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Background Prediction of endoscopic postoperative recurrence (POR) and prophylactic treatment based on clinical risk profile have thus far been inconclusive. This study aimed to examine the association between clinical risk profile and the development of endoscopic POR in a Crohn’s disease population without postoperative treatment and to identify individual risk factors of endoscopic POR. Methods Medical records of 142 patients with Crohn’s disease during follow-up after ileocecal or ileocolonic resection without prophylactic treatment at 3 referral centers were reviewed. Endoscopic POR was defined as a modified Rutgeerts score ≥i2b. Clinical risk profiles were distilled from current guidelines. Both uni- and multivariate logistic regression analysis were used to assess the relationship between risk profiles and endoscopic POR. Results Endoscopic POR was observed in 68 out of 142 (47.9%) patients. Active smoking postsurgery (odds ratio [OR], 3.01; 95% confidence interval [CI], 1.24-7.34; P = 0.02), a Montreal classification of A3 (OR, 3.05; 95% CI, 1.07-8.69; P = 0.04), and previous bowel resections (OR, 2.58; 95% CI, 1.07-6.22; P = 0.03) were significantly associated with endoscopic POR. No significant association was observed between endoscopic POR and any guideline defined as a high-/low-risk profile. However, patients with a combination of any 3 or more European Crohns & Colitis Organisation– (OR, 4.87; 95% CI, 1.30-18.29; P = 0.02) or British Society of Gastroenterology–defined (OR 3.16; 95% CI, 1.05-9.49; P = 0.04) risk factors showed increased odds of developing endoscopic POR. Conclusions Our results suggest that patients with a combination of any 3 or more European Crohns & Colitis Organisation– or British Society of Gastroenterology–defined risk factors would probably benefit from immediate prophylactic treatment.

Background & Aims: Intestinal ultrasound (IUS) is noninvasive, cost-effective, and accurate to determine disease activity in ulcerative colitis (UC). In this study, we prospectively evaluated IUS for treatment response in a longitudinal cohort by using endoscopy and histology as gold standards. Methods: Consecutive patients with moderate to severe UC (endoscopic Mayo score [EMS] ≥2) starting tofacitinib treatment were included. Patients were evaluated at baseline and after 8 weeks of tofacitinib induction by means of clinical, biochemical, endoscopic (EMS and UC endoscopic index for severity), histologic (Robarts Histopathologic Index) and IUS assessments. Readers of IUS, endoscopy, and histology were blinded for all other outcomes. The primary outcome was difference in bowel wall thickness (BWT) for endoscopic improvement vs no endoscopic improvement. Endoscopic remission was defined as EMS = 0, improvement as EMS ≤1, and response as a decrease of EMS ≥1. Results: Thirty patients were included, with 27 patients completing follow-up. BWT correlated with EMS (ρ = 0.68, P

Background: Vedolizumab for inflammatory bowel disease (IBD) is often intensified based on distinct pharmacokinetics in children. Prior adult-specific population pharmacokinetic models have identified limited covariates of drug clearance. Aims: To establish a population pharmacokinetic model for children and young adults to identify novel covariates of drug clearance to better account for paediatric-specific inter-patient variability in vedolizumab pharmacokinetics; a key secondary exploratory aim was to identify microbial signatures of pharmacokinetic outcomes in a subset of patients. Methods: The study included data from 463 observed vedolizumab concentrations (59 peaks and 404 troughs) from 74 patients with IBD (52 with Crohn's disease and 22 with ulcerative colitis or unclassified IBD, median age 16 years). Pharmacokinetic analysis was conducted with non-linear mixed effects modelling. For the evaluation of the exposure–response relationship, clinical outcomes were evaluated by trough levels, clearance and vedolizumab exposure. Whole-genome metagenomic sequencing was conducted at baseline and week 2. Results: A two-compartment population pharmacokinetic model was identified with a clear correlation between CL and weight, erythrocyte sedimentation rate, and hypoalbuminemia. Trough concentrations before infusion 3 (37 μg/ml) and before infusion 4 (20 μg/ml) best predicted steroid-free clinical remission at infusion 4. Using faecal metagenomics, we identified an early (baseline and week 2) abundance of butyrate-producing species and pathways that were associated with an infusion 4 trough concentration >20 μg/ml. Conclusions: This novel paediatric vedolizumab pharmacokinetic model could inform precision dosing. While additional studies are needed, an abundance of faecal butyrate producers is associated with early response to vedolizumab, suggesting that microbial analysis may be beneficial to biological selection.

Crohn's disease (CD) can lead to bowel damage, stricturing, and obstruction thereby resulting in surgery and hospitalization. The Randomized Evaluation of an Algorithm for Crohn's Treatment (REACT) trial showed that early combined immunosuppression (ECI) with symptom-based treatment escalation for 24 months resulted in a lower risk of surgery, hospitalization, or CD-related complications compared with conventional management (CM).1 Treatment earlier in the disease course may be associated with reduced risk of complications compared with later initiation, although data are sparse.2 We performed a post hoc analysis of REACT to evaluate the impact of baseline disease duration on surgery, hospitalization, or CD-related complications in patients treated with ECI compared with CM.

BACKGROUND & AIMS: Mirikizumab is an antibody against the p19 subunit of interleukin 23 that has demonstrated clinical efficacy and was well tolerated following 12 weeks of induction treatment in a phase 2 trial of patients with moderate to severe ulcerative colitis. We present results of the open-label extended induction period in patients who did not initially respond to treatment with mirikizumab. METHODS: This study was a continuation of I6T-MC-AMAC, a double-blind trial, performed at 75 sites in 14 countries, in which patients with moderate to severe ulcerative colitis were randomly assigned to 12 weeks induction therapy with 50 mg, 200 mg, or 600 mg mirikizumab or placebo. Patients without a clinical response (a 9-point decrease in Mayo subscore of ≥2 points and ≥35% from baseline and either a decrease of rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1) at week 12 were offered the opportunity to participate in an open-label, extended induction study for another 12 weeks, in which they received either 600 mg intravenous mirikizumab (n = 20) or, following a protocol amendment, 1000 mg intravenous mirikizumab (n = 64) every 4 weeks. At week 24, patients with a clinical response continued the extension maintenance period and received 200 mg subcutaneous mirikizumab. Endpoints included clinical remission (Mayo subscores of 0 for rectal bleeding, 0 or 1 with a 1-point decrease from baseline), clinical response, endoscopic remission (Mayo endoscopic subscore of 0), or endoscopic improvement (endoscopic subscore of 0 or 1), at study weeks 24 and 52. Data were analysed for patients who received mirikizumab or placebo during the induction phase of the study. RESULTS: Among participants who did not respond to induction mirikizumab, 50.0% of those who received the 12-week extension of 600 mg mirikizumab and 43.8% who received the extension of 1000 mg mirikizumab achieved a clinical response; 15.0% and 9.4% achieved clinical remission, respectively. Endoscopic improvement was achieved by 20.0% of subjects in the 600 mg mirikizumab group and 15.6% subjects in the 1000 mg mirikizumab group. Among initial nonresponders to mirikizumab who had clinical response at study week 24 and continued into maintenance therapy, 65.8% maintained the clinical response, 26.3% achieved clinical remission, and 34.2% had endoscopic improvement at week 52. No new safety concerns were identified. CONCLUSIONS: Extended doses of mirikizumab (600 mg and 1000 mg) for an additional 12 weeks produce a clinical response in up to 50% of patients who did not have a clinical response to 12 weeks of induction doses (50 mg, 200 mg, or 600 mg). Most of the responders to the extended doses maintained clinical response for up to 52 weeks. Clinicaltrials.gov no: NCT02589665. ispartof: CLINICAL GASTROENTEROLOGY AND HEPATOLOGY vol:20 issue:1 pages:105-+ ispartof: location:United States status: published

Background The lack of standardized methods for clinical trial design and disease activity assessment has contributed to an absence of approved medical therapies for the prevention of postoperative Crohn’s disease (CD). We developed recommendations for regulatory trial design for this indication and for endoscopic assessment of postoperative CD activity. Methods An international panel of 19 gastroenterologists was assembled. Modified Research and Development/University of California Los Angeles methodology was used to rate the appropriateness of 196 statements using a 9-point Likert scale in 2 rounds of voting. Results were reviewed and discussed between rounds. Results Inclusion of patients with a history of completely resected ileocolonic CD in regulatory clinical trials for the prevention of postoperative recurrence was appropriate. Given the absence of approved medical therapies, a placebo-controlled design with a primary end point of endoscopic remission at 52 weeks was appropriate for drug development for this indication; however, there was uncertainty regarding the appropriateness of a coprimary end point of symptomatic and endoscopic remission and the use of currently available patient-reported outcome measures. The modified Rutgeerts Score, endoscopic assessment of the anastomosis, and a minimum of 5cm of neoterminal ileum were also appropriate; although the appropriateness of other indices including the Simple Endoscopic Score for CD for endoscopic assessment of postoperative CD activity was uncertain. Conclusions A framework for regulatory trial design for the prevention of postoperative CD recurrence and endoscopic assessment of disease activity has been developed. Research to empirically validate end points for these trials is needed.

Introduction: Treatment of ulcerative colitis (UC) aims to control symptoms and to suppress intestinal inflammation. Despite considerable advances, a proportion of patients do not respond to currently available drugs. The interleukin (IL)-23 axis plays a significant role in the pathogenesis of UC and has thus become an important target for drug development. Areas covered: The review briefly summarizes the pathophysiology of the IL-12/23 axis and provides a synopsis of the available evidence for efficacy and safety of ustekinumab, mirikizumab (LY3074828), risankizumab (BI655066/ABBV066), brazikumab (MEDI2070; formerly AMG139) and guselkumab (CNTO1959) in UC. We also provide an overview of ongoing and anticipated trials in this field. Expert opinion: A Phase 2 trial with mirikizumab and a Phase 3 trial with ustekinumab have demonstrated the efficacy of anti-IL-23 agents in achieving clinical and endoscopic outcomes in UC with a favorable safety profile. Trials of other anti-IL-23 agents in UC are under way and designed to explore head-to-head efficacy with existing biologics, as well as the prospect of combination biological therapy. Apart from data on longer term efficacy and safety, future trials should also explore strategies to inform the positioning of IL-23 antagonists in therapeutic algorithms.

Background: Cortiment®MMX® (budesonide MMX®) is currently approved for the induction of remission in mild-to-moderate ulcerative colitis (UC) patients when 5-ASA treatment is not sufficient. Data in real-life settings are lacking. Methods: This was a multicentre observational prospective cohort study conducted in Europe and Canada. Effectiveness, safety, and tolerability of Cortiment®MMX® in a real-life setting of patients treated for mild-to-moderate UC was investigated. Patients were prescribed Cortiment®MMX® in accordance with the Summary of the Product Characteristics (SmPC). The primary endpoint was the clinical benefit of Cortiment® MMX® in routine practice (improvement ≥ 3 points in the clinical sub-scores of the Ulcerative Colitis Disease Activity Index, UCDAI). Results: Data from 326 patients with mild-to-moderate UC were analysed for the primary endpoint. Clinical benefit was achieved in 60.1% (196/326) of patients at the end of Cortiment®MMX® treatment. Clinical remission (UCDAI clinical sub-score ≤ 1), full symptoms resolution (rectal bleeding (RB) = 0 and stool frequency (SF) = 0) and symptoms resolution (RB = 0 + SF ≤ 1) at the end of the Cortiment®MMX® treatment were achieved in 51.8%, 45.1% and 63.2% of patients, respectively. The median time to symptoms resolution was 30 days (range 29.0–36.0 days). Fifty patients (14.3%) had to discontinue Cortiment®MMX® due to adverse events; 17.5% of patients (n = 61) reported at least one adverse event related to the study drug. Conclusions: This was the first time that a large cohort study was conducted with Cortiment®MMX® in a real-life setting. It demonstrated that Cortiment®MMX® is effective, safe and well tolerated in about 60% of UC patients.

Background and Aims Risankizumab, an interleukin-23 antibody, demonstrated efficacy and acceptable safety in a phase 2 study of patients with moderate-to-severe refractory Crohn’s disease. This open-label extension investigated the long-term safety, pharmacokinetics, immunogenicity and efficacy of risankizumab in responders to risankizumab in the parent phase 2 study. Methods Enrolled patients had achieved clinical response [decrease in Crohn’s Disease Activity Index from baseline ≥100] without clinical remission [Crohn’s Disease Activity Index Results Sixty-five patients were enrolled, including four who had lost response in the parent study and were first reinduced with risankizumab 600 mg every 4 weeks [three infusions]. Patients received risankizumab for a median of 33 months [total: 167.0 patient-years]. The rate of serious adverse events was 24.6 events/100 patient-years; the majority were gastrointestinal in nature. Rates of serious infections, opportunistic infections and fungal infections were 4.2, 1.8, and 6.6 events/100 patient-years, respectively. No deaths, malignancies, adjudicated major adverse cardiovascular events, latent/active tuberculosis or herpes zoster were reported. Treatment-emergent anti-drug antibodies developed in eight patients [12.3%]; none were neutralizing. Efficacy outcomes were maintained during the study, including the proportions of patients [observed analysis] with clinical remission [>71%] and endoscopic remission [>42%]. Conclusions Long-term maintenance treatment with subcutaneous risankizumab 180 mg every 8 weeks was well tolerated by patients with Crohn’s disease, with no new safety signals. Clinical trial registration number: NCT02513459

Background and Aims Amiselimod is an oral selective S1P1 receptor modulator with potentially fewer adverse effects than fingolimod. We evaluated the safety, tolerability, and clinical efficacy of amiselimod in participants with moderate to severe active Crohn’s disease. Methods This was a phase IIa, multicentre, randomised, double-blind, parallel group, placebo-controlled study comparing amiselimod 0.4 mg with placebo over a 14-Week treatment period. The primary endpoint of the study was the proportion of participants with clinical response (Crohn’s Disease activity Index [CDAI] 100) from baseline at Week 12. Results A total of 180 patients were screened and 78 were randomised [40 to amiselimod 0.4 mg and 38 to placebo]. There was no significant difference in the proportion of patients achieving CDAI 100 at Week 12 on amiselimod 0.4 mg and on placebo [48.7% vs. 54.1%, respectively] (odds ratio [OR] [95% confidence interval]: 0.79 [0.31, 1.98]). The results from the secondary endpoint analyses supported the results of the primary endpoint analysis. Treatment with amiselimod 0.4 mg was generally well tolerated, with 71.8% of participants completing the 14-week treatment period. Seven participants had serious adverse events and four discontinued treatment in the amiselimod group. Conclusions Amiselimod 0.4 mg for 12 weeks was not superior to placebo for the induction of clinical response [CDAI 100] in Crohn’s disease. Treatment with amiselimod 0.4 mg was generally well tolerated and no new safety concerns related to amiselimod were reported in this study.

BACKGROUND AND AIMS: Immunogenicity with formation of anti-drug antibodies (ADA) to biologics is an important reason for treatment failure in inflammatory bowel disease (IBD). Our aim was to assess the rate of ADA, the effect of combination therapy with immunomodulators on ADA and the influence of ADA on efficacy and safety of biologics for IBD treatment. METHODS: MEDLINE, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to April 2020 for trials of biologics that assessed immunogenicity. The overall certainty of evidence was evaluated using Grading of Recommendations, Assessment, Development and Evaluations (GRADE). The primary outcome was rate of ADA. Secondary outcomes included efficacy and safety outcomes among patients with detectable versus undetectable ADA. For dichotomous outcomes, pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated. RESULTS: Data from 68 studies were analysed and 33 studies (5850 patients) were included in the meta-analysis. Pooled ADA rates for biologic monotherapy were 28.0% for infliximab, 7.5% for adalimumab, 3.8% for golimumab, 10.9% for certolizumab, 6.2% for ustekinumab and 16.0% for natalizumab. Pooled ADA rates were 8.4% for vedolizumab and 5.0% for etrolizumab for combo- and monotherapy combined. In all biologics, ADA rates were underestimated by use of drug sensitive ADA assays and higher dose and/or frequency. ADA rate was significantly reduced in patients treated with combination therapy for infliximab (RR 0.52; 95% CI 0.44, 0.62), adalimumab (RR: 0.31; 95% CI 0.14, 0.69), golimumab (RR: 0.29; 95% CI 0.10, 0.83), certolizumab pegol (RR: 0.30; 95% CI 0.14, 0.67) and natalizumab (RR: 0.20; 95% CI 0.11, 0. 39). ADA to infliximab were associated with lower clinical response rates (RR: 0.75; 95% CI 0.61, 0.91) and higher rates of infusion reactions (RR: 2.36; 95% CI 1.85, 3.01). CONCLUSIONS: Differences in analytical methods to detect ADA hamper comparison of true ADA rates across biologics in IBD. Use of combination therapy with immunomodulators appeared to reduce ADA positivity for most biologics. For infliximab, ADA were associated with reduced drug efficacy and increased adverse events.

BACKGROUND & AIMS: Histologic features of inflammation (histologic inflammation) are associated with clinical relapse in patients with ulcerative colitis (UC). Concentration of fecal calprotectin (FC) can be used to identify patients with mucosal inflammation. We aimed to assess the accuracy of FC measurements in identifying patients with histologic inflammation and to develop a model to predict outcomes of therapy. METHODS: We performed a post hoc analysis of data from a phase 4 trial of the efficacy of multimatrix mesalamine in patients with mild to moderate UC (the MOMENTUM trial). We obtained clinical, endoscopic, and histologic data from week 8 (n = 639) and week 52 (n = 373) of the trial. We used area under the receiver operating characteristic curves to determine the accuracy and optimal cut-off values of FC in identifying patients with different therapeutic outcomes (clinical remission, endoscopic healing, deep remission, or histologic remission) at week 8 and week 52. We performed multivariable logistic regression analyses to identify factors associated with these outcomes. RESULTS: Median FC concentrations were lower in patients who achieved outcomes of clinical remission, endoscopic healing, deep remission, or histologic remission vs patients who did not. FC concentrations identified patients with endoscopic healing and histologic remission with area under the receiver operating characteristic curve values of 0.77 and 0.76 at week 8, and 0.79 and 0.80 at week 52, respectively. The optimal FC cut-off concentrations for identification of patients with histologic remission were 75 μg/g at week 8 and 99 μg/g at week 52. In the subpopulation with an endoscopy score of 0, median FC concentrations were lower in patients with histologic remission than in patients with microscopic inflammation at week 8 (30 vs 140 μg/g; area under the receiver operating characteristic, 0.72) and week 52 (21.5 vs 134.5 μg/g; area under the receiver operating characteristic, 0.71). At both time points, the optimal FC cut-off concentration was approximately 75 μg/g. Our final prediction model for week 52 histologic remission comprised endoscopic score at week 8, FC concentration at week 8, and histologic activity at baseline and week 8. CONCLUSIONS: A post hoc analysis of data from a phase 4 trial found that, even in patients with complete endoscopic healing of UC, FC concentration can be used to discriminate patients with ongoing microscopic inflammation from patients with histologic remission. The optimal cut-off concentration of FC is between 75 and 100 μg/g. ClinicalTrials.gov no: NCT01124149. ispartof: CLINICAL GASTROENTEROLOGY AND HEPATOLOGY vol:19 issue:11 pages:2333-2342 ispartof: location:United States status: published

Background and Aims Patient-reported outcomes are recommended endpoints in Crohn’s disease [CD] trials. The association between patient-reported general well-being relative to symptoms of diarrhoea and abdominal pain [AP] in patients with moderate to severe CD was explored. Methods Patients from three randomized, placebo-controlled, double-blind adalimumab or upadacitinib studies with average daily very soft/liquid stool frequency [SF] ≥4 and/or AP score ≥2 at baseline were included. Using electronic diaries, patients reported general well-being [seven-point Likert scale; 1 = worst; 7 = best] in item 10 of the Inflammatory Bowel Disease Questionnaire [IBDQ]. Changes in well-being and clinical outcomes of SF and AP from baseline to week 12 or 16, and the relationship between well-being and clinical outcomes were evaluated using cumulative distribution function and probability density function curves. Results In total, 858 patients with CD were included [adalimumab, n = 695; upadacitinib, n = 163]. Patients who achieved clinical remission [SF ≤2.8, AP score ≤1.0, neither worse than baseline] were more likely than those not in clinical remission to report IBDQ item 10 response in the 6–7 group category but not IBDQ categories ≤5. Higher IBDQ score for item 10 [6–7] was associated with lower SF and AP score. Greater point increases in IBDQ item 10 were associated with a greater percentage decrease in clinical parameters; a ≥25–30% decrease in SF or AP was associated with a ≥1-point improvement in IBDQ. Conclusions An association between improvements in patient-reported general well-being and clinical remission/response was observed using outcomes of SF and AP, supporting the clinical remission/response endpoint definitions used in clinical studies of CD. Clinical Trial Registrations [ClinicalTrials.gov]: NCT00077779 [CHARM]; NCT00348283 [EXTEND]; NCT02365649 [CELEST].

Background Intestinal ultrasound [IUS] is a promising and non-invasive cross-sectional imaging modality in the diagnosis and monitoring of ulcerative colitis [UC]. Unlike endoscopy, where standardized scoring for evaluation of disease activity is widely used, scoring for UC with IUS is currently unavailable. Therefore, we conducted a study to assess the reliability of IUS in UC among expert sonographists in order to identify robust parameters. Methods Thirty patients with both clinically active [25] and quiescent [five] UC were included. Six expert sonographers first agreed upon key IUS parameters and grading, including bowel wall thickness [BWT], colour Doppler signal [CDS], inflammatory fat [i-fat], loss of bowel wall stratification [BWS], loss of haustrations and presence of lymph nodes. Thirty video-recorded cases were blindly reviewed. Results Inter-observer agreement was almost perfect for BWT (intra-class correlation coefficient [ICC]: 0.96) and substantial for CDS [κ = 0.63]. Agreement was moderate for presence of lymph nodes [κ = 0.41] and fair for presence of i-fat [κ = 0.36], BWS [κ = 0.24] and loss of haustrations [κ = 0.26]. Furthermore, there was substantial agreement for presence of disease activity on IUS [κ = 0.77] and almost perfect agreement for disease severity [ICC: 0.93]. Most individual parameters showed a strong association with IUS disease activity as measured by the six readers. Conclusion IUS is a reliable imaging modality to assess disease activity and severity in UC. Important individual parameters such as BWT and CDS are reliable and could be incorporated in a future UC scoring index. Standardized acquisition and assessment of UC utilizing IUS with established reliability is important to expand the use of IUS globally.

Background and Aims Quantifying placebo rates and the factors influencing them are essential to inform trial design. We provide a contemporary summary of clinical, endoscopic, histological and safety placebo rates in induction and maintenance clinical trials of ulcerative colitis, and identify factors influencing them. Methods MEDLINE, EMBASE and the Cochrane library were searched from April 2014 to April 2020, updating a prior meta-analysis that searched from inception to April 2014. We included placebo-controlled trials of aminosalicylates, corticosteroids, immunosuppressives, small-molecules and biologics in adults with ulcerative colitis. Placebo rates were pooled using random-effects and mixed-effects meta-regression models to assess the associated study-level. Results In 119 trials [92 induction, 27 maintenance] clinical, endoscopic and histological remission placebo rates for induction trials were 11% (95% confidence interval [CI] 9–13%), 19% [95% CI 15–23%] and 15% [95% CI 11–19%], respectively; for maintenance trials, clinical and endoscopic placebo remission rates were 18% [95% CI 12–25%] and 20% [95% CI 15–25%], respectively. Higher endoscopic subscore and a higher rate of exposure to prior biologic therapy at enrolment were associated with lower clinical and endoscopic placebo remission rates. Absence of central reading was associated with an increase in placebo endoscopic response and remission rates. More follow-up visits and increasing trial duration were associated with higher clinical placebo rates. Conclusions Placebo rates in ulcerative colitis trials vary according to the endpoint assessed, whether it is for assessment of response or remission, and whether the trial is designed for induction or maintenance. These contemporary rates across different endpoints and drug classes will help to inform trial design.

Background and Aims This analysis examined the long-term safety and efficacy of ozanimod in patients with moderately to severely active ulcerative colitis [UC] with ≥ 4 years of follow-up in the phase 2 TOUCHSTONE open-label extension [OLE]. Methods Patients receiving placebo or ozanimod HCl 0.5 mg or 1 mg during the double-blind period could enter the OLE [ozanimod HCl 1 mg daily]. Partial Mayo score [pMS] clinical response and remission were assessed through OLE week 200 and summarized descriptively using observed cases [OC] and non-responder imputation [NRI]. Endoscopy was required at OLE week 56 and the end of treatment. Parameters associated with endoscopy were summarized at weeks 56 and 104 [OC], and week 56 [NRI]. C-reactive protein and faecal calprotectin were assessed. Adverse events were monitored throughout the study. Results Of 197 patients receiving double-blind treatment, 170 entered the OLE. Discontinuation rates were 28% at year 1 and 15–18% annually through year 4. Partial Mayo measures indicated clinical response and remission rates at OLE week 200 of 93.3% and 82.7%, respectively, using OC and 41% and 37% with the more conservative NRI analysis. At weeks 56 and 104, respectively, histological remission rates were 46.3% and 38.5%, and endoscopic improvement rates were 46.4% and 46.5% [OC]. No new safety signals were identified during ≥ 4 years of follow-up. Conclusions There was a high rate of continued study participation and long-term benefit with ozanimod HCl 1 mg daily based on clinical, histological and biomarker measures in patients with moderately to severely active UC in the TOUCHSTONE OLE. [NCT02531126]

Background and Aims Many inflammatory bowel disease [IBD] patients in remission have persisting symptoms, compatible with irritable bowel syndrome [IBS-type symptoms]. We aimed to compare the effectiveness of gut-directed hypnotherapy vs standard medical treatment [SMT] for IBS-type symptoms in IBD patients. Methods In this multicentre, randomized, controlled, open-label trial, patients aged 12–65 years with IBD in clinical remission [global assessment] and biochemical remission [faecal calprotectin ≤100 µg/g, or ≤200 µg/g without inflammation at endoscopy] with IBS according to Rome III criteria were randomized to hypnotherapy or SMT. Primary outcome was the proportion with ≥50% reduction on a visual analog scale for symptom severity, as measured with the Irritable Bowel Syndrome Severity Scoring System [IBS-SSS] at week 40 [i.e. 6 months after finishing the intervention], compared to baseline. Secondary outcomes included total IBS-SSS score, quality of life, adequate relief, IBS-related cognitions, and depression and anxiety scores. Results Eighty patients were included, of whom 70 received at least one session of the allocated treatment and were included in the modified intention-to-treat-population. Seven patients were excluded because of missing baseline data required for the primary outcome. The primary outcome was met in nine [27%] of 33 patients randomized to SMT and nine [30%] of 30 patients randomized to hypnotherapy [p = 0.81]. Adequate relief was reported in 60% and 40% of subjects, respectively. Exploratory analyses of secondary outcomes revealed no apparent differences between the two treatment groups. Conclusions Hypnotherapy was not superior to SMT in the treatment of IBS-type symptoms in IBD patients. Both treatment strategies are reasonable options from a clinical perspective.

Background Positive effects of hyperbaric oxygen (HBO) on perianal fistulas in Crohn’s disease (CD) have been described, but the effect on rectovaginal fistulas (RVFs) has not yet been studied. The aim was to investigate the efficacy, safety and feasibility of HBO in patients with RVF in CD. Methods In this prospective study, consecutive CD patients between November 2018 and February 2020 presenting with RVF at the outpatient fistula clinic of the Amsterdam University Medical Centre were included and selected to receive treatment with 30 daily HBO sessions, if fistulas were actively draining and any concomitant treatment regimen was stable at least 6 weeks prior to start of HBO. Patients with a stoma were excluded. The primary endpoint was clinical closure at 3-month follow-up, defined as cessation of complaints and/or closure of the external orifice if visible at baseline. Secondary outcomes were improvement of concomitant perianal fistulas as measured by the perianal disease activity index (PDAI) and fistula drainage assessment (FDA), as well as improvement in patient-reported outcomes (visual analogue scale (VAS), inflammatory bowel disease questionnaire (IBDQ), faecal incontinence quality of life scale (FIQL) and female sexual functioning index (FSFI)) at 3-month follow-up. Results Out of 14 eligible patients, nine patients (median age 50 years) were treated, all of whom had previously had one or more unsuccessful medical and/or surgical treatments for their RVF. Clinical closure occurred in none of the patients at 3-month follow-up. There was no improvement in PDAI and patient-reported outcomes (VAS, IBDQ, FIQL and FSFI). Two patients had concomitant perianal fistulas; using FDA, one patient had a clinical response and one patient was in clinical remission 3 months after HBO. There were two treatment-related adverse events during HBO concerning claustrophobia and fatigue. Furthermore, two patients had a surgical intervention due to RVF and two patients were treated with antibiotics for a urinary tract infection during follow-up. One patient had a dose reduction of ustekinumab because of decreased luminal complaints. Conclusion Treatment with HBO was feasible, but in this therapy-refractory cohort without deviating ostomy no clinical closure of RVF or improvement in quality of life was seen 3 months after HBO. Treatment with HBO alone in this specific group of patients therefore appears to be ineffective.

BACKGROUND & AIMS: Higher infliximab trough levels are associated with clinical and endoscopic remission in patients with Crohn's disease (CD). We investigated pharmacodynamic features of infliximab and radiological healing. METHODS: We performed a substudy of the TAILORIX trial (patients with active luminal CD in Europe, treated with infliximab), analyzing baseline and week 54 magnetic resonance enterography (MRE) data. MREs were scored using the MaRIA score by blinded central readers. Radiologic response and remission were defined, based on MaRIA criteria in all segments, as scores below 11 and 7, respectively. We collected data on infliximab trough levels, biomarkers, and endoscopic findings. Our primary aim was to evaluate pharmacodynamic features associated with radiologic response and remission, based on MRE assessments at baseline and at 54 weeks after initiation of infliximab therapy. RESULTS: We analyzed data from 36 patients (50% female; median age 35.7 years; interquartile age range, 25.6-48.6 years; median disease duration, 1.5 months; interquartile duration range, 0.6-22.4 months). At week 54 of treatment, 36.4% of patients had a radiologic response, 30.3% of patients were in remission, and 71% had endoscopic features of remission. At baseline, there was a correlation between the CD endoscopic index of severity and MaRIA scores (κ = 0.46; P = .008), but we found no correlation at week 54 (κ = 0.06; P = .75). Radiologic remission correlated with infliximab trough level at week 14 (P = .049) when the infliximab trough level cut-off value was set at 7.8 μg/mL (area under the curve, 0.74; 75% sensitivity; 86% specificity; 90% negative predictive value; 57% positive predictive value). Radiologic response correlated with infliximab trough levels at week 14 (P = .048) when the infliximab trough level cut-off value was set at 7.8 μg/mL (area under the curve, 0.73; 70% sensitivity; 90% specificity; 86% negative predictive value; 78% positive predictive value) and with continuous pharmacologic evidence of response (infliximab trough levels above 5.0 μg/mL at all time points) (P = .034). CONCLUSIONS: In a substudy of data from the TAILORIX trial of patients with active luminal CD, we identified a relationship between exposure to infliximab and radiologic evidence of outcomes. ispartof: CLINICAL GASTROENTEROLOGY AND HEPATOLOGY vol:19 issue:5 pages:947-+ ispartof: location:United States status: published

As microbiome research has moved from associative to mechanistic studies, the activities of specific microbes and their products have been investigated in the development of inflammatory bowel diseases, cancer, metabolic syndrome, and neuropsychiatric disorders. Findings from microbiome research have already been applied to the clinic, such as in fecal microbiota transplantation for treatment of recurrent Clostridium difficile infection. We review the evidence for associations between alterations in the intestinal microbiome and gastrointestinal diseases and findings from clinical trials of fecal microbiota transplantation. We discuss opportunities for treatment of other diseases with fecal microbiota transplantation, based on findings from small clinical and preclinical studies.

Background and Aims Management of Crohn’s disease and ulcerative colitis has typically relied upon treatment intensification driven by symptoms alone. However, a ‘treat-to-target’ management approach may help to address underlying inflammation, minimise disease activity at early stages of inflammatory bowel disease, limit progression, and improve long-term outcomes. Methods A systematic literature review was conducted to identify data relevant to a treat-to-target approach in inflammatory bowel disease, published between January 1, 2007 and May 15, 2017. Results Consistent with recommendations of the Selecting Therapeutic Targets in Inflammatory Bowel Disease [STRIDE] working group, studies have investigated factors influencing the achievement of both endoscopic and histological mucosal healing and patient-level outcomes in inflammatory bowel disease [IBD]. Histological healing and biomarker levels have also been shown to be modifiable outcomes. Although there is a lack of prospectively derived evidence validating mucosal healing as a treatment target, data are emerging to suggest that targeting mucosal healing or inflammation rather than symptoms may be cost-effective in some settings. The review highlighted several strategies that may support the implementation of a treat-to-target approach in IBD. The prospective randomised CALM study demonstrated how tight control [whereby treatment decisions are based on close monitoring of inflammatory biomarkers] leads to improvements in endoscopic and clinical outcomes. The review also considered the influence of coordinated care from a multidisciplinary team and patient engagement with improved adherence, as well as the role of therapeutic drug monitoring in inflammatory bowel disease management. Conclusions A treat-to-target strategy may impact on disease progression and improve outcomes in inflammatory bowel disease. Prospective studies including long-term data are required to ensure that the most appropriate targets and strategies are identified.

Background: Faecal calprotectin (FC) is a marker of mucosal inflammation. Objective: The aim of this study was to determine the diagnostic accuracy of FC to (a) differentiate between perianal fistulizing Crohn's disease (pCD) and cryptoglandular perianal fistulas; and (b) detect mucosal inflammation in pCD. Methods: Patients with active perianal fistulas who had FC measured and a complete ileocolonoscopy within 10 weeks were retrospectively included. Results: Fifty-six patients were included (pCD, n = 37) of whom 19 pCD patients exhibited ulcers. FC was significantly higher in pCD compared to cryptoglandular fistulas (µg/g) (708.0 (207.0–1705.0) vs 32.0 (23.0–77.0), p < 0.001). Area-under-the-curve (AUC) value for FC receiver operating characteristic (ROC) statistics was 0.900. Optimal FC cut-off was ≥ 150 µg/g. To differentiate pCD from cryptoglandular fistulas in the absence of luminal inflammation, optimal cut-off remained ≥ 150 µg/g (AUC = 0.857, sensitivity = 0.81, specificity = 0.89, positive predictive value (PPV) = 93.8% and negative predictive value (NPV) = 70.8%). In pCD, FC was significantly increased in the presence of ulcers (1672.0 vs 238.0, p = 0.004). Optimal cut-off was ≥ 250 µg/g (AUC = 0.776; sensitivity = 0.89, specificity = 0.56, PPV - 68.0% and NPV = 83.0%). Conclusion: FC discriminates pCD from cryptoglandular fistulas, even in the absence of intestinal ulcers. In active pCD, an elevated FC does not accurately predict the presence of ulcers and should be interpreted with caution.

Background and Aims Currently used non-invasive tools for monitoring children with inflammatory bowel disease [IBD], such as faecal calprotectin, do not accurately reflect the degree of intestinal inflammation and do not provide information on disease location. Ultrasound [US] might be of added value. This systematic review aimed to assess the diagnostic test accuracy of transabdominal US in detecting intestinal inflammation in children with IBD in both diagnostic and follow-up settings. Methods We systematically searched PubMed, Embase [Ovid], Cochrane Library, and CINAHL [EBSCO] databases for studies assessing diagnostic accuracy of transabdominal US for detection of intestinal inflammation in patients diagnosed or suspected of IBD, aged 0–18 years, with ileo-colonoscopy and/or magnetic resonance enterography [MRE] as reference standards. Studies using US contrast were excluded. Risk of bias was assessed with QUADAS-2. Results The search yielded 276 records of which 14 were included. No meta-analysis was performed, because of heterogeneity in study design and methodological quality. Only four studies gave a clear description of their definition for an abnormal US result. The sensitivity and specificity of US ranged from 39-93% and 90–100% for diagnosing de novo IBD, and 48–93% and 83–93% for detecting active disease during follow-up, respectively. Conclusions The diagnostic accuracy of US in detecting intestinal inflammation as seen on MRE and/or ileo-colonoscopy in paediatric IBD patients remains inconclusive, and there is currently no consensus on defining an US result as abnormal. Prospective studies with adequate sample size and methodology are needed before US can be used in the diagnostics and monitoring of paediatric IBD.

Objectives: Anti-TNF agents are effective to treat perianal Crohn’s disease (CD). Evidence suggests that Crohn’s disease patients with perianal fistulas need higher infliximab (IFX) serum concentrations compared to patients without perianal CD to achieve complete disease control. Our aim was to compare anti-TNF serum concentrations between patients with actively draining and closed perianal fistulas. Methods: A retrospective survey was performed in CD patients with perianal disease treated with IFX or adalimumab (ADL). Fistula closure was defined as absence of active drainage at gentle finger compression and/or fistula healing on magnetic resonance imaging. Results: We identified 66 CD patients with a history of perianal fistulas treated with IFX (n = 47) and ADL (n = 19). Median IFX serum trough concentrations ([interquartile range]) were higher in patients with closed fistulas (n = 32) compared to patients with actively draining fistulas (n = 15): 6.0 µg/ml [5.4–6.9] versus 2.3 µg/ml [1.1–4.0], respectively (p

Background and aims Rectal resection in inflammatory bowel disease [IBD] is frequently complicated by disturbed perineal wound healing. Close rectal dissection, where the mesorectum remains in situ, is hypothesized to reduce complications by minimizing dead space, compared to total mesorectal excision. The aim of this study was to analyse post-operative outcomes of both techniques. In addition, immune activity in mesorectal tissue was assessed. Methods Perineal complications and healing were retrospectively assessed in a series of 74 IBD patients undergoing proctectomy using close rectal dissection or total mesorectal excision. The mesorectums of 15 patients were analysed by fluorescence-activated cell sorting, immunofluorescence and in situ hybridization. Based on the clinical and in vitro findings, a novel surgical approach for Crohn's disease patients with disturbed perineal healing after proctectomy was developed. Results In Crohn's disease, perineal complications were more frequent after close rectal dissection than after total mesorectal excision [59.5% vs 17.6%; p = 0.007] with lower healing rates [51.4% vs 88.2%; p = 0.014]. No differences were observed in ulcerative colitis. The mesorectal tissue in Crohn's disease contained enhanced numbers of tumour necrosis factor α-producing CD14+ macrophages, with less expression of the wound-healing marker CD206. Based on these findings, mesorectal excision with omentoplasty was performed in eight patients with perineal complications after close rectal dissection, resulting in complete perineal wound closure in six. Pro-inflammatory characteristics remained present in the mesorectum after close rectal dissection in these patients. Conclusions In Crohn's disease, close rectal dissection resulted in more perineal complications, associated with a pro-inflammatory immune status of the mesorectal tissue. Excision of this pro-inflammatory mesenteric tissue resulted in improved perineal healing rates.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease associated with considerable disease burden. We review some current misconceptions about UC in adults with the aim of optimizing care for patients. Although UC and Crohn’s disease (CD) are considered discrete diseases, distinctions between them are not always clear-cut and phenotypes may change over time. Patient management should take into account disease manifestations, disease severity and extent, and response to prior treatments. Although disease extent often defines severity, distal UC is not always less disabling than extensive disease as patients can progress to more extensive disease. In addition, severe proctitis can give rise to severe and debilitating symptoms, with a substantial impact on health-related quality of life. UC carries an increased risk of colorectal cancer (CRC) compared with CD; however, more recent data indicate a similar risk of CRC in CD with colonic involvement as with UC. Corticosteroids are widely used to induce remission in UC, and prolonged use of steroids in patients with UC is common, but corticosteroid-free maintenance of remission is an important therapeutic goal. Although biologic therapies provide a valuable treatment option in UC, they are not clinically effective in all patients and are also associated with secondary loss of response.

BACKGROUND: Combining clinical, endoscopic, and histological data associated with ulcerative colitis disease activity in a composite index could be a more sensitive way to detect efficacy in small numbers of patients during early drug development. Our aim was to derive and externally validate a novel index for this purpose. METHODS: Index development was done with data from a phase 2 placebo-controlled trial of ozanimod in patients with moderate-to-severe ulcerative colitis (n=179). Multivariable logistic regression modelling determined associations between candidate index items and absence of rectal bleeding (Mayo Clinic rectal bleeding subscore of 0), with items with a p value of less than 0·10 being taken forward into the final model. Model fit was internally validated and then externally validated in an independent phase 2 clinical trial dataset (MLN02, n=146) by measuring the area under the curve of the receiver operating characteristic (AUROC). FINDINGS: In the derivation cohort, multivariable analysis indicated that the Mayo Clinic stool frequency subscore (odds ratio [OR] 0·43, 95% CI 0·30-0·61; p

Background: Golimumab (GLM) is approved for the treatment of moderate to severe ulcerative colitis (UC). Higher serum concentrations of anti-tumor necrosis factor (TNF) agents are associated with improved clinical and endoscopic outcomes. Correlations between GLM serum concentrations and clinical and endoscopic outcomes were investigated during induction and maintenance treatment. In addition, a population pharmacokinetic model was developed to identify factors associated with the pharmacokinetics of GLM in UC. Methods: A prospective observational trial (GO-KINETIC) was conducted in patients with moderate to severe UC receiving induction and maintenance treatment with GLM. Clinical and endoscopic outcomes were evaluated, fecal GLM concentrations were measured and pharmacokinetic data were analyzed. Results: A total of 20 patients were enrolled. At week 8 (after induction treatment), 12 out of 20 patients (60%) showed an endoscopic response (≥1 point reduction in endoscopic Mayo score). Patients with endoscopic response at week 8 had numerically higher median GLM serum concentrations at week 2 compared to endoscopic non-responders: 9.1 µg/ml [5.9–12.3] vs. 7.1 µg/mL [5.2–9.0]; p =.384, respectively. At week 52, 3/20 patients (15%) achieved endoscopic remission (endoscopic Mayo score ≤1) and continued GLM treatment. Population pharmacokinetic analysis showed an inverse association between albumin concentrations and GLM clearance. GLM concentrations were undetectable in fecal samples. Conclusions: After induction therapy, 60% of the patients showed endoscopic response. During maintenance therapy, about one third of patients discontinued GLM treatment because of loss of response. These patients might benefit from dose optimization.

Background: Thiopurine-induced leukopenia, a frequently observed and potentially life-threatening adverse event, complicates the clinical management of IBD patients. Aim: To assess risk factors for thiopurine-induced leukopenia in IBD. Methods: MEDLINE, EMBASE, BIOSIS and Cochrane library were searched for studies reporting at least one risk factor for thiopurine-induced leukopenia. Pooled odds ratio (OR) was calculated for each potential risk factor using a random effects model. Studies that were not eligible for meta-analysis were described qualitatively. Results: Seventy articles were included, 34 (11 229 patients) were included in meta-analyses. A significantly higher thiopurine-induced leukopenia risk was found for TPMT (OR 3.9, 95% [CI] 2.5-6.1) and for NUDT15 R139C (OR 6.9, 95% CI 5.2-9.1), G52A (OR 3.2, 95% CI 1.3-7.9) and 36_37ins/delGGAGTC variant carriers (OR 5.6, 95% CI 2.8-11.4). A potential association between high 6-thioguanine nucleotides (6-TGN) or 6-methylmercaptopurine (6-MMP) levels and leukopenia was observed, since most studies reported higher metabolite levels in leukopenic patients (6-TGN: 204-308 (Lennard method) and 397 (Dervieux method), 6-MMP: 4020-10 450 pmol/8 x 108 RBC) compared to controls (6-TGN: 170-212 (Lennard method) and 269 (Dervieux method), 6-MMP: 1025-4550 pmol/8 x 108 RBC). Conclusions: TPMT and NUDT15 variants predict thiopurine-induced leukopenia. High 6-TGN and 6-MMP levels might induce leukopenia, although exact cut-off values remain unclear. Potential preventive measures to reduce the risk of thiopurine-induced leukopenia include pre-treatment TPMT and NUDT15 genotyping. Routine thiopurine metabolite measurement might be efficient, yet cut-off levels must be validated in advance.

Objective: We investigated relapse rates after anti-tumor necrosis factor (anti-TNF) withdrawal in inflammatory bowel disease (IBD) patients, response to restart of anti-TNF treatment and predictors for relapse. Methods: IBD patients in remission receiving infliximab or adalimumab treatment for ≥1 year who discontinued treatment were included. Relapse rates and predictors for relapse were studied using survival and Cox regression analysis. Results: In total, 101 patients were included (77 CD, 24 UC). A total of 56 patients (55%) experienced a relapse (CD 38, UC 18) with a median time to relapse of 32 and 18 months in CD and UC, respectively. Of patients that were retreated with the same anti-TNF agent, 84% responded. A trough serum concentration ≥2 µg/ml within 1 year prior to anti-TNF discontinuation was associated with a higher relapse rate in CD patients (HR 2.89; p =.018), which was more evident in patients requiring retreatment with biologicals, bowel-related surgery or experimental medication (HR: 4.18; p =.009). A young age (

Background & Aims: Guselkumab, a selective p19 interleukin-23 antagonist, is approved for the treatment of plaque psoriasis and psoriatic arthritis. This study evaluated the efficacy and safety of guselkumab in patients with moderately to severely active Crohn's disease with inadequate response or intolerance to conventional or biologic therapy. Methods: GALAXI-1, a phase 2, double-blind, placebo-controlled study, randomized patients 1:1:1:1:1 to intravenous guselkumab 200 mg, 600 mg, or 1200 mg at weeks 0, 4, and 8; intravenous ustekinumab approximately 6 mg/kg at week 0 and 90 mg subcutaneously at week 8; or placebo. Change from baseline in Crohn's Disease Activity Index score (primary end point), clinical remission, clinical response, Patient Reported Outcomes-2 remission, clinical-biomarker response, endoscopic response (major secondary end points), and safety in guselkumab-treated patients vs placebo were evaluated through week 12. Ustekinumab was a reference arm. Results: Of 309 patients evaluated, approximately 50% had disease refractory to prior biologic therapy. At week 12, significantly greater reductions in Crohn's Disease Activity Index from baseline (least squares means: 200 mg: –160.4, 600 mg: –138.9, and 1200 mg: –144.9 vs placebo: –36.2; all, P < .05) and significantly greater proportions of patients achieved clinical remission in each guselkumab group vs placebo (Crohn's Disease Activity Index

BACKGROUND AND AIMS: There are no universally accepted guidelines regarding surveillance of ulcerative colitis [UC] patients after restorative proctocolectomy and ileal pouch-anal anastomosis [IPAA]. There also exists a lack of validated quality assurance standards for performing pouchoscopy. To better understand IPAA surveillance practices in the face of this clinical equipoise, we carried out a retrospective cohort study at five inflammatory bowel disease [IBD] referral centres.METHODS: Records of patients who underwent IPAA for UC or IBD unclassified [IBDU] were reviewed, and patients with RESULTS: We included 272 patients. Median duration of pouch follow-up was 10.5 [3.3-23.6] years; 95/272 [35%] had never undergone pouchoscopy for any indication; 191/272 [70%] had never undergone pouchoscopy with surveillance as the specific indication; and 3/26 [12%] high-risk patients had never undergone pouchoscopy. Two cases of adenocarcinoma were identified, occurring in the rectal cuff of low-risk patients. Patients under the care of surgeons appeared more likely to undergo surveillance, but rates of incomplete reporting were higher among surgeons [78%] than gastroenterologists [54%, p = 0.002].CONCLUSIONS: We observed wide variation in surveillance of UC/IBDU-IPAA patients. In addition, the rate of neoplasia formation among 'low-risk' patients was higher than may have been expected. We therefore concur with previous recommendations that pouchoscopy be performed at 1 year postoperatively, to refine risk-stratification based on clinical factors alone. Reports should document findings in all regions of the pouch and biopsies should be taken.