term postoperative recurrence in CD.

Management of enterocutaneous fistulas in Crohn's disease is challenging. Most patients still need intestinal resection in the biologic era.The aim of this study was to evaluate the efficacy of endoscopic treatment for enterocutaneous fistulas.This is a retrospective study of medical records.This study was conducted in a single institution.All consecutive patients with Crohn's disease with an enterocutaneous fistula who underwent endoscopic fistula closure with the use of an over-the-scope clip or a hemostatic clip were included.The main outcome measured was the clinical success 3 months after the procedure, which was defined as the complete closure of all fistulas at physical examination and complete cessation of the drainage from the external opening, without surgery.Eight patients (men, 25%; median age 45 years [interquartile range, 33-51]) were followed. Fistulas were localized at the ileocolonic or colocolonic anastomosis in 7 patients and at the stomach in 1 patient. Seven patients were treated with an over-the-scope clip, and one was treated with a hemostatic clip. Technical success was achieved in all cases. Clinical success at 3 months was achieved in 75% of cases (6/8 patients). After a median 16-month (interquartile range, 13-23) follow-up, 3 of 8 (37.5%) patients had enterocutaneous fistula closure and 2 of 8 (25%) needed intestinal resection. No complications were observed.The retrospective nature, the small sample size of the study, and the heterogeneity of the population limit the interpretation of the results.Endoscopic treatment of enterocutaneous fistulas is feasible with a short-term effectiveness. Additional studies are needed to confirm these results. See Video Abstract at http://links.lww.com/DCR/B614.ANTECEDENTES:Es desafiante el manejo de las fístulas enterocutáneas en enfermedad de Crohn. En la era biológica, la mayoría de los pacientes todavía requieren de resección intestinal.OBJETIVO:Evaluar la eficacia por tratamiento endoscópico de fístulas enterocutáneas.ENTORNO CLINICO:Estudio retrospectivo de registros médicos.AJUSTE:Realizado en una sola institución.PACIENTES:Se incluyeron todos los pacientes consecutivos con fístula enterocutánea en enfermedad de Crohn, sometidos a cierre endoscópico de la fístula con clip sobre el endoscopio o clip hemostático.PRINCIPALES MEDIDAS DE VALORACION:El éxito clínico a los 3 meses después del procedimiento. Definido al examen físico, como el cierre completo de todas las fístulas y cese completo del drenaje por la abertura externa, sin cirugía.RESULTADOS:Se estudiaron a ocho pacientes (hombres, 25%, mediana de edad de 45 años (rango intercuartílico, 33-51)). En 7 pacientes, las fístulas se localizaron en la anastomosis ileocolónica o colocolónica y un paciente, en el estómago. Siete pacientes fueron tratados con clip sobre el endoscopio y uno con clip hemostático. Se logró éxito técnico en todos los casos. Se logró éxito clínico a los 3 meses en 75% de los casos (6/8 pacientes). Después de una mediana de 16 meses (rango intercuartílico, 13-23), de seguimiento 3/8 (37,5%) pacientes presentaron cierre de fístulas enterocutáneas y 2/8 (25%) requirieron resección intestinal. No se observaron complicaciones.LIMITACIONES:Estudio retrospectivo, pequeño tamaño de la muestra y heterogeneidad de la población, limitaron la interpretación de los resultados.CONCLUSIONES:Es posible el tratamiento endoscópico de fístulas enterocutáneas con efectividad a corto plazo. Se requieren nuevos estudios para confirmar estos resultados. Consulte Video Resumen en http://links.lww.com/DCR/B614. (Traducción-Dr. Fidel Ruiz Healy).

Therapeutic drug monitoring (TDM) has emerged as a strategy for treatment optimization in inflammatory bowel diseases to maximize benefit and to reach more stringent, objective end points. Optimal drug concentrations in inflammatory bowel disease vary according to treatment target, disease phenotype, inflammatory burden, and timing of sampling during the treatment cycle. This review provides an update on TDM with biologic and oral small molecules, evaluates the role of reactive vs proactive TDM, and identifies the gaps in current evidence. In the future, adaptations to how we use TDM may contribute further to the goal of personalized treatment in patients with IBD.

Background Mesentery thickening and enlarged lymphnodes are typical findings of Crohn's disease (CD), but their role is unknown. Aim of the present study was to evaluate their prevalence and significance on postoperative complications and long-term surgical recurrence after CD surgery. Methods 1272 consecutive, unselected patients were retrospectively reviewed, divided into 4 groups based on the presence or absence of a thickened mesentery and enlarged lymphnodes, and stratified for primary or recurrent surgical procedure. In all patients but those treated with strictureplasty the mesentery and lymphnodes were removed. Patients’ characteristics, peri-operative findings, and long-term recurrence were compared by univariate and multivariate analysis. Results Thickened mesentery and enlarged lymphnodes were not present in all cases, were typical of ileal location and penetrating behaviour, had a constant decrease over recurrences, were independent of either pre-operative medical therapy or surgical approach, did not increase the duration of surgery and complications, presented similar 20-years recurrence rate to normal mesentery and lymphnodes. Lymphopathy was associated to a worst nutritional status during disease recurrences. At multivariate analysis, age, location, and behaviour, but not mesenteric characteristics, were related to an increased risk of surgical recurrence. Conclusions This study provides new information on mesentery and lymphnodes in CD patients. Further studies are needed to clarify the appropriate surgical approach.

Intestinal fibrosis is considered an inevitable complication of Crohn’s disease (CD) that results in symptoms of obstruction and stricture formation. Endoscopic or surgical treatment is required to treat the majority of patients. Progress in the management of stricturing CD is hampered by the lack of effective antifibrotic therapy; however, this situation is likely to change because of recent advances in other fibrotic diseases of the lung, liver, and skin. In this review, we summarize data from randomized controlled trials (RCTs) of antifibrotic therapies in these conditions. Multiple compounds have been tested for antifibrotic effects in other organs. According to their mechanisms, they were categorized into growth factor modulators, inflammation modulators, 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, intracellular enzymes and kinases, renin-angiotensin system (RAS) modulators, and others. From our review of the results from the clinical trials and discussion of their implications in the gastrointestinal tract, we have identified several molecular candidates that could serve as potential therapies for intestinal fibrosis in CD.

Background & Aims Mucosal healing is associated with better outcomes in Crohn’s disease (CD). Colonoscopy is invasive and poorly tolerated. Bowel ultrasound (US) is a noninvasive tool that increasingly is being used for CD assessment. We assessed the predictive role of baseline bowel US findings on disease course in a large prospective cohort of CD patients for 12 months. Methods Ileocolonic CD consecutive patients were followed up for 12 months after performing bowel US. The negative course of CD, defined as the need for steroids and/or change of therapy and/or hospitalization and/or the need for surgery, was assessed. We evaluated this composite end point and subsequently considered each individual end point separately. Predictors of negative disease course were analyzed by logistic regression analysis. Results There were 225 ileal and/or colonic CD consecutive patients included in the study. We analyzed the association between baseline bowel US parameters and endoscopic activity (defined as a Simplified Endoscopic Activity score for CD > 2) to set up a noninvasive quantitative ultrasound-based score (bowel ultrasound score). The multivariable analysis identified the following independent predictors of a worse outcome throughout the 12-month period as follows: bowel ultrasound score greater than 3.52 (odds ratio [OR], 6.97; 95% CI, 2.87–16.93; P Conclusions Bowel US predicts the 12-month course in CD.

BACKGROUND: Disability in patients with medically refractory ulcerative colitis (UC) after total proctocolectomy (TPC) with ileal pouch anal anastomosis (IPAA) is not well understood. The aim of this study was to compare disability in patients with IPAA vs medically managed UC, and identify predictors of disability. METHODS: This was a multi-center cross-sectional study performed at five academic institutions in New York City. Patients with medically or surgically treated UC were recruited. Clinical and socioeconomic data were collected and the inflammatory bowel disease disability index (IBD-DI) was administered to eligible patients. Predictors of moderate-severe disability (IBD-DI≥35) were assessed in univariable and multivariable models. RESULTS: A total of 94 patients with IPAA and 128 patients with medically managed UC completed the IBD-DI. Among patients with IPAA and UC, 35 (37.2%) and 30 (23.4%) had moderate-severe disability, respectively. Patients with IPAA had significantly greater IBD-DI scores compared to patients with medically managed UC (29.8 vs 17.9, p

Despite pharmacological advances, strictures in Crohn's Disease (CD) continues to be an important problem that leads in a high percentage of patients to undergo endoscopic and/or surgical treatments. There are currently no clinical scores or diagnostic tools that allow predicting which patients will develop this complication, and when a stricture is diagnosed, it is usually already well established and clinically relevant. The current role of pharmacological treatment is limited to treat inflammation and once there is significant fibrosis, the only therapeutic options are endoscopic and/or surgical. To establish a correct therapeutic algorithm and based on the current scientific evidence available, the Spanish Group Working on Crohn's Disease and Ulcerative Colitis (GETECCU) has decided to conduct this position statement on the treatment of strictures in CD. This document embraces the three mentioned therapeutic approaches, medical, endoscopic and surgical. Recommendations and therapeutic algorithms are established to help us to choose the most appropriate option based on the characteristics of the stricture and the patient.

Objective: Assessment of the upper gastrointestinal tract (UGI) may enable more personalized treatment strategies in pediatric inflammatory bowel disease (IBD). However, data on the frequency and significance of these findings remain limited. Methods: Data on 132 pediatric IBD patients with systematic UGI sampling were collected and the baseline characteristics and presence of complications compared between those with and without histological UGI findings. The control group comprised 162 children who received no diagnoses. Results: Seventy-six children had ulcerative colitis (UC), 47 Crohn’s disease (CD) and nine IBD unclassified. UGI findings were more common in IBD patients than controls (69.7% vs. 30.9%, respectively, p

Background and Aims Invariant natural killer T [iNKT] cells perform pleiotropic functions in different tissues by secreting a vast array of pro-inflammatory and cytotoxic molecules. However, the presence and function of human intestinal iNKT cells capable of secreting immunomodulatory molecules such as IL-10 has never been reported so far. Here we describe for the first time the presence of IL10-producing iNKT cells [NKT10 cells] in the intestinal lamina propria of healthy individuals and of Crohn’s disease [CD] patients. Methods Frequency and phenotype of NKT10 cells were analysed ex vivo from intestinal specimens of Crohn’s disease [n = 17] and controls [n = 7]. Stable CD-derived intestinal NKT10 cell lines were used to perform in vitro suppression assays and co-cultures with patient-derived mucosa-associated microbiota. Experimental colitis models were performed by adoptive cell transfer of splenic naïve CD4+ T cells in the presence or absence of IL10-sufficient or -deficient iNKT cells. In vivo induction of NKT10 cells was performed by administration of short chain fatty acids [SCFA] by oral gavage. Results Patient-derived intestinal NKT10 cells demonstrated suppressive capabilities towards pathogenic CD4+ T cells. The presence of increased proportions of mucosal NKT10 cells associated with better clinical outcomes in CD patients. Moreover, an intestinal microbial community enriched in SCFA-producing bacteria sustained the production of IL10 by iNKT cells. Finally, IL10-deficient iNKT cells failed to control the pathogenic activity of adoptively transferred CD4+ T cells in an experimental colitis model. Conclusions These results describe an unprecedentd IL10-mediated immunoregulatory role of intestinal iNKT cells in controlling the pathogenic functions of mucosal T helper subsets and in maintaining the intestinal immune homeostasis.

Background: Severe acute respiratory syndrome coronavirus 2 pandemic is affecting public health systems and mental health significantly. Patients with inflammatory bowel disease are witnessing vigorous organizational changes in inflammatory bowel disease centers and experiencing all psychosocial effects of the crisis. We conducted a single-center cross- sectional study in order to assess inflammatory bowel disease patients’ concerns, behavior, and satisfaction with provided healthcare during severe acute respiratory syndrome coronavirus 2 pandemic. Methods: All inflammatory bowel disease patients treated in our center from April 1 to June 1, 2020, were invited to fulfill an anonymous online questionnaire. Results: A total of 132 participants have completed the questionnaire, 63.2% were female, 57.9% had Crohn’s disease (CD) During the first wave of the pandemic, 74.2% of participants perceived themselves as a high-risk group for acquiring coronavirus disease 2019 only because they suffered from inflammatory bowel disease, and 66.2% thought inflammatory bowel disease medications make them more susceptible to coronavirus disease 2019. This especially concerned patients treated with biologics (B = 2.068, P < .01). Females were more stressed (B = −1.451, P < .01) and concerned (B = −1.488, P < .01) about the pandemic, and they also reported more potential benefits from professional psychological help (B = −2.664, P = .02). Six patients (5.3%) discontinued inflammatory bowel disease therapy on their own initiative. Seventy-eight (68.4%) patients were completely satisfied and 14 (12.3%) were partially satisfied with the quality of healthcare provided in our inflammatory bowel disease center. Conclusion: Female inflammatory bowel disease patients tend to be more emotionally vulnerable during severe acute respiratory syndrome coronavirus 2 pandemic. Although psychological support should be continuously available to all inflammatory bowel disease patients, female gender may warrant special attention. Providing patients with adequate and early information during pandemic probably leads to better compliance and higher satisfaction. Keywords: COVID-19, Crohn’s disease, inflammatory bowel disease, psychological distress, quality of life, ulcerative colitis

Essai clinique - Phase I; International audience; Background and aim: Expression of FimH adhesin by invasive Escherichia coli in the gastrointestinal tract of patients with Crohn's disease (CD) facilitates binding to epithelial glycoproteins and release of pro-inflammatory cytokines. Sibofimloc is a first-in-class FimH blocker that showed little systemic absorption in healthy volunteers. The current study evaluated systemic absorption, safety, and effect on inflammatory biomarkers of sibofimloc in patients with CD.Methods: This was an open-label, multicenter phase 1b study in adults with active CD. In part 1, two patients received a single oral dose of 3000-mg sibofimloc followed by 1500 mg b.i.d. for 13 days. In part 2, six patients received 1500-mg sibofimloc b.i.d. for 13 days. Blood was drawn for pharmacokinetic and biomarker analysis, and stool was collected for biomarker and microbiome analysis.Results: Eight patients with active ileal or ileocolonic CD were enrolled into the study. Systemic sibofimloc exposure was low. Sibofimloc was well tolerated with only grade 1-2 events observed. Several pro-inflammatory biomarkers, including IL-1β, IL-6, IL-8, TNF-α, IFN-γ, and calprotectin, were decreased in stool by end of study.Conclusions: This first study of the novel FimH blocker, sibofimloc, in patients with active CD demonstrated minimal systemic exposure with good tolerance, while decreasing several inflammatory biomarkers. EudraCT number: 2017-003279-70.

Resumen Introducción: la enfermedad inflamatoria intestinal (EII) es una enfermedad inmunomediada, cuya incidencia en Latinoamérica ha aumentado en los últimos años. Objetivo: analizar las características demográficas y clínicas de los pacientes con EII tratados en un hospital universitario y presentar los datos epidemiológicos con respecto a otros centros en Colombia. Pacientes y métodos: estudio descriptivo de pacientes con EII (1996-2019) en el Hospital Universitario Fundación Santa Fe de Bogotá. Análisis de datos de centros de Medellín, Cali, Bogotá y Cartagena. Resultados: de 386 pacientes, 277 presentaron colitis ulcerativa (CU), 102 enfermedad de Crohn (EC) y 7 colitis no clasificable. La EII fue más frecuente en mujeres (53 %). La mortalidad fue menor de 1 %. El compromiso de la CU fue principalmente la pancolitis (42,6 %). Entre mayor la extensión de la enfermedad, más alta fue la tasa de hospitalización y cirugías (OR 3,70; p < 0,01). El 13 % de los pacientes con CU recibió biológicos. El compromiso por la EC fue principalmente ileocolónico (43,6 %) e ileal (43,6 %). El patrón clínico predominante de la EC fue estenosante (50%). El 45 % recibió biológicos y 56% cirugía. La colangitis esclerosante primaria (CEP) se encontró en 4 % de los pacientes (n = 15). Dos pacientes con CEP desarrollaron cáncer colorrectal (OR 4,18; p 0,008), mientras que 13 pacientes con CU desarrollaron cáncer de colon y 7 cambios displásicos. 3 pacientes con EC desarrollaron cáncer de colon. Conclusiones: se compararon los resultados en relación con otros centros de referencia. Encontramos tendencias similares en el comportamiento clínico y en el tratamiento de la EII, con mayores tazas de hospitalizaciones y cirugías en nuestros casos. Abstract Introduction: Inflammatory bowel disease (IBD) is an immune-mediated disease whose incidence in Latin America has increased in recent years. Aim: To analyze the demographic and clinical characteristics of patients with IBD treated in a university hospital and present the epidemiological data compared to other centers in Colombia. Patients and methods: Descriptive study of patients with IBD (1996-2019) at the Hospital Universitario Fundación Santa Fe de Bogotá. Analysis of data from centers in Medellín, Cali, Bogotá, and Cartagena. Results: Of 386 patients, 277 presented with ulcerative colitis (UC), 102 with Crohn’s disease (CD), and seven with unclassifiable colitis. IBD was more frequent in women (53 %). Mortality was less than 1 %. The involvement of UC was mainly pancolitis (42.6 %). The greater the extent of the disease, the higher the hospitalization and surgery rates (OR 3.70, P < 0.01). Thirteen percent of patients with UC received biologics. Compromise due to CD was mainly ileocolonic (43.6 %) and ileal (43.6 %). The predominant clinical pattern of CD was structuring (50%). Forty-five percent received biologicals and 56 % surgery. Primary sclerosing cholangitis (PSC) was found in 4 % of patients (n = 15). Two patients with PSC developed colorectal cancer (OR 4.18; p 0.008), while 13 patients with UC developed colon cancer and seven dysplastic changes. Three patients with CD developed colon cancer. Conclusions: The results were compared to other reference centers. We found similar trends in the clinical behavior and treatment of IBD, with higher hospitalization and surgery rates in our cases.