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BackgroundAccurate and reproducible measurement of expression of pro-inflammatory cytokines in colonic biopsies from patients with ulcerative colitis (UC) is essential for proof-of-concept and mechanism-of-action studies. Few studies have rigorously established the number of biopsies required for accurate and reproducible biomarker measurements.AimTo validate methods for measuring changes in gene expression in colonic biopsy samples.MethodsTwelve colonic biopsies were obtained from each of six healthy controls, six patients with inactive UC and seven patients with active UC. Mayo endoscopic scores were used as a clinical reference standard. Quantitative PCR was used to assess mRNA expression of eight known inflammatory genes. The power to detect a reduction in gene expression in active vs. inactive UC was calculated using a linear mixed effect model.ResultsmRNA analysis of colonic biopsies is a sensitive and feasible approach for measuring inflammatory gene expression in colonic biopsies. Inflammatory biomarkers correlate with Mayo endoscopic subscores for each colonic region. For most genes, three rectal biopsies from two to four patients are required to detect changes in gene expression corresponding to active vs. inactive UC to achieve a power of 80% with an alpha of 0.05.ConclusionOur data suggest that systematic measurement of inflammatory biomarkers at the mRNA level can be a valuable tool for hypothesis testing, and assessment of clinical activity and response to therapy in ulcerative colitis.

Among substance abusing youth, HIV remains a threat, due in part to the multiple risk factors often found in this population. Therefore, drug detoxification facilities are important sites in which to characterize the extent of drug and sexual co-occurring risk behaviors among patients. We distributed a self-administered, anonymous questionnaire to patients at two state-funded Rhode Island detoxification facilities to examine the HIV-related risk behaviors of adolescent and young adult substance abusers, and to examine the influence of gender on these behaviors. We found that sixty-two percent of all respondents reported injecting drugs in the past six months, and 67% of current IDUs reported sharing syringes in the past six months. Forty-six percent and 70%0 of sexually active youth reported never using condoms in the past six months for vaginal and anal sex, respectively. Females were significantly more likely to report a lifetime history of injecting drugs, exchanging sex for drugs or money, and having sex with an IDU. The high rates of sharing injection equipment and the prevalence of risky sexual activity underscore the need to develop interventions that specifically address the needs of young substance abusing males and females. [ABSTRACT FROM AUTHOR]

Objectives: Existing endoscopic scores for ulcerative colitis (UC) objectively categorize disease severity based on the presence or absence of endoscopic findings; therefore, it may not reflect the range of clinical severity within each category. However, inflammatory bowel disease (IBD) expert endoscopists categorize the severity and diagnose the overall impression of the degree of inflammation. This study aimed to develop an artificial intelligence (AI) system that can accurately represent the assessment of the endoscopic severity of UC by IBD expert endoscopists., Methods: A ranking-convolutional neural network (ranking-CNN) was trained using comparative information on the UC severity of 13,826 pairs of endoscopic images created by IBD expert endoscopists. Using the trained ranking-CNN, the UC Endoscopic Gradation Scale (UCEGS) was used to express severity. Correlation coefficients were calculated to ensure that there were no inconsistencies in assessments of severity made using UCEGS diagnosed by the AI and the Mayo Endoscopic Subscore, and the correlation coefficients of the mean for test images assessed using UCEGS by four IBD expert endoscopists and the AI., Results: Spearman's correlation coefficient between the UCEGS diagnosed by AI and Mayo Endoscopic Subscore was approximately 0.89. The correlation coefficients between IBD expert endoscopists and the AI of the evaluation results were all higher than 0.95 (P < 0.01)., Conclusions: The AI developed here can diagnose UC severity endoscopically similar to IBD expert endoscopists., (© 2023 The Authors. Digestive Endoscopy published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Background: Epithelial barrier dysfunction contributes to a dysregulated intestinal immune response in ulcerative colitis (UC). GB004 is an orally administered, small molecule, gut-targeted stabiliser of hypoxia-inducible factor-1α, a transcription factor with protective roles at the epithelial layer of the inflamed gut., Aims: To evaluate safety, pharmacokinetics, pharmacodynamics and efficacy of GB004 in patients with active UC., Methods: This double-blind, placebo-controlled study randomised patients 2:1 to receive an oral solution of GB004 120 mg or placebo once daily for 28 days. Eligible patients had a Robarts Histopathology Index score ≥4 with neutrophils in the epithelium, total Mayo Clinic score 3-12, Mayo Clinic endoscopic subscore ≥1, and blood in the stool, despite treatment with 5-aminosalicylates, corticosteroids or immunosuppressants., Results: Thirty-four patients were randomised. GB004 120 mg for 28 days was generally well-tolerated. Adverse events occurred in 27.3% (3/11) and 39.1% (9/23) of patients in the placebo and GB004 groups respectively. Nausea and dysgeusia were most commonly reported in the GB004 group (0% for placebo and 21.7% [5/23] and 13.0% [3/23] respectively for GB004). There were no treatment-related serious adverse events or deaths. GB004 exhibited minimal accumulation, with higher colonic concentrations relative to plasma. Exploratory pharmacodynamic and efficacy analyses demonstrated GB004 target engagement and numerically higher proportions of patients achieving improvement in multiple measures of disease activity, respectively, at day 28 for GB004 compared to placebo., Conclusion: Results from this phase 1b trial support evaluation of the full therapeutic potential of GB004 for the treatment of UC. A phase 2 study (NCT04556383) is ongoing. Clinicaltrials.gov NCT03860896., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Abstract: With the early success of their trials for the treatment of ulcerative colitis, corticosteroids gained popularity as a treatment for inflammatory bowel disease (IBD). However, when used chronically, corticosteroids are not effective in maintaining remission and associated with toxic effects. Steroid-free remission has become a major treatment goal. Prolonged corticosteroid use is currently a sign of suboptimal quality of care. Trends over the past 2 decades, spanning the emergence of biologic therapies for IBD, are explored here in the University of Manitoba IBD Epidemiologic Database., (Copyright © 2021 by The American College of Gastroenterology.)

Background and Aims: Although several endoscopic and histopathologic indices are available for evaluating the severity of inflammation in mouse models of colitis, the reliability of these scoring instruments is unknown. Our aim was to evaluate the reliability of the individual items in the existing indices and develop new scoring systems by selection of the most reliable index items., Methods: Two observers scored the histological slides [n = 224] and endoscopy videos [n = 201] from treated and untreated Interleukin[IL]-10 knock-out and T-cell transferred SCID mice. Intra-rater and inter-rater reliability for endoscopy and histology scores, and each individual item, were measured using intraclass correlation coefficients [ICCs]. The Mouse Colitis Histology Index [MCHI] and Mouse Colitis Endoscopy Index [MCEI] were developed using the most reliable items. Both were correlated to the colon density and to each other and were evaluated for their ability to detect changes in pathobiology., Results: The intraclass correlation coefficients (ICCs) for inter-rater agreement (95% CIs) for the total histology and endoscopy scores were 0.90 [0.87-0.92] and 0.80 [0.76-0.84], respectively. The MCHI and MCEI were highly correlated with colon density, with a Spearman Rho = 0.81[0.75-0.85] and 0.73 [0.66-0.79], respectively, and with each other, Spearman Rho = 0.71 [0.63-0.77]. The MCHI and MCEI were able to distinguish between the experimental groups within the models, with pairwise differences between the treated and untreated groups being statistically significant [p < 0.001]., Conclusions: These histological and endoscopic indices are valid and reliable measures of intestinal inflammation in mice, and they are responsive to treatment effects in pre-clinical studies.

Background: Clinical trial endpoints for Crohn's disease (CD) activity correlate poorly with mucosal inflammation; to assess treatment efficacy, patient-reported outcomes and endoscopic assessments are preferred. This study assessed the impact on treatment efficacy estimations of using different definitions of clinical and endoscopic remission and endoscopic response, and of using site- or central-based endoscopy evaluation., Methods: This post hoc analysis of data fromEXTEND (extend the safety and efficacy of adalimumab through endoscopic healing), a placebo (PBO)-controlled, randomized trial of adalimumab (ADA) for mucosal healing, included adults with moderate-to-severe CD. Subsets of patients meeting specified Simplified Endoscopic Score for CD (SES-CD) inclusion criteria, according to site or central reading, and baseline stool frequency (SF) and/or abdominal pain score (AP) thresholds were evaluated. Various endpoint definitions based on the Crohn's Disease Activity Index (CDAI), its SF and AP components, SES-CD, and composite endpoints were compared between treatment groups., Results: Increased stringency of Week 12 clinical endpoints compared to CDAI<150 to SF≤3.0/1.5&AP≤1.0 reduced PBO response rates by ≥12% and increased treatment effects by ≤10%. Amending the SES-CD endpoint from ≤4 to ≤2 reduced the treatment effect from 24% to 8%. Composite endpoints further diminished response rates and effect sizes. Site-based evaluation was associated with lower remission rates versus central reading in the PBO group and, thus, greater ADA-related treatment effects., Conclusions: This analysis is the first to demonstrate that increasing the stringency of clinical and endoscopic endpoint definitions in CD trials, especially lowering SF or SES-CD definitions, reduces the ability to detect treatment-related change in CD activity; focus on endpoints that reflect clinical change is warranted.

Background: Magnetic resonance enterography is increasingly utilized for assessment of luminal Crohn's disease activity. The Magnetic Resonance Index of Activity and the London Index are the most commonly used outcome measures in clinical trials. We assessed the reliability of these indices and several additional items., Methods: A consensus process clarified scoring conventions and identified additional items based on face validity. Four experienced radiologists evaluated 50 images in triplicate, in random order, at least 1 month apart, using a central image management system. Intra- and interrater reliability were assessed by calculating and comparing intraclass correlation coefficients., Results: Intrarater intraclass correlation coefficients (95% confidence intervals) for the Magnetic Resonance Index of Activity, London, and London "extended" indices and a visual analogue scale were 0.89 (0.84 to 0.91), 0.87 (0.83 to 0.90), 0.89 (0.85 to 0.92), and 0.86 (0.81 to 0.90). Corresponding interrater intraclass correlation coefficients were 0.71 (0.61 to 0.77), 0.67 (0.55 to 0.75), 0.70 (0.61 to 0.76), and 0.71 (0.62 to 0.77). Reliability for each index was greatest in the terminal ileum and poorest in the rectum. All 3 indices were highly correlated with the visual analogue scale; 0.79 (0.71 to 0.85), 0.78 (0.71 to 0.84), and 0.79 (0.72 to 0.85) for the Magnetic Resonance Index of Activity, London, and the London "extended" indices, respectively., Conclusions: "Substantial" interrater reliability was observed for all 3 indices. Future studies should assess responsiveness to treatment in order to confirm their utility as evaluative indices in clinical trials and clinical practice., (© 2018 Crohn’s & Colitis Foundation of America. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Objective: Although several pharmacological agents have emerged as potential adjunctive therapies to a gluten-free diet for coeliac disease, there is currently no widely accepted measure of disease activity used in clinical trials. We conducted a systematic review of coeliac disease activity indices to evaluate their operating properties and potential as outcome measures in registration trials., Design: MEDLINE, EMBASE and the Cochrane central library were searched from 1966 to 2015 for eligible studies in adult and/or paediatric patients with coeliac disease that included coeliac disease activity markers in their outcome measures. The operating characteristics of histological indices, patient-reported outcomes (PROs) and endoscopic indices were evaluated for content and construct validity, reliability, responsiveness and feasibility using guidelines proposed by the US Food and Drug Administration (FDA)., Results: Of 19 123 citations, 286 studies were eligible, including 24 randomised-controlled trials. Three of five PROs identified met most key evaluative criteria but only the Celiac Disease Symptom Diary (CDSD) and the Celiac Disease Patient-Reported Outcome (CeD PRO) have been approved by the FDA. All histological and endoscopic scores identified lacked content validity. Quantitative morphometric histological analysis had better reliability and responsiveness compared with qualitative scales. Endoscopic indices were infrequently used, and only one index demonstrated responsiveness to effective therapy., Conclusions: Current best evidence suggests that the CDSD and the CeD PRO are appropriate for use in the definition of primary end points in coeliac disease registration trials. Morphometric histology should be included as a key secondary or co-primary end point. Further work is needed to optimise end point configuration to inform efficient drug development., Competing Interests: Competing interests: PH has received consulting fees from Abbvie and Takeda; speakers fees from Ferring, Falk Pharma, Vifor Pharma, Tillotts Pharma, Chiesi, Takeda and Abbvie. BGL is an employee of Robarts Clinical Trials and has received lecture fees from Mitsubishi Tanabe Pharma Corporation. CP is an employee of Robarts Clinical Trials and has no relevant disclosures. RK has received honoraria from AbbVie, Janssen and Takeda Pharma. GDH has received consulting fees from AbbVie, ActoGeniX NV, Amgen, AM-Pharma BV, Boehringer-Ingelheim, ChemoCentryx, Centocor/Jansen Biologics, Cosmo Technologies, Elan/Biogen, EnGene, Ferring Pharmaceuticals, Gilead Sciences, Given Imaging, GSK, Merck Research Laboratories, Merck Serono, Millenium Pharmaceuticals, Novo Nordisk, NPS Pharmaceuticals, PDL Biopharma, Pfizer, Receptos, Salix Pharmaceuticals, Schering Plough, Shire Pharmaceuticals, Sigmoid Pharma, Teva Pharmaceuticals, Tillotts Pharma AG and UCB Pharma; research grants from AbbVie, GSK, Falk, Janssen, Merck and Given Imaging; and lecture/speakers bureaux fees from AbbVie, Jansen, Merck, Takeda, UCB and Shire. WJS has received grant support from Exact Sciences, the American College of Gastroenterology and the Broad Foundation; grant support and personal fees from Receptos, Amgen, Prometheus Laboratories, AbbVie, Boehringer Ingelheim, Takeda, Atlantic Pharmaceuticals, Janssen, Bristol-Myers Squibb, Genentech, Pfizer and Nutrition Science Partners; and personal fees from Kyowa Hakko Kirin, Millennium Pharmaceuticals, Celgene Cellular Therapeutics, Santarus, Salix Pharmaceuticals, Catabasis Pharmaceuticals, Vertex Pharmaceuticals, Warner Chilcott, Gilead Sciences, Cosmo Pharmaceuticals, Ferring Pharmaceuticals, Sigmoid Biotechnologies, Tillotts Pharma, Am Pharma BV, Dr. August Wolff, Avaxia Biologics, Zyngenia, Ironwood Pharmaceuticals, Index Pharmaceuticals, Nestle, Lexicon Pharmaceuticals, UCB Pharma, Orexigen, Luitpold Pharmaceuticals, Baxter Healthcare, Ferring Research Institute, Amgen, Novo Nordisk, Mesoblast, Shire, Ardelyx, Actavis, Seattle Genetics, MedImmune (AstraZeneca), Actogenix NV, Lipid Therapeutics, Eisai, Qu Biologics, Toray Industries, Teva Pharmaceuticals, Eli Lilly, Chiasma, TiGenix, Adherion Therapeutics, Immune Pharmaceuticals, Celgene, Arena Pharmaceuticals, Ambrx, Akros Pharma, Vascular Biogenics, Theradiag, Forward Pharma, Regeneron, Galapagos, Seres Health, Ritter Pharmaceuticals, Theravance, Palatin, Biogen and the University of Western Ontario (owner of Robarts Clinical Trials). DAL has recently accepted an employee position at Takeda and received research support/consultancy fees from Alba Therapeutics, Alvine Pharmaceuticals, INOVA Diagnostics, Genzyme, Coronado Biosciences, Sidney Frank Foundation and Pfizer. BGF has received grant/research support from Millennium Pharmaceuticals, Merck, Tillotts Pharma AG, AbbVie, Novartis Pharmaceuticals, Centocor, Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGenix and Wyeth Pharmaceuticals; consulting fees from Millennium Pharmaceuticals, Merck, Centocor, Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, UCB Pharma, AbbVie, Astra Zeneca, Serono, Genentech, Tillotts Pharma AG, Unity Pharmaceuticals, Albireo Pharma, Given Imaging, Salix Pharmaceuticals, Novonordisk, GSK, Actogenix, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead, Pfizer, Shire, Wyeth, Zealand Pharma, Zyngenia, GiCare Pharma and Sigmoid Pharma; and speakers bureaux fees from UCB, AbbVie and J&J/Janssen. VJ has received scientific advisory board fees from AbbVie and Sandoz; speakers fees from Takeda and Janssen. Robarts Clinical Trials began in 1986 as an academic research unit within the Robarts Research Institute, which is affiliated with University Hospital and the University of Western Ontario. A subsequent international (USA and Netherlands) expansion in 2012 necessitated establishment of a corporate entity to meet international federal/taxation regulations. All profits from Robarts Clinical Trials are directed towards academic research. The University of Western Ontario is the sole shareholder. None of the authors with affiliation to Robarts Clinical Trials have an equity position in the corporation., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objectives: Flow cytometry (FC) aids in characterization of cellular and molecular factors involved in pathologic immune responses. Although FC has potential to facilitate early drug development in inflammatory bowel disease, interlaboratory variability limits its use in multicenter trials. Standardization of methods may address this limitation. We compared variability in FC-aided quantitation of T-cell responses across international laboratories using three analytical strategies., Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from three healthy donors, stimulated with phorbol 12-myristate 13-acetate and ionomycin at a central laboratory, fixed, frozen, and shipped to seven international laboratories. Permeabilization and staining was performed in triplicate at each laboratory using a common protocol and centrally provided reagents. Gating was performed using local gating with a local strategy (LGLS), local gating with a central strategy (LGCS), and central gating (CG). Median cell percentages were calculated across triplicates and donors, and reported for each condition and strategy. The coefficient of variation (CV) was calculated across laboratories. Between-strategy comparisons were made using a two-way analysis of variance adjusting for donor., Results: Mean interlaboratory CV ranged from 1.8 to 102.1% depending on cell population and gating strategy (LGLS, 4.4-102.1%; LGCS, 10.9-65.6%; CG, 1.8-20.9%). Mean interlaboratory CV differed significantly across strategies and was consistently lower with CG., Conclusions: Central gating was the only strategy with mean CVs consistently lower than 25%, which is a proposed standard for pharmacodynamic and exploratory biomarker assays.

Objectives: There is no clear consensus regarding the most appropriate measure(s) of eosinophilic esophagitis (EoE) disease activity. We aimed to identify all scoring indices used for the measurement of disease activity in EoE, appraise their operating properties, and discuss their value as outcome measures., Methods: MEDLINE, EMBASE, and CENTRAL (The Cochrane library) were searched from inception to 11 May 2016. Randomized controlled trials (RCTs), cohort, case-control, and cross-sectional studies that reported outcomes to measure EoE disease activity or response to treatment were eligible. Operating properties of histologic, endoscopic, and patient reported/symptomatic and health-related quality of life measures were critically appraised according to guidelines proposed by the United States Food and Drug Administration., Results: Of 4,373 citations, 130 studies were eligible, of which 20 were RCTs. Although no index met all evaluative criteria, we found that: (1) the EoE histologic scoring system (EoEHSS) is the most valid histologic measure; (2) the Endoscopic Reference Score (EREFS) is the most reliable and responsive endoscopy measure; and (3) the Eosinophilic Esophagitis Activity Index (EEsAI) or the Dysphagia Symptoms Questionnaire (DSQ) had superior construct validity and responsiveness in adults. The Pediatric Quality of Life Inventory EoE was the most valid pediatric symptomatic measure., Conclusions: Current evidence supports the use of the EoEHSS and EREFS as measures of histologic and endoscopic EoE disease activity, respectively, and the EEsAI, DSQ, or Pediatric Quality of Life Inventory EoE as measures of adult and pediatric symptoms. Additional research is needed to optimize endpoint configuration to facilitate development of new therapies.

Objectives: The Crohn's Disease Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score for Crohn's Disease (SES-CD) are commonly used to assess Crohn's disease (CD) activity; however neither instrument is fully validated. We evaluated the responsiveness to change of the SES-CD and CDEIS using data from a trial of adalimumab, a drug therapy of known efficacy., Methods: Paired video recordings (N=112) of colonoscopies (baseline and week 8-12) obtained from patients with CD who participated in a trial of adalimumab therapy were reviewed in random order, in duplicate, by four central readers (56 pairs of videos by 2 groups of readers). Responsiveness of the SES-CD and the CDEIS was evaluated by comparing correlations between the observed and pre-specified predictions of change scores for these endoscopic indices with a global endoscopic evaluation of severity (GELS), a patient reported outcome (PRO2), and the Crohn's disease activity index (CDAI), and by calculation of the standardized effect size, and Guyatt's Responsiveness statistic (GRS) using 2 definitions of change; (1) treatment assignment and (2) an absolute change in total PRO2 of 50. The potential application of effect size estimates was demonstrated by calculating hypothetical sample sizes for comparing two independent groups. The impact of removing stenosis as an index item and adjusting for the number of segments observed was also assessed., Results: Changes in both endoscopic instruments and the GELS were highly correlated. The SES-CD displayed numerically higher effect sizes for both definitions of change. The standardized effect size and GRS estimates (95% confidence interval) for the SES-CD based on treatment assignment were 0.84 (0.53, 1.15) and 0.79 (0.48, 1.09). Corresponding values for the CDEIS were 0.72 (0.42, 1.02) and 0.75 (0.45, 1.06). The standardized effect size and GRS estimates for the SES-CD based on an absolute change in total PRO2 of 50 points or greater were 0.76 (0.49, 1.02) and 0.93 (0.64, 1.21). Corresponding values for CDEIS were 0.70 (0.44, 0.97), 0.83 (0.55, 1.10). Removal of stenosis as an index item and adjusting for observed segments did not improve responsiveness estimates., Conclusions: Although both the SES-CD and CDEIS are valid measures of endoscopic disease activity that are moderately responsive to changes in endoscopic disease activity, the SES-CD displayed numerically greater responsiveness in this data set.

Background: Magnetic resonance imaging (MRI) is the gold standard for assessment of perianal fistulising Crohn's disease (CD). The Van Assche index is the most commonly used MRI fistula index., Aims: To assess the reliability of the Van Assche index, and to modify the instrument to improve reliability and create a novel index for fistulising CD., Methods: A consensus process developed scoring conventions for existing Van Assche index component items and new items. Four experienced radiologists evaluated 50 MRI images in random order on three occasions. Reliability was assessed by estimates of intraclass correlation coefficients (ICCs). Common sources of disagreement were identified and recommendations made to minimise disagreement. A mixed effects model used a 100 mm visual anologue scale (VAS) for global severity as outcome and component items as predictors to create a modified Van Assche index., Results: Intraclass correlation coefficients (95% confidence intervals) for intra-rater reliability of the original and modified Van Assche indices and the VAS were 0.86 (0.81-0.90), 0.90 (0.86-0.93) and 0.86 (0.82-0.89). Corresponding ICCs for inter-rater reliability were 0.66 (0.52-0.76), 0.67 (0.55-0.75) and 0.58 (0.47-0.66). Sources of disagreement included number, location, and extension of fistula tracts, and rectal wall involvement. A modified Van Assche index (range 0-24) was created that included seven component items., Conclusions: Although "almost perfect" intra-rater reliability was observed for the assessment of MRI images for fistulising CD using the Van Assche index, inter-rater reliability was considerably lower. Our modification of this index should result in a more optimal instrument., (© 2017 John Wiley & Sons Ltd.)

Introduction: Crohn's disease (CD) and ulcerative colitis (UC), the main forms of inflammatory bowel disease (IBD), are chronic, progressive and disabling disorders of the gastrointestinal tract. Although data from randomised controlled trials (RCTs) provide the foundation of evidence that validates medical therapy for IBD, considerable heterogeneity exists in the measured outcomes used in these studies. Furthermore, in recent years, there has been a paradigm shift in IBD treatment targets, moving from symptom-based scoring to improvement or normalisation of objective measures of inflammation such as endoscopic appearance, inflammatory biomarkers and histological and radiographic end points. The abundance of new treatment options and evolving end points poses opportunities and challenges for all stakeholders involved in drug development. Accordingly, there exists a need to harmonise measures used in clinical trials through the development of a core outcome set (COS)., Methods and Analysis: The development of an IBD-specific COS includes four steps. First, a systematic literature review is performed to identify outcomes previously used in IBD RCTs. Second, semistructured qualitative interviews are conducted with key stakeholders, including patients, clinicians, researchers, pharmaceutical industry representatives, healthcare payers and regulators to identify additional outcomes of importance. Using the outcomes generated from literature review and stakeholder interviews, an international two-round Delphi survey is conducted to prioritise outcomes for inclusion in the COS. Finally, a consensus meeting is held to ratify the COS and disseminate findings for application in future IBD trials., Ethics and Dissemination: Given that over 30 novel therapeutic compounds are in development for IBD treatment, the design of robust clinical trials measuring relevant and standardised outcomes is crucial. Standardising outcomes through a COS will reduce heterogeneity in trial reporting, facilitate valid comparisons of new therapies and improve clinical trial quality., Competing Interests: Competing interests: CM has no conflicts of interest to declare. RP has received scientific advisory board fees from Abbott/AbbVie, Amgen, Janssen, Merck, Pfizer, Prometheus Laboratories, Salix Pharma, Shire, Takeda, WarnerChilcott; consulting fees from Abbott/AbbVie, Amgen, Aptalis, Astra Zeneca,Baxter, BMS, Centocor, Elan/Biogen, Eisai, Ferring, GSK, Janssen, Merck,Millennium, Pfizer, Proctor & Gamble, Prometheus Therapeutics andDiagnostics, Schering-Plough, Shire, Takeda, UCB Pharma, Warner Chilcott;research grants from Abbott/AbbVie, Amgen, Aptalis, Astra Zeneca, Baxter, BMS,Centocor, Eisai, Elan/Biogen, Ferring, GSK, Janssen, Merck, Millennium, Pfizer,Proctor & Gamble, Prometheus, Shire, Schering-Plough, Takeda, UCB Pharma,Warner Chilcott; and 495 speaker’s bureau fees from Abbott/AbbVie, Amgen, Aptalis, Astra Zeneca, Baxter, BMS, Centocor, Eisai, Elan/Biogen, Ferring, GSK, Janssen, Merck, Millennium, Pfizer, Proctor & Gamble, Prometheus, Schering-Plough, Shire, Takeda, UCB Pharma, Warner Chilcott. RF has received scientific advisory board fees from Abbott/AbbVie, Celltrion, Ferring, Janssen, Shire, VSL#3; consulting fees from Abbott/AbbVie, Celltrion, Ferring, Janssen, Shire, VSL#3; and research grant support from Abbott/AbbVie, Alba Therapeutics, BMS, Celltrion, Centocor, Genentech, GSK, Janssen, Merck, Millennium, Novartis, Pfizer, Proctor & Gamble, Roche, VSL#3. CP has no conflicts of interest todeclare. RK has received consulting fees from AbbVie, Takeda, and Janssen. BL has received consulting fees from AbbVie, Takeda, Nestle Health Sciences, and Prometheus Labs. WS has served as a consultant to AbbVie Inc., ActoGeniX NV,AGI Therapeutics, Inc, Alba Therapeutics Corporation, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas Pharma, Athersys, Inc, AtlanticHealthcare Limited, Axcan Pharma (now Aptalis), BioBalance Corporation,Boehringer-Ingelheim Inc, Bristol Meyers Squibb, Celgene, CelekPharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis,Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, EaglePharmaceuticals, Eisai Medical Research Inc, Elan Pharmaceuticals, EnGene, Inc,Eli Lilly, Enteromedics, Exagen Diagnostics, Inc, Ferring Pharmaceuticals,Flexion Therapeutics, Inc, Funxional Therapeutics Limited, Genzyme Corporation, Genentech (now Roche), Gilead Sciences, Given Imaging, Glaxo Smith Kline, HumanGenome Sciences, Ironwood Pharmaceuticals (previously Microbia Inc), Janssen(previously Centocor), KaloBios Pharmaceuticals, Inc, Lexicon Pharmaceuticals,Lycera Corporation, Meda Pharmaceuticals (previously Alaven Pharmaceuticals), Merck Research Laboratories, MerckSerono, Millennium Pharmaceuticals(subsequently merged with Takeda), Nisshin Kyorin Pharmaceuticals Co, Ltd, NovoNordisk A/S, NPS Pharmaceuticals, Optimer Pharmaceuticals, OrexigenTherapeutics, Inc, PDL Biopharma, Pfizer, Procter and Gamble, PrometheusLaboratories, ProtAb Limited, Purgenesis Technologies, Inc, Receptos, Relypsa,Inc, Salient Pharmaceuticals, Salix Pharmaceuticals, Inc, Santarus, ScheringPlough Corporation (acquired by Merck), Shire Pharmaceuticals, Sigmoid PharmaLimited, Sirtris Pharmaceuticals, Inc (a GSK company), SLA Pharma (UK) Limited,Targacept, Teva Pharmaceuticals, Therakos, Tillotts Pharma AG (acquired by Zeria Pharmaceutical Co, Ltd), TxCell SA, UCB Pharma, Viamet Pharmaceuticals,Vascular Biogenics Limited (VBL), Warner Chilcott UK Limited; has receivedspeaker’s fees from AbbVie Inc, Bristol Meyers Squibb and Janssen (previously Centocor); and financial support for research from AbbVie Inc, Bristol Meyers Squibb, Genentech, Glaxo Smith Kline, Janssen (previously Centocor), Millennium Pharmaceuticals (now Takeda), Novartis, Pfizer, Procter and Gamble Pharmaceuticals, Shire Pharmaceuticals and UCB Pharma. Brian Feagan hasreceived grant/research support from Millennium Pharmaceuticals, Merck,Tillotts Pharma AG, AbbVie, Novartis Pharmaceuticals, Centocor Inc, Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGenix and Wyeth Pharmaceuticals Inc; consulting fees from Millennium Pharmaceuticals, Merck, Centocor Inc, Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, Bristol-MyersSquibb, Celgene, UCB Pharma, AbbVie, Astra Zeneca, Serono, Genentech, TillottsPharma AG, Unity Pharmaceuticals, Albireo Pharma, Given Imaging Inc, Salix Pharmaceuticals, Novonordisk, GSK, Actogenix, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead, Pfizer, Shire, Wyeth, Zealand Pharma, Zyngenia, GiCare Pharma Inc and Sigmoid Pharma; and speakers bureau fees from UCB, AbbVie and J&J/Janssen. VJ has received scientific advisory board feesfrom AbbVie, Sandoz, Takeda, Janssen; speakers fees from Takeda, Janssen,Shire, Ferring., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Disease activity can be determined using clinical, endoscopic or histologic criteria in patients with ulcerative colitis (UC). Persistent disease activity is associated with poor outcomes. Histologic disease activity has been shown to be associated with relapse, colectomy and colorectal cancer. The ability to objectively evaluate microscopic disease activity using histology is important for both clinical practice and clinical trials. However, the operating properties of the currently available histologic indices remain unclear., Objectives: A systematic review was undertaken to identify and evaluate the development and operating characteristics of histologic disease activity indices used to assess disease activity in people with ulcerative colitis., Search Methods: We searched MEDLINE, EMBASE, PubMed, CENTRAL and the Cochrane IBD Review Group Specialized Trials Register from inception to 2 December 2016 for applicable studies. There were no language or document type restrictions., Selection Criteria: Any study design (e.g. randomized controlled trials, cohort studies, case series) that evaluated a histologic index in patients with UC were considered for inclusion. Eligible patients were adults (> 18 years), diagnosed with UC using conventional clinical, radiographic, endoscopic and histologic criteria., Data Collection and Analysis: Two authors (MHM and CEP) independently reviewed the titles and abstracts of the studies identified from the literature search. A standardized form was used to assess eligibility of trials for inclusion and for data extraction.Two authors (MHM and CEP) independently extracted and recorded data, which included the number of patients enrolled, number of patients per treatment arm, patient characteristics including age and gender distribution, and the name of the histologic index. Outcomes (i.e. intra-rater reliability, inter-rater reliability, internal consistency, content validity, criterion validity, construct validity, responsiveness, and feasibility) were recorded for each trial., Main Results: In total, 126 reports describing 30 scoring indices were identified through the screening process. Eleven of the 30 scoring indices have undergone some form of index validation. Intra-rater reliability was assessed for eight scoring indices. Inter-rater reliability was evaluated for all 11 of the scoring indices. Three of the indices underwent content validation. Two of the included scoring indices assessed criterion validity. Six of the included scoring indices explored content validity. Two of the included scoring indices were tested for responsiveness., Authors' Conclusions: The Nancy Index and the Robarts Histopathology Index have undergone the most validation in that four operating properties including reliability, content validity, construct validity (hypothesis testing) and criterion validity have been tested. However, none of the currently available histologic scoring indices have been fully validated. In order to determine the optimal endpoint for histologic healing in UC, more research is required. The optimal index would need to be fully validated.

Background: Minimising placebo response is essential for drug development., Aim: To conduct a meta-analysis to determine placebo response and remission rates in trials and identify the factors affecting these rates., Methods: MEDLINE, EMBASE and CENTRAL were searched from inception to April 2014 for placebo-controlled trials of pharmacological interventions for Crohn's disease. Placebo response and remission rates for induction and maintenance trials were pooled by random-effects and mixed-effects meta-regression models to evaluate effects of study-level characteristics on these rates., Results: In 100 studies containing 67 induction and 40 maintenance phases and 7638 participants, pooled placebo remission and response rates for induction trials were 18% [95% confidence interval (CI) 16-21%] and 28% (95% CI 24-32%), respectively. Corresponding values for maintenance trials were 32% (95% CI 25-39%) and 26% (95% CI 19-35%), respectively. For remission, trials enrolling patients with more severe disease activity, longer disease duration and more study centres were associated with lower placebo rates, whereas more study visits and longer study duration was associated with higher placebo rates. For response, findings were opposite such that trials enrolling patients with less severe disease activity and longer study duration were associated with lower placebo rates. Placebo rates varied by drug class and route of administration, with the highest placebo response rates observed for biologics., Conclusions: Placebo rates vary according to whether trials are designed for induction or maintenance and the factors influencing them differ for the endpoints of remission and response. These findings have important implications for clinical trial design in Crohn's disease., (© 2017 John Wiley & Sons Ltd.)

Background: Although optimal medical management of acute severe ulcerative colitis (UC) is ill-defined, infliximab has become a standard of care. Accumulating evidence suggests an increased rate of infliximab clearance in patients with acute severe UC and a reduced colectomy rate with an intensified infliximab induction regimen., Aim: To assess the strength of the current evidence for the relationship between infliximab pharmacokinetics, dosing strategies and disease behaviour in patients with acute severe UC., Methods: We systematically searched MEDLINE and conference proceedings from 2000 to 2016 for relevant articles describing the pharmacokinetics of infliximab in acute severe UC and/or infliximab dose intensification strategies in acute severe UC. Eligible articles described randomised controlled trials, and cohort, cross-sectional, and case-controlled studies., Results: Of 400 citations identified, 76 studies were eligible. Increased infliximab clearance occurs in patients with acute severe UC, and is driven by the total inflammatory burden and leakage of drug into the colonic lumen. Several cohort studies suggest that infliximab dose intensification is beneficial to at least 50% of acute severe UC patients and the results of case-controlled studies indicate that an intensified infliximab dosing regimen with 1-2 additional infusions in the first 3 weeks of treatment could reduce the early (3-month) colectomy rate by up to 80%, although these data require prospective validation., Conclusions: Uncontrolled studies suggest a benefit for infliximab dose optimisation in patients with acute severe UC. A randomised controlled trial in acute severe UC patients comparing a personalised infliximab dose-optimisation strategy with conventional dosing is a research priority., (© 2017 John Wiley & Sons Ltd.)

The highest attrition rates during drug development programmes occur at the proof of concept stage. Given the large number of molecules under development for Crohn's disease, a need exists to improve the efficiency of early drug development by fast-tracking promising agents and terminating ineffective ones. Multiple opportunities are available to achieve these goals, including the use of more responsive outcome measures, and the incorporation of sophisticated pharmacokinetic modelling and/or highly specific pharmacodynamic markers into exposure-based dosing regimens and novel trial designs. In this article we review these strategies and propose an integrated paradigm of early drug development in Crohn's disease., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Crohn's disease and ulcerative colitis are heterogeneous inflammatory bowel diseases, and therapeutic requirements vary among patients. We have a limited capacity to predict disease progression for individual patients, therefore it is important that they are evaluated for the presence of active disease when symptoms are mild or even absent, when patients are more likely to respond to new treatment interventions. It then is important to monitor responses to treatment, to quickly identify those therapies that are ineffective, modify or change therapy, and avoid disease complications. Studies are underway to assess the effects of different monitoring strategies. Because of the heavy burden of severe inflammatory bowel disease on patients' health and quality of life, and the association between intestinal healing and disease progression in high-risk patients, a treat-to-target strategy (based on tissue healing) is likely to be optimal., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: Although the Geboes score (GS) and modified Riley score (MRS) are commonly used to evaluate histological disease activity in UC, their operating properties are unknown. Accordingly, we developed an alternative instrument., Design: Four pathologists scored 48 UC colon biopsies using the GS, MRS and a visual analogue scale global rating. Intra-rater and inter-rater reliability for each index and individual index items were measured using intraclass correlation coefficients (ICCs). Items with high reliability were used to develop the Robarts histopathology index (RHI). The responsiveness/validity of the RHI and multiple histological, endoscopic and clinical outcome measures were evaluated by analyses of change scores, standardised effect size (SES) and Guyatt's responsiveness statistic (GRS) using data from a clinical trial of an effective therapy., Results: Inter-rater ICCs (95% CIs) for the total GS and MRS scores were 0.79 (0.63 to 0.87) and 0.80 (0.69 to 0.87). The correlation estimates between change scores in RHI and change score in GS and MRS were 0.75 (0.67 to 0.82) and 0.84 (0.79 to 0.88), respectively. The SES and GRS estimates for GS, MRS and RHI were: 1.87 (1.54 to 2.20) and 1.23 (0.97 to 1.50), 1.29 (1.02 to 1.56) and 0.88 (0.65 to 1.12), and 1.05 (0.79 to 1.30) and 0.88 (0.64 to 1.12), respectively., Conclusions: The RHI is a new histopathological index with favourable operating properties., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Crohn's disease (CD) is frequently complicated by intestinal strictures, which are commonly treated by endoscopic balloon dilation (EBD). However, available data on this area of treatment is limited. The aim of this study was to depict the heterogeneity of endoscopic management of CD-associated strictures among international CD specialists to identify common treatment standards., Methods: IBD experts of the International Organization for the Study of Inflammatory Bowel Disease (IOIBD), the European Crohn's and Colitis Organization (ECCO), and from the Prospective Value In IBD trials (PROVIT) completed a web-based questionnaire to evaluate their endoscopic experience, practice setting, and number of EBDs performed annually. Additionally, two case scenarios and technical practice parameters were investigated., Results: A total of 126 subjects from 15 countries completed the survey. The maximal length of dilated stricture was 4.5 ± 1.7 cm. The most commonly used maximal balloon size was graded as 15-18 mm. While 87.2 % of the participants favored EBD for anastomotic strictures, only 58.6 % did so in the case of naïve strictures. Only 35.7 % of physicians dilated actively inflamed strictures. Interventional endoscopists were more likely to dilate only clinically symptomatic strictures (p = 0.046). Surgeons favored surgical treatment of de novo ileocecal strictures compared to gastroenterologists (p = 0.026), reported a shorter stricture length being amendable by EBD (p = 0.045), and more frequently used concomitant therapies (p = 0.001). Operator experience increased the likelihood of EBD use in actively inflamed strictures (p = 0.002), maximum length of stricture, and maximum balloon size (p = 0.001)., Conclusions: EBD is a widely used treatment approach for stricturing CD. Individual approaches differ significantly based on background of the operator, experience level, and practice setting.

Endoscopic assessment of the presence and severity of endoscopic lesions has become an essential part of clinical trials in ulcerative colitis and Crohn's disease, for both patient eligibility and outcome measures. Variability in lesion interpretation between and within observers and the potential bias of local investigators in patient assessment have long been recognized. This variability can be reduced, although not completely removed, by independent evaluation of the examinations by experienced off-site (central) readers, properly trained in regard to lesion definition and identification, that should be removed from direct patient contact and blinded to any other clinical or study data. Adding endoscopic demonstration of active disease to eligibility criteria has the potential to reduce placebo response rates, whereas in outcome assessment it has the potential to provide a more precise estimation of the treatment effect, increasing the efficiency of the study. Central endoscopy reading is still at the beginning of its development, and the paradigms of central reading need refinement in terms of the number of readers, the process by which a final score is assigned, the selection and sequence of central readers, and the endoscopic indices of choice., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: The Crohn's Disease Endoscopic Index of Severity [CDEIS] and Simplified Endoscopic Score for Crohn's Disease [SES-CD] demonstrate consistent overall intra- and inter-rater reliability. However, the reliability of some index items is relatively poor. We evaluated scoring conventions to improve the reliability of these items., Methods: Five gastroenterologists with no previous experience scoring the CDEIS or SES-CD were trained on their use. A total of 65 video recordings of colonoscopies were scored blindly by each gastroenterologist before and after additional training on index scoring conventions. Intra-class correlation coefficients [ICCs] assessed the effect of application of these conventions on the reliability of the CDEIS, SES-CD, and a Global Evaluation of Lesion Severity [GELS] score., Results: Following training on scoring conventions, inter-rater ICCs (95% confidence interval [CI]) for the total SES-CD score increased from 0.78 [0.71, 0.85] to 0.85 [0.79, 0.89]. The ICCs for the total CDEIS and GELS scores were not affected: corresponding inter-rater ICCs were 0.74 [0.65, 0.81] and 0.49, [0.38, 0.61] before and 0.73 [0.65, 0.81] and 0.53 [0.42, 0.64] following application of scoring conventions. Estimations of ulcer depth, surface area, anatomical location, and stenosis were important sources of variability., Conclusions: Use of scoring conventions previously developed by expert central readers enhanced the reliability of the SES-CD but did not similarly affect the CDEIS or GELS. As the SES-CD is more likely to be reliable than the CDEIS and can be optimised with targeted training, it is the preferred instrument for use in clinical trials., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Endoscopic assessment of mucosal disease activity is widely used to determine eligibility and response to therapy in clinical trials of treatment for Crohn's disease. However, the operating properties of the currently available endoscopic indices remain unclear., Objectives: A systematic review was undertaken to evaluate the development and operating characteristics of the Crohn's Disease Endoscopic Index of Severity (CDEIS) and Simple Endoscopic Scale for Crohn's Disease (SES-CD)., Search Methods: Electronic searches of the MEDLINE (1966 to December 2015), EMBASE (1980 to December 2015), and Cochrane CENTRAL Register of Controlled Trials (Issue 12, 2015) databases were supplemented by manual reviews of reference listings and conference proceedings (Digestive Disease Week, United European Gastroenterology Week, European Crohn's and Colitis Organization)., Selection Criteria: Any study design (e.g. randomized controlled trials, cohort studies, case series) that evaluated either or both the CDEIS or SES-CD in patients with Crohn's disease was considered for inclusion. Eligible participants were adult patients (> 16 years), diagnosed with Crohn's disease using conventional clinical, radiographic, and endoscopic criteria., Data Collection and Analysis: Two authors (RK, JKM) independently reviewed the titles and abstracts of the studies identified from the literature search. The full texts of potentially relevant citations were reviewed for inclusion and the study investigators were contacted to clarify any unclear data. Any disagreements were resolved by discussion and consensus with a third author. A standardized form was used to assess eligibility of trials for inclusion in the study and for data extraction.Two authors independently extracted and recorded data (RK, SAN). The number of patients enrolled; number of patients per treatment arm; patient characteristics including age and gender distribution; endoscopic index; and outcomes such as intra-rater reliability, inter-rater reliability responsiveness, validity, feasibility, construct validity, and criterion validity were recorded for each trial., Main Results: Forty-three reports of 30 studies fulfilled the inclusion criteria.For the SES-CD, inter-rater reliability was assessed in four studies. In the development study for the SES-CD (Daperno 2004), the overall ICC (0.9815, 95% CI 0.9705 to 0.9884) and the kappa for the regions is high; however the paired raters were in the same room which introduces the potential for bias.For the CDEIS, inter-rater reliability was assessed in six studies. Daperno 2014 reported that the ICC for the CDEIS was 0.985 (95% CI 0.939-1.000) for average measures of video score and was 0.835 (95% CI 0.540-0.995) for single measures of video score.With respect to validity, correlation between the CDEIS and clinical measures, including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), was also reported. The estimates of correlation with CRP were r = 0.521 (Sipponen 2010b), r = 0.553 (Sipponen 2008a) and r = 0.608 (Sipponen 2008c). For the SES-CD, the corresponding values for correlation with CRP ranged from r = 0.46 (Jones 2008) to r = 0.68 (Green 2011).Responsiveness data for the CDEIS were available in nine studies. Seven studies demonstrated statistically significant decreases in the CDEIS score after administration of a treatment of known efficacy. Minimal responsiveness data were available for the SES-CD. Sipponen 2010a and Sipponen 2010b demonstrated statistically significant changes in the SES-CD score after subjects were administered a treatment of known efficacy.No studies were identified that explicitly evaluated the feasibility for either the SES-CD or the CDEIS. The SES-CD requires fewer calculations and may therefore be easier to use than the CDEIS., Authors' Conclusions: Although they are used in clinical trials, the CDEIS and SES-CD remain incompletely validated. Future research is required to determine the operating properties and to define the optimal index.

Objective: The Crohn's Disease Endoscopic Index of Severity (CDEIS) and Simple Endoscopic Score for Crohn's Disease (SES-CD) are commonly used to assess Crohn's disease (CD) activity; however, neither instrument has been fully validated. We assessed intra-rater and inter-rater reliability of these indices., Design: Video recordings of colonoscopies obtained from 50 patients with CD who participated in an induction trial of a biological therapy were triplicated and reviewed in random order by four central readers. Data were used to assess intra-rater and inter-rater reliability for CDEIS, SES-CD and a global evaluation of lesion severity (GELS). Subsequently, readers participated in a consensus process that identified common sources of disagreement., Results: Intraclass correlation coefficients (ICCs) for intra-rater reliability for CDEIS, SES-CD and GELS (95% CIs) were 0.89 (0.86 to 0.93), 0.91 (0.89 to 0.95) and 0.81 (0.77 to 0.89), respectively, with standard error of measurement (SEM) of 2.10, 2.42 and 1.15. The corresponding ICCs for inter-rater reliability were 0.71 (0.63 to 0.76), 0.83 (0.75 to 0.88) and 0.62 (0.52 to 0.70), with SEM of 3.42, 3.07 and 1.63, respectively. Correlation between CDEIS and GELS was 0.75, between SES-CD and GELS was 0.74 and between CDEIS and SES-CD was 0.92. The most common sources of disagreement were interpretation of superficial ulceration, definition of disease site at the ileocolonic anastomosis, assessment of anorectal lesions and grading severity of stenosis., Conclusions: Central reading of CDEIS and SES-CD had 'substantial' to 'almost perfect' intra-rater and inter-rater reliability; however, the responsiveness of these instruments is yet to be determined., Trial Registration Number: Clinicaltrials.gov NCT01466374., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Matrix metalloproteinase-9 is a proteolytic enzyme whose expression is increased in ulcerative colitis., Aim: To evaluate the safety and efficacy of GS-5745, a fully humanised anti-matrix metalloproteinase-9 monoclonal antibody, in moderately-to-severely active ulcerative colitis., Methods: We randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS-5745 or placebo. Multiple-dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS-5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS-5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS-5745. Exploratory analyses in the multiple-dose cohorts included clinical response (≥3 points or 30% decrease from baseline in Mayo Clinic score and ≥1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore ≤1) and clinical remission (a complete Mayo Clinic score ≤2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS-5745 were explored using histological and molecular approaches., Results: Twenty-three of the 42 patients (55%) receiving multiple doses of GS-5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS-5745 showed target-mediated drug disposition, approximately dose-proportional increases in maximum plasma concentration and more than dose-proportional increases in the area under the plasma drug concentration-time curve. Clinical response occurred in 18/42 patients (43%) receiving GS-5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS-5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS-5745 had reductions in matrix metalloproteinase-9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation., Conclusion: This phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS-5745 in the treatment of ulcerative colitis., (© 2016 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Purpose: To compare the benefits and harms of anti-tumor necrosis factor (TNF)-α and anti-integrin agents as induction and maintenance therapy in adult patients with Crohn's disease., Methods: We searched MEDLINE and the Cochrane Central Register of Controlled Trials from inception through July 2015 for randomized clinical trials in patients with Crohn's disease who reported response or remission with anti-TNF-α or anti-integrin agents administered as induction and/or maintenance therapy. Data on the study population, interventions, outcome measures, adverse events, and study methods were extracted independently by 2 authors., Findings: Among 2503 citations identified, 23 met the eligibility criteria. Random-effects model meta-analyses and network meta-analyses were performed. No statistically significant difference was observed between anti-TNF-α and anti-integrin agents with respect to induction and maintenance of response (odds ratio [OR] = 1.20 [95% CI, 0.73-1.96] from 14 trials and OR = 1.23 [95% CI, 0.50-3.03] from 8 trials, respectively) or remission (OR = 1.13 [95% CI, 0.72-1.76] from 17 trials and OR = 1.18 [95% CI, 0.55-2.50] from 9 trials, respectively). No difference was observed in the indirect comparison of trials that reported results on the subgroup of anti-TNF-α naive patients. The proportions of patients with adverse events, infections, and treatment discontinuations were similar between the agents., Implications: Our indirect treatment comparisons did not find a statistically significant difference between anti-TNF-α and anti-integrin agents for induction or maintenance therapy. In the absence of head-to-head comparisons, it remains unclear which patient is more likely to respond better to any of these agents., (Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.)

Background and Aims: Minimisation of the placebo responses in randomised controlled trials [RCTs] is essential for efficient evaluation of new interventions. Placebo rates have been high in ulcerative colitis [UC] clinical trials, and factors influencing this are poorly understood. We quantify placebo response and remission rates in UC RCTs and identify trial design factors influencing them., Methods: MEDLINE, EMBASE, and the Cochrane Library were searched from inception through April 2014 for placebo-controlled trials in adult patients with UC of a biological agent, corticosteroid, immunosuppressant, or aminosalicylate. Data were independently doubly extracted. Quality was assessed using the Cochrane risk of bias tool., Results: In all, 51 trials [48 induction and 10 maintenance phases] were identified. Placebo response and remission rates were pooled according to random-effects models, and mixed-effects meta-regression models were used to evaluate effects of study-level characteristics on these rates. Pooled estimates of placebo remission and response rates for induction trials were 10% (95% confidence interval [CI] 7-13%) and 33% [95% CI 29-37%], respectively. Corresponding values for maintenance trials were 19% [95% CI 11-30%] and 22% [95% CI 17-28%]. Trials enrolling patients with more active disease confirmed by endoscopy [endoscopy subscore ≥ 2] were associated with lower placebo rates. Conversely, placebo rates increased with increasing trial duration and number of study visits., Conclusions: Objective assessment of greater disease activity at trial entry by endoscopy lowered placebo rates, whereas increasing trial duration and more interactions with healthcare providers increased placebo rates. These findings have important implications for design and conduct of clinical trials., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Conventional management of Crohn's disease features incremental use of therapies. However, early combined immunosuppression (ECI), with a TNF antagonist and antimetabolite might be a more effective strategy. We compared the efficacy of ECI with that of conventional management for treatment of Crohn's disease., Methods: In this open-label cluster randomised controlled trial (Randomised Evaluation of an Algorithm for Crohn's Treatment, REACT), we included community gastroenterology practices from Belgium and Canada that were willing to be assigned to either of the study groups, participate in all aspects of the study, and provide data on up to 60 patients with Crohn's disease. These practices were randomly assigned (1:1) to either ECI or conventional management. The computer-generated randomisation was minimised by country and practice size. Up to 60 consecutive adult patients were assessed within practices. Patients who were aged 18 years or older; documented to have Crohn's disease; able to speak or understand English, French, or Dutch; able to access a telephone; and able to provide written informed consent were followed up for 2 years. The primary outcome was the proportion of patients in corticosteroid-free remission (Harvey-Bradshaw Index score ≤ 4) at 12 months at the practice level. This trial is registered with ClinicalTrials.gov, number NCT01030809., Findings: This study took place between March 15, 2010, and Oct 1, 2013. Of the 60 practices screened, 41 were randomly assigned to either ECI (n=22) or conventional management (n=19). Two practices (one in each group) discontinued because of insufficient resources. 921 (85%) of the 1084 patients at ECI practices and 806 (90%) of 898 patients at conventional management practices completed 12 months follow-up and were included in an intention-to-treat analysis. The 12 month practice-level remission rates were similar at ECI and conventional management practices (66·0% [SD 14·0] and 61·9% [16·9]; adjusted difference 2·5%, 95% CI -5·2% to 10·2%, p=0·5169). The 24 month patient-level composite rate of major adverse outcomes defined as occurrence of surgery, hospital admission, or serious disease-related complications was lower at ECI practices than at conventional management practices (27·7% and 35·1%, absolute difference [AD] 7·3%, hazard ratio [HR]: 0·73, 95% CI 0·62 to 0·86, p=0·0003). There were no differences in serious drug-related adverse events., Interpretation: Although ECI was not more effective than conventional management for controlling Crohn's disease symptoms, the risk of major adverse outcomes was lower. The latter finding should be considered hypothesis-generating for future trials. ECI was not associated with an increased risk of serious drug-related adverse events or mortality., Funding: AbbVie Pharmaceuticals., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: Histopathology is potentially an important outcome measure in UC. Multiple histological disease activity (HA) indices, including the Geboes score (GS) and modified Riley score (MRS), have been developed; however, the operating properties of these instruments are not clearly defined. We assessed the reproducibility of existing measures of HA., Design: Five experienced pathologists with GI pathology fellowship training and expertise in IBD evaluated, on three separate occasions at least two weeks apart, 49 UC colon biopsies and scored the GS, MRS and a global rating of histological severity using a 100 mm visual analogue scale (VAS). The reproducibility of each grading system and for individual instrument items was quantified by estimates of intraclass correlation coefficients (ICCs) based on two-way random effects models. Uncertainty of estimates was quantified by 95% two-sided CIs obtained using the non-parametric cluster bootstrap method. Biopsies responsible for the greatest disagreement based on the ICC estimates were identified. A consensus process was used to determine the most common sources of measurement disagreement. Recommendations for minimising disagreement were subsequently generated., Results: Intrarater ICCs (95% CIs) for the total GS, MRS and VAS scores were 0.82 (0.73 to 0.88), 0.71 (0.63 to 0.80) and 0.79 (0.72 to 0.85), respectively. Corresponding inter-rater ICCs were substantially lower: 0.56 (0.39 to 0.67), 0.48 (0.35 to 0.66) and 0.61 (0.47 to 0.72). Correlation between the GS and VAS was 0.62 and between the MRS and VAS was 0.61., Conclusions: Although 'substantial' to 'almost perfect' ICCs for intrarater agreement were found in the assessment of HA in UC, ICCs for inter-rater agreement were considerably lower. According to the consensus process results, standardisation of item definitions and modification of the existing indices is required to create an optimal UC histological instrument., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Patient-reported outcomes (PROs) have an increasingly important role in the evaluation of new therapies for inflammatory bowel disease. The US Food and Drug Administration has issued formal guidance to describe the role of PRO instruments in evaluation of claims for product labelling. However, no validated PRO exists for ulcerative colitis., Aim: To investigate whether the PROs from the Mayo Clinic Score (MCS) for UC can be modified, to develop an interim PRO for use in clinical trials, alone or in combination with endoscopy., Methods: Data from an induction trial of a mesalazine (mesalamine) formulation were used to compare effect sizes between mesalazine and placebo for PRO items (stool frequency and rectal bleeding) alone and in combination with endoscopy. The operating properties of the PRO were validated using data from a phase 2 trial of MLN02, a humanised antibody to the α4β7 integrin in patients with UC., Results: A two-item PRO (PRO2) consisting of rectal bleeding = 0 and stool frequency ≤1 or ≤2, combined with an endoscopy subscore ≤1 yielded statistically significant differences between active drug and placebo. This combination yielded the most similar effect sizes and placebo rates for remission, compared to the primary trials. Use of PRO items alone yielded high placebo remission rates in both data sets, although rates were lower when the items were combined and remission defined as PRO2 = 0., Conclusion: Patient-reported outcomes items derived from the Mayo Clinic Score combined with endoscopy as a co-primary endpoint may be an appropriate interim outcome measure for ulcerative colitis trials., (© 2015 John Wiley & Sons Ltd.)

Background: Anti-tumour necrosis factor (anti-TNF) monoclonal antibodies have shown efficacy in inflammatory bowel diseases (IBD). As these therapies lose patent protection, biosimilar versions of the originator products are being developed, such as the infliximab biosimilar CT-P13; however, some uncertainty exists regarding their pharmacology in IBD., Aim: To review the literature on anti-TNF biosimilars focusing on pharmacokinetics, pharmacodynamic properties and comparative effectiveness, related to their use in IBD., Methods: A PubMed literature search was performed using the following terms individually or in combination: 'biosimilars,' 'CT-P13,' 'Crohn's disease,' 'inflammatory bowel disease,' 'ulcerative colitis,' 'anti-TNFα therapy,' 'infliximab,' 'adalimumab,' 'pharmacokinetics,' 'immunogenicity.', Results: Bioequivalence of CT-P13 and infliximab was shown in ankylosing spondylitis (AS) and therapeutic equivalence in rheumatoid arthritis (RA). Preliminary results of CT-P13 in IBD come from small post-marketing registries and case series with a relatively short-term follow-up period and suggest comparable efficacy and safety to infliximab. Inter- and intra-individual differences in exposure and response are well known for the original molecules but dosing regimens and concomitant medications are different for RA compared to IBD, limiting the ability to translate some of the pharmacology data in RA to IBD. Uncertainty exists about cross-reactivity of anti-drug antibodies and whether similar exposure-response relationships will be observed for biosimilars and efficacy thresholds for therapeutic drug monitoring can be used interchangeably., Conclusions: It is likely that biosimilars will be widely used for the treatment of IBD due to their cost savings and comparable efficacy. Nevertheless, robust post-marketing studies and pharmacovigilance are warranted in the coming years., (© 2015 John Wiley & Sons Ltd.)

Objective: Although low infliximab trough concentrations and antibodies to infliximab (ATI) are associated with poor outcomes in patients with Crohn's disease (CD), the clinical relevance of ATI in patients with adequate infliximab concentrations is uncertain. We evaluated this question using an assay sensitive for identification of ATI in the presence of infliximab., Design: In an observational study, 1487 trough serum samples from 483 patients with CD who participated in four clinical studies of maintenance infliximab therapy were analysed using a fluid phase mobility shift assay. Infliximab and ATI concentrations most discriminant for remission, defined as a C-reactive protein concentration of ≤ 5 mg/L, were determined by receiver operating characteristic curves. A multivariable regression model evaluated these factors as independent predictors of remission., Results: Based upon analysis of 1487 samples, 77.1% of patients had detectable and 22.9% had undetectable infliximab concentrations, of which 9.5% and 71.8%, respectively, were positive for ATI. An infliximab concentration of > 2.79 μg/mL (area under the curve (AUC) = 0.681; 95% CI 0.632 to 0.731) and ATI concentration of < 3.15 U/mL (AUC = 0.632; 95% CI 0.589 to 0.676) were associated with remission. Multivariable analysis showed that concentrations of both infliximab trough (OR 1.8; 95% CI 1.3 to 2.5; p < 0.001) and ATI (OR 0.57; 95% CI 0.39 to 0.81; p = 0.002) were independent predictors of remission., Conclusions: The development of ATI increases the probability of active disease even at low concentrations and in the presence of a therapeutic concentration of drug during infliximab maintenance therapy. Evaluation of strategies to prevent ATI formation, including therapeutic drug monitoring with selective infliximab dose intensification, is needed., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background and Aims: Mucosal healing is an important treatment end-point in inflammatory bowel disease, and achieving mucosal healing has been demonstrated to improve disease-related outcomes. Considerable uncertainty exists, however, regarding the optimal approach for the assessment of mucosal healing., Aims: To compare currently available diagnostic tools for the assessment of mucosal healing and outline the ideal approach to integrating these tools into clinical trials and clinical practice., Methods: Review article., Results: Endoscopy represents the criterion standard for the assessment of mucosal healing, and frequent endoscopic assessment is associated with a higher rate of achieving mucosal healing. The use of mucosal biopsy allows for the identification of persistent histologic disease activity, but the incremental clinical benefit of achieving histologic healing is yet to be determined. Magnetic resonance enterography has a high sensitivity for ulcer healing in endoscopically inaccessible disease activity. However, the presence of mucosal lesions cannot be reliably excluded based on this modality alone, and further small-bowel endoscopy should be considered in symptomatic patients. Video capsule endoscopy or device-assisted enteroscopy can be used, with device-assisted enteroscopy being preferred in stricturing Crohn's disease because of the risk of capsule retention or in patients in whom small-bowel malignancy is a possibility., Conclusions: Endoscopy remains the criterion standard for the assessment of mucosal healing. Several alternative diagnostic modalities have become available that can be of value in specific clinical circumstances, particularly in patients with small-bowel involvement., (Copyright © 2015 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

The traditional management of Crohn's disease, which is based on progressive, step-wise treatment intensification with re-evaluation of response according to symptoms, does not improve long-term outcomes of Crohn's disease and places patients at risk for bowel damage. The introduction of novel therapies and the development of new approaches to treatment in rheumatoid arthritis led to better outcomes for patients. Prominent among these is a "treat to target" strategy that is based on regular assessment of disease activity by using objective clinical and biological outcome measures and the subsequent adjustment of treatments. This approach is complementary to the concept of early intervention in high-risk patients. This review evaluates current literature on this topic and proposes a definition for the concept of treating to targets for Crohn's disease., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Ulcerative colitis is a chronic, idiopathic, inflammatory bowel disease characterized by a relapsing and remitting course. A substantial proportion of patients fail conventional therapies despite therapy with immunosuppressives and tumor necrosis factor antagonists. Accordingly, newer therapeutic agents that target disease-specific inflammation and minimize adverse events are required. Central to the pathogenesis of ulcerative colitis is an aberrant host response to commensal microorganisms with a resultant dysregulation of gut immune homeostasis and lymphocyte trafficking. Recently, a newer biologic, vedolizumab, which blocks lymphocyte trafficking, has been developed for use in moderate to severe ulcerative colitis. The efficacy of this agent has been demonstrated to be similar to that of other currently available biologics, and the selectivity of this agent in blocking lymphocyte migration to the gut has substantially reduced treatment-related adverse events. The drug has now been approved for use in the United States and Europe, and, although the exact positioning of this biologic in clinical practice is yet to be defined, it represents an important new chapter in our armamentarium of treatment options for this population. In this review, we will highlight key considerations to be made by providers when using this agent in clinical practice., (© 2015 Pharmacotherapy Publications, Inc.)

Background: The ability to measure the expression of proinflammatory cytokines from intestinal biopsies in patients with Crohn's disease in an accurate and reproducible way is critical for proof-of-concept and mechanism-of-action trials; however, the number of biopsies from a segment of the ileum or colon required to yield reproducible results has not been rigorously evaluated. We examined intestinal biopsies from patients with Crohn's disease to validate methods for detecting changes in inflammatory gene expression., Methods: To evaluate the reproducibility of gene expression measurements, intestinal biopsies were obtained from designated segments from 6 healthy controls, 6 patients with active Crohn's disease, and 6 patients with inactive Crohn's disease. Disease activity was based on the simple endoscopic score for Crohn's disease. Expression of 7 proinflammatory genes was measured from each biopsy using quantitative polymerase chain reaction. Using a linear mixed effects model, the power to detect transcriptional changes corresponding to active and inactive Crohn's disease was calculated., Results: Total simple endoscopic score for Crohn's disease score corresponds with expression of most inflammatory biomarkers. For most genes, 2 to 5 biopsies are needed to reduce sampling error to <25% for most genes. To measure changes in mRNA expression corresponding to active versus inactive Crohn's disease, 1 to 2 intestinal biopsies from 3 patients before and after treatment are needed to yield power of at least 80%., Conclusions: Measuring proinflammatory gene expression from mucosal biopsies from patients with Crohn's disease is practicable and provides objective biomarkers that can be used in proof-of-concept and mechanism-of-action trials to assess response to therapy.

Background: Crohn's disease (CD) is associated with a substantial healthcare burden that affects the patient, healthcare systems and society in general., Aim: To provide a systematic evaluation of published data relating to the economic and health-related quality-of-life (HRQoL) burden of CD in selected European countries (Germany, France, UK, Italy, Spain) and the USA since 2000., Methods: We undertook a systematic review of publications relating to CD, its economic burden and impact on HRQoL. Research questions focused on the disease costs from a societal perspective and HRQoL burden in adults and pediatric/adolescent patients according to disease stage/severity. Total, direct and indirect costs were identified, as well as the impact of CD on HRQoL measured using both generic and disease-specific instruments., Results: Overall, 61 publications met the research criteria (38 on costs, 23 on HRQoL). CD in the USA and Europe together was associated with annual total costs of nearly 30 billion, more than half due to indirect costs. HRQoL was consistently and statistically significantly lower among CD patients compared with normal populations, due to physical, emotional and social effects., Conclusions: CD is a global health problem with high societal costs and substantial HRQoL burden. High-value care pathways including cost-effective therapies will help to induce and maintain remission, reduce complications of disease and improve HRQoL.

: Primary nonresponse and primary nonremission are important limitations of tumor necrosis factor (TNF) antagonists, occurring in 10% to 40% and 50% to 80% of patients with inflammatory bowel disease, respectively. The magnitude of primary nonresponse differs between phase III clinical trials and cohort studies, indicating differences, e.g., in definition, patient population or blinding. The causes of nonresponse can be attributed to the drug (pharmacokinetics, immunogenicity), the patient (genetics, disease activity), the disease (type, location, severity), and/or the treatment strategy (dosing regimen, combination therapy). Primary nonresponse has been attributed to "non-TNF-driven disease" which is an overly simplified and potentially misleading approach to the problem. Many patients with primary nonresponse could successfully be treated with dose optimization during the induction phase or switching to another TNF antagonist. Therefore, primary nonresponse is frequently not a non-TNF-driven disease. Recent studies from rheumatoid arthritis and preliminary data from inflammatory bowel disease evaluating therapeutic drug monitoring have suggested that early measurement of drug and anti-drug antibody concentrations could help to define primary nonresponse and rationalize patient management of this problem. Moreover, a modeling approach including pharmacological parameters and patient-related covariants could potentially be predictive for response to the treatment. We describe an overview of this evolution in thinking, underpinned by previous findings, and assess the potential role of early measurement of drug and antidrug antibody concentrations in the definition and management of primary nonresponse.