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PURPOSE OF THE REVIEW: As treatment options for Inflammatory Bowel Disease (IBD) expand each class of medication will have specific safety concerns and side-effect profiles that need to be considered for optimal treatment of patients. We will review the most recent safety data for the newly approved immunomodulator therapies for the treatment of IBD. RECENT FINDINGS: There are a growing number of publications outlining safety concerns for medications used to treat IBD. We reviewed safety profile of anti-tumor necrosis factor antibodies (TNF) with specific attention to combination therapy (anti-TNF plus immunomodulator). Recent publications have demonstrated increased risk of serious infection and malignancy (lymphoma and overall cancer rates) in patients receiving anti-TNF combination therapy when compared with patients receiving anti-TNF monotherapy or immunomodulator monotherapy. Recent publications on Janus Kinase Inhibitors indicate an increased risk of infection, specifically Herpes Zoster, and increased risk of major cardiovascular events and venous thromboembolic events resulting in a black box warning for the medication. In contrast, anti-interleukin 12/23 agents and gut selective anti-integrin antibody agents have demonstrated a favorable side-effect profile with low rates of infection and malignancy. The latest class of medications to be approved, sphingosine 1-phosphate (S1P) receptor modulators, have cardiac and infectious precautions. The field of IBD treatment is rapidly evolving with several mechanistic classes of medications now available. While corticosteroids continue to be associated with the greatest, overall, safety risks, each of the newer mechanistic classes have unique safety concerns. In the future, as we gain more experience with these agents, we will need to continue to evaluate the safety profile of our therapies used alone or in combination to make informed treatment decisions with our patients.

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BACKGROUND: Patients with inflammatory bowel disease (IBD) have an increased risk of colorectal cancer. We sought to assess the comparative efficacy of virtual chromoendoscopy (VCE) vs high definition white light endoscopy (HDWLE) or dye-spraying chromoendoscopy (DCE) through a meta-analysis and rating the quality of evidence. METHODS: A systematic review of the literature was performed through February 15, 2019. Primary outcomes were number of patients in whom dysplasia was identified and number of dysplastic lesions identified in these patients. We included only randomized control trials (RCTs) and performed meta-analysis using RevMan5.3. RESULTS: Of the 3205 studies identified, 11 RCTs were included, with a total of 1328 patients. Per patient analysis, VCE was not statistically different compared with DCE (risk ratio [RR] 0.77; 95% CI, 0.55-1.08) or HDWLE (RR 0.72; 95% CI, 0.45-1.15). However, per dysplasia analysis, VCE was not statistically different compared with DCE (RR 0.72; 95% CI, 0.47-1.11) and inferior compared with HDWLE (RR 0.62; 95% CI, 0.44-0.88). The quality of evidence was moderate in the HDWLE and low to moderate in the DCE studies. CONCLUSION: Based on this meta-analysis, VCE was as good as HDWLE and DCE in identifying dysplasia per patient analysis. However, per dysplasia analysis, VCE was inferior compared with HDWLE and no different from DCE. Further studies need to examine the efficacy of each individual VCE technique.

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Acute severe ulcerative colitis (ASUC) is a potentially life-threatening presentation of ulcerative colitis that in nearly all cases requires inpatient management and coordinated care from hospitalists, gastroenterologists, and surgeons. Even with ideal care, a substantial proportion of patients will ultimately require colectomy, but most patients can avoid surgery with intravenous corticosteroid treatment and if needed, appropriate rescue therapy with infliximab or cyclosporine. In-hospital management requires not only therapies to reduce the inflammation at the heart of the disease process, but also to avoid complications of the disease and its treatment. Care for ASUC must be anticipatory, with patient education and evaluation starting at the time of admission in advance of the possible need for urgent medical or surgical rescue therapy. Here we outline a general approach to the treatment of patients hospitalized with ASUC, highlighting the common pitfalls and critical points in management.

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Anti-tumor necrosis factor (TNF) therapy has revolutionized the medical treatment of the inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis. Twenty years ago, infliximab became the first anti-TNF agent approved for IBD. Data from randomized controlled trials, large observational cohort studies, postmarketing registries, and meta-analyses show that infliximab is a very effective treatment for moderate to severe IBD with a good safety profile. Infliximab has been also used to treat pouchitis following an ileal pouch-anal anastomosis (IPAA) after restorative proctocolectomy and to prevent postoperative recurrence following an ileocolonic resection for CD with good results. Nevertheless, up to 30% of patients show no clinical benefit following induction and up to 50% lose response over time. Both these unwanted outcomes can be largely explained by inadequate drug concentrations and frequently by the development of antibodies to infliximab. Loss of response can be managed efficiently and often prevented by applying therapeutic drug monitoring. Recently, the first biosimilars of infliximab have been approved and are utilized in clinical practice with comparable efficacy and safety with the originator. This review will mainly focus on the efficacy of infliximab in IBD.

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BACKGROUND: Patients with ulcerative colitis have an increased risk of colorectal cancer. We sought to assess the comparative efficacy of standard white-light endoscopy (SDWLE) or high-definition white-light endoscopy (HDWLE) versus dye-based chromoendoscopy through a meta-analysis and rate the quality of evidence using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system. METHODS: A systematic review of the literature in PubMed, EMBASE, and Web of Science was performed in April 2018. The primary outcome was the number of patients in whom dysplasia was identified using a per patient analysis in randomized controlled trials (RCT) and analyzed separately for non-RCTs. Analysis was performed using RevMan 5.3 reporting random-effects risk ratios. RESULTS: Of the 27,904 studies identified, 10 studies were included 6 of which were RCTs (3 SDWLE and 3 HDWLE). Seventeen percent (84/494) of patients were noted to have dysplasia using chromoendoscopy compared with 11% (55/496) with white-light endoscopy (relative risk [RR] 1.50; 95% confidence interval [CI], 1.08-2.10). When analyzed separately, chromoendoscopy (n = 249) was more effective at identifying dysplasia than SDWLE (n = 248) (RR, 2.12; 95% CI, 1.15-3.91), but chromoendoscopy (n = 245) was not more effective compared with HDWLE (n = 248) (RR, 1.36; 95% CI, 0.84-2.18). The quality of evidence was moderate. In non-RCTs, dysplasia was identified in 16% (114/698) of patients with chromoendoscopy compared with 6% (62/1069) with white-light endoscopy (RR, 3.41; 95% CI, 2.13-5.47). Chromoendoscopy (n = 58) was more effective than SDWLE (n = 141) for identification of dysplasia (RR, 3.52; 95% CI, 1.38-8.99), and chromoendoscopy (n = 113) was also more effective than HDWLE (n = 257) (RR, 3.15; 95% CI, 1.62-6.13). The quality of the evidence was very low. CONCLUSION: Based on this meta-analysis, non-RCTs demonstrate a benefit of chromoendoscopy over SDWLE and HDWLE, whereas RCTs only show a small benefit of chromoendoscopy over SDWLE, but not over HDWLE.

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BACKGROUND AND AIMS: Therapeutic drug monitoring [TDM] has proven to be effective for optimising anti-tumour necrosis factor [TNF] therapy in inflammatory bowel disease [IBD]. Nevertheless, the majority of data refer to infliximab and reactive testing or association studies. We aimed to compare the long-term outcome of patients with IBD who received at least one proactive TDM of adalimumab, with standard of care, defined as empirical dose escalation and/or reactive TDM. METHODS: This was a multicentre retrospective cohort study. Patients on maintenance adalimumab therapy from June 2006 to December 2015 were eligible. We analysed time to treatment failure from start of adalimumab until the end of follow-up [July 2016]. Treatment failure was defined as drug discontinuation for secondary loss of response or serious adverse event or need for IBD-related surgery. Serum adalimumab concentrations and antibodies to adalimumab were measured using the Prometheus homogeneous mobility shift assay. RESULTS: A total of 382 patients with IBD [Crohn's disease, n = 311, 81%] were included and received either at least one proactive TDM [n = 53] or standard of care [empirical dose escalation, n = 279; reactive TDM, n = 50]. Patients were followed for a median of 3.1 years [interquartile range, 1.4-4.8 years]. Multiple Cox regression analyses showed that at least one proactive TDM was independently associated with a reduced risk for treatment failure (hazard ratio [HR]: 0.4; 95% confidence interval [CI]: 0.2-0.9; p = 0.022). CONCLUSIONS: This multicentre, retrospective cohort study reflecting real-life clinical practice provides the first evidence that proactive TDM of adalimumab may be associated with a lower risk of treatment failure compared with standard of care in patients with IBD.

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The present study describes a technique for analysis of vocal responses to auditory feedback pitch perturbations in which individual trials are first sorted according to response direction and then separately averaged in groups of upward or downward responses. In experiment 1, the stimulus direction was predictable (all upward) but magnitude was randomized between +100, +200, or +500 cents (unpredictable). Results showed that pitch-shift stimuli (PSS) of +100 and +200 cents elicited significantly larger opposing (compensatory) responses than +500 cent stimuli, but no such effect was observed for "following" responses. In experiment 2, subjects were tested in three blocks of trials where for the first two, PSS magnitude and direction were predictable (block 1+100 and block 2-100 cents), and in block 3, the magnitude was predictable (±100 cents) but direction was randomized (upward or downward). Results showed there were slightly more opposing than following responses for predictable PSS direction, but randomized directions led to significantly more opposing than following responses. Results suggest that predictability of stimulus direction and magnitude can modulate vocal responses to feedback pitch perturbations. The function and causes of the opposing and following responses are unknown, but there may be two different neural mechanisms involved in their production.

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Accurate vocal production relies on several factors including sensory feedback and the ability to predict future challenges to the control processes. Repetitive patterns of perturbations in sensory feedback by themselves elicit implicit expectations in the vocal control system regarding the timing, quality and direction of perturbations. In the present study, the predictability of voice pitch-shifted auditory feedback was experimentally manipulated. A block of trials where all pitch-shift stimuli were upward, and therefore predictable was contrasted against an unpredictable block of trials in which the stimulus direction was randomized between upward and downward pitch-shifts. It was found that predictable perturbations in voice auditory feedback led to a reduction in the proportion of compensatory vocal responses, which might be indicative of a reduction in vocal control. The predictable perturbations also led to a reduction in the magnitude of the N1 component of cortical Event Related Potentials (ERP) that was associated with the reflexive compensations to the perturbations. We hypothesize that formation of expectancy in our study is accompanied by involuntary allocation of attentional resources occurring as a result of habituation or learning, that in turn trigger limited and controlled exploration-related motor variability in the vocal control system.

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