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Adhesion molecules play a key role in the pathogenetic mechanisms of inflammatory bowel disease (IBD), both in Crohn's disease (CD) and ulcerative colitis (UC). In the last decade, some progress has been made in understanding their key role in leukocyte trafficking control in terms of basic research, but evidence of clinical efficacy is lacking. In the last 2 years, new molecules directed against integrins and integrin receptors have been developed and investigated in clinical trials, showing that anti-α4β7 integrin agents can be effective and safe for the induction and maintenance of remission in active CD and UC. Preliminary data show that anti-MAdCAM, anti-β7 and anti-integrin receptor agents are not all effective in IBD. Such results open new perspectives on clinical management of IBD, and new directions in understanding the role of adhesion molecules and leukocyte recruitment both in CD and UC.

Background and Aims Bowel damage in Crohn's disease [CD] is defined as the presence of intestinal strictures, fistulas or abscesses. Early disease may represent a window of opportunity for timely intervention. We evaluated disease activity and severity by the Lemann Index [LI] and the Magnetic Resonance Index of Activity [MaRIA] score, and their prognostic value in early CD. Methods All consecutive patients diagnosed with CD in two referral centres, assessed by magnetic resonance imaging or computerized tomography, were prospectively included. Disease activity and bowel damage in early CD, the correlation between the LI and the MaRIA score, and the value of cross-sectional imaging findings in predicting disease progression were assessed. Statistical analyses employed time-to-event methods. Results We included 142 consecutive CD patients. Median time from diagnosis to baseline imaging was 0.3 years; median follow-up time was 4.9 years. At diagnosis, 39.4% of CD patients had bowel damage. At multivariable analysis, bowel damage and the LI were independent prognostic factors for intestinal surgery (hazards ratio [HR]: 3.21 and 1.11, respectively, p

Antiadhesion molecules are effective and safe in patients with ulcerative colitis (UC). Etrolizumab, a monoclonal antibody targeting both α4β7 and αEβ7, represents a promising therapy for patients with UC, since this novel mechanism of action may be effective in blocking leukocyte recruitment both at the vascular and at the mucosal level. Preliminary studies show that etrolizumab is effective in inducing clinical response and remission, and mucosal healing. Moreover, new predictors of response have recently been identified, opening the way to a tailored therapeutic approach. This review of the literature aims to present and discuss the most recent evidence on etrolizumab in UC, focusing on the clinical implications of the use of etrolizumab in UC.

International audience; In the last decade, the introduction of the first anti-tumor necrosis factor (TNF)-α agent infliximab has revolutionized the treatment of ulcerative colitis (UC). However, this drug is not a magic bullet since up to 50% of UC patients do not respond (primary failure) or lose response to infliximab (secondary failure). Hence the demand for novel drugs to fill the unmet medical need. New biological agents are now available for the treatment of moderate-to-severe UC. Adalimumab and golimumab are anti-TNF-α monoclonal antibodies, as is infliximab, whereas vedolizumab blocks the integrin α4β7/mucosal addressin cell adhesion molucule-1 (MAdCAM). Additions to the therapeutic arsenal boost the chances of successful treatment of UC, but lead to difficulty choosing the most appropriate biological drug: which biologic to use first and when and how to switch. In the absence of head-to-head trials to answer these questions, a network meta-analysis of the available RCTs can provide estimates of relative efficacy between interventions. Other factors, including convenience and satisfaction for the patient, route of administration, the cost of treatment, and the safety and efficacy profile, should all be considered. The aim of this review is to discuss the data from randomized controlled trials (RCTs) of available biological agents for the treatment of moderate-to-severe UC in adults, in order to support clinical decision making.

AIM: To determine the efficacy of calcium supplementation in reducing the recurrence of colorectal adenomas. " METHODS: We conducted a systematic review and meta-analysis of published studies. We searched PubMed, Scopus, the Cochrane Library, the WHO International Clinical Trials Registry Platform, and the ClinicalTrials. gov website, through December 2015. Randomized, placebo-controlled trials assessing supplemental calcium intake for the prevention of recurrence of adenomas were eligible for inclusion. Two reviewers independently selected studies based on predefined criteria, extracted data and outcomes (recurrence of colorectal adenomas, and advanced or ""high-risk"" adenomas), and rated each trial's risk-of-bias. Between-study heterogeneity was assessed, and pooled risk ratio (RR) estimates with their 95% confidence intervals (95% CI) were calculated using fixed-and random-effects models. To express the treatment effect in clinical terms, we calculated the number needed to treat (NNT) to prevent one adenoma recurrence. We also assessed the quality of evidence using GRADE." RESULTS: Four randomized, placebo-controlled trials met the eligibility criteria and were included. Daily doses of elemental calcium ranged from 1200 to 2000 mg, while the duration of treatment and follow-up of participants ranged from 36 to 60 mo. Synthesis of intention-to-treat data, for participants who had undergone follow-up colonoscopies, indicated a modest protective effect of calcium in prevention of adenomas (fixed-effects, RR = 0.89, 95% CI: 0.82-0.96 random-effects, RR = 0.87, 95% CI: 0.77-0.98 high quality of evidence). The NNT was 20 (95% CI: 12-61) to prevent one colorectal adenoma recurrence within a period of 3 to 5 years. On the other hand, the association between calcium treatment and advanced adenomas did not reach statistical significance (fixed-effects, RR = 0.92, 95% CI: 0.75-1.13 random-effects, RR = 0.92, 95% CI: 0.71-1.18 moderate quality of evidence). CONCLUSION: Our results suggest a modest chemo-preventive effect of calcium supplements against recurrent colorectal adenomas over a period of 36 to 60 mo. Further research is warranted. AIM: To determine the efficacy of calcium supplementation in reducing the recurrence of colorectal adenomas. METHODS: We conducted a systematic review and meta-analysis of published studies. We searched PubMed, Scopus, the Cochrane Library, the WHO International Clinical Trials Registry Platform, and the ClinicalTrials.gov website, through December 2015. Randomized, placebo-controlled trials assessing supplemental calcium intake for the prevention of recurrence of adenomas were eligible for inclusion. Two reviewers independently selected studies based on predefined criteria, extracted data and outcomes (recurrence of colorectal adenomas, and advanced or "high-risk" adenomas), and rated each trial's riskof- bias. Between-study heterogeneity was assessed, and pooled risk ratio (RR) estimates with their 95% confidence intervals (95%CI) were calculated using fixed- and random-effects models. To express the treatment effect in clinical terms, we calculated the number needed to treat (NNT) to prevent one adenoma recurrence. We also assessed the quality of evidence using GRADE. RESULTS: Four randomized, placebo-controlled trials met the eligibility criteria and were included. Daily doses of elemental calcium ranged from 1200 to 2000 mg, while the duration of treatment and follow-up of participants ranged from 36 to 60 mo. Synthesis of intention-to-treat data, for participants who had undergone follow-up colonoscopies, indicated a modest protective effect of calcium in prevention of adenomas (fixed-effects, RR = 0.89, 95%CI: 0.82-0.96; randomeffects, RR = 0.87, 95%CI: 0.77-0.98; high quality of evidence). The NNT was 20 (95%CI: 12-61) to prevent one colorectal adenoma recurrence within a period of 3 to 5 years. On the other hand, the association between calcium treatment and advanced adenomas did not reach statistical significance (fixed-effects, RR = 0.92, 95%CI: 0.75-1.13; random-effects, RR = 0.92, 95%CI: 0.71-1.18; moderate quality of evidence). CONCLUSION: Our results suggest a modest chemopreventive effect of calcium supplements against recurrent colorectal adenomas over a period of 36 to 60 mo. Further research is warranted.

Background: In 2013, a ECCO survey showed that a minority of IBD specialists was aware and confident about the benefits and issues of biosimilars. We aimed to look at the evolution of IBD specialists' thinking about biosimilars one year after they had become available in the European Union. Methods: A 14-question anonymous survey was posted on the ECCO website. Members voluntarily responded in response to ECCO office invitations to participate in their surveys. Information on gender, job position, country, and experience with biologics also were collected. Results: Out of the 118 responders, only 17% of responders had no access to biosimilars. Most responders regarded cost-sparing [92.4%] as the main advantage of biosimilars, considered immunogenicity [69%] to be their main concern, and estimated that post-marketing pharmacovigilance, well-designed randomized clinical trials and further studies of risk profile were needed [30.5%, 27%, 32.2%, respectively, a 30-40% reduction since 2013]. Only 35% of physicians think biosimilars should carry distinct International Nonproprietary Names, as compared with 66% in 2013, and 89.8% disagreed with automatic substitution of the originator with a biosimilar by a pharmacist. The originator and biosimilar were considered interchangeable by 44.4% of responders, as compared with 6% in 2013. Only 32.2% were against the extrapolation across indications, and only 25% would not extrapolate data across IBD. Finally, only 19.5% felt little or no confidence in the use of biosimilars, as compared with 63% in 2013. Conclusion: IBD specialists are generally well informed and educated about biosimilars. Compared with in 2013, there are now fewer concerns and more confidence about their use in clinical practice.

Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP (RPS6KA2) and DMRs (VMP1, ITGB2 and TXK) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci; VMP1/microRNA-21 methylation associates with two polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data shows that IBD-associated hypermethylation within the TXK promoter region negatively correlates with gene expression in whole-blood and CD8+ T cells, but not other cell types. Thus, site-specific DNA methylation changes in IBD relate to underlying genotype and associate with cell-specific alteration in gene expression., Epigenetic perturbations may be an important factor in diseases where both genes and environment play a role. Here, Ventham and colleagues show that DNA methylation changes in inflammatory bowel disease are related to the underlying genotype, and are associated with cell-specific changes to gene expression.

International audience; BACKGROUND:Crohn's disease (CD) is a chronic disabling and progressive IBD. Only strategies looking beyond symptoms and based on tight monitoring of objective signs of inflammation such as mucosal lesions may have the potential for disease modification. Endoscopic evaluation is currently the gold standard to assess mucosal lesions and has become a major therapeutic endpoint in clinical trials. Several endoscopic indices have been proposed to evaluate disease activity; unvalidated and arbitrary definitions have been used in clinical trials for defining endoscopic response and endoscopic remission in CD.METHODS:In these recommendations from the International Organization for the Study of Inflammatory Bowel Disease, we first reviewed all technical aspects of available endoscopic scoring systems in the literature. Second, in order to achieve consensus on endoscopic definitions of remission and response in trials, a two-round vote based on a Delphi method was performed among 14 specialists in the field of IBDs.RESULTS:At the end of the voting process, the investigators ranked first a >50% decrease in Simple Endoscopic Score for Crohn's Disease (SES-CD) or Crohn's Disease Endoscopic Index of Severity for the definition of endoscopic response, and an SES-CD 0-2 for the definition of endoscopic remission in CD. All experts agreed on a Rutgeerts' score i0-i1 for the definition of endoscopic remission after surgery.

Background: Since immunomodulators and antitumor necrosis factor (TNF) agents are increasingly used to treat inflammatory bowel disease (IBD), it is recommended to administer antipneumococcal vaccination to prevent opportunistic pneumonia. There is some evidence that concomitant immunosuppression may impair the immune response to vaccination. We aimed to evaluate the response rates to pneumococcal vaccination in four different treatment groups (mesalamine, azathioprine, infliximab, infliximab plus azathioprine). Methods: In all, 96 patients with IBD (54 with Crohn's disease; 42 with ulcerative colitis) were administered a 23-valent polysaccharide pneumococcal vaccine (PSV-23). The levels of antipneumococcal antibodies were measured prior to and at least 3 weeks after vaccination. Response rates and risk factors for impaired immunosuppression were investigated. Patients on mesalamine were used as a control group. Results: Patients administered infliximab or the combination immunosuppressive therapy had significantly lower response rates to vaccination (57.6% and 62.5%, respectively) compared with the group on mesalamine (88.6%; P < 0.05 for both comparisons). Azathioprine alone did not influence the response rate to vaccination (78.9%; P = 0.43 vs. mesalamine group). Mean antibody titers after vaccination were significantly lower in patients under infliximab or combined immunosuppression than controls (P < 0.05). Immunosuppression with infliximab or combination therapy significantly decreased the likelihood of responding to vaccination (odds ratio [OR] = 0.17, 95% confidence interval [CI] 0.04–0.64, P = 0.009, and OR = 0.21, 95% CI 0.05–0.91, P = 0.038, respectively). Pneumococcal vaccination was generally safe and well tolerated. Conclusions: Anti-TNF therapy alone or in combination with azathioprine impairs the response to pneumococcal vaccination in patients with IBD. All patients with IBD should therefore be vaccinated before starting anti-TNF therapy. (Inflamm Bowel Dis 2012;)

Background/Aims: Systemic corticosteroids are highly effective at inducing clinical remission in cases of acute exacerbation of Crohn’s disease (CD) and ulcerative colitis (UC); however, their use is limited by their frequent and sometimes severe side effects. Thus, a second generation of corticosteroids with less systemic effects has been developed. This review analyzed all of the studies on the new formulations of steroids with limited absorption (budesonide, budesonide MMX®, beclomethasone dipropionate and erythrocyte-mediated delivery of dexamethasone) in patients with CD and UC. Methods: All relevant articles published in English between September 1960 and April 2011 were reviewed. Results: Budesonide is superior to placebo, and as effective as systemic corticosteroids in inducing clinical remission in patients with ileo-colonic CD, but evidence of mucosal healing is limited. When administered as an MMX formula, budesonide can also effectively induce clinical remission in patients with UC, but budesonide alone is not effective in maintaining clinical remission in CD or UC. Beclomethasone dipropionate seems to be effective in patients with mild-to-moderate left-sided and extensive UC, while data on erythrocyte-mediated delivery of dexamethasone are encouraging but still limited. The safety profile for all these products is good but more studies are needed. Conclusion: Steroids remain the mainstay for the induction of clinical remission in cases of acute relapse of both CD and UC. Second-generation corticosteroids are an interesting alternative, with the advantage of high topical activity, less systemic toxicity and limited side effects.

Aliment Pharmacol Ther 2011; 34: 1–10 Summary Background The addition of antitumour necrosis factor-α (TNF-α) agents to the therapeutic armamentarium against Crohn’s disease has been a revolution in its management. However, approximately 25 to 40% of patients who initially benefit from anti-TNF-α treatment develop intolerable adverse events or loose their response during maintenance therapy. Aim To summarise the current knowledge on the mechanisms underlying loss of response in these patients and the therapeutic strategies available to counteract this clinical challenge. Method A literature search using PubMed, MedLine and Embase databases has been performed. Results Anti-infliximab antibodies formation and autoantibodies (ANA, anti-DNA and other autoantibodies) have been associated with loss of response. Individual differences in drug metabolism may contribute to loss of response. Smoking may be a risk factor for loss of response. Dose escalation, reduction of infusion intervals and switch to other anti-TNF-α agents are effective as rescue strategies. Conclusions Loss of response appears to result from different causes not fully established by now. Optimization of therapies, or switch to other anti-TNF-α, are currently the best studied strategies in case of loss of response, and can be successful in 40–60% of patients who lose response.

Background: Studies comparing magnetic resonance enterography (MRE) and computerized tomography enterography (CTE) for Crohn's disease (CD) are scarce. Methods: The aim of this study was to prospectively compare the sensitivity, specificity, and accuracy of abdominal MRE and CTE to assess disease activity and complications (fistulas, strictures) in ileocolonic CD. A total of 44 patients (23 male; 21 female; mean age 44) with ileocolonic CD underwent both MR and CT in a short time interval (mean 5 days). A 16-slice CT with intravenous contrast and an MRI with oral and paramagnetic intravenous contrast were performed. Ileocolonoscopy was used as the reference standard. Sensitivity values of CT and MR for detection of extraenteric signs of disease were compared with the McNemar test, with results of imaging studies, surgery, and physical examination as reference standards. Results: No significant differences in sensitivity, specificity, and accuracy were observed between MRE and CTE regarding the following parameters at the patient level: localization of CD (P = 1.0), bowel wall thickening (P = 1.0), bowel wall enhancement (P = 1.0), enteroenteric fistulas (P = 0.08), detection of abdominal nodes (P = 1.0), and perivisceral fat enhancement (P = 0.31). MR was significantly superior compared to CT in detecting strictures (P = 0.04). Per segment analysis showed that MRE was significantly superior to CTE in detecting ileal wall enhancement (P = 0.02). Conclusions: MR and CT are equally accurate to assess disease activity and bowel damage in CD. MR may be superior to CT in detecting intestinal strictures and ileal wall enhancement. MR may represent an alternative technique to CT in assessing ileocolonic CD. (Inflamm Bowel Dis 2011;17:1073-1080) BACKGROUND: Studies comparing magnetic resonance enterography (MRE) and computerized tomography enterography (CTE) for Crohn's disease (CD) are scarce.METHODS: The aim of this study was to prospectively compare the sensitivity, specificity, and accuracy of abdominal MRE and CTE to assess disease activity and complications (fistulas, strictures) in ileocolonic CD. A total of 44 patients (23 male; 21 female; mean age 44) with ileocolonic CD underwent both MR and CT in a short time interval (mean 5 days). A 16-slice CT with intravenous contrast and an MRI with oral and paramagnetic intravenous contrast were performed. Ileocolonoscopy was used as the reference standard. Sensitivity values of CT and MR for detection of extraenteric signs of disease were compared with the McNemar test, with results of imaging studies, surgery, and physical examination as reference standards.RESULTS: No significant differences in sensitivity, specificity, and accuracy were observed between MRE and CTE regarding the following parameters at the patient level: localization of CD (P = 1.0), bowel wall thickening (P = 1.0), bowel wall enhancement (P = 1.0), enteroenteric fistulas (P = 0.08), detection of abdominal nodes (P = 1.0), and perivisceral fat enhancement (P = 0.31). MR was significantly superior compared to CT in detecting strictures (P = 0.04). Per segment analysis showed that MRE was significantly superior to CTE in detecting ileal wall enhancement (P = 0.02).CONCLUSIONS: MR and CT are equally accurate to assess disease activity and bowel damage in CD. MR may be superior to CT in detecting intestinal strictures and ileal wall enhancement. MR may represent an alternative technique to CT in assessing ileocolonic CD.

Introduction: Three anti TNF-alpha agents have currently been approved for the treatment of moderate-to-severe or complicated Crohn's disease (CD): infliximab, certolizumab and adalimumab. Infliximab is effective in CD, but for reasons linked to its chimeric structure, response to treatment may be lost overtime and as a result, it can sometimes be unable to provide long term durable treatment of CD. Adalimumab, a fully human anti TNF-alpha antibody, demonstrates similar treatment efficacy as infliximab and certolizumab, and can easily be self-administered at home. Aim and Methods: A literature search in the Cochrane, MEDLINE, PUBMED, Ovid MEDLINER (R) and EMBASE databases has been performed on the efficacy, safety and the impact adalimumab has on the quality of life and natural history of CD. Abstracts presented at the DDW, UEGW and ECCO Congresses have also been reviewed as well as references from review articles, meta-analysis studies and published RCTs. Results: Adalimumab induced remission of CD in 64% of patients, and maintained remission in more than 80% of initial responders. Adalimumab did not significantly increase the risk of adverse events compared with conventional medication up to 3 years of follow-up. Adalimumab reduces more than 50% the risk for hospitalisation and surgery due to CD. It is also effective for fistula closure, for the healing of the mucosa, and improving quality of life. Conclusion: Adalimumab is effective in the induction and maintenance of clinical remission in CD and is generally well tolerated. It has been proved to have a positive impact by improving quality of life of patients, and reducing the need for hospitalisation and surgery due to CD. According to the European Crohn's and Colitis Organisation (ECCO), infliximab or adalimumab can be used for the treatment of fistulizing CD. Introduction: Three anti TNF-α agents have currently been approved for the treatment of moderate-to-severe or complicated Crohn's disease (CD): infliximab, certolizumab and adalimumab. Infliximab is effective in CD, but for reasons linked to its chimeric structure, response to treatment may be lost overtime and as a result, it can sometimes be unable to provide long term durable treatment of CD. Adalimumab, a fully human anti TNF-α antibody, demonstrates similar treatment efficacy as infliximab and certolizumab, and can easily be self-administered at home. Aim and Methods: A literature search in the Cochrane, MEDLINE, PUBMED, Ovid MEDLINER® and EMBASE databases has been performed on the efficacy, safety and the impact adalimumab has on the quality of life and natural history of CD. Abstracts presented at the DDW, UEGW and ECCO Congresses have also been reviewed as well as references from review articles, meta-analysis studies and published RCTs. Results: Adalimumab induced remission of CD in 64% of patients, and maintained remission in more than 80% of initial responders. Adalimumab did not significantly increase the risk of adverse events compared with conventional medication up to 3 years of follow-up. Adalimumab reduces more than 50% the risk for hospitalisation and surgery due to CD. It is also effective for fistula closure, for the healing of the mucosa, and improving quality of life. Conclusion: Adalimumab is effective in the induction and maintenance of clinical remission in CD and is generally well tolerated. It has been proved to have a positive impact by improving quality of life of patients, and reducing the need for hospitalisation and surgery due to CD. According to the European Crohn's and Colitis Organisation (ECCO), infliximab or adalimumab can be used for the treatment of fistulizing CD.

The advent of anti-TNF-α monoclonal antibodies has dramatically changed the management of inflammatory bowel diseases (IBD). Unlike Crohn's disease (CD), only one anti-TNF-α agent, infliximab, is currently approved for active moderate-to-severe ulcerative colitis (UC). Adalimumab is a fully human anti-TNF-α antibody that is effective and safe for the treatment of luminal and fistulising CD.This review of the literature summarizes available data on of efficacy and safety profile adalimumab in patients with UC.Adalimumab may be effective in inducing and maintaining clinical remission in patients with moderate-to-severe UC. It may also induce mucosal healing and reduce the need for colectomy in patients with severe disease. The safety profile of the drug in UC is consistent with previous experience with this drug in CD.Adalimumab may be effective and well tolerated in UC. Its efficacy in maintaining clinical remission needs to be confirmed in a randomized controlled trial.

Patients treated with infliximab for Crohn's disease (CD) frequently require intensified dosage due to loss of response. There are scant data regarding the efficacy of shortening the dosing interval to 6 weeks.

Inflammatory bowel diseases are chronic diseases that affect the gastrointestinal tract. Mesalamine, corticosteroids, immunosuppressants and biological agents are currently used to treat these diseases. Due to inadequacies of the currently available delivery systems, a large number of patients do not respond to treatment, especially when they are affected by distal colonic disease. Multimatrix (MMX™) technology comprises hydrophilic and lipophilic excipients, enclosed within a gastro-resistant, pH-dependent coating. This new delivery technology has been used to modify some commonly used drugs, including mesalamine and budesonide, as well as heparin, which are now being investigated for their utility in the management of IBD. Aim: The aim of this review is to explore the MMX delivery technology and its efficacy for the treatment of IBD. Results: The results of various studies involving MMX drugs have been published. Mesalamine MMX induces clinical and endoscopic remission in patients with mild to moderate ulcerative colitis (UC) compared with placebo. Positive results have also been observed with MMX budesonide in two phase I studies. In a pilot study involving ten patients with UC, efficacy of heparin-MMX as an IBD therapy was observed. Conclusion: MMX is a promising new delivery system that can improve efficacy of current and new drugs, augmenting targeting to the affected tract, thereby increasing response and remission rates for those drugs in patients with IBD.

White adipose tissue (WAT) is an important endocrine organ that secretes approximately 30 biologically active peptides and proteins, collectively termed "adipokines". These are either produced exclusively by WAT (mainly adiponectin, leptin and resistin) or also by other tissues [e.g. tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, plasminogen activator inhibitor (PAI)-1, angiotensinogen]. Adipokines play a central role in body homeostasis including the regulation of food intake and energy balance, insulin action, lipid and glucose metabolism, angiogenesis and vascular remodelling, regulation of blood pressure and coagulation. Excess WAT, especially visceral obesity, is linked to obesity-related health problems through insulin resistance (IR) [leading to type 2 diabetes mellitus (T2DM)] and systemic low-grade inflammation [leading to cardiovascular disease (CVD)]. The adipokines are important mediators of these adverse effects. This review describes the role of proinflammatory adipokines in the pathogenesis of IR and of the chronic inflammatory state associated with visceral obesity. Moreover, it summarises treatment options for the normalisation of adipokine levels, which might confer an additional clinical benefit in the effort to prevent or treat obesity-related T2DM and CVD.

Summary Background Anti TNF-α agents are used successfully for several autoimmune diseases, including IBD and psoriasis. An emerging challenge is the increasing incidence of anti TNF-α induced psoriasis. A total of 120 cases have been currently reported, of whom 18 patients were treated with biological agents for IBD. Objectives To analyse all cases of anti TNF-α induced psoriasis in patients with IBD in the literature and to investigate potential mechanisms of action. Methods A literature review was performed in the PubMed, Medline, Cochrane and EMBASE databases, with simple analysis of demographic data, drug administration and psoriasis onset. Risk and incidence patient/year/duration (pyd) was calculated. Results A total of 18 patients with IBD treated by anti TNF-α agents developed drug-induced psoriasis of which, 17 patients developed with infliximab, one with adalimumab. The most frequent time of onset is between 3rd and 4th infusion of infliximab. Withdrawal of infliximab led to regression of lesions in 16 patients. In six patients, infliximab was reintroduced with no further recurrence of psoriasis. Conclusions Although anti TNF-α induced psoriasis is extremely rare, understanding the mechanism will be a key step towards better realizing the role played by TNF-α and its pharmacological inhibitors in immune-mediated diseases.

International audience; Crohn's disease [CD] is a chronic progressive and destructive condition. Half of all CD patients will develop bowel damage at 10 years. As in rheumatic diseases, preventing the organ damage consequent to CD complications [fistula, abscess, and/or stricture] is emerging as a new therapeutic goal for these patients in clinical practice. This might be the only way to alter disease course, as surgery is often required for disease complications. Similar to the joint damage in rheumatoid arthritis, bowel damage has also emerged as a new endpoint in disease-modification trials such as the REACT trial. Recently, the Lemann Index [LI] has been developed to measure CD-related bowel damage, and to assess damage progression over time, in order to evaluate the impact of therapeutic strategies in terms of preventing bowel damage. While validation is pending, recent reports suggested that bowel damage is reversible by anti-tumour necrosis factor [TNF] therapy. The L,mann index may play a key role in CD management, and should be implemented in all upcoming disease-modification trials in CD.

Crohn's Disease (CD) and Ulcerative Colitis (UC) are chronic, relapsing conditions resulting from uncontrolled inflammation of the intestinal mucosa. Both conditions are associated with significant disability and patients with CD face higher mortality rates compared to the general population. The increasing understanding of the immunological basis of the disease led to the introduction of biologic therapies targeting key pathways of the natural and adaptive immune response such as Tumor Necrosis Factor alpha (TNF-alpha) inhibitors and, more recently, integrin-receptor antagonists. Treatment with TNF-alpha inhibitors improved clinical and patient-reported outcomes for many patients who did not benefit from conventional therapy. However, a sizeable share of patients still face suboptimal outcomes due to primary or secondary therapy failure. With the introduction of VDZ, a biologic treatment targeting novel IBD-relevant biologic pathways, it is crucial to understand how to integrate such innovations into current clinical practice. To this end, a panel of 14 Italian experts in the management of IBD met for a roundtable discussion. Recommendations concerning the management of moderate-to-severe IBD based on experts' opinions and literature review are discussed in the present report. (C) 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

International audience; BACKGROUND AND AIMS:Diagnostic delay is frequent in patients with Crohn's disease (CD). We developed a tool to predict early diagnosis.METHODS:A systematic literature review and 12 CD specialists identified 'Red Flags', i.e. symptoms or signs suggestive of CD. A 21-item questionnaire was administered to 36 healthy subjects, 80 patients with irritable bowel syndrome (non-CD group) and 85 patients with recently diagnosed (

International audience; Background and aims:Bowel damage [BD] will develop in the majority of Crohn’s disease [CD] patients. Recently, the Lémann Index [LI] was developed to measure BD.Methods:This was a prospective single-center cohort study. All included patients underwent full evaluation for bowel damage before starting anti-TNF therapy and every year thereafter. BD at baseline and during follow-up was measured using the LI. We assessed the impact of anti-TNF therapy on BD. We also assessed the sensitivity to change of the LI and the relationship between BD progression and disease outcomes, including the need for surgery.Results:Thirty CD patients were enrolled [13 on infliximab, 17 on adalimumab]. Median baseline LI was 9.1 [range, 1.6–34.1]. Median follow up was 32.5 months [range, 10–64].By a ROC curve analysis, a LI >4.8 defined CD subjects with BD. Any change >0.3 in the LI was related to BD change [AUC 0.98]. During follow-up, 83% of subjects had BD regression and 17% had BD progression. Anti-TNF therapy significantly reduced LI at 12 months [p=0.007]. Subjects with BD progression were more likely to undergo major abdominal surgery through the follow-up period [HR 0.19, p=0.005].Conclusion:The LI has good sensitivity to change. Anti-TNFs agents are able to reverse BD in some CD patients. BD progression as measured by the LI may be predictive of major abdominal surgery in these patients.

Crohn’s disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBDs) that share common pathogenesis and clinical behaviour.1 Both innate and adaptive immunity appear to play a key role in triggering and maintaining chronic inflammation in IBD. The involvement of both these arms of the immune system is common to other immune-mediated diseases (IMIDs), such as rheumatoid arthritis, ankylosing spondylitis and psoriasis, hence the use of similar therapeutic strategies, including the use of steroids, immunomodulators and monoclonal antibodies in all these diseases.2 In particular, psoriasis can be associated with IBD as an independent concomitant IMID, or can be a manifestation of underlying IBD, or even a paradoxical adverse event of anti-tumour necrosis factor (TNF) therapy.3,4 Such an association could be related to shared genetic abnormalities, common cytokine-driven inflammation [such as the interleukin 23 (IL-23) and Th17 pathway] or environmental factors. However, the link between psoriasis and IBD is currently far from clear. It is known that psoriasis is observed at a frequency about eight times higher among patients with CD than in the general population.5 In addition, families with psoriasis or CD are at higher risk of developing other inflammatory diseases. Lee et al .6 showed that 10% of … Corresponding author: Gionata Fiorino, MD, PhD, IBD Center, Department of Gastroenterology, Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy. Tel. +39(0)282245555; Fax +39(0)282242591; Email: gionataf{at}gmail.com

Inflammatory bowel diseases are characterized by a chronic relapsing course, high morbidity and impaired quality of life. Their incidence is rising, and about 25% of cases are diagnosed in pediatric age. Anti-TNF-alpha antibodies, such as infliximab and adalimumab (ADA), are usually administered in patients refractory to conventional therapies. However, increasing evidence suggests that they can be introduced earlier in the course of the disease, especially in patients with aggressive and extensive disease since diagnosis. ADA is a fully human anti-TNF-alpha antibody recently approved for pediatric Crohn's disease not only in patients unresponsive to infliximab, but also as a first-line anti-TNF-alpha therapy. In this review, we aim to summarize the current knowledge on the use of ADA in pediatric Crohn's disease and to discuss open issues regarding safety as well as future perspectives.

Inflammatory bowel diseases (IBD) present a typically relapsing-remitting behavior and are characterized by a disabling and progressive course. Anti-tumor necrosis factor (TNF)-alpha agents have drastically changed the therapeutic management of IBD. However, a significant proportion of patients does not have a primary response, some patients lose response overtime and/or experience side effects. Recently, anti-adhesion molecules were investigated and showed efficacy with a good safety profile. Vedolizumab was recently approved for both Crohn's disease (CD) and ulcerative colitis (Uc) and several other molecules are under evaluation in this field. Anti-adhesion molecules could represent a potential therapeutic option for future therapy in IBD. In this review we report the efficacy and safety of major anti-adhesion drugs in active IBD patients.

International audience; OBJECTIVES: The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a "treat-to-target" clinical management strategy using an evidence-based expert consensus process. METHODS: A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7-10 on a 10-point rating scale (where 10=agree completely). RESULTS: The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn's disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit) and endoscopic remission (defined as a Mayo endoscopic subscore of 0-1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission, defined as resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target. CONCLUSIONS: Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients' quality of life.Am J Gastroenterol advance online publication, 25 August 2015; doi:10.1038/ajg.2015.233

The standard tools assessing the activity of Crohn's disease (CD) measure the severity of symptoms (the Crohn's Disease Activity Index) or the degree of endoscopic lesions (the Crohn's Disease Endoscopic Index of Severity, the Simplified Endoscopy Score), not the global bowel damage. It is necessary to find new instruments able to assess the structural and functional damage to the intestine and the progression over time. We reviewed recent publications on the accuracy of abdominal ultrasound (US), computed tomography enterography (CTE), and magnetic resonance imaging enterography (MRE) for the assessment of CD. US, CTE and MRE have been shown to have a high and comparable diagnostic accuracy for both the diagnosis and complications of CD, but US and MRE have the major advantage of not imparting ionizing radiation. In summary, findings from these imaging modalities with endoscopic lesions and surgical history incorporating into the Lémann score will allow measuring the global bowel damage at specific time and the progression of disease over time and assessing the impact of different strategies.

The management of Crohn’s disease [CD] patients has been rapidly evolving in recent years. Besides the development of new drugs with new mechanisms of action for patients who do not respond to conventional therapies, several studies have been conducted to evaluate the best strategies to optimise response and remission.1,2 It is currently clear that the combination of infliximab and azathioprine is significantly more effective in inducing and maintaining clinical response and remission in naive CD patients compared with infliximab and azathioprine monotherapies.1 This combination is also effective in reducing the immunogenicity of infliximab,3 thus reducing the risk of loss of response over time. Matsumoto et al. 4 reported the results of a randomised open-label trial [DIAMOND] to evaluate whether the combination of adalimumab and azathioprine may be more effective than adalimumab monotherapy in inducing and maintaining clinical remission, and endoscopic response, at Weeks 26 and 52; 167 CD patients were randomised to … Corresponding author: Prof. Silvio Danese, PhD, Department of Biomedical Sciences, Humanitas University, Via Manzoni 113, 20089 Rozzano, Milan, Italy. Tel.: +390282244771; fax: +390282242591; email: sdanese{at}hotmail.com

Introduction Efficacy and safety of infliximab in ulcerative colitis (UC) is well-established. We conducted a multicenter retrospective cohort study across 7 European countries, and Israel, to examine whether infliximab discontinuation can be considered for patients who achieve sustained remission. Methods The disease course of patients who discontinued infliximab was compared against that of patients who continued scheduled treatment (control group). We examined the incidence rates of relapse, hospitalisation and colectomy, the comparative effectiveness of different therapeutic strategies after discontinuation, and assessed the rates of response, remission and adverse effects after infliximab re-initiation. Statistical analyses employed time-to-event methods Results In total, 193 patients were included, 111 discontinued infliximab. The incidence rate of relapse was significantly higher after discontinuation (23.3 per 100 person-years) as compared to the control group (7.2 per 100 person-years) both in univariable (log-rank p Conclusion Infliximab discontinuation in UC patients with sustained clinical remission is associated with increased risk of relapse. Treatment re-initiation is effective and safe. Disclosure of Interest G. Fiorino Consultant for: MSD, AbbVie, Takeda, Janssen, Mundipharma, Sandoz, Pfizer, P. Cortes: None Declared, P. Ellul Grant/research support from: MSD, AbbVie, C. Felice Consultant for: MSD, AbbVie, P. Karatzas: None Declared, M. Silva: None Declared, P. Lakatos Grant/research support from: MSD, AbbVie, Hospira, Consultant for: MSD, AbbVie,Celltrion, EGIS, Falk Pharma GmbH, Ferring, Genentech, Hospira, F. Bossa Consultant for: MSD, Abbvie, Mundipharma, and Takeda, S. Sebastian Grant/research support from: MSD, AbbVie, Speaker bureau with: MSD, B. Ungar: None Declared, F. Furfaro: None Declared, K. Karmiris Consultant for: MSD, AbbVie, Takeda, K. Katsanos: None Declared, M. Muscat: None Declared, D. Christodoulou: None Declared, G. Maconi: None Declared, U. Kopylov Consultant for: Janssen, Abbvie, Takeda and CTS, F. Magro: None Declared, G. Mantzaris: None Declared, A. Armuzzi Grant/research support from: MSD, Consultant for: Abbvie, Celltrion, Ferring, Hospira, Janssen, Lilly, MSD, Mundipharma, Pfizer, Sofar, Takeda, M. M. Bosca-Watts: None Declared, S. Ben-Horin Grant/research support from: AbbVie and Celltrion, Consultant for: AbbVie, Celltrion, Janssen, Takeda and Schering-Plough, S. Bonovas: None Declared, S. Danese Consultant for: Schering-Plough, Abbott Laboratories, Merck, UCB-pharma, Ferring, Cellerix, Millenium Takeda, Nycomed, Pharmacosmos, Actelion, Danone, Alpha Wasserman, Genentech, Grunenthal, Pfizer, Astra Zeneca, Novo Nordisk, Cosmo Pharmaceuticals, Vifor, and Johnson & Johnson, Speaker bureau with: Schering-Plough, Abbott Laboratories, Merck, UCB-pharma, Ferring, Cellerix, Millenium Takeda, Nycomed, Pharmacosmos, Actelion, Danone, Alpha Wasserman, Genentech, Grunenthal, Pfizer, Astra Zeneca, Novo Nordisk, Cosmo Pharmaceuticals, Vifor, and Johnson & Johnson

International audience; Crohn's disease (CD) is a chronic, disabling, progressive and destructive disease. The general goal of conventional step-up strategy in CD treatment is to treat and control symptoms. This strategy did not change the disease course and is now being replaced with a treat-to-target approach. Achieving deep remission (clinical remission and absence of mucosal ulcerations) is the target in CD in 2014. Inducing and maintaining deep remission is needed to prevent long-term outcomes such as bowel damage and disability in CD. Diagnostic delay is a common issue in CD and is associated with an increased risk of bowel damage over time. Identification of poor prognostic factors, risk stratification together with the development of "red flags" may result in early intervention with disease-modifying agents such as anti-TNF agents with the final aim of preventing overtreatment and avoiding undertreatment. Similar to rheumatoid arthritis, by catching the therapeutic window of opportunity in early CD and achieving deep remission, this could be the best way to change disease course (hospitalizations, surgeries, bowel damage, and disability) and patients' life.

The present article aims to review the literature on the relationship between psychology and inflammatory bowel disease (IBD). In particular, the first section is dedicated to explore the role of psychological factors in the etiopathology of the disease, its development and the efficacy of treatments, while the second analyzes existing literature on the role of psychological interventions in the care of IBD patients. Although the role of psychological factors in IBD appears controversial, literature seems to distinguish between antecedents of the disease (stress and lifestyle behavior), potential mediators of disease course (family functioning, attachment style, coping strategies, and illness perception), outcomes of IBD and concurrent factors (anxiety, depression and quality of life). Four types of psychological interventions are described: Stress management, Psychodynamic, Cognitive behavioral and Hypnosis based. Data on the role and efficacy of psychological interventions in IBD patients show little evidence both on reduction of the disease activity and benefits on psychological variables. Psychological interventions seem to be beneficial in the short term especially for adolescents. The importance of considering the connections between psychology and IBD from a broader perspective reflecting the complexity of the phenomenon at multiple levels is discussed.