Background and Aims Ileocolonic resection is frequently needed in the course of Crohn's disease [CD] treatment and post-operative recurrence is extremely common. Our main objective was to analyse gene expression in the mucosa of CD patients at the time of surgery and at post-operative endoscopy, in order to identify predictors and mechanisms of early endoscopic recurrence. Methods We conducted transcriptome analyses on ileal mucosa samples collected from inflamed sections of the surgical specimens [n = 200], from ileal resection margins [n = 149] and in the neo-terminal ileum 6 months after surgery [n = 122]; these were compared with non-inflammatory bowel disease controls [n = 25]. The primary endpoint was post-operative endoscopic recurrence at 6 months. We applied regression models to identify gene signatures predicting endoscopic recurrence. Results Chronic inflammation was associated with strong expression of inflammatory genes [IL-6, IL-8, IL-1B] and decreased expression of genes involved in metabolic processes, but with a high inter-individual heterogeneity. Gene signatures associated with early endoscopic recurrence were mainly characterized by upregulation of TNF alpha, IFN gamma, IL23A and IL17A. Pathway analyses showed that upregulation of mitochondrial dysfunction within the inflamed sections and JAK/STAT at the ileal margin were predictive of post-operative recurrence. A combined model integrating these top pathway signatures improved the prediction of endoscopic recurrence [area under the curve of 0.79]. STAT3 phosphorylation at the surgical ileal margin was associated with severe recurrence at 6 months. Conclusion We identified several biological pathways in surgical ileal mucosa specimens associated with an increased risk of disease recurrence. Integration of the JAK/STAT and mitochondrial dysfunction pathways in the clinical model improved the prediction of post-operative recurrence.

INTRODUCTION:While endoscopic balloon dilation (EBD) is widely used to manage ileal strictures, EBD of colorectal strictures remains poorly investigated in Crohn's disease (CD).METHODS:We performed a retrospective study that included all consecutive CD patients who underwent EBD for native or anastomotic colorectal strictures in 9 tertiary centers between 1999 and 2018. Factors associated with EBD failure were also investigated by logistic regression.RESULTS:Fifty-seven patients (25 women, median age: 36 years (InterQuartile Range, 31-48) were included. Among the 60 strictures, 52 (87%) were native, 39 (65%) measured < 5 cm and the most frequent location was the left colon (27%). Fifty-seven (95%) were non-passable by the scope and 35 (58%) were ulcerated. Among the 161 EBDs performed (median number of dilations per stricture: 2, IQR 1-3), technical and clinical success were achieved for 79% (n = 116/147) and 77% (n = 88/115), respectively. One perforation occurred (0.6% per EDB and 2% per patient). After a median follow-up of 4.3 years (IQR 2.0-8.4), 24 patients (42%) underwent colonic resection and 24 (42%) were asymptomatic without surgery. One colon lymphoma and one colorectal cancer were diagnosed (3.5% of patients) from endoscopic biopsies and at the time of surgery, respectively. No factor was associated with technical or clinical success.CONCLUSION:EDB of CD-associated colorectal strictures is feasible, efficient and safe, with more than 40% becoming asymptomatic without surgery.

LINKED CONTENT This article is linked to Wils et al and Seow & Ma papers. To view these articles, visit https://doi.org/10.1111/apt.16192 and https://doi.org/10.1111/apt.16207

AbstractBackground and AimsThe identification of Crohn's disease (CD)‐associated adherent and invasive Escherichia coli (AIEC) is time‐consuming and requires ileal biopsies. We aimed to identify a faster and less invasive methods to detect ileal colonization by AIEC in CD patients.MethodsCD patients requiring ileo‐colonoscopy were consecutively enrolled in this prospective multicenter study. Samples from saliva, serum, stools, and ileal biopsies of CD patients were collected.ResultsAmong 102 CD patients, the prevalence of AIEC on ileal biopsies was 24.5%. The abundance and global invasive ability of ileal‐associated total E. coli were respectively ten‐fold (p = 0.0065) and two‐fold (p = 0.0007) higher in AIEC‐positive (vs. AIEC‐negative), while abundance of total E. coli in the feces was not correlated with AIEC status in the ileum. The best threshold of ileal total E. coli was 60 cfu/biopsy to detect AIEC‐positive patients, with high negative predictive value (NPV) (94.1%[80.3–99.3]), while the global invasive ability (>9000 internalized bacteria) was able to detect the presence of AIEC with high positive predictive value (80.0% [55.2–100.0]). Overall, 78.1% of the AIEC + patients were colonized by two or less different AIEC strains. The level of serum anti‐total E. coli antibodies (AEcAb) was higher in AIEC‐positive patients (p = 0.038) with a very high negative predictive value (96.6% [89.9–100.0]) (p = 0.038) for a cut‐off value > 1.9 × 10−3.ConclusionsMore than two thirds of AIEC‐positive CD patients were colonized by two or less AIEC strains. While stools samples are not accurate to screen AIEC status, the AEcAb level appears to be an attractive, rapid and easier biomarker to identify patients with Crohn's disease harboring AIEC.

AbstractBackgroundPreventing postoperative recurrence (POR) is a major concern in Crohn's disease (CD). While azathioprine is an option, no data is available on ustekinumab efficacy in this situation.AimsWe compared the effectiveness of ustekinumab versus azathioprine in preventing endoscopic POR in CD.MethodsWe retrospectively collected data from all consecutive CD patients treated with ustekinumab after intestinal resection in 9 centers. The control group (azathioprine alone) was composed of patients who participated in a randomized controlled trial conducted in the same centers comparing azathioprine alone or in combination with curcumin. Propensity score analyses (inversed probability of treatment weighting = IPTW) were applied to compare the two groups. The primary endpoint was endoscopic POR (Rutgeerts' index ≥ i2) at 6 months.ResultsOverall, 32 patients were included in the ustekinumab group and 31 in the azathioprine group. The propensity score analysis was adjusted on the main risk factors (smoking, fistulizing phenotype, prior bowel resection, resection length >30 cm and ≥2 biologics before surgery) and thiopurines or ustekinumab exposure prior to surgery making the two arms comparable (∣d∣ < 0.2). After IPTW, the rate of endoscopic POR at 6 months was lower in patients treated with ustekinumab compared to azathioprine (28.0% vs. 54.5%, p = 0.029). After IPTW, the rates of i2b‐endoscopic POR (Rutgeerts' index ≥ i2b) and severe endoscopic POR (Rutgeerts' index ≥ i3) were 20.8% versus 42.5% (p = 0.066) and 16.9% versus 27.9% (p = 0.24), in the ustekinumab and azathioprine groups, respectively.ConclusionUstekinumab seemed to be more effective than azathioprine in preventing POR in this cohort of CD patients.

Fistulizing perianal Crohn's disease (FPCD) – defined as the presence of perianal fistula (PF) and/or abscesses – is an aggressive and debilitating complication of Crohn's disease (CD) and affects >25% of patients with CD within two decades of diagnosis [1,2]. Symptoms of FPCD include rectal pain, persistent drainage from external fistula openings, and urinary tract infections [1]. Besides impaired quality of life, FPCD leads to frequent relapses, and surgical intervention is often required [1].

Background and Aims Different types of histologic lesions at the ileal margin, detected by histology, have been associated with increased rates of recurrence after ileocaecal surgery in patients with Crohn's disease (CD). We aimed to characterize histologic features of the ileal margin and to evaluate their association with disease recurrence. Methods We collected histologic data from 211 patients with ileal or ileocolonic CD who underwent ileocolonic resections at hospitals in France from September 2010 through December 2016. Ileal margins were analyzed. Early endoscopic recurrence was defined by a Rutgeerts score of i2 or more, 6 months after surgery. We also collected data from 10 adults with healthy ileum who underwent ileocecal resection for colonic tumors (controls). Clinical relapse was defined by CD-related symptoms confirmed by imaging, endoscopy, therapy intensification, CD-related complication, or subsequent surgery. Results Six months after surgery, 49% of patients had endoscopic recurrence; 5 years after surgery, 57% of patients had clinical relapse. Ileal margins were macroscopically affected in 20.9% of patients. CD transmural lesions at the margin (defined by mucosal ulceration or cryptitis, submucosal fibrosis and lymphoplasmacytic infiltrate of the subserosa) were observed in 13.6% of patients. Endoscopic recurrence was observed in 75% of patients with CD transmural lesions vs 46% of patients without (P =.005). In multivariate analysis, CD transmural lesions at the margin were independently associated with early endoscopic recurrence (OR, 3.83; 95% CI, 1.47-11.05; P =.008) and clinical recurrence (OR 2.04; 95% CI, 1.09-3.99; P =.026). Conclusion In patients with CD, transmural lesions at the ileal margin were associated with an increased risk of post-operative recurrence. Histologic features of the ileal margin should be included in making decisions about post-operative therapy.

For inflammatory bowel disease, traditional dose escalation approaches that are based on clinical symptoms are being replaced by more aggressive treat-to-target approaches, in which treatment is adjusted promptly when predefined clinical and mucosal targets are not met. There is, however, an ongoing need to combine up-to-date treat-to-target strategies with easy-to-implement recommendations. Herein, we present consensus-recommendations for treatment targets that reflect current best practices in France. Methods Thirty-four gastroenterologists practicing in France participated in a meeting during which consensus statements about treat-to-target strategies for following patients with Crohn's disease (CD) and ulcerative colitis were developed. Targets, their definitions, and the timeframes for reaching them were defined. Consensus was defined as ≥66% of experts agreeing with a statement. Results For both diseases, the agreed targets were: patient related outcomes on disease (PRO-1), patient related outcomes on gastrointestinal symptoms (PRO-2), endoscopic healing and biomarkers of inflammation. Nutritional status has been defined as a target for CD only. Histological healing and transmural healing were not defined as targets. Deadlines to achieve targets and monitoring frequency have been agreed as well. Conclusions These consensus statements provide simple, easy-to-follow guidelines that should help gastroenterologists in France implement treat-to-target approaches, optimize treatments, and thus, reduce the burden of disease.

Background: There are few data concerning patients with Crohn's disease (CD) complicated by a stricture of the upper gastrointestinal tract (UGT). Aims: We evaluated the outcome and management of CD patients complicated by a stricture of the UGT. Methods: We performed a retrospective multicenter study including all CD patients with a non-passable symptomatic UGT stricture on endoscopy. Primary outcome measure was surgery-free survival from diagnosis of stricture. Efficacy of medical, endoscopic, and surgical treatments, and identification of predictors of surgery were also evaluated. Results: 60 CD patients with an UGT stricture were included. 60% of the strictures were located in the duodenum. With a median follow-up of 5.5 (IQR: 3.0-12.0) years since stricture diagnosis, surgical-free survival was 75% and 64% at 1 and 5 years, respectively. At the end of the follow up, 27 (45%) patients underwent surgery. 77 endoscopic procedures were performed in 30 patients with an immediate success of 81% and a clinical benefit in 84% of the procedures. In multivariate analysis, anti-TNF treatment initiation was associated with a reduced risk of surgery. Conclusion: CD UGT strictures are mainly located in the duodenum. Medical and endoscopic treatments allow to avoid surgery in half of the patients (C) 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Summary Background The prevalence of inflammatory bowel diseases (IBD) is high in women of childbearing age. Achieving clinical remission from conception to delivery using current medications is a major issue in IBD. Aims To assess maternal and neonatal complications and management of vedolizumab or ustekinumab) in pregnant women with IBD receiving these agents. Methods We performed a retrospective cohort study among GETAID centres including women with IBD who received ustekinumab or vedolizumab during pregnancy or within the 2 months before conception and compared outcomes to women exposed to anti‐TNF treatment during pregnancy. Results Seventy‐three pregnancies in 68 women with IBD were analysed: 29 on ustekinumab resulting in 26 (90%) live births, two (7%) spontaneous abortions and one (3%) elective termination; 44 on vedolizumab resulting in 38 (86%) live births, five (11%) spontaneous abortions and one (3%) medical interruption. The control group included 88 pregnancies exposed to anti‐TNF in 76 women with IBD. The median age at conception, the proportion of women who smoked or in clinical activity at conception was comparable between groups. Only the proportion of patients exposed to >2 anti‐TNF agents was significantly increased among the ustekinumab and vedolizumab groups compared to control group (22% and 10% vs 3%, P < 0.005). Rates of prematurity, spontaneous abortion, congenital malformations and maternal complications were comparable between groups. Conclusion We report 73 pregnancies in patients receiving vedolizumab or ustekinumab without a negative signal on maternal or neonatal outcomes. Further prospective studies are needed on the outcomes of pregnancies with new biologic drugs.

BACKGROUND:The notion of Crohn's disease (CD) as a chronic, progressive and disabling condition has led to the development of new indexes: the Lémann Index measuring cumulative bowel damage and the Inflammatory Bowel Disease (IBD) Disability Index, assessing functional disability.AIMS:To measure the Lémann Index and the IBD Disability Index in a large prospective cohort of CD patients and to assess the correlation between these two indexes.METHODS:We performed a prospective study in a tertiary referral centre including all consecutive CD outpatients. We assessed the Lémann Index and the IBD Disability Index questionnaire in all patients.RESULTS:One hundred and thirty CD patients were consecutively included. The mean Lémann Index (±SD) was 11.9 ± 14.1 and ranged from 0 to 72.5 points. Factors associated with a high bowel damage score were: disease duration, anal location, previous intestinal resection, clinical and biological disease activity, exposure to immunosuppressants, and exposure to anti-TNF (P < 0.005). Among patients exposed to anti-TNF, the Lémann Index was lower in those who were exposed in the first 2 years of their disease (P = 0.015). The mean IBD Disability Index was 28.8 ± 6.3 and ranged from 0 to 71 points. The factors associated with high disability score were: female gender, anal location, extra digestive manifestations, clinical and biological disease activity and exposure to anti-TNF (P < 0.005). No correlation was observed between the Lémann Index and IBD Disability Index (P = 0.15).CONCLUSIONS:This is the first study to prospectively evaluate the Lémann Index and the IBD Disability Index in a large cohort of CD patients in a tertiary centre. Early introduction of anti-TNF treatment was associated with lower bowel damage scores, and no correlation was observed between the Lémann Index and the IBD Disability Index. Further dedicated prospective studies are necessary to confirm these results.

Abstract Background The Lémann index (LI) is the first instrument developed to measure cumulative structural bowel damage in Crohn’s disease (CD).1 We here report its validation. Methods This was an international, multicentre, prospective cross-sectional observational study. At each centre, 10 inclusions, stratified by known or suspected CD location and duration, were planned. Clinical examination and abdominal MRI had to be performed in all patients, and upper endoscopy, colonoscopy, and pelvic MRI according to CD location. Upper tract (UT), small bowel (SB), colon/rectum (CR), and anus (AN) were divided into 3, 20, 6 and 1 segments, respectively. History of previous surgery was collected per segment. For each segment, 1 gastroenterologist and 1 radiologist per centre, identified the presence of predefined stricturing and/or penetrating lesions of maximal severity (grade 1 to 3) at each investigation. They provided a damage evaluation for each non-resected segment ranging from 0 to 10, 10 corresponding to the damage of a completely resected segment. Investigator organ damage evaluation was calculated as the sum of segmental damage evaluations. Finally, investigators provided a global damage evaluation from 0 to 10 for each patient according to the 4 organ damage scores, calculated as a function of investigator organ damage evaluations, resections and a total number of segments. The correlation between the investigator global damage evaluation and the LI was high on the construction sample, since coefficients to derive the LI were estimated by maximising this correlation, and is expected to be lower on data obtained in new patients by new investigators. Thus, the LI would be validated if the linear regression model of investigator global damage evaluation on LI shows a still high correlation. The same applies to investigator damage evaluation of each organ and each organ component of the LI. Results 134 patients were included in 15 centres, 7 to 10 per centre. Correlation coefficients between investigator organ damage evaluation and each organ component of the LI were 0.91, 0.96, 0.95, and 0.81, for UT, SB, CR and AN, respectively. The correlation coefficient between investigator global damage evaluation and the LI was 0.98 (Figure 1). Proportions of the investigator organ damage evaluation variance explained by each organ component of the LI were 82%, 91%, 89%, 65%, for UT, SB, CR, AN, respectively. This proportion was 96% for the investigator global damage evaluation and the LI. Conclusion The Lémann index is now a validated index to assess cumulative bowel damage in CD that can be used in epidemiological studies and disease modification trials. Reference

INTRODUCTION: The impact of severity and location of Crohn's disease (CD) endoscopic ulcers on endoscopic remission in patients treated with antitumor necrosis factor is poorly known. We aimed to describe the endoscopic evolution of CD lesions in a prospective cohort of patients treated with infliximab (IFX) in combo therapy. METHODS: We conducted a post hoc analysis of the TAILORIX randomized controlled trial, which studied biologic-naïve patients with active CD and endoscopic ulcers receiving IFX combo therapy. Ileocolonoscopies were performed at week 0, 12, and 54. Endoscopic healing was defined as the absence of ulcers and complete endoscopic remission as CD Endoscopic Index of Severity (CDEIS) <3. Ileocolonic segments were scored separately for remission by blinded readers. RESULTS: A total of 122 (median disease duration: 7 months) patients were included, corresponding with 379 diseased segments. The median (IQR) CDEIS scores at week 0, 12, and 54 were 9.9 (6.1–14.4), 2.4 (0.2–4.6), and 0.2 (0.0–3.7), respectively. At weeks 12 and 54, the rates of endoscopic healing and complete endoscopic remission were 41% and 61% and 61% and 73%, respectively. Median CDEIS scores were similar among patients with deep ulcers at baseline and those with only superficial ulcers at week 12 and 54. Segmental remission rates were lower both at week 12 and 54 in the ileum compared with colonic segments (P < 0.01 all comparisons) and in the rectum (P = 0.02 and P = 0.03). DISCUSSION: In biologic-naive patients with CD treated with IFX combo therapy, the severity of endoscopic lesions at the baseline did not influence healing rates. Endoscopic remission occurs less frequently in the ileum compared with the colon.

BACKGROUND & AIMS: Higher infliximab trough levels are associated with clinical and endoscopic remission in patients with Crohn's disease (CD). We investigated pharmacodynamic features of infliximab and radiological healing. METHODS: We performed a substudy of the TAILORIX trial (patients with active luminal CD in Europe, treated with infliximab), analyzing baseline and week 54 magnetic resonance enterography (MRE) data. MREs were scored using the MaRIA score by blinded central readers. Radiologic response and remission were defined, based on MaRIA criteria in all segments, as scores below 11 and 7, respectively. We collected data on infliximab trough levels, biomarkers, and endoscopic findings. Our primary aim was to evaluate pharmacodynamic features associated with radiologic response and remission, based on MRE assessments at baseline and at 54 weeks after initiation of infliximab therapy. RESULTS: We analyzed data from 36 patients (50% female; median age 35.7 years; interquartile age range, 25.6-48.6 years; median disease duration, 1.5 months; interquartile duration range, 0.6-22.4 months). At week 54 of treatment, 36.4% of patients had a radiologic response, 30.3% of patients were in remission, and 71% had endoscopic features of remission. At baseline, there was a correlation between the CD endoscopic index of severity and MaRIA scores ( k = 0.46; P =.008), but we found no correlation at week 54 ( k = 0.06; P =.75). Radiologic remission correlated with infliximab trough level at week 14 (P =.049) when the infliximab trough level cut-off value was set at 7.8 mg/mL (area under the curve, 0.74; 75% sensitivity; 86% specificity; 90% negative predictive value; 57% positive predictive value). Radiologic response correlated with infliximab trough levels at week 14 (P=.048) when the infliximab trough level cut-off value was set at 7.8 mg/mL (area under the curve, 0.73; 70% sensitivity; 90% specificity; 86% negative predictive value; 78% positive predictive value) and with continuous pharmacologic evidence of response (infliximab trough levels above 5.0 mg/mL at all time points) (P = .034). CONCLUSIONS: In a substudy of data from the TAILORIX trial of patients with active luminal CD, we identified a relationship between exposure to infliximab and radiologic evidence of outcomes.

findings emphasize the importance of Nrf2 in maintaining nNOS a mediated GE in female obese T2DM rodents.CNM and CUR are potential dietary compounds that can alleviate diabetic gastroparesis in women.

INTRODUCTION:New therapeutic options for patients with Crohn's disease (CD) with perianal lesions failing anti-tumor necrosis factor (TNF) agents are needed. We aimed to assess the effectiveness of ustekinumab in perianal CD (pCD) and predictors of clinical success in a real-life multicenter cohort.METHODS:We conducted a national multicenter retrospective cohort study in patients with either active or inactive pCD who received ustekinumab. In patients with active pCD at treatment initiation, the success of ustekinumab was defined by clinical success at 6 months assessed by the physician's judgment without additional medical or surgical treatment for pCD. Univariate and multivariable logistic regression analyses were performed to identify predictors of success. In patients with inactive pCD at ustekinumab initiation, the pCD recurrence-free survival was calculated using the Kaplan-Meier method.RESULTS:Two hundred seven patients were included, the mean age was 37.7 years, the mean duration of CD was 14.3 years, and the mean number of prior perianal surgeries was 2.8. Two hundred five (99%) patients had previously been exposed to at least 1 anti-TNF and 58 (28%) to vedolizumab. The median follow-up time was 48 weeks; 56/207 (27%) patients discontinued therapy after a median time of 43 weeks. In patients with active pCD, success was reached in 57/148 (38.5%) patients. Among patients with setons at initiation, 29/88 (33%) had a successful removal. The absence of optimization was associated with treatment success (P = 0.044, odds ratio 2.74; 95% confidence interval: 0.96-7.82). In multivariable analysis, the number of prior anti-TNF agents (≥3) was borderline significant (P = 0.056, odds ratio 0.4; 95% confidence interval: 0.15-1.08). In patients with inactive pCD at initiation, the probability of recurrence-free survival was 86.2% and 75.1% at weeks 26 and 52, respectively.DISCUSSION:Ustekinumab appears as a potential effective therapeutic option in perianal refractory CD. Further prospective studies are warranted.