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Cross-sectional magnetic resonance enterography (MRE) and intestinal ultrasonography (IUS) provide valuable and noninvasive information to accurately assess disease activity, severity, and extent; detect complications; and monitor the response to treatment, as well as predict the postoperative recurrence of Crohn’s disease and a negative disease course. Therefore, both imaging modalities are emerging as pivotal diagnostic tools to achieve the emerging therapeutic target of transmural healing associated with better disease outcomes. Despite its numerous potential advantages over endoscopy and even MRE and its good availability, IUS is still widely underused to monitor and manage inflammatory bowel disease (IBD) patients and help in making clinical decisions in routine practice. This situation is clearly due to the absence of validated, reliable, and responsive indices, as well as the lack of trained gastroenterologists and radiologists, as IUS is a component of radiologist expertise in several countries but not yet integrated into the training program of gastroenterologists. However, there is an increasing body of evidence in the literature that IUS and MRE are both becoming essential imaging resources to help clinicians in making reliable decisions. Here, we discuss the up-to-date evidence about the usefulness and performance of cross-sectional imaging, focusing on the ability of bowel US and MRE to aid clinical decision-making for the optimal management and monitoring of IBD.

Early ileocolonoscopy within the first year after surgery is the gold standard to evaluate recurrence after ileocolonic resection for Crohn's disease (CD). The aim of the study was to evaluate the association between the presence and severity of anastomotic and ileal lesions at early postoperative ileocolonoscopy and long-term outcomes. The REMIND group conducted a prospective multicenter study. Patients operated for ileal or ileocolonic CD were included. An ileocolonoscopy was performed 6 months after surgery. An endoscopic score describing separately the anastomotic and ileal lesions was built. Clinical relapse was defined by the CD-related symptoms, confirmed by imaging, endoscopy or therapeutic intensification; CD-related complications; or subsequent surgery. Among 225 included patients, long-term follow-up was available in 193 (median follow-up: 3.82 years [interquartile range: 2.56-5.41]). Median clinical recurrence-free survival was 47.6 months. Clinical recurrence-free survival was significantly shorter in patients with ileal lesions at early postoperative endoscopy whatever their severity was (I(1) or I(2,3,4)) as compared to patients without ileal lesions (I(0)) (I(0) vs I(2,3,4): P = 0.0003; I(0) vs I(1): P = 0.0008 and I(1) vs I(2,3,4): P = 0.43). Patients with exclusively ileal lesions (A(0)I(1,2,3,4)) had poorer clinical long-term outcomes than patients with exclusively anastomotic lesions (A(1,2,3)I(0)) (P = 0.009). A score describing separately the anastomotic and ileal lesions might be more appropriate to define postoperative endoscopic recurrence. Our data suggest that patients with ileal lesions, including mild ones (I(1)), could beneficiate from treatment step-up to improve long-term outcomes.

Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions of the gastrointestinal tract that are multifactorial in nature. The pathophysiology involves interactions between the host immune system and environmental factors, including the gut microbiota, in genetically predisposed individuals. Advances in understanding these interactions have led to the development of novel therapeutic targets, ranging from anti-TNFα to more recent anti-interleukin 23 treatments. However, some patients still experience resistance to these therapies. Monogenic intestinal diseases (MIDs), which present with more severe symptoms than IBD and typically begin early in life, result from significant disruptions of intestinal homeostasis. MIDs are driven by mutations in a single gene, offering a unique opportunity to explore the mechanisms underlying intestinal homeostasis in health. In this review, we provide a comprehensive overview of the mechanisms of intestinal homeostasis by examining the cellular and molecular features of IBD and MID pathophysiologies.

IntroductionThe pharmacokinetic equivalence of dose intensification with adalimumab (ADA) 80 mg every other week (EOW) compared to weekly 40 mg has only been supported by modeling systems.Aim of the StudyTo compare the trough levels of ADA (TLA) and the occurrence of anti-ADA antibodies (AAA) between these two treatment regimens.Patients and MethodsThis was a prospective study including all consecutive patients with inflammatory bowel disease (IBD) who had reached a longstanding and deep remission under treatment with ADA 40 mg once a week. In these patients, the ADA regimen was changed from 40 mg/week to 80 mg EOW. TLA and AAA levels using a drug-tolerant assay were monitored before and ten weeks after from the change in the ADA regimen and the results compared by a Wilcoxon paired test. ResultsSixty-two patients (60% CD, mean age 35 years) were included. Before and ten weeks after the changes of ADA regimen, the median TLA were (6.9 µg/mL versus 7.0 µg/mL, respectively; P = 0.34) and the AAA levels (3.4 µg/ml-eq versus 3.0 µg/ml-eq, respectively; P = 0.25.) were quite similar. Likewise, quartiles of TLA (Kendall test r = 0.91; P < 0.001) and AAA (r = 0.78; P < 0.001) did not differ before and after ADA regimen. When stratifying all the patients into 4 groups based on drug/antibody levels (immunogenic, subtherapeutic, therapeutic, or supratherapeutic), no patient needed for returning to the previous weekly regimen. In terms of acceptability, more than 60% of patients preferred an injection EOW compared once a week. ConclusionsIn IBD patients who achieved a deep clinical remission under ADA 40 mg once a week, the pharmacokinetic of ADA was similar when ADA regimen was changed to 80 mg EOW. Given the patient’s preference for the latter regimen, a modification of injection regimen should be systematically proposed.

INTRODUCTION:The objective of this study was to describe the efficacy and safety of infliximab (IFX) reintroduction in Crohn's disease (CD) after stopping for loss of response or intolerance.METHODS:We conducted a prospective multicenter observational cohort study including adult patients with clinically (CD Activity Index >150) and objectively active luminal CD in whom IFX was reintroduced after at least 6 months of discontinuation. The reasons for the initial discontinuation could be a secondary loss of response or IFX intolerance. The reintroduction schedule included 3 IFX infusions at weeks 0, 4, and 8, after a systematic premedication. The primary end point was the efficacy of IFX retreatment at week 26 defined by a CD Activity Index of <150 in the absence of IFX discontinuation or use of corticosteroids, surgery, or other biologic.RESULTS:At week 26, 24 patients (35%) among the 69 analyzed reached the primary end point. No significant difference was observed between rates of clinical remission at week 26 in patients with prior LOR (n = 48) and those with IFX intolerance (n = 21) (35% and 33%, P = 0.87, respectively). Thirty-two acute infusion reactions were recorded in 27 patients, leading to withdrawal of IFX in 20 patients. No pharmacokinetic characteristic at baseline but detection of positive anti-drug antibodies at week 4 was predictive of IFX failure or infusion reaction at week 26.DISCUSSION:In this first prospective cohort study, IFX retreatment was safe and effective in one-third of the patients with CD, regardless the reason of prior discontinuation. Early detection of anti-drug antibodies can predict subsequent IFX reintroduction failure and infusion reactions.

Genome-wide association studies have identified over 200 genomic loci associated with inflammatory bowel disease (IBD). High-effect risk alleles define key roles for genes involved in bacterial response and innate defense. More high-throughput in vivo systems are required to rapidly evaluate therapeutic agents. We visualize, in zebrafish, the effects on epithelial barrier function and intestinal autophagy of one-course and repetitive injury. Repetitive injury induces increased mortality, impaired recovery of intestinal barrier function, failure to contain bacteria within the intestine and impaired autophagy. Prostaglandin E2 (PGE2) administration protected against injury by enhancing epithelial barrier function and limiting systemic infection. Effects of IBD therapeutic agents were defined: mesalamine showed protective features during injury, whereas 6-mercaptopurine displayed marked induction of autophagy during recovery. Given the highly conserved nature of innate defense in zebrafish, it represents an ideal model system with which to test established and new IBD therapies targeted to the epithelial barrier. This article has an associated First Person interview with the first author of the paper.

Background and aimsWe aimed to analyze circulating CD4+ T cell subsets and cytokines during the course of Crohn’s disease (CD).Methods and resultsCD4+ T cell subsets, ultrasensitive C-reactive protein (usCRP), and various serum cytokines (IL-6, IL-8, IL-10, IL-13, IL-17A, IL-23, TNFα, IFNγ, and TGFβ) were prospectively monitored every 3 months for 1 year, using multicolor flow cytometry and an ultrasensitive Erenna method in CD patients in remission at inclusion. Relapse occurred in 35 out of the 113 consecutive patients (31%). For patients in remission within 4 months prior to relapse and at the time of relapse, there was no significant difference in Th1, Th17, Treg, and double-positive CD4+ T cell subsets co-expressing either IFNγ and FOXP3, IL-17A and FOXP3, or IFNγ and IL-17A. On the contrary, in patients who remained in remission, the mean frequency and number of double-positive IL-17A+FOXP3+ CD4+ T cells and the level of usCRP were significantly higher ( p ≤ 0.01) 1 to 4 months prior to relapse. At the time of relapse, only the IL-6 and usCRP levels were significantly higher ( p ≤ 0.001) compared with those patients in remission. On multivariate analysis, a high number of double-positive IL-17A+FOXP3+ CD4+ T cells (≥1.4 cells/mm3) and elevated serum usCRP (≥3.44 mg/L) were two independent factors associated with risk of relapse.ConclusionsDetection of circulating double-positive FOXP3+IL-17A+ CD4+ T cell subsets supports that T cell plasticity may reflect the inflammatory context of Crohn’s disease. Whether this subset contributes to the pathogenesis of CD relapse needs further studies.

ObjectivesIn patients with IBD experiencing an immune-mediated loss of response (LOR) to antitumour necrosis factor (anti-TNF), algorithms recommend a switch of anti-TNF without immunosuppressive drug. The aim of our study was to compare in these patients two strategies: either switch to a second anti-TNF alone or with addition of azathioprine (AZA). After randomisation outcomes (time to clinical and pharmacokinetic failure) were compared between the two groups during a 2-year follow-up period.DesignConsecutive IBD patients in immune-mediated LOR to a first optimised anti-TNF given in monotherapy were randomised to receive either AZA or nothing with induction by a second anti-TNF in both arms. Clinical failure was defined for Crohn’s disease (CD) as a Harvey-Bradshaw index ≥5 associated with a faecal calprotectin level >250 µg/g stool and for UC as a Mayo score >5 with endoscopic subscore >1 or as the occurrence of adverse events requiring to stop treatment. Unfavourable pharmacokinetics of the second anti-TNF were defined by the appearance of undetectable trough levels of anti-TNF with high antibodies (drug-sensitive assay) or by that of antibodies (drug-tolerant assay).ResultsNinety patients (48 CDs) were included, and 45 of them received AZA after randomisation. The second anti-TNF was adalimumab or infliximab in 40 and 50 patients, respectively. Rates of clinical failure and occurrence of unfavourable pharmacokinetics were higher in monotherapy compared with combination therapy (p<0.001; median time of clinical failure since randomisation 18 vs >24 months). At 24 months, survival rates without clinical failure and without appearance of unfavourable pharmacokinetics were respectively 22 versus 77% and 22% versus 78% (p<0.001 for both) in monotherapy versus combination therapy. Only the use of combination therapy was associated with favourable outcomes after anti-TNF switch.ConclusionIn case of immune-mediated LOR to a first anti-TNF, AZA should be associated with the second anti-TNF.Trial registration number03580876.

Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions of the gastrointestinal tract that are multifactorial in nature. The pathophysiology involves interactions between the host immune system and environmental factors, including the gut microbiota, in genetically predisposed individuals. Advances in understanding these interactions have led to the development of novel therapeutic targets, ranging from anti-TNFα to more recent anti-interleukin 23 treatments. However, some patients still experience resistance to these therapies. Monogenic intestinal diseases (MIDs), which present with more severe symptoms than IBD and typically begin early in life, result from significant disruptions of intestinal homeostasis. MIDs are driven by mutations in a single gene, offering a unique opportunity to explore the mechanisms underlying intestinal homeostasis in health. In this review, we provide a comprehensive overview of the mechanisms of intestinal homeostasis by examining the cellular and molecular features of IBD and MID pathophysiologies.

Background In Europe, gastric cancer remains diagnosed at advanced stage (serosal and/or lymph node involvement). Despite curative management combining perioperative systemic chemotherapy and gastrectomy with D1-D2 lymph node dissection, 5-year survival rates of T3 and/or N + patients remain under 30%. More than 50% of recurrences are peritoneal and/or locoregional. The use of adjuvant hyperthermic intraperitoneal chemotherapy that eliminates free cancer cells that can be released into peritoneal cavity during the gastrectomy and prevents peritoneal carcinomatosis recurrences, was extensively evaluated by several randomized trials conducted in Asia. Two meta-analysis reported that adjuvant hyperthermic intraperitoneal chemotherapy significantly reduces the peritoneal recurrences and significantly improves the overall survival. As it was previously done for the evaluation of the extension of lymph node dissection, it seems very important to validate on European or caucasian patients the results observed in trials performed in Asia. Methods/design GASTRICHIP is a prospective, open, randomized multicenter phase III clinical study with two arms that aims to evaluate the effects of hyperthermic intraperitoneal chemotherapy with oxaliplatin on patients with gastric cancer involving the serosa and/or lymph node involvement and/or with positive cytology at peritoneal washing, treated with perioperative systemic chemotherapy and D1-D2 curative gastrectomy. Peroperatively, at the end of curative surgery, patients will be randomized after preoperatively written consent has been given for participation. Primary endpoint will be overall survival from the date of surgery to the date of death or to the end of follow-up (5 years). Secondary endpoint will be 3- and 5-year recurrence-free survival, site of recurrence, morbidity, and quality of life. An ancillary study will compare the incidence of positive peritoneal cytology pre- and post-gastrectomy in two arms of the study, and assess its impact on 5-year survival. The number of patients to be randomized was calculated to be 306. Trial registration EudraCT number: 2012-005748-12, ClinicalTrials.gov identifier: NCT01882933 .