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Background & Aims: The Rutgeerts' scoring system is used to evaluate patients with Crohn's disease (CD) following ileocolic resection, based on endoscopic findings at the anastomosis and in the neoterminal ileum. We investigated rates of clinical and surgical recurrence of CD after surgery and effect of therapy modification based on post-operative endoscopic findings., Methods: We collected data from 365 adults with CD (20% with Rutgeerts' score i0, 10% with score i1, 49% with score i2, 12% with score i3, 9% with score i4) who underwent ileocolonoscopy within 12 months of ileocolic resection with anastomosis from 2000 through 2013 at 2 centers in Belgium and France. Patients were followed for 3 y or more after the ileocolonoscopy. Clinical post-operative recurrence (POR) was defined as occurrence of CD symptoms along with biologic, radiologic, and/or endoscopic features of disease activity; modified surgical POR was defined as either an endoscopic or surgical intervention., Results: After a median follow-up time of 88 months, 48% of patients had clinical POR and 26% had modified surgical POR. Rates of survival without clinical POR or a modified surgical POR were lower in patients with Rutgeerts' scores of i2, i3, or i4 compared to patients with scores of i0 or i1 (P < .001 and P = .02). New immunosuppressant or biological therapy was initiated following endoscopy in 129/254 patients (51%) with Rutgeerts' score of i2, i3, or i4 vs 7/111 patients (6%) with scores of i0 or i1 (odds ratio for new therapy, 14.9; 95% CI, 7.1-36.8; P < .001). A modest decrease in risk of clinical POR was observed for patients with Rutgeerts scores of i3 or i4 after initiation of immunosuppressive or biological therapy based on endoscopic findings (Breslow P = .03), but this was not observed for patients with scores of i2 (Breslow P = .46)., Conclusions: Use of immunosuppressants and tumor necrosis factor antagonists to treat patients with an asymptomatic endoscopic post-operative recurrence of CD did not reduce long-term risk of clinical recurrence in patients with Rutgeerts' scores of i2, but it had a small effect in patients with scores of i3 or i4., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Endoscopic evaluation for postoperative recurrence of Crohn's disease (CD) is routinely integrated into clinical practice. The Rutgeerts score (RS) was developed to grade the severity of endoscopic postoperative CD recurrence and has been integrated into clinical practice guidelines and utilized as an endpoint in interventional trials. 1,2 However, the operating properties of the RS have not been fully assessed. Furthermore, the RS i2 grade groups purely anastomotic ulcerations with those in the neoterminal ileum, whereas the modified Endoscopic Postoperative Recurrence Score (mEPRS) distinguishes lesions limited to the ileocolic anastomosis (i2a) from those in the neoterminal ileum (i2b). Accurate characterization of endoscopic recurrence is an important determinant for initiating postoperative medical therapy. Therefore, variability in endoscopic scoring may result in inappropriate therapeutic decisions. 3 We evaluated the reliability of endoscopic assessment of postoperative CD recurrence among independent blinded central readers., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: The Crohn's Disease Activity Index (CDAI) has been criticized for being weakly correlated with bowel inflammation. We assessed correlation between Simple Endoscopic Score for Crohn's Disease (SES-CD) and individual CDAI items stratified by disease location to better understand this relationship., Methods: We pooled patient-level data from 3 placebo-controlled Crohn's disease (CD) trials that tested adalimumab, upadacitinib, and risankizumab. Disease location was defined as ileum only, colon only, or ileocolonic based upon colonoscopy at study entry. Pearson correlation coefficients and linear regression assessed correlations between items of the CDAI and SES-CD., Results: A total of 353 patients were included (20.7% ileal, 30.6% colonic, 48.7% ileocolonic disease). Crohn's Disease Activity Index and SES-CD scores were moderately correlated (R = 0.33; P < 0.001). Among CDAI items, the strongest correlations with SES-CD were seen with very soft or liquid stool frequency (SF) and patient-reported outcome 2 (PRO2; which includes SF and abdominal pain score; both R = 0.36; P < 0.001); these correlations were numerically stronger in colonic disease (SF: R = 0.46; P < 0.001; PRO2: R = 0.44; P < 0.001) than in ileal disease (SF: R = 0.14; P = 0.23; PRO2: R = 0.21; P = 0.07), although a test for interaction was not significant. In adjusted linear regression models, the proportion of mucosa that was inflamed and the proportion of mucosa with ulceration were positively correlated, whereas the presence of strictures was inversely correlated with SF., Conclusions: The SF item of the CDAI is moderately correlated with SES-CD and independently correlated with mucosal ulceration, inflammation, and strictures. Understanding why bowel inflammation as measured endoscopically does not correlate more strongly with patients' symptoms could help develop scales that link CD pathology to patient experience., (© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Background and Aims: Following induction/maintenance treatment in the UNITI/IM-UNITI studies of ustekinumab for Crohn's disease, patients entered a long-term extension for up to 5 years from induction. Efficacy through 152 and safety through 156 weeks are reported., Methods: At IM-UNITI Week 44, 567 ustekinumab-treated patients entered the long-term extension and continued to receive blinded subcutaneous ustekinumab on their assigned dose interval, without any subsequent dose adjustment. Placebo-treated patients discontinued after study unblinding [after IM-UNITI Week 44 analyses]. Efficacy data in the long-term extension [LTE] were collected every 12 weeks [q12w] before unblinding and then at q12w/q8w dosing visits., Results: Through Week 156, 29.6% of ustekinumab-treated patients discontinued. In an intent-to-treat analysis of randomised patients from IM-UNITI Weeks 0-152, 38.0% of ustekinumab induction responders receiving the drug q12w and 43.0% q8w were in remission at Week 152. Among patients entering the long-term extension in their original randomised groups, 61.9% of q12w and 69.5% of q8w patients were in remission at Week 152. Across all ustekinumab-treated patients [randomised and non-randomised] entering the long-term extension, remission rates at Week 152 were 56.3% and 55.1% for q12w and q8w, respectively. Safety events [per 100 patient-years] were similar among all ustekinumab-treated patients entering the long-term extension and placebo [overall adverse events 389.70 vs 444.17; serious adverse events, 18.97 vs 19.54; serious infections, 4.21 vs 3.97]. Rates of antibodies to ustekinumab through Week 156 remained low, 4.6% in all randomised ustekinumab-treated patients; lowest among patients in the original randomised q8w group [2/82, 2.4%]., Conclusions: Continued treatment with subcutaneous ustekinumab maintained clinical response and remission through 3 years in a majority of patients who responded to induction therapy and was well-tolerated. ClinicalTrials.gov number NCT01369355., (Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background & Aims: Although ustekinumab is an effective therapy for moderate to severe Crohn's disease (CD), its effects on the microscopic manifestations of CD are unknown., Methods: We evaluated the effects of ustekinumab on histologic CD activity in an analysis of data from 251 participants in phase 3 induction and maintenance studies. Two endoscopic biopsy samples were collected at weeks 0, 8, and 44 from the ileum, splenic flexure, and rectum (18 biopsy samples from each patient). Histologic activity was assessed based on global histology activity scores (GHASs)., Results: At week 8, the mean GHAS was significantly reduced after ustekinumab induction treatment (from 10.4 ± 7.0 to 7.1 ± 5.9; P < .001) but not in patients who received placebo (from 9.2 ± 6.4 to 7.8 ± 6.2). At week 44 in the randomized maintenance therapy population, the mean GHAS remained reduced from week 8 in patients who received subcutaneous ustekinumab (90 mg every 8 weeks; from 7.4 ± 7.7 to 6.1 ± 4.7) but not every 12 weeks (from 5.3 ± 3.9 to 8.7 ± 4.1) or placebo (from 9.2 ± 3.8 to 10.9 ± 7.1). In the pooled (randomized and nonrandomized) maintenance therapy population, histologic improvement continued in patients given ustekinumab every 8 weeks (from 7.1 ± 6.2 to 5.2 ± 4.2; P < .0001) but not in those given ustekinumab every 12 weeks (from 6.1 ± 5.7 to 7.2 ± 5.1) or placebo (from 8.2 ± 4.2 to 8.9 ± 6.8). A significantly greater proportion of patients achieved histologic response (≥50% decrease in GHAS from baseline) at week 44 if they received ustekinumab every 8 weeks (50% in the randomized maintenance population and 54% in the pooled maintenance population) compared with every 12 weeks (17% and 39% in the randomized and pooled populations, respectively) or placebo (0% and 22% in the randomized and pooled populations, respectively) (P = .0137 for every 8 weeks vs placebo and P = .3529 for every 12 weeks vs placebo in the randomized population; P = .0168 for every 8 weeks vs placebo and P = .3069 for every 12 weeks vs placebo in the pooled population). Regional and overall mean GHASs correlated with the simple endoscopic score for CD (r = .6255, P < .0001). Multivariate analysis found an association between histologic improvement and endoscopic or histologic burden at baseline., Conclusions: In an analysis of data from participants in phase 3 induction and maintenance trials, we found histologic improvement in a greater proportion of patients given ustekinumab vs placebo. The largest improvements occurred in patients who received ustekinumab maintenance therapy every 8 weeks. ClinicalTrials.gov nos. NCT01369329, NCT01369342, and NCT01369355., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: In nonresponders to golimumab induction for ulcerative colitis, we assessed clinical response rates and golimumab serum concentrations when the 100-mg dose was used early in the course of maintenance., Methods: This post-hoc analysis of golimumab maintenance dosing [in the PURSUIT-M study] examined clinical outcomes and golimumab concentrations in early [Week 6] responders and nonresponders to induction, including subgroups based on body weight., Results: In nonresponders to golimumab induction [assessed at Week 6], the 100-mg maintenance dose [starting at Week 6] resulted in a meaningful proportion [28.1%] of patients achieving a partial Mayo response at Week 14. After 1 year of maintenance, clinical outcome [response, remission, mucosal healing, corticosteroid-free state] rates in these "late" [Week 14] responders were similar to those in early [Week 6] responders. Golimumab concentrations in early nonresponders were approximately half those of early responders, suggesting that early nonresponders had more rapid golimumab clearance. Examined by body weight, the early nonresponders weighing <80 kg and receiving 100 mg had golimumab concentrations similar to the early responders [weighing <80 kg or ≥80 kg and receiving 50 mg or 100 mg, respectively]., Conclusions: Early use of the 100-mg maintenance dose leads to positive clinical outcomes in a meaningful proportion of patients who did not respond to golimumab at Week 6. Early nonresponders <80 kg who received the 100-mg maintenance dose achieved adequate golimumab concentrations and a clinically meaningful proportion of these patients had a late clinical response.PURSUIT-M protocol number C0524T18; ClinicalTrials.gov, NCT00488631; EudraCT, 2006-003399-37., (Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Antidrug antibody (ADA) detection with standard bridging enzyme immunoassays (EIA) can yield false-negative results or underestimate titers through drug interference. A more sensitive assay was needed to determine clinical impact of antigolimumab antibodies., Methods: A high-sensitivity, drug-tolerant EIA (DT-EIA) was developed and cross-validated against the original EIA, and samples from induction/maintenance studies in golimumab-treated patients with ulcerative colitis were analyzed for ADAs using both methods. Immunogenicity results were compared, and pharmacokinetic, efficacy, and safety associations were evaluated., Results: An 8-fold increase in ADA-positive patients (21.8% DT-EIA vs 2.8% EIA) reflected DT-EIA improved sensitivity and drug tolerance. Most newly detected ADA-positive patients (using DT-EIA) had low antibody titers, whereas most with high antibody titers were ADA-positive with original EIA. With DT-EIA, week 44 median trough serum golimumab concentrations among ADA-positive patients were approximately half vs ADA-negative (0.51 vs 0.85 µg/mL [50 mg q4w]; 0.85 vs 1.60 µg/mL [100 mg q4w]). Antidrug antibody impact on golimumab concentrations was more notable at titers ≥1:100. During induction, ADAs had no notable impact on efficacy. During maintenance, proportions of patients maintaining clinical response through week 54 were lower using DT-EIA: 38.1% ADA-positive and 52.8% ADA-negative. Antidrug antibody status had no impact on injection-site reaction incidence., Conclusions: A more sensitive DT-EIA identified higher proportions of ADA-positive patients. A trend of decreasing drug concentrations with increasing ADA titers was observed. Pharmacokinetic impact was better elucidated with DT-EIA. Although development of ADA did not preclude efficacy, a trend toward decreased efficacy in ADA-positive vs ADA-negative patients was observed during maintenance treatment. Antidrug antibody status did not impact safety., (© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: Early treatment of Crohn's disease [CD] is required in order to optimize patient outcomes. To this end, we need to gain a better understanding of the molecular changes at the onset of CD., Methods: As a model for the earliest mucosal CD lesions, we study post-operative recurrent CD [Rutgeerts score ≥ i2b]. We are the first to analyse gene and microRNA [miRNA] expression profiles in ileal biopsies from these patients, and compare them with those of newly diagnosed [≤18 months] and late-stage [>10 years after diagnosis] CD patients., Results: Except for one gene [WNT5A], there are no differential genes in CD patients without post-operative recurrence [i0], showing that previous disease did not influence gene expression in the neoterminal ileum, and that this model can be used to study early mucosal CD lesions. Gene expression and co-expression network dysregulation is more pronounced in newly diagnosed and late-stage CD than in post-operative recurrent CD, with most important modules associated with [a]granulocyte adhesion/diapedesis, and cholesterol biosynthesis. In contrast, we found a role for snoRNAs/miRNAs in recurrent CD, highlighting the potential importance of regulatory RNAs in early disease stages. Immunohistochemistry confirmed the expression of key dysregulated genes in damaged/regenerating epithelium and immune cells in recurrent CD., Conclusions: Aside from regulatory RNAs, there are no clear gene signatures separating post-operative recurrent, newly diagnosed, and late-stage CD. The relative contribution of dysregulated genes and networks differs, and suggests that surgery may reset the disease at the mucosal site, and therefore post-operative recurrent CD might be a good model a good model to study to study early mucosal CD lesions., (Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The postoperative endoscopic recurrence score, commonly referred to as the Rutgeerts score, was designed to predict clinical recurrence risk in Crohn's disease (CD) patients undergoing ileocolonic resection based on early endoscopic findings at the anastomosis and in the neoterminal ileum. 1 In the pivotal publication, the i2 category, including aphthous lesions in the terminal ileum as well as ileocolonic anastomosis lesions, had a heterogeneous recurrence risk. Because anastomotic ulcers were suspected to be postsurgical ischemic lesions and less predictive of progressive disease, 2 a modified Rutgeerts score (mRS) was proposed: i2a, lesions confined to the anastomosis ±<5 isolated aphthous ulcers in the ileum; i2b, more than 5 aphthous ulcers in the ileum with normal mucosa in between, ± anastomotic lesions. 3,4 ., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Analyses of Crohn's Disease [CD] studies of anti-TNF agents, including adalimumab, have reported higher remission rates among patients with shorter disease duration. To further explore the relationship between disease duration and clinical efficacy, we analysed a larger patient cohort., Methods: Data were pooled from 10 clinical trials in patients with moderately to severely active CD who received treatment with either adalimumab or placebo. Analyses of efficacy using Crohn's Disease Activity Index [CDAI] endpoints [remission, clinical response [CR]-70, CR-100, patient-reported outcome [PRO] remission] or Harvey-Bradshaw Index [HBI] endpoints [remission/response] were conducted for induction and maintenance treatment periods. Logistic regression was used for comparisons between adalimumab and placebo treatment. Cochran-Armitage trend tests were used for comparisons between disease-duration subgroups [<1 year, ≥1-<2 years, 2-≤5 years, and >5 years]., Results: During induction, the proportion of patients achieving CDAI remission was higher in adalimumab- versus placebo-treated patients [p <0.001] and was highest [adalimumab: 45.8%] in the <1 year subgroup compared with longer disease-duration subgroups [≥1-<2 years: 31.0%; 2-≤5 years: 23.1%; >5 years: 23.6%, Cochran-Armitage p = 0.026]. In the majority of maintenance treatment analyses, patients with <1 year disease duration had the highest efficacy responses, with statistically significant differences in remission rates across disease-duration subgroups., Conclusions: This analysis demonstrates that earlier initiation of adalimumab treatment shortly after diagnosis in patients with moderately to severely active CD leads to improved long-term clinical outcomes., (© European Crohn’s and Colitis Organisation (ECCO) 2019.)

Background: We aim to identify the differences in colonic mucosal transcriptome between Crohn's disease (CD) and ulcerative colitis (UC) for a better understanding of the molecular pathology., Methods: Differentially expressed genes (DEG) in the colonic mucosa of CD and UC were identified with a global gene expression microarray dataset generated from the colon biopsies of CD and UC patients and normal controls. The DEGs were then processed to identify altered pathways and modularized DEGs and pathways. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis with an independent cohort of samples was performed to validate the microarray data., Results: At the pathway level, virus infection and autoimmune pathways were upregulated in CD but not in UC when compared with controls. Some of the relevant DEGs (such as TAP1 and TAP2) were elevated in both CD and UC, with CD exhibiting more pronounced elevations. Gene expression levels in viral infection pathways were correlated with those of autoimmune pathways. In contrast, pattern recognition-mediated innate immune pathways (TLR4 and TLR2) were significantly elevated in UC but not in CD. Similar results were observed with an independent cohort by qRT-PCR., Conclusions: Our data support the hypothesis that viral infection induced autoimmunity may represent a pathomechanism for IBD, especially CD. However, pattern recognition-mediated innate immunity targeting microbiome may play a more important role in UC compared with CD. Our findings identified different intervention targets for CD and UC, which may lead to more effective treatments for IBD patients., (© 2018 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Responders to induction treatment sustain continuous clinical response (CCR) through 1 year in about 50% of patients in PURSUIT-M trial with golimumab maintenance in ulcerative colitis (UC). This post hoc analysis of PURSUIT-M describes the 1-year clinical, endoscopic, quality of life (QoL), and biomarker and 4-year clinical outcome in patients with sustained response to golimumab therapy for UC., Methods: We compared clinical, endoscopic, QoL, and calprotectin outcomes in CCR and non-CCR patients through 54 weeks in PURSUIT-M. Persistence on golimumab therapy and clinical response at 4 years was assessed for CCR and non-CCR patients. The relationship of colectomy with CCR status was determined., Results: Among patients receiving golimumab maintenance, greater proportions of patients with vs without CCR at week 54 achieved clinical remission (67.1% vs 1.9%), corticosteroid-free remission (61.6% vs 1.9%), endoscopic remission (Mayo endoscopy score 0 [47.9% vs 1.3%]), and normal QoL (inflammatory bowel disease questionnaire score ≥170 [75.0% vs 24.4%]). CCR but not non-CCR patients maintained normalized calprotectin levels during maintenance. Among patients who entered the long-term extension study, a greater proportion of patients with vs without CCR maintained PGA 0 through week 216 (58% vs 42%). Colectomy was performed in 47 induction nonresponders and in 13 induction responders. None of the patients going onto colectomy achieved CCR through 54 weeks in PURSUIT-M., Conclusions: Continuous clinical response is associated with favorable short- and long-term clinical, endoscopic, QoL, and biomarker responses that may result in changing the course of disease and may prevent colectomy in patients with moderate to severe UC treated with golimumab. 10.1093/ibd/izy229&#95;video1izy229.video15806022773001.

Golimumab, a tumor necrosis factor antagonist, is an effective treatment for patients with moderate-to-severe ulcerative colitis (UC); however, more than 50% of initial responders lose their response to the drug within the first year of therapy. A gene expression signature identified in colon biopsies collected before treatment was associated with response to infliximab, and was subsequently refined to associate with mucosal healing in response to golimumab. We performed a phase 2a open-label study of 103 golimumab-treated patients with moderate-to-severe UC to test whether the baseline gene expression signature could be used to predict which patients would achieve mucosal healing, clinical response, and clinical remission at weeks 6 and 30 of treatment. The gene expression signature identified patients who went on to achieve mucosal healing at treatment week 6 with an area under the receiver operating characteristic curve (AUC ROC ) of 0.688 (P = .002) and at week 30 with an AUC ROC of 0.671 (P = .006). The signature identified patients with mucosal healing with 87% sensitivity, but only 34% specificity, limiting its clinical utility. The baseline gene expression signature did not identify patients who went on to achieve clinical remission or clinical response with statistical significance. Further studies are needed to identify biomarkers that can be used to predict which patients with UC will respond to treatment with anti-tumor necrosis factor agents. ClinicalTrials.gov no: NCT01988961., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: We evaluated the ability of ustekinumab, a monoclonal antibody against the p40 subunit of interleukins 12 and 23, to induce endoscopic healing in patients with moderate to severe Crohn's disease (CD)., Methods: We performed an endoscopy substudy of 334 patients with moderate to severe CD participating in 3 randomized controlled phase 3 studies to determine the safety and efficacy of ustekinumab induction and maintenance therapy. All patients underwent colonoscopy at baseline and week 8 of the induction studies and at week 44 of the maintenance study; all colonoscopies were assessed by a blinded central reader. During the induction studies, patients were randomly assigned to groups given intravenous ustekinumab (130 mg or 6 mg/kg) or placebo. At the baseline time point of the maintenance study (week 8 of the induction studies), patients with a clinical response to ustekinumab were randomly assigned to groups given subcutaneous ustekinumab (90 mg every 12 weeks or 8 weeks) or placebo. Additional maintenance analysis populations were patients who did not respond to ustekinumab or placebo during the induction studies, and patients who responded to placebo during the induction studies; we performed a post-hoc pooled analysis of randomly assigned and non-randomly assigned patients of the maintenance study. We analyzed data from patients with an ulcer in at least 1 segment at baseline of the induction studies. The primary end point was change in the Simplified Endoscopic Activity Score for Crohn's Disease (SES-CD), from baseline, at week 8. We also assessed the efficacy of maintenance therapy., Results: Patients given ustekinumab had a greater reduction in SES-CD from the induction baseline time point until week 8 than placebo (reduction of 2.8 in patients given ustekinumab vs a reduction of 0.7 points in patients given placebo; P = .012). Results were similar among patients in different induction studies and patients given different doses of ustekinumab. At week 44, reductions in the SES-CD from the induction baseline were greater in patients given ustekinumab (for combined groups, a reduction of 2.5; P = .176 and for every 8 weeks, a reduction of 3.1; P = .107) than patients given placebo (reduction of 1.9 points). Maintenance results were similar for the larger pooled post-hoc analysis., Conclusions: In an analysis of data from 3 trials of patients with moderate to severe CD, ustekinumab (intravenous induction and subcutaneous maintenance) reduces SES-CD compared with placebo. We observed significant reductions in endoscopic disease activity at week 8 of induction therapy with ustekinumab. (ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355)., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: To evaluate the safety and efficacy of 3 additional years of subcutaneous golimumab maintenance in patients with moderately to severely active ulcerative colitis., Methods: The PURSUIT-maintenance long-term extension enrolled patients who had completed placebo or golimumab 50 mg or 100 mg treatment every 4 weeks [q4w] through Week 52 and evaluations at Week 54 [n = 666]; treatment continued through Week 212. Patients receiving placebo were discontinued after study unblinding. Efficacy endpoints, golimumab concentrations, and anti-drug antibodies were summarized as observed for golimumab-induction responders who continued golimumab therapy during the long-term extension. Observations relating to safety were summarized for all treated patients., Results: Overall, 63% of patients who were receiving golimumab at the beginning of the extension remained on treatment through the end of the study. Among all treated patients in the extension, rates of adverse events of special interest [e.g. tuberculosis, demyelination, and malignancy] were infrequent. Nine deaths occurred during the extension [1 placebo, 1 golimumab 50 mg, and 7 golimumab 100 mg]. Serum golimumab concentrations were dose-proportional and were maintained over time. During the extension through Week 228, anti-drug antibody rates with golimumab 50 mg and 100 mg were 4.4% and 3.7%, respectively. Among golimumab-induction responders, 99.3% had no disease or mild disease activity as per the Physician's Global Assessment, 92.5% were corticosteroid-free, and 76.1% had an Inflammatory Bowel Disease Questionnaire score of ≥170 at Week 216., Conclusions: Subcutaneous golimumab treatment of moderately to severely active ulcerative colitis for up to 3 additional years during the extension maintained clinical benefit with no new safety signals observed.ClinicalTrials.gov number NCT00488631., (Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background & Aims: The Trough Concentration Adapted Infliximab Treatment (TAXIT) trial demonstrated that maintaining infliximab trough concentrations at 3 to 7 μg/mL is most effective at inducing remission in patients with inflammatory bowel diseases (IBDs), with fewer flares than clinic-based dosing. We performed a follow-up analysis of study participants to explore the correlation between trough dosing strategy and mucosal healing, continued infliximab use, and rates of hospitalization, surgery, and steroid use., Methods: This was a retrospective single-center study of 226 patients with IBD who completed the maintenance phase of TAXIT, performed at the University Hospitals of Leuven in Belgium. Baseline patient characteristics, laboratory test results, and endoscopic data were obtained at the end of that study between June 2012 and December 2013 (n = 125). Long-term outcome data (IBD-related hospitalization, abdominal surgery, and systemic steroid use) were collected from the time of the last TAXIT study visit (August 2012-April 2013) until April 1, 2016. We also collected data on continued use of infliximab and trough concentrations., Results: At baseline, 91% of patients in the clinic-based dosing group and 90% of patients in the trough concentration-based dosing group had mucosal healing. After a median follow-up time of 41 months (interquartile range, 39-42 mo), infliximab treatment was continued by 81 of 108 patients (75%) from the clinic-based dosing group and 86 of 107 (80%) from the trough concentration-based dosing group. However, within 1 year, infliximab was discontinued by 10 of 27 patients (37%) from the clinic-based dosing group and 2 of 21 patients (10%) from the trough concentration-based dosing group (P = .04). The rates of hospitalization, surgery, and steroid use were below 15% in both groups., Conclusions: At the end of a trial of clinic-based dosing vs trough concentration-based dosing of infliximab in patients with IBD, most patients had mucosal healing. Most patients (≥75%) in both groups continued taking infliximab for more than 3 years after the trial, but a significantly higher proportion of patients in the clinic-based dosing group discontinued infliximab in the first year after the end of the trial. Both groups had low rates of hospitalization, surgery, and steroid use., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: In Phase 3 studies of ustekinumab, a fully human monoclonal IL-12/23p40 antibody approved for moderate-to-severe Crohn's disease, patients entered a long-term extension after completing 8 weeks of induction and 44 weeks of maintenance treatment. Efficacy through 92 weeks and safety through 96 weeks of IM-UNITI maintenance are reported., Methods: UNITI-1 (TNF-antagonist failures) and UNITI-2 (conventional therapy failures) patients (N = 1281) entered IM-UNITI, including 397 ustekinumab intravenous induction responders randomised to subcutaneous ustekinumab 90 mg every 12 weeks, every 8 weeks, or placebo and 884 nonrandomised patients. Dose-adjustment to 90 mg every 8 weeks occurred in patients randomised to 90 mg every 12 weeks and placebo patients with loss of response (Weeks 8-32). All Week 44 completers could enter the long-term extension without further dose adjustment. Placebo patients discontinued following study unblinding., Results: A total of 718 patients (all treated) entered the long-term extension (298 randomised and 420 not randomised). Overall, 86.5% (621/718) completed Week 96. The proportions of randomised patients in clinical remission were generally maintained from Week 44 through 92 in ustekinumab 90 mg every 12 weeks (77.4% to 72.6%), every 8 weeks (84.1% to 74.4%), and prior dose adjustment groups (63.4% to 53.5%). At Week 92, the proportions of patients in clinical remission were similar in the ustekinumab 90 mg every 12 weeks and every 8 weeks groups and lower in patients with prior dose adjustment. Proportions of patients in clinical remission at Week 92 for all treated every 8 weeks (64.4%) and every 12 weeks (64.3%) groups were lower than randomised every 8 weeks (74.4%) and every 12 weeks (72.6%) groups, but similarly maintained. Safety events (per hundred patient-years) were similar among all placebo and ustekinumab patients (Week 0-96), including adverse events (484.39 vs 447.76), serious adverse events (19.24 vs 18.82), and serious infections (4.09 vs 4.02). No dose effect was observed., Conclusions: Subcutaneous ustekinumab maintained clinical response and remission through Week 92. No new safety signals were observed. ClinicalTrials.gov number NCT01369355., (© 2018 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Patients with long-standing UC have an increased risk for the development of colonic neoplastic lesions. Chromoendoscopy (CE) has been proven to enhance neoplasia detection while the role of virtual chromoendoscopy (VC) is still to be defined., Objective: To compare the performance of CE to VC for the detection of neoplastic lesions in patients with long-standing UC., Design: A multicentre prospective randomised controlled trial. 131 patients with long-standing UC were randomised between CE with methylene blue 0.1% (n=66) or VC with narrow band imaging (NBI) (n=65). Biopsies were taken from visible lesions and surrounding mucosa. No random biopsies were performed. The primary outcome was the difference in total number of neoplastic lesions detected in each group., Results: There was no significant difference between NBI and CE for neoplasia detection. Mean number of neoplastic lesions per colonoscopy was 0.47 for CE and 0.32 for NBI (p=0.992). The neoplasia detection rate was not different between CE (21.2%) and NBI (21.5%) (OR 1.02 (95% CI 0.44 to 2.35, p=0.964). Biopsies from the surrounding mucosa yielded no diagnosis or dysplasia. The per lesion neoplasia detection was 17.4% for CE and 16.3% for NBI (OR 1.09 (95% CI 0.59 to 1.99, p=0.793). The total procedural time was on average 7 min shorter in the NBI group., Conclusion: CE and NBI do not differ significantly for detection of colitis-associated neoplasia. Given the longer withdrawal time for CE and easier applicability, NBI may possibly replace classical CE., Trial Registration Number: NCT01882205; Results., Competing Interests: Competing interests: RB has received speaker’s fee and research support from Olympus, not related to this trial., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

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: Adalimumab is used to treat moderate to severe Crohn's disease (CD) and ulcerative colitis (UC) when conventional therapies fail., Aim: To update long-term adalimumab safety from CD and UC trials; the previous report was CD only, 3160 patients/3402 patient-years (PYs)., Methods: Treatment-emergent adverse events (AEs; first dose to 70 days after last dose/December 31, 2015) in adults in phase 2/3 and 3/3b trials and open-label extensions were coded using Medical Dictionary for Regulatory Activities (MedDRA-v18.1). Rates were assessed as events/100 (E/100 PYs)., Results: The database (16 trials; CD, N = 3606; UC, N = 1739) represented 4145 and 3397 PYs of exposure, respectively. For CD, incidences of any AEs with adalimumab were 60.8%-65.1%, depending on dose, and 71.5% with placebo; for UC, the incidences were 53.5%-54.8% and 56.1%, respectively. Rates of any AEs (CD, 605 E/100 PYs; UC, 361 E/100 PYs), serious AEs (CD, 36.1 E/100 PYs; UC, 18.9 E/100 PYs), and malignancies (CD, 1.2 E/100 PYs; UC, 1.0 E/100 PYs) were similar between current and prior analyses. Apparent rate of opportunistic infections was lowered to 0.3 and 0.2 E/100 PYs for CD and UC, respectively, by recent MedDRA changes excluding oral candidiasis and tuberculosis. Standardised incidence ratios for malignancies were similar to the general population (CD, 1.45 [95% CI, 0.90-2.22]; UC, 1.36 [95% CI, 0.84-2.07]). Demyelinating disorders were uncommon (CD, 0.1 E/100 PYs; UC, <0.1 E/100 PYs)., Conclusions: Patients with moderately to severely active Crohn's disease or ulcerative colitis continued to experience acceptable safety with adalimumab, without new safety signals., (© 2017 John Wiley & Sons Ltd.)

Objective: Lymphocyte recruitment to the inflamed gut is increased in UC. Inhibition of this cell trafficking by vedolizumab (VDZ) was successful in inducing and maintaining remission and in induction of endoscopic mucosal healing. There are no data on histological healing with VDZ. We studied histological changes following VDZ therapy and compared gene expression in patients with UC before and after therapy., Design: Forty-one patients with UC from GEMINI I and LTS were studied before and at three time points (weeks 6/12/52) following VDZ therapy. Colonic biopsies were scored using the Geboes index and correlated with Mayo endoscopic subscore. Gene expression was analysed using Affymetrix gene arrays., Results: Fifty-five per cent of patients achieving endoscopic healing (= Mayo endoscopic subscore 0-1) with VDZ at the studied time points also had histological healing (= Geboes grade 0-1). In most healers, some residual histological changes (eg, disturbed architecture and increased mononuclear cell infiltrate) were still observed, although this was less at week 52. VDZ restored expression of many inflammatory genes in patients with endoscopic healing only at week 52 and not before. In VDZ healers, the expression of many genes remained dysregulated at weeks 6/12/52 compared with controls., Conclusions: VDZ induces histological healing in >50% of patients with endoscopic healing, with maximal effect at week 52. VDZ also restored, although incompletely, the colonic expression of many immune-related genes in patients with UC achieving endoscopic healing at week 52. However, persistent histological and gene dysregulations did remain even in healers, suggesting that maintenance therapy will be necessary to control the intestinal inflammation., Trial Registration Numbers: NCT00783718 and NCT00790933; post-results., Competing Interests: Competing interests: GDH—consulting fees: Genentech, Centocor, Galapagos. MF—grant support: Takeda; lecture fees: Abbvie, Boehringer-Ingelheim, Chiesi, Falk, Ferring, Janssen, Mitsubishi Tanabe, MSD, Takeda, Tillotts, Zeria; consulting fees: Abbvie, Boehringer-Ingelheim, Ferring, Janssen, MSD. GVA—grant support: Abbvie, MSD; lecture fees: Abbvie, Ferring, MSD, Janssen, Takeda; consulting fees: Abbvie, MSD, Takeda. PR—grant support: Abbvie, Centocor, Merck, UCB; lecture fees: Centocor, Merck, Abbvie; consulting fees: Centocor, Merck, UCB, Abbvie, Millenium/Takeda, Genentech/Hoffman LaRoche, Merck/Serono, Bristol Myers Squibb, Robarts, Tillotts, Pfizer, Falk Pharma. SV—grant support from Abbvie, MSD; lecture fees: Abbvie, MSD, Takeda, Ferring, Falk Pharma, Hospira, Tillotts; grant support from Abbvie, MSD; consulting fees: Abbvie, MSD, Takeda, Ferring, Genentech/Roche, Shire, Pfizer, Galapagos, Mundipharma, Hospira, Celgene, Second Genome, Janssen., (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: Biomarkers of intestinal inflammation, such as faecal calprotectin and C-reactive protein, have been recommended for monitoring patients with Crohn's disease, but whether their use in treatment decisions improves outcomes is unknown. We aimed to compare endoscopic and clinical outcomes in patients with moderate to severe Crohn's disease who were managed with a tight control algorithm, using clinical symptoms and biomarkers, versus patients managed with a clinical management algorithm., Methods: CALM was an open-label, randomised, controlled phase 3 study, done in 22 countries at 74 hospitals and outpatient centres, which evaluated adult patients (aged 18-75 years) with active endoscopic Crohn's disease (Crohn's Disease Endoscopic Index of Severity [CDEIS] >6; sum of CDEIS subscores of >6 in one or more segments with ulcers), a Crohn's Disease Activity Index (CDAI) of 150-450 depending on dose of prednisone at baseline, and no previous use of immunomodulators or biologics. Patients were randomly assigned at a 1:1 ratio to tight control or clinical management groups, stratified by smoking status (yes or no), weight (<70 kg or ≥70 kg), and disease duration (≤2 years or >2 years) after 8 weeks of prednisone induction therapy, or earlier if they had active disease. In both groups, treatment was escalated in a stepwise manner, from no treatment, to adalimumab induction followed by adalimumab every other week, adalimumab every week, and lastly to both weekly adalimumab and daily azathioprine. This escalation was based on meeting treatment failure criteria, which differed between groups (tight control group before and after random assignment: faecal calprotectin ≥250 μg/g, C-reactive protein ≥5mg/L, CDAI ≥150, or prednisone use in the previous week; clinical management group before random assignment: CDAI decrease of <70 points compared with baseline or CDAI >200; clinical management group after random assignment: CDAI decrease of <100 points compared with baseline or CDAI ≥200, or prednisone use in the previous week). De-escalation was possible for patients receiving weekly adalimumab and azathioprine or weekly adalimumab alone if failure criteria were not met. The primary endpoint was mucosal healing (CDEIS <4) with absence of deep ulcers 48 weeks after randomisation. Primary and safety analyses were done in the intention-to-treat population. This trial has been completed, and is registered with ClinicalTrials.gov, number NCT01235689., Findings: Between Feb 11, 2011, and Nov 3, 2016, 244 patients (mean disease duration: clinical management group, 0·9 years [SD 1·7]; tight control group, 1·0 year [2·3]) were randomly assigned to monitoring groups (n=122 per group). 29 (24%) patients in the clinical management group and 32 (26%) patients in the tight control group discontinued the study, mostly because of adverse events. A significantly higher proportion of patients in the tight control group achieved the primary endpoint at week 48 (56 [46%] of 122 patients) than in the clinical management group (37 [30%] of 122 patients), with a Cochran-Mantel-Haenszel test-adjusted risk difference of 16·1% (95% CI 3·9-28·3; p=0·010). 105 (86%) of 122 patients in the tight control group and 100 (82%) of 122 patients in the clinical management group reported treatment-emergent adverse events; no treatment-related deaths occurred. The most common adverse events were nausea (21 [17%] of 122 patients), nasopharyngitis (18 [15%]), and headache (18 [15%]) in the tight control group, and worsening Crohn's disease (35 [29%] of 122 patients), arthralgia (19 [16%]), and nasopharyngitis (18 [15%]) in the clinical management group., Interpretation: CALM is the first study to show that timely escalation with an anti-tumour necrosis factor therapy on the basis of clinical symptoms combined with biomarkers in patients with early Crohn's disease results in better clinical and endoscopic outcomes than symptom-driven decisions alone. Future studies should assess the effects of such a strategy on long-term outcomes such as bowel damage, surgeries, hospital admissions, and disability., Funding: AbbVie., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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: Intestinal barrier defects are common in patients with inflammatory bowel disease (IBD). To identify which components could underlie these changes, we performed an in-depth analysis of epithelial barrier genes in IBD., Methods: A set of 128 intestinal barrier genes was selected. Polygenic risk scores were generated based on selected barrier gene variants that were associated with Crohn's disease (CD) or ulcerative colitis (UC) in our study. Gene expression was analyzed using microarray and quantitative reverse transcription polymerase chain reaction. Influence of barrier gene variants on expression was studied by cis-expression quantitative trait loci mapping and comparing patients with low- and high-risk scores., Results: Barrier risk scores were significantly higher in patients with IBD than controls. At single-gene level, the associated barrier single-nucleotide polymorphisms were most significantly enriched in PTGER4 for CD and HNF4A for UC. As a group, the regulating proteins were most enriched for CD and UC. Expression analysis showed that many epithelial barrier genes were significantly dysregulated in active CD and UC, with overrepresentation of mucus layer genes. In uninflamed CD ileum and IBD colon, most barrier gene levels restored to normal, except for MUC1 and MUC4 that remained persistently increased compared with controls. Expression levels did not depend on cis-regulatory variants nor combined genetic risk., Conclusions: We found genetic and transcriptomic dysregulations of key epithelial barrier genes and components in IBD. Of these, we believe that mucus genes, in particular MUC1 and MUC4, play an essential role in the pathogenesis of IBD and could represent interesting targets for treatment.

Introduction: Vedolizumab has proven efficacy in inflammatory bowel disease [IBD], but long-term mucosal healing in Crohn's disease [CD], as well as the incidence of colorectal neoplasia in IBD, among patients treated with vedolizumab have not been studied. We aimed to document mucosal healing and to explore the risk of colorectal neoplasia with vedolizumab maintenance therapy., Methods: Surveillance colonoscopy was prospectively scheduled for patients with longstanding ulcerative coltis [UC] or CD at a tertiary referral centre, in the open-label extension phase (vedolizumab 300 mg intravenously [IV] every 4 weeks) of the Gemini studies [GEMINI LTS, study number NCT00790933]. Mayo score ≤ 1 or ulcer disappearance [in CD] was defined as mucosal healing. Targeted biopsies were graded for inflammation and dysplasia., Results: Of 68 patients [29 CD/39 UC] treated for ≥ 1 year [median 3.2 years, range 1.1-6.1], 58 [24 CD/34 UC] were endoscopically monitored. Durable endoscopic healing corrected by non-responder imputation was found in 7/24, 29% [CD] and 17/34, 50% [UC]. Combined histological and mucosal healing was observed in 5/24 [CD] and 11/34 [UC] of those with endoscopic healing. Low-grade dysplasia was detected in 10% of patients and high-grade dysplasia in the resection specimen of one patient with biopsy-proven low-grade dysplasia., Conclusions: Long-term endoscopic and histological healing was observed in a proportion of patients treated with vedolizumab long-term. The dysplasia risk with vedolizumab deserves further study., (Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com)

Background: High concentration mesalazine formulations are more convenient than conventional low concentration formulations for the treatment of ulcerative colitis (UC)., Aim: To compare the efficacy and safety of 1600 mg and 400 mg tablet mesalazine formulations., Methods: Patients with mild-to-moderate active UC (Mayo Clinic Score >5; N=817) were randomised to 3.2 g of oral mesalazine, administered as two 1600 mg tablets once, or four 400 mg tablets twice daily. We hypothesised that treatment with the 1600 mg tablet was non-inferior (within a 10% margin) to the 400 mg tablet for induction of clinical and endoscopic remission at week 8. Open-label treatment with the 1600 mg tablet continued for 26-30 weeks based on induction response. Predictors of treatment response were also explored., Results: At week 8, remission occurred in 22.4% and 24.6% of patients receiving the 1600 mg and 400 mg tablets, respectively (absolute difference -2.2%, 95% CI: -8.1% to 3.8%, non-inferiority P=.005). Endoscopic and histopathologic disease activity, leucocyte concentration and age were significantly associated with clinical remission (P=.022, .042, .014 and .023, respectively). At week 38, 43.9% (296/675) of patients who continued treatment with the 1600 mg formulation were in remission, including 70.3% (142/202) of patients who received a reduced dose of mesalazine (1.6 g/d). The overall incidence of serious adverse events was low., Conclusions: Induction therapy with 3.2 mg mesalazine using two 1600 mg tablets once-daily was statistically and clinically non-inferior to a twice-daily regimen using four 400 mg tablets (NCT01903252)., (© 2017 John Wiley & Sons Ltd.)

Background and Aims: This 11-week Phase IIa induction study evaluated the efficacy and safety of eldelumab in patients with active Crohn's disease., Methods: Adults with Crohn's Disease Activity Index 220-450 were randomised 1:1:1 to placebo or eldelumab 10 or 20 mg/kg intravenously on Days 1 and 8, and alternate weeks thereafter. All patients underwent ileocolonoscopy at baseline. Patients with active inflammation according to the Simplified Endoscopic Score for Crohn's Disease criteria [the originally planned endoscopy cohort] underwent another ileocolonoscopy at Week 11 at the investigator's discretion. All ileocolonoscopies were centrally read. The primary objective was identification of the eldelumab target exposure for induction of remission [absolute Crohn's Disease Activity Index score < 150]. Rates of clinical response [reduction of ≥ 100 from baseline or absolute score < 150 Crohn's Disease Activity Index], remission, and endoscopic improvements were also assessed., Results: A total of 121 patients were randomised. The eldelumab exposure-remission relationship was not significant at Week 11. Numerically higher remission and response rates were reported with eldelumab 20 mg/kg [29.3% and 41.5%, respectively] and 10 mg/kg [22.5% and 47.5%] versus placebo [20.0% and 35.0%]. A higher proportion of patients with a baseline Simplified Endoscopic Score for Crohn's Disease > 2 who received eldelumab achieved a 50% improvement in score and greater reductions from baseline endoscopy scores overall versus placebo. Adverse events were comparable across treatment groups., Conclusions: No exposure-remission relationship was seen with eldelumab. Eldelumab induction treatment demonstrated trends towards clinical and endoscopic efficacy. Safety was consistent with that reported previously. ClinicalTrials.gov identifier: NCT01466374., (Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com)

Objective: Vedolizumab is a gut-selective antibody to α 4 β 7 integrin for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). We report an integrated summary of the safety of vedolizumab., Design: Safety data (May 2009-June 2013) from six trials of vedolizumab were integrated. Adverse events were evaluated in patients who received ≥1 dose of vedolizumab or placebo and were reported as exposure-adjusted incidence rates as the number of patients experiencing the event per 100 person-years (PYs) of exposure. Predictors of serious infection were assessed using a Cox proportional hazards model., Results: In total, 2830 patients had 4811 PYs of vedolizumab exposure (median exposure range, 1-1977 days). No increased risk of any infection or serious infection was associated with vedolizumab exposure. Serious clostridial infections, sepsis and tuberculosis were reported infrequently (≤0.6% of patients). No cases of progressive multifocal leucoencephalopathy were observed. Independent risk factors for serious infection in UC were prior failure of a tumour necrosis factor α antagonist (HR, 1.99; 95% CIs 1.16 to 3.42; p=0.0122) and narcotic analgesic use (HR, 2.68; 95% CI 1.57 to 4.58; p=0.0003), and in CD were younger age (HR, 0.97; 95% CI 0.95 to 0.98; p<0.0001), corticosteroid (HR, 1.88; 95% CI 1.35 to 2.63; p=0.0002) or narcotic analgesic use (HR, 2.72; 95% CI 1.90 to 3.89; p<0.0001). Investigator-defined infusion-related reactions were reported for ≤5% of patients in each study. Eighteen vedolizumab-exposed patients (<1%) were diagnosed with a malignancy., Conclusions: Vedolizumab has a favourable safety profile with low incidence rates of serious infections, infusion-related reactions and malignancies over an extended treatment period., Trial Registration Number: NCT01177228, NCT00619489, NCT00783718, NCT00783692, NCT01224171, NCT00790933., (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 and Aims: Mucosal healing [MH] is an important goal for patients with Crohn's disease [CD], yet is incompletely characterised. We investigated whether MH differed by segments across the colon and ileum in patients who received adalimumab maintenance treatment in the EXTEND study., Methods: In this double-blind study in adults with moderate to severe ileocolonic CD and mucosal ulceration, all patients received adalimumab induction [Week 0, 160 mg; Week 2, 80 mg]. At Week 4, patients were randomised to 40 mg adalimumab or placebo every other week until Week 52. In this post-hoc analysis, MH was assessed by CD Endoscopic Index of Severity [CDEIS], Simple Endoscopic Score for CD [SES-CD], and Colonic and Ileal Global Histologic Disease Activity Scores [CGHAS/IGHAS]., Results: Baseline endoscopic severity was similar across segments. At Week 52, mean changes in CDEIS surface involved and ulcerated surface were -68.5% to -90.6% in the rectum, sigmoid/left colon, and transverse colon compared with -22.3% to -50.0% in the right colon and ileum. Favourable shifts by Week 52 in ulcer size and ulcerated surfaces per SES-CD were more pronounced in the rectum, sigmoid/left colon, and transverse colon vs the right colon and ileum. At Week 52, CGHAS and IGHAS healing was more common in the colon [28.3%] vs the ileum [21.2%]., Conclusions: This analysis suggests differing propensities of the ileocolonic segments to heal endoscopically during adalimumab treatment. In the sigmoid/left and transverse colon, higher MH rates may be achieved, compared with the ileum, in patients with moderate to severe CD., (© European Crohn’s and Colitis Organistion (ECCO) 2016.)

Background and Aims: To assess golimumab pharmacokinetics [PK] and exposure-response [ER] in adults with moderate-to-severe ulcerative colitis [UC] from the Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment [PURSUIT] studies., Methods: We analysed golimumab PK and ER data of patients with moderate-to-severe UC from the PURSUIT-subcutaneous induction [N = 1064] and maintenance [N = 464] studies. Induction analyses evaluated serum golimumab concentration [SGC] and efficacy data through Week [wk] 6 following subcutaneous doses at wk0 and wk2; maintenance analyses assessed data through wk54 following 4-weekly dosing. ER relationships were assessed using trend, logistic regression, and receiver-operating-characteristic curve analyses., Results: Median SGCs peaked at induction wk2 for golimumab 100/50mg, 200/100mg, and 400/200mg. Wk6 median SGCs were 0.78, 1.78, and 4.01 μg/ml, respectively. SGCs were sustained, reaching steady state approximately 8wks after golimumab maintenance commenced [wk14 of golimumab] regardless of induction dose. Median trough SGCs from maintenance wks8-44 ranged from 0.69 to 0.83 µg/ml [50 mg] and 1.33-1.58 µg/ml [100 mg]. SGCs were approximately dose proportional, and higher SGCs were associated with higher efficacy response rates during induction and maintenance. Factors associated with golimumab exposure were body weight, antibody-to-golimumab status, serum albumin, alkaline phosphatase, faecal markers, C-reactive protein, and pancolitis. SGCs of 2.5 µg/ml [induction wk6] and 1.4 µg/ml [maintenance steady-state trough] are potential target concentrations. Immunomodulators had no apparent impact on SGC with golimumab 100mg, whereas drug levels were slightly higher with golimumab 50mg with vs without immunomodulators., Conclusions: SGCs are approximately dose proportional, and a positive SGC-efficacy relationship exists during induction/maintenance golimumab treatment of adult UC patients. Optimal SGC targets require validation in prospective studies., (© European Crohn’s and Colitis Organisation (ECCO) 2016.)

Background and Aims: Mucosal healing is associated with favourable therapeutic outcomes in patients with ulcerative colitis [UC]. We investigated whether adalimumab concentrations during induction therapy are associated with short-term mucosal healing [STMH] in UC patients., Methods: This was a retrospective, single-centre study including consecutive UC patients treated with adalimumab from June 2005 to May 2014, who underwent an endoscopy both at baseline and after induction therapy [weeks 8-14] and at least one serum sample available at week 2 and/or week 4. STMH was defined as Mayo endoscopic sub-score of ≤1 with a baseline sub-score of ≥2. Adalimumab concentrations were evaluated using an in-house developed enzyme-linked immunosorbent assay., Results: The study population consisted of 43 patients, the majority of whom [n = 38] were prior infliximab failures; the rest showed primary non-response [PNR, n = 5]. Twelve patients [27.9%] achieved STMH. Patients with STMH had higher adalimumab concentrations at week 4 compared to those without [10.6 vs 7.4 μg/ml, p = 0.014]. A receiver operating characteristic [ROC] analysis identified an adalimumab concentration threshold at week 4 of 9.4 μg/ml (area under the ROC curve [AUROC]: 0.778) and 7.5 μg/ml [AUROC: 0.798], after excluding patients with PNR to infliximab, to be associated with STMH. Multiple logistic regression analysis, after excluding patients with PNR to infliximab, identified adalimumab concentration ≥7.5 μg/ml at week 4 (odds ratio [OR]: 15.7; 95% confidence interval [CI]: 1.3-185; p = 0.029) and baseline endoscopic Mayo score 3 [OR: 0.13; 95% CI: 0.02-0.98; p = 0.047] as factors independently associated with STMH., Conclusions: This study, reflecting real-life clinical practice, demonstrated that post-induction adalimumab concentrations are associated with STMH, while higher baseline mucosal inflammation is related to lack of STMH in UC., (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.)

Objective: Pouchitis is the most common complication after colectomy with ileal pouch-anal anastomosis (IPAA) for UC and the risk is the highest within the 1st year after surgery. The pathogenesis is not completely understood but clinical response to antibiotics suggests a role for gut microbiota. We hypothesised that the risk for pouchitis can be predicted based on the faecal microbial composition before colectomy., Design: Faecal samples from 21 patients with UC undergoing IPAA were prospectively collected before colectomy and at predefined clinical visits at 1 month, 3 months, 6 months and 12 months after IPAA. The predominant microbiota was analysed using community profiling with denaturing gradient gel electrophoresis followed by quantitative real-time PCR validation., Results: Cluster analysis before colectomy distinguished patients with pouchitis from those with normal pouch during the 1st year of follow-up. In patients developing pouchitis, an increase of Ruminococcus gnavus (p<0.001), Bacteroides vulgatus (p=0.043), Clostridium perfringens (p=0.011) and a reduction of two Lachnospiraceae genera (Blautia (p=0.04), Roseburia (p=0.008)) was observed. A score combining these five bacterial risk factors was calculated and presence of at least two risk factors showed a sensitivity and specificity of 100% and 63.6%, respectively., Conclusions: Presence of R. gnavus, B. vulgatus and C. perfringens and absence of Blautia and Roseburia in faecal samples of patients with UC before surgery is associated with a higher risk of pouchitis after IPAA. Our findings suggest new predictive and therapeutic strategies in patients undergoing colectomy with IPAA., (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: Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn's disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy., Methods: We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn's Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150)., Results: The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P=0.005 and P=0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups., Conclusions: Among patients with moderately to severely active Crohn's disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329 , NCT01369342 , and NCT01369355 .).

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 & Aims: Most patients with Crohn's disease (CD) eventually require an intestinal resection. However, CD frequently recurs after resection. We performed a randomized trial to compare the ability of infliximab vs placebo to prevent CD recurrence., Methods: We evaluated the efficacy of infliximab in preventing postoperative recurrence of CD in 297 patients at 104 sites worldwide from November 2010 through May 2012. All study patients had undergone ileocolonic resection within 45 days before randomization. Patients were randomly assigned (1:1) to groups given infliximab (5 mg/kg) or placebo every 8 weeks for 200 weeks. The primary end point was clinical recurrence, defined as a composite outcome consisting of a CD Activity Index score >200 and a ≥70-point increase from baseline, and endoscopic recurrence (Rutgeerts score ≥i2, determined by a central reader) or development of a new or re-draining fistula or abscess, before or at week 76. Endoscopic recurrence was a major secondary end point., Results: A smaller proportion of patients in the infliximab group had a clinical recurrence before or at week 76 compared with the placebo group, but this difference was not statistically significant (12.9% vs 20.0%; absolute risk reduction [ARR] with infliximab, 7.1%; 95% confidence interval: -1.3% to 15.5%; P = .097). A significantly smaller proportion of patients in the infliximab group had endoscopic recurrence compared with the placebo group (30.6% vs 60.0%; ARR with infliximab, 29.4%; 95% confidence interval: 18.6% to 40.2%; P < .001). Additionally, a significantly smaller proportion of patients in the infliximab group had endoscopic recurrence based only on Rutgeerts scores ≥i2 (22.4% vs 51.3%; ARR with infliximab, 28.9%; 95% confidence interval: 18.4% to 39.4%; P < .001). Patients previously treated with anti-tumor necrosis factor agents or those with more than 1 resection were at greater risk for clinical recurrence. The safety profile of infliximab was similar to that from previous reports., Conclusions: Infliximab is not superior to placebo in preventing clinical recurrence after CD-related resection. However, infliximab does reduce endoscopic recurrence. ClinicalTrials.gov ID NCT01190839., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: The safety and efficacy of subcutaneous golimumab through 2 years of maintenance therapy was evaluated in patients with moderate-to-severe ulcerative colitis (UC)., Methods: Patients completing treatment through week 52 (placebo, golimumab 50, 100, every-4-weeks (q4w)) and evaluations at week 54 were eligible for this long-term extension (LTE) trial. Patients receiving placebo or golimumab 50 mg with worsening disease during the LTE could receive golimumab 100 mg. Efficacy assessments included the Mayo physician's global assessment (PGA) subscore, inflammatory bowel disease questionnaire (IBDQ), and corticosteroid use. Patients who were randomized to golimumab at PURSUIT-Maintenance baseline and continued receiving golimumab during the LTE were analyzed for efficacy (using intention-to-treat and "as observed" analyses; N=195) and safety (N=200). Patients treated with golimumab at any time from induction baseline through week 104 (N=1240) constituted the overall safety population., Results: Baseline demographics and disease characteristics of patients entering the LTE receiving golimumab were similar to those of all patients randomized to golimumab maintenance at baseline. At week 104, 80.5% (157/195) of patients had a PGA=0/1 (range weeks 56-104: 80.5-91.8%) and 56.4% (110/195) had a PGA=0 (weeks 56-104: range: 53.8-58.5%). Through week 104, 86% of patients maintained inactive or mild disease activity. Among 174 corticosteroid-free patients at week 54, 88.5% remained corticosteroid-free at week 104. At week 104, 62.2% (120/193) had an IBDQ score ≥170. Tuberculosis, opportunistic infection, and malignancy rates were low, and the overall safety profile was similar to that reported through week 54. Two non-melanoma skin cancers, one metastatic colon cancer, and two deaths (biventricular heart dysfunction, sepsis) occurred between weeks 54 and 104., Conclusion: Subcutaneous golimumab q4w through 2 years maintained clinical benefit and reduced corticosteroid use among patients who did well in the maintenance study. No new safety signals were observed.

Background & Aims: Histamine sensitizes the nociceptor transient reporter potential channel V1 (TRPV1) and has been shown to contribute to visceral hypersensitivity in animals. We investigated the role of TRPV1 in irritable bowel syndrome (IBS) and evaluated if an antagonist of histamine receptor H1 (HRH1) could reduce symptoms of patients in a randomized placebo-controlled trial., Methods: By using live calcium imaging, we compared activation of submucosal neurons by the TRPV1 agonist capsaicin in rectal biopsy specimens collected from 9 patients with IBS (ROME 3 criteria) and 15 healthy subjects. The sensitization of TRPV1 by histamine, its metabolite imidazole acetaldehyde, and supernatants from biopsy specimens was assessed by calcium imaging of mouse dorsal root ganglion neurons. We then performed a double-blind trial of patients with IBS (mean age, 31 y; range, 18-65 y; 34 female). After a 2-week run-in period, subjects were assigned randomly to groups given either the HRH1 antagonist ebastine (20 mg/day; n = 28) or placebo (n = 27) for 12 weeks. Rectal biopsy specimens were collected, barostat studies were performed, and symptoms were assessed (using the validated gastrointestinal symptom rating scale) before and after the 12-week period. Patients were followed up for an additional 2 weeks. Abdominal pain, symptom relief, and health-related quality of life were assessed on a weekly basis. The primary end point of the study was the effect of ebastine on the symptom score evoked by rectal distension., Results: TRPV1 responses of submucosal neurons from patients with IBS were potentiated compared with those of healthy volunteers. Moreover, TRPV1 responses of submucosal neurons from healthy volunteers could be potentiated by their pre-incubation with histamine; this effect was blocked by the HRH1 antagonist pyrilamine. Supernatants from rectal biopsy specimens from patients with IBS, but not from the healthy volunteers, sensitized TRPV1 in mouse nociceptive dorsal root ganglion neurons via HRH1; this effect could be reproduced by histamine and imidazole acetaldehyde. Compared with subjects given placebo, those given ebastine had reduced visceral hypersensitivity, increased symptom relief (ebastine 46% vs placebo 13%; P = .024), and reduced abdominal pain scores (ebastine 39 ± 23 vs placebo 62 ± 22; P = .0004)., Conclusions: In studies of rectal biopsy specimens from patients, we found that HRH1-mediated sensitization of TRPV1 is involved in IBS. Ebastine, an antagonist of HRH1, reduced visceral hypersensitivity, symptoms, and abdominal pain in patients with IBS. Inhibitors of this pathway might be developed as a new treatment approach for IBS. ClinicalTrials.gov no: NCT01144832., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Mucosal healing is an independent predictor of sustained clinical remission in patients with ulcerative colitis (UC) treated with infliximab. We investigated whether infliximab concentrations during induction therapy are associated with short-term mucosal healing (STMH) in patients with UC., Methods: We performed a retrospective, single-center analysis of data collected from a tertiary referral center from 101 patients with UC who received scheduled induction therapy with infliximab at weeks 0, 2, and 6 and had an endoscopic evaluation at baseline and after induction therapy. STMH was defined as Mayo endoscopic sub-score ≤1, assessed at weeks 10-14, with baseline sub-score ≥2. Infliximab concentrations were evaluated in serum samples collected at weeks 0, 2, 6, and 14 of infliximab therapy by using an enzyme-linked immunosorbent assay we developed., Results: Fifty-four patients (53.4%) achieved STMH. Patients with STMH had a higher median infliximab concentration at weeks 2, 6, and 14 than patients without STMH. A receiver operating characteristic (ROC) analysis identified infliximab concentration thresholds of 28.3 (area under the ROC curve [AUROC], 0.638), 15 (AUROC, 0.688), and 2.1 μg/mL (AUROC, 0.781) that associated with STMH at weeks 2, 6, and 14, respectively. Multiple logistic regression analysis identified infliximab concentration ≥15 at week 6 (P = .025; odds ratio, 4.6; 95% confidence interval, 1.2-17.1) and ≥2.1 μg/mL at week 14 (P = .004; odds ratio, 5.6; 95% confidence interval, 1.7-18) as independent factors associated with STMH., Conclusions: In an analysis of data from real-life clinical practice, we associated infliximab concentrations during the induction therapy with STMH in patients with UC., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Faecal microbiota transplantation is a successful therapy for patients with refractory Clostridium difficile infections. It has also been suggested as a treatment option for inflammatory bowel disease, given the role of the intestinal microbiota in this disease. We assessed the impact of faecal microbiota transplantation in patients with inflammatory bowel disease and studied predictors of clinical (non-)response in microbial profiles of donors and patients., Methods: Fourteen refractory patients (8 with ulcerative colitis and 6 with Crohn's disease) underwent ileocolonoscopy with faecal microbiota transplantation through a nasojejunal (n = 9) or rectal (n = 5) tube. Efficacy was assessed by endoscopic healing at week 8, clinical activity scores and C-reactive protein measurement. Faecal microbiota was analysed by 16S rDNA pyrosequencing., Results: There was no significant improvement among the 6 patients with Crohn's disease at week 8 following faecal microbiota transplantation. One patient experienced temporary clinical remission for 6 weeks. In contrast, 2/8 patients with ulcerative colitis had endoscopic remission at week 8, and of the 6 remaining patients with ulcerative colitis, 1 reported temporary remission for 6 weeks. The donor microbiota richness and the number of transferred phylotypes were associated with treatment success. Persistent increased C-reactive protein 2 weeks after transplantation was predictive of failure of response., Conclusion: Faecal microbiota transplantation led to endoscopic and long-term (>2 years) remission in 2 out of 8 ulcerative colitis patients. Higher donor richness was associated with successful transplant. Therefore, faecal microbiota transplantation with donor prescreening could be a treatment option for selected refractory ulcerative colitis patients., (Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The genetic component of Crohn's disease (CD) is well known, with 140 susceptibility loci identified so far. In addition to single nucleotide polymorphisms typically studied in genome-wide scans, copy number variation is responsible for a large proportion of human genetic variation., Methods: We performed a genome-wide search for copy number variants associated with CD using array comparative genomic hybridization. One of the found regions was validated independently through real-time PCR. Serum levels of the found gene were measured in patients and control subjects., Results: We found copy number differences for the C4S and C4L gene variants of complement component C4 in the central major histocompatibility complex region on chromosome 6p21. Specifically, we saw that CD patients tend to have lower C4L and higher C4S copies than control subjects (P = 5.00 × 10 and P = 9.11 × 10), which was independent of known associated classical HLA I and II alleles (P = 7.68 × 10 and P = 6.29 × 10). Although C4 serum levels were not different between patients and control subjects, the relationship between C4 copy number and serum level was different for patients and control subjects with higher copy numbers leading to higher serum concentrations in control subjects, compared with CD patients (P < 0.001)., Conclusions: C4 is part of the classical activation pathway of the complement system, which is important for (auto)immunity. Low C4L or high C4S copy number, and corresponding effects on C4 serum level, could lead to an exaggerated response against infections, possibly leading to (auto)immune disease.

Background & Aims: Endoscopy limited to the rectosigmoid colon is the standard technique used to measure endoscopic healing in ulcerative colitis (UC) clinical trials. We evaluated whether rectosigmoidoscopy adequately measures UC activity in the more proximal colon., Methods: We analyzed data from a phase 2, placebo-controlled study that evaluated the efficacy and safety of etrolizumab in patients with moderate to severely active UC who had not responded to standard therapy. Central readers determined Mayo Clinic endoscopic subscores (MCSe) and ulcerative colitis endoscopic index of severity (UCEIS) scores from the rectosigmoid and proximal colon in videos of 331 examinations performed at baseline, week 6, and week 10. Rates of endoscopic healing (MCSe ≤ 1, MCSe = 0) and scores from rectosigmoidoscopy and colonoscopy analyses were compared among 239 examinations with endoscopic assessment proximal to the rectosigmoid colon., Results: There was a high degree of correlation between findings from rectosigmoidoscopy vs colonoscopy in assessment of disease activity based on MCSe of 2 or higher (r = 0.84) or MCSe of 1 or higher (r = 0.96), or the UCEIS score (r = 0.92). In 230 of 239 videos, findings from rectosigmoidoscopy agreed with those from colonoscopy in the detection of active disease (MCSe ≥ 2; n = 205) or healing (MCSe ≤ 1; n = 25). In 9 videos (2 taken at baseline, 7 taken after treatment), colonoscopy found proximal disease activity not detected by rectosigmoidoscopy. Post-treatment discordance was more frequent in the placebo group, affecting assessment of efficacy at week 10. When endoscopic healing was defined as MCSe of 0, there were discordant findings from only 1 video., Conclusions: There is a high degree of correlation in assessments of UC activity made by rectosigmoidoscopy vs colonoscopy. For detection of endoscopic healing (MCSe ≤ 1), colonoscopy found persistent proximal lesions in the placebo group, which affected efficacy analyses. When endoscopic healing was defined as MCSe of 0, the concordance between rectosigmoidoscopy and colonoscopy was nearly perfect., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Etrolizumab is a humanized monoclonal antibody against the β7 integrin subunit that has shown efficacy vs placebo in patients with moderate to severely active ulcerative colitis (UC). Patients with colon tissues that expressed high levels of the integrin αE gene (ITGAE) appeared to have the best response. We compared differences in colonic expression of ITGAE and other genes between patients who achieved clinical remission with etrolizumab vs those who did., Methods: We performed a retrospective analysis of data collected from 110 patients with UC who participated in a phase 2 placebo-controlled trial of etrolizumab, as well as from 21 patients with UC or without inflammatory bowel disease (controls) enrolled in an observational study at a separate site. Colon biopsies were collected from patients in both studies and analyzed by immunohistochemistry and gene expression profiling. Mononuclear cells were isolated and analyzed by flow cytometry. We identified biomarkers associated with response to etrolizumab. In the placebo-controlled trial, clinical remission was defined as total Mayo Clinic Score ≤2, with no individual subscore >1, and mucosal healing was defined as endoscopic score ≤1., Results: Colon tissues collected at baseline from patients who had a clinical response to etrolizumab expressed higher levels of T-cell-associated genes than patients who did not respond (P < .05). Colonic CD4(+) integrin αE(+) cells from patients with UC expressed higher levels of granzyme A messenger RNA (GZMA mRNA) than CD4(+) αE(-) cells (P < .0001); granzyme A and integrin αE protein were detected in the same cells. Of patients receiving 100 mg etrolizumab, a higher proportion of those with high levels of GZMA mRNA (41%) or ITGAE mRNA (38%) than those with low levels of GZMA (6%) or ITGAE mRNA (13%) achieved clinical remission (P < .05) and mucosal healing (41% GZMA(high) vs 19% GZMA(low) and 44% ITGAE(high) vs 19% ITGAE(low)). Compared with ITGAE(low) and GZMA(low) patients, patients with ITGAE(high) and GZMA(high) had higher baseline numbers of epithelial crypt-associated integrin αE(+) cells (P < .01 for both), but a smaller number of crypt-associated integrin αE(+) cells after etrolizumab treatment (P < .05 for both). After 10 weeks of etrolizumab treatment, expression of genes associated with T-cell activation and genes encoding inflammatory cytokines decreased by 40%-80% from baseline (P < .05) in patients with colon tissues expressing high levels of GZMA at baseline., Conclusions: Levels of GZMA and ITGAE mRNAs in colon tissues can identify patients with UC who are most likely to benefit from etrolizumab; expression levels decrease with etrolizumab administration in biomarker(high) patients. Larger, prospective studies of markers are needed to assess their clinical value., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: A subgroup of patients with inflammatory bowel disease (IBD) treated with anti-tumor necrosis factor (TNF) antibodies develop skin lesions, but the lesions and their clinical course are not well-characterized., Objective: To describe patients treated with anti-TNF antibodies who did and did not develop skin lesions., Design: Retrospective cohort., Setting: Single IBD tertiary referral center., Patients: 917 consecutive patients with IBD who initiated anti-TNF therapy., Measurements: Skin lesions, patient demographic characteristics, treatments, clinical course, and serologic and genetic markers., Results: During a median follow-up of 3.5 years (interquartile range [IQR], 0.5 to 7.4 years), skin lesions associated with the use of anti-TNF therapy developed in 264 of 917 (29%) patients (psoriasiform eczema, 30.6%; eczema, 23.5%; xerosis cutis, 10.6%; palmoplantar pustulosis, 5.3%; psoriasis, 3.8%; other, 26.1%). Lesions typically developed at flexural regions, genitalia, and the scalp, especially the psoriasiform lesions. Thirty-one percent of women and 26% of men developed lesions. Median cumulative doses (2864 mg/y [IQR, 2203 to 3819 mg/y] and 2927 mg/y [IQR, 2377 to 3667 mg/y]) and trough levels (4.2 µg/mL [IQR, 2.6 to 5.8 µg/mL] and 4.0 µg/mL [IQR, 1.6 to 5.9 µg/mL]) of infliximab were similar in patients with and without lesions. All but 28 patients (11%) were successfully managed without needing to stop therapy because of lesions., Limitation: Retrospective nature and no matched control group of patients not receiving anti-TNF therapy., Conclusion: Skin lesions occur frequently in association with anti-TNF therapy but rarely require discontinuation of therapy. Close surveillance and early referral to a dedicated dermatologist are recommended., Primary Funding Source: Research Foundation Flanders (FWO), Belgium; Geconcerteerde Onderzoekacties of KU Leuven; and Janssen Biologics.

Background: Reliable tools for patient selection are critical for clinical drug trials., Aim: To evaluate a consensus-based, standardised magnetic resonance enterography (MRE) protocol for selecting patients for inclusion in Crohn's disease (CD) multicenter clinical trials., Methods: This study recruited 20 patients [Crohn's Disease Activity Index (CDAI) scores: <150 (n = 8); 150-220 (n = 4); 220-450 (n = 8)], to undergo ileocolonoscopy and two MREs (with and without colonic contrast) within a 14-day period. Procedures were scored centrally using, Magnetic Resonance Index of Activity (MaRIA), and both Crohn's Disease Endoscopic Index of Severity (CDEIS) and Simplified Endoscopic Score (SES-CD)., Results: 37 MREs were acquired. Both MREs were evaluable in 16 patients for calculation of test-retest and inter-reader reliability scores. The MaRIA scores for the terminal ileum had excellent test-retest and inter-reader reliability, with correlations >0.9. The proximal ileum showed strong within-reader agreement (0.90-0.96), and fair between-reader agreement (0.59-0.72). MRE procedures were tolerable. MaRIA scores correlated with CDEIS and SES-CD (0.63 and 0.71), but not with CDAI (0.34). MRE identified 3 patients with intra-abdominal complications, who would otherwise have been included in clinical trials. Furthermore, both MRE and ileocolonoscopy identified active bowel wall inflammation in 2 patients with CDAI <150, and none in 1 patient with CDAI > 220. Data quality was good/excellent in 85% of scans, and fair or better in 96%., Conclusions: Magnetic resonance enterography of high-quality and reproducibility was feasible in a global multi- centre setting, with evidence for improved selectivity over CDAI and ileocolonoscopy in identifying appropriate CD patients for inclusion in therapeutic intervention trials., (© 2015 John Wiley & Sons Ltd.)

Background and Aims: Centralized endoscopic scoring may reduce variability, but evidence is lacking in patients with Crohn's disease. We assessed the agreement of endoscopic scorings between site endoscopists and one central reader by using data from the adalimumab Crohn's disease clinical trial EXTEND., Methods: Agreement between readers for Crohn's Disease Endoscopic Index of Severity (CDEIS)-scored endoscopies from 6 sites and Simple Endoscopic Score for Crohn's Disease (SES-CD)-scored endoscopies from 19 sites in EXTEND was evaluated at baseline and weeks 12 and 52. Agreement on total scores was calculated by using intraclass correlation coefficient (ICC). Kappa statistic or Spearman correlation coefficient measured the agreement between readers for each ileocolonic segment on CDEIS variables including deep ulceration, surface involved, and ulcerated surface and SES-CD variables including ulcerated surface, size of ulcers, and affected surface., Results: ICCs on mean scores at baseline and weeks 12 and 52 were 0.78, 0.92, and 0.86 (CDEIS), and 0.77, 0.86, and 0.82 (SES-CD), respectively. Site endoscopists consistently reported higher scores. High agreement was observed for most segments and all time points for CDEIS variables and SES-CD large ulcers. Weak agreement occurred for the right side of the colon at all time points for CDEIS deep ulceration and SES-CD large ulcers and at baseline and week 12 for CDEIS ulcerated surface. Fair/moderate agreement occurred for SES-CD ulcerated surface and moderate/high agreement for affected surface for all segments and time points., Conclusions: Site and central readers showed high agreement on total CDEIS and SES-CD scores overall, whereas variability for individual segments was observed. Weakest agreement occurred at baseline, with a greater difference for SES-CD than for CDEIS score. (, Clinical Trial Registration Number: NCT00348283.)., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Anti-tumor necrosis factor (TNF) therapy has become a standard therapy for severe inflammatory bowel diseases (IBD), but its effect on B lymphocytes is largely unexplored. In this study we investigated peripheral blood B cells, B-cell subsets, and CD40 expression in patients with IBD before and during anti-TNF therapy with infliximab (IFX)., Methods: Blood was taken from healthy controls (n = 52) and patients with active IBD before (n = 46) and/or during anti-TNF therapy (n = 55). B-cell markers were detected by immunofluorescent staining and FACS analysis. Patients were classified as responders or nonresponders to anti-TNF therapy., Results: We found a numerical deficiency of circulating CD19 B cells, a lower activation state (CD40 expression) and lower proportions of CD5 B cells and IgMIgDCD27 preswitched memory cells among B cells in active patients with IBD before IFX therapy compared with healthy controls. IFX treatment increased CD19 B-cell numbers as well as the proportions of named B-cell subsets in responders but not in nonresponders. IFX more effectively upregulated CD40 expression in responders than in nonresponders. Restoration of B cells correlated with the biological response to therapy (C-reactive protein). Trough serum levels of IFX correlated with the number of B cells during therapy., Conclusions: A lower number of circulating B cells, a low CD40 expression, and a decrease in the proportion of CD5 and in the preswitched memory subset characterize active IBD. Restoration of these abnormalities correlates with the clinical response to anti-TNF therapy. The mechanism for this effect on B cells should be further explored.

Background and Aims: Although costly and uncomfortable for the patient, the current standard to assess mucosal healing in Crohn's disease [CD] patients is endoscopy. The aim of this study was to evaluate NGAL-MMP-9 as surrogate marker for mucosal healing in CD patients., Methods: Serum NGAL-MMP-9 levels were determined with sandwich enzyme-linked immunosorbent assay before and up to 5 years after first infliximab infusion in 108 active CD patients [median age at first infliximab 36 years, 57% female] and 43 healthy controls [HC, median age 27 years, 60% female]. Serum samples were matched to the time of endoscopy and complete endoscopic healing was defined as absence of ulcerations. Histological healing was defined as absence of epithelial damage [D'Haens score]., Results: At baseline, median [interquartile range] NGAL-MMP-9 levels were significantly higher in active CD patients vs HC (77.6 [36.9-141.0] vs 25.5 [17.8-42.8] ng/ml; p < 0.001). After treatment, NGAL-MMP-9 levels significantly decreased in completely healed CD patients [n = 38] (84.5 [36.7-138.4] to 23.4 [7.4-42.5] ng/ml; p < 0.001) and--to a lesser extent--in non-healed CD patients [n = 36] (100.9 [43.4-152.6] to 43.8 [27.0-96.8] ng/ml; p = 0.001). Receiver operating characteristic analysis defined a NGAL-MMP-9 cut-off level of 45 ng/ml corresponding to complete endoscopic healing (area under the curve [AUC] = 0.79, 82% sensitivity, 65% specificity) and histological healing [AUC = 0.72, 79% sensitivity, 53% specificity]. At baseline, C-reactive protein [CRP] was not elevated in 33% of active CD patients, whereas 53% of these patients did have elevated NGAL-MMP-9 levels., Conclusions: In the search for surrogate markers to assess mucosal healing in inflammatory bowel disease, NGAL-MMP-9 supplements and outperforms CRP in both ulcerative colitis and CD patients., (Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Inflammatory bowel disease (IBD) is characterized by a chronic inflammation of the gut, partly driven by defects in the innate immune system. Considering the central role of inflammasome signaling in innate immunity, we studied inflammasome components in IBD mucosa., Methods: Expression of genes encoding inflammasome sensor subunits was investigated in colonic mucosal biopsies from 2 cohorts of patients with IBD and controls., Results: A significant upregulation (>2-fold change in expression, false discovery rate <0.05) of the PYHIN inflammasomes AIM2 and IFI16 in active IBD versus controls was found. Also IFI16 was significantly increased in inactive IBD versus controls. Moreover, responders to anti-tumor necrosis factor therapy showed decreased expression of these inflammasomes although IFI16 remained significantly increased in responders showing endoscopic healing versus controls. AIM2 was mainly expressed in epithelial cells, whereas IFI16 was expressed in both lymphocytes and epithelial cells. Functional activation of predominant AIM2/IFI16-mediated inflammasomes in active IBD colon was shown by the presence of the downstream effectors CASP1 and HMGB-1 in inflamed mucosa., Conclusions: Our results highlight the importance of PYHIN inflammasome signaling in IBD and also link anti-tumor necrosis factor responsiveness to inflammasome signaling. Together, this points to the potential value of the inflammasome pathway as a new therapeutic target for IBD treatment.