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Item does not contain fulltext BACKGROUND: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis. METHODS: We conducted a randomised, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centres worldwide. We included adults (age 18-80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary endpoint was the proportion of patients who had both clinical response at week 10 (MCS ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1); efficacy was analysed using a modified intention-to-treat population (all randomised patients who received at least one dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT02136069, and is now closed to recruitment. FINDINGS: Between Dec 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n=199) or infliximab (n=198). 95 (48%) patients in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 (18·6%) of 199 patients in the etrolizumab group and 39 (19·7%) of 198 in the infliximab group met the primary endpoint (adjusted treatment difference -0·9% [95% CI -8·7 to 6·8]; p=0·81). The number of patients reporting one or more adverse events was similar between treatment groups (154 [77%] of 199 in the etrolizumab group and 151 [76%] of 198 in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 [28%] patients in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was one death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment. INTERPRETATION: To our knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary endpoint, etrolizumab performed similarly to infliximab from a clinical viewpoint. FUNDING: F Hoffmann-La Roche.

The prevalence of inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis, in Canada, is over 0.75% in 2021. Many individuals with IBD are immunocompromised. Consequently, the World Health Organization’s declaration of a global pandemic uniquely impacted those with IBD. Crohn’s and Colitis Canada (CCC) formed the COVID-19 and IBD Taskforce to provide evidence-based guidance during the pandemic to individuals with IBD and their families. The Taskforce met regularly through the course of the pandemic, synthesizing available information on the impact of COVID-19 on IBD. At first, the information was extrapolated from expert consensus guidelines, but eventually, recommendations were adapted for an international registry of worldwide cases of COVID-19 in people with IBD. The task force launched a knowledge translation initiative consisting of a webinar series and online resources to communicate information directly to the IBD community. Taskforce recommendations were posted to CCC’s website and included guidance such as risk stratification, management of immunosuppressant medications, physical distancing, and mental health. A weekly webinar series communicated critical information directly to the IBD community. During the pandemic, traffic to CCC’s website increased with 484,755 unique views of the COVID-19 webpages and 126,187 views of the 23 webinars, including their video clips. CCC’s COVID-19 and IBD Taskforce provided critical guidance to the IBD community as the pandemic emerged, the nation underwent a lockdown, the economy reopened, and the second wave ensued. By integrating public health guidance through the unique prism of a vulnerable population, CCC’s knowledge translation platform informed and protected the IBD community.

At the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there were many unknowns: transmission vectors of the virus, appropriate intervention strategies and if being immunocompromised due to inflammatory bowel disease (IBD), for example, or medications put a person at increased risk for severe COVID-19. Imposing and relaxing of public health restrictions at different times and in different regions in Canada led to different epidemiologies of the virus in different provinces and territories. In order to understand the waxing and waning of waves of the COVID-19 pandemic, it is necessary to understand the effective reproductive number (Rt) and the countervailing forces that exert upward or downward pressure on the spread of the virus at a given point in time. As many regions in Canada deal with a third wave, the primary forces affecting the Rt of severe acute respiratory syndrome coronavirus 2 are variants of concern and the increasing vaccinations of Canadians leading to increased population-level immunity. Fortunately, for the IBD population, current research suggests that those with IBD are not at increased risk of contracting COVID-19, nor of having a more severe disease course when compared to the general population.

The value of ustekinumab (UST) therapeutic drug monitoring (TDM) in clinical practice remains unclear. This study examined the impact of UST TDM on clinical decision making in patients with Crohn’s disease (CD). A total of 110 consecutive UST-treated CD patients were enrolled in this multicenter, single-arm cross-sectional study. During a single study visit, clinical decisions, disease characteristics, and serum and fecal samples were obtained. The primary outcome was congruency of the actual and two hypothetical clinical decisions based on provision of UST TDM (with and without fecal calprotectin [FCP]) to participating clinicians. Decisions were compared against those of a review panel. A sub-study retrospectively measured the associations of clinical outcomes at the next follow-up visit with serum UST concentration [UST]. No differences in the pattern of decisions by clinicians were observed before and after provision of UST TDM (P = 1.0) or UST TDM + FCP (P = 0.86). However, 39% (TDM) and 50% (TDM + FCP) of hypothetical decisions differed from the initial decisions. The review panel’s decisions differed with the addition of TDM + FCP (P = 0.0006), but not TDM alone (P = 0.16). The sub-study (n = 53) failed to detect an association between therapeutic serum [UST] at the initial study visit and clinical outcomes at the next visit. In consecutive CD patients treated with UST, the addition of TDM into routine clinical practice did not significantly impact clinical decisions and there was no association between short-term clinical outcomes and serum [UST]. Further studies are warranted before clinicians routinely implement UST TDM into clinical practice.

Background Targeting histological remission or response in Crohn's disease (CD) is not recommended in clinical practice guidelines or as an outcome in clinical trials due to uncertainties regarding index validity and prognostic relevance. Aims To conduct a modified RAND/University of California Los Angeles appropriateness process with the goal of producing a framework to standardise histological assessment of CD activity in clinical trials. Methods A total of 115 statements generated from literature review and expert opinion were rated on a scale of 1-9 by a panel of 11 histopathologists and 6 gastroenterologists. Statements were classified as inappropriate, uncertain or appropriate based upon the median panel rating and degree of disagreement. Results The panellists considered it important to measure histological activity in clinical trials to determine efficacy and that absence of neutrophilic inflammation is an appropriate histological target. They were uncertain whether the Global Histological Activity Score was an appropriate instrument for measuring histological activity. The Geboes Score and Robarts Histopathology Index were considered appropriate. Two biopsies from five segments should be biopsied, and the colon and the ileum should be analysed separately for all indices. Endoscopic mucosal appearance should guide biopsy procurement site with biopsies taken from the ulcer edge, or the most macroscopically inflamed area in the absence of ulcers. Conclusion We evaluated the appropriateness of items for assessing histological disease activity in CD clinical trials. These items will be used to develop a novel histological index.

Limited data suggest that non-melanoma skin cancer (NMSC) risk is higher in patients with inflammatory bowel disease (IBD) particularly in those on a tumor necrosis factor-α antagonist (TNF antagonist). It remains unknown whether TNF antagonist exposure alters the clinical course of NMSC in patients with IBD or if this therapy should be discontinued. To assess the impact of TNF antagonist exposure on NMSC severity, recurrence and need for ancillary treatments. Patients with IBD seen at London Health Sciences Centre, London, Canada were assessed for a history of NMSC and pre-diagnosis TNF antagonist exposure. NMSC severity (low risk and high risk), ancillary NMSC therapies, including chemo or radiotherapy, and changes to IBD therapy were assessed. Eleven of 472 patients with IBD reviewed were diagnosed with NMSC. Sixty-four percent (7/11) were on a TNF antagonist at the time of NMSC diagnosis. All patients with TNF antagonist exposure, (7/7) presented with a high-risk lesion based on National Comprehensive Cancer Network (NCCN) clinical practice guidelines. The incidence of positive margins was 42.9% (3/7) and 14.3% (1/7) required ancillary therapy. No metastatic disease was seen. TNF antagonist therapy was discontinued in a single patient due to NMSC diagnosis. Recurrent NMSC lesions were not seen in any of the TNF antagonist exposed patients. In this case series, TNF antagonist exposure may be associated with a severe NMSC clinical course. Larger studies are needed to confirm whether TNF antagonist discontinuation should be considered in the setting of NMSC diagnosis in IBD.

Background: Interleukin 17 (IL-17) inhibitors provide an excellent treatment option for patients with psoriasis and psoriatic arthritis, resulting in high levels of efficacy for skin clearance and joint improvement. Safety has also been established in clinical trials for this group of biologic agents; however, rare case reports of exacerbation or induction of inflammatory bowel disease (IBD) have been reported in the literature. No causal relationship has been established. When IL-17 inhibitors were investigated for the management of IBD, no benefit was found and worsening of disease was noted for some patients. IBD is more common in patients with psoriasis and, therefore, it remains unknown if these drugs cause de novo IBD or if the reported cases of IBD in patients on IL-17 therapy is due to the background risk in this predisposed population who may have already had an underlying or subclinical disease. Methods/Results: A literature search was conducted for the terms ‘IL-17 inhibitor,’ ‘ixekizumab,’ ‘secukinumab,’ ‘brodalumab’ and ‘inflammatory bowel disease,’ ‘ulcerative colitis,’ and ‘Crohn’s disease’ in PubMed and Google Scholar. Cases of newonset or exacerbation of IBD were identified in the literature along with postmarketing pharmacovigilance data. These cases will be reviewed in this paper. Conclusions: IL-17 inhibitors have proven efficacy for the treatment of psoriasis and psoriatic arthritis with a strong safety profile. However, rare cases of IBD onset and exacerbation in patients on IL-17 inhibitors have been reported in the literature, highlighting the need to select patients and therapeutic choices appropriately when treating this population.

Summary Background Etrolizumab is a gut-targeted, anti-β7 integrin, monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab in patients with moderately to severely active ulcerative colitis who had been previously treated with anti-tumour necrosis factor (TNF) agents. Methods HICKORY was a multicentre, phase 3, double-blind, placebo-controlled study in adult (18–80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6–12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) previously treated with TNF inhibitors. Patients were recruited from 184 treatment centres across 24 countries in North America, South America, Europe, Asia, Oceania, and the Middle East. Patients needed to have an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In cohort 1, patients received open-label etrolizumab 105 mg every 4 weeks for a 14-week induction period. In cohort 2, patients were randomly assigned (4:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks for the 14-week induction phase. Patients in either cohort achieving clinical response to etrolizumab induction were eligible for the maintenance phase, in which they were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks through to week 66. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants (induction randomisation only), baseline disease activity, week 14 MCS remission status (maintenance randomisation only), and induction cohort (maintenance randomisation only). All patients and study site personnel were masked to treatment assignment. Primary endpoints were remission (Mayo Clinic total score [MCS] ≤2, with individual subscores of ≤1 and a rectal bleeding subscore of 0) at week 14, and remission at week 66 among patients with a clinical response (MCS with ≥3-point decrease and ≥30% reduction from baseline, plus ≥1 point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) at week 14. Efficacy was analysed using a modified intent-to-treat population. Safety analyses included all patients who received at least one dose of study drug during the induction phase. This study is registered at ClinicalTrials.gov , NCT02100696 . Findings HICKORY was conducted from May 21, 2014, to April 16, 2020, during which time 1081 patients were screened, and 609 deemed eligible for inclusion. 130 patients were included in cohort 1. In cohort 2,479 patients were randomly assigned to the induction phase (etrolizumab n=384, placebo n=95). 232 patients were randomly assigned to the maintenance phase (etrolizumab to etrolizumab n=117, etrolizumab to placebo n=115). At week 14, 71 (18·5%) of 384 patients in the etrolizumab group and six (6·3%) of 95 patients in the placebo group achieved the primary induction endpoint of remission (p=0·0033). No significant difference between etrolizumab and placebo was observed for the primary maintenance endpoint of remission at week 66 among patients with a clinical response at week 14 (27 [24·1%] of 112 vs 23 [20·2%] of 114; p=0·50). Four patients in the etrolizumab group reported treatment-related adverse events leading to treatment discontinuation. The proportion of patients reporting at least adverse event was similar between treatment groups for induction (etrolizumab 253 [66%] of 384; placebo 63 [66%] of 95) and maintenance (etrolizumab to etrolizumab 98 [88%] of 112; etrolizumab to placebo 97 [85%] of 114). The most common adverse event in both groups was ulcerative colitis flare. Most adverse events were mild or moderate. During induction, the most common serious adverse event was ulcerative colitis flare (etrolizumab ten [3%] of 384; placebo: two [2%] of 95). During maintenance, the most common serious adverse event in the etrolizumab to etrolizumab group was appendicitis (two [2%] of 112) and the most common serious adverse events in the etrolizumab to placebo group were ulcerative colitis flare (two [2%] of 114) and anaemia (two [2%] of 114). Interpretation HICKORY demonstrated that a significantly higher proportion of patients with moderately to severely active ulcerative colitis who had been previously treated with anti-TNF agent were able to achieve remission at week 14 when treated with etrolizumab compared with placebo; however, there was no significant difference between groups in remission at week 66 among patients with a clinical response at week 14. Funding F Hoffmann-La Roche.

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.

BACKGROUND: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab for maintenance of remission in patients with moderately to severely active ulcerative colitis. METHODS: We conducted a randomised, placebo-controlled, double-blind, phase 3 study (LAUREL) across 111 treatment centres worldwide. We included adults (age 18-80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. During open-label induction, participants received subcutaneous etrolizumab 105 mg once every 4 weeks. Participants who had clinical response at week 10 (MCS with ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) proceeded into the double-blind maintenance phase and were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or matched placebo until week 62. Randomisation was stratified by baseline concomitant treatment with corticosteroids, treatment with immunosuppressants, baseline disease activity, and week 10 remission status. All participants and study site personnel were masked to treatment assignment. The primary endpoint was remission at week 62 (MCS ≤2, with individual subscores ≤1, and rectal bleeding subscore of 0) among patients with a clinical response at week 10, measured in the modified intention-to-treat population (all randomised patients who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, NCT02165215, and is now closed to recruitment. FINDINGS: Between Aug 12, 2014, and June 4, 2020, 658 patients were screened for eligibility and 359 were enrolled into the induction phase. 214 (60%) patients had a clinical response at week 10 and were randomly assigned to receive etrolizumab (n=108) or placebo (n=106) in the maintenance phase. 80 (74%) patients in the etrolizumab group and 42 (40%) in the placebo group completed the study through week 62. Four patients in the placebo group did not receive study treatment and were excluded from the analyses. At week 62, 32 (29·6%) of 108 patients in the etrolizumab group and 21 (20·6%) of 102 in the placebo group were in remission (adjusted treatment difference 7·7% [95% CI -4·2 to 19·2]; p=0·19). A greater proportion of patients reported one or more adverse events in the placebo group (82 [80%] of 102) than in the etrolizumab group (70 [65%] of 108); the most common adverse event in both groups was ulcerative colitis (16 [15%] patients in the etrolizumab group and 37 [36%] in the placebo group). Ten (9%) patients in the etrolizumab group and eight (8%) in the placebo group reported one or more serious adverse events. No deaths were reported in either treatment group. INTERPRETATION: No significant differences were observed between maintenance etrolizumab and placebo in the primary endpoint of remission at week 62 among patients who had a clinical response at week 10. Etrolizumab was well tolerated in this population and no new safety signals were identified. FUNDING: F Hoffmann-La Roche. ispartof: LANCET GASTROENTEROLOGY & HEPATOLOGY vol:7 issue:1 pages:28-37 ispartof: location:Netherlands status: published

BACKGROUND: Endoscopy is routine in trials of ulcerative colitis therapies. AIM: To investigate agreement between central and local Mayo endoscopic subscore (MES) reads in the OCTAVE programme METHODS: Flexible sigmoidoscopy was performed in tofacitinib induction (OCTAVE Induction 1&2, NCT01465763 and NCT01458951), maintenance (OCTAVE Sustain, NCT01458574) and open-label, long-term extension (OCTAVE Open, NCT01470612) studies. Kappa statistics and Bowker's tests evaluated agreement/disagreement between centrally and locally read MES, with potential determinants of differences analysed by logistic regression. RESULTS: Moderate-to-substantial agreement was observed between central and local reads at screening (77.1% agreement; kappa 0.62 [95% confidence interval 0.59-0.66]), OCTAVE Induction 1&2 week (Wk) 8 (63.8%; 0.62 [0.59-0.66]), OCTAVE Sustain Wk 52 (55.6%; 0.56 [0.50-0.62]) and for induction non-responders at OCTAVE Open month 2 (59.9%; 0.54 [0.48-0.60]). Where disagreements occurred, local reads were systematically lower than central reads at OCTAVE Induction 1&2 Wk 8, OCTAVE Sustain Wk 52 and OCTAVE Open month 2 (Bowker's P

Fistulizing complications develop in approximately one third of patients with Crohn's disease (CD), resulting in morbidity and impaired quality of life.1 Sites of fistulae most commonly include perianal fistulae, but also enterocutaneous, enteroenteric, enterovesical, and rectovaginal. Its management requires combined medical and surgical strategies to prevent abscess formation and induce healing. Biologic agents have improved the medical treatment of CD-related fistulae, but many patients still require surgical intervention. Hence, there is considerable interest in the development of novel pharmaceutical agents to treat fistulizing CD.

BACKGROUND Janus kinase (JAK) inhibitors represent a novel therapeutic class for treatment of inflammatory bowel disease. AIMS To determine the efficacy and safety of JAK inhibitors compared to placebo for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). METHODS PubMed, Embase and CENTRAL were systematically searched to November 1, 2018. Randomised placebo-controlled trials (RCTs) of JAK inhibitors in adult patients with CD or UC were eligible. Open-label extension studies without a placebo comparator arm were excluded. Clinical, endoscopic, and safety outcomes were extracted and rates relative to placebo were pooled using a random-effects model. RESULTS A total of 12 RCTs (5 CD, 7 UC) were included. Patients were randomised to placebo (n = 844), tofacitinib (n = 1882), filgotinib (n = 130), peficitinib (n = 176), upadacitinib (n = 387) or TD-1473 (n = 31). JAK inhibitor treatment was associated with induction of clinical remission in CD (RR, relative risk 1.38 [95% confidence interval CI 1.04-1.83], P = 0.025, I2 = 14%) and UC (RR 3.07 [95% CI 2.03-4.63], P

Background and Aims Nocebo effects, adverse outcomes occurring in patients receiving inert therapy, contribute to adverse event [AE] reporting in randomized controlled trials [RCTs]. High placebo AE rates may result in inaccurate estimation of treatment-related AEs. We estimate the pooled rate of AEs in patients randomized to placebo compared to active therapy in inflammatory bowel disease [IBD] RCTs. Methods MEDLINE, EMBASE and CENTRAL were searched to March 1, 2017 for RCTs of conventional medical therapies for Crohn’s disease [CD] or ulcerative colitis [UC]. Rates of AEs, serious AEs [SAEs], AE-related trial withdrawal, infections and worsening IBD were pooled using a random-effects model. Results We included 124 CD [n = 26 042] and 71 UC RCTs [n = 16 798]. The pooled placebo AE rate was 70.6% (95% confidence interval [CI]: 65.3%, 75.4%) and 54.5% [47.8%, 61.1%] in CD and UC RCTs, respectively. There was no significant risk difference [RD] in AE, SAE or AE-related withdrawal rates between CD patients receiving placebo or active drug. A 1.6% [95% CI: 0.1%, 3.1%] increase in AE rates was observed among UC patients randomized to active therapy. Patients receiving active therapy had a higher risk of infection (RD 1.0% [95% CI: 0.4%, 1.7%] for CD, 2.9% [95% CI: 1.4%, 4.4%] for UC) although a lower risk of worsening CD (RD −3.2% [95% CI: −4.8%, −1.5%]) or UC (RD –3.7% [95% CI: –5.7%, –1.8%]). Conclusions AEs are commonly reported by patients randomized to either placebo or active treatment in IBD RCTs. Clinically relevant differences in AE, SAE and AE-related withdrawal were not observed.

BACKGROUND Physicians may be reluctant to prescribe combined immunosuppression in older patients with Crohn's disease due to perceived risk of treatment-related complications. AIM To evaluate the impact of age on risk of Crohn's disease-related complications in patients treated with early combined immunosuppression vs conventional management in a post hoc analysis of the randomised evaluation of an algorithm for Crohn's treatment (REACT), a cluster-randomised trial. METHODS We compared efficacy (time to major adverse outcome of Crohn's disease-related surgery, hospitalisation or serious complications; corticosteroid-free clinical remission) and safety outcomes at 24 months, between patients aged

Vedolizumab, a humanized monoclonal antibody to the α4β7 integrin, reduces lymphocyte trafficking to the intestine. This gut-selective mechanism of action offers a safer alternative to other biologics used to treat ulcerative colitis (UC) and Crohn's disease (CD). We reviewed efficacy and safety data from randomized controlled trials (RCTs), open-label extension (OLE) and observational studies, and pooled analyses of vedolizumab therapy. In UC, RCTs demonstrate that vedolizumab is effective for induction and maintenance of remission, regardless of prior tumor necrosis factor (TNF) antagonist exposure. In CD, vedolizumab is moderately effective as an induction therapy and demonstrates efficacy as a maintenance agent. Secondary analyses indicate that prolonged induction therapy may result in greater efficacy, particularly in TNF antagonist-exposed patients. Comparative efficacy studies and network meta-analyses show similar efficacy to other biologic therapies. OLE studies in UC and CD demonstrate the durability of maintenance efficacy and low serious adverse event (SAE) rates. In an integrated safety analysis of controlled data, there was no significant difference in adverse event, SAE, infection and serious infection rates between vedolizumab and placebo. No drug-specific safety signals were identified. Immunogenicity rates were low and no cases of progressive multifocal leukoencephalopathy directly attributable to vedolizumab are reported in the literature. Vedolizumab is effective for induction and maintenance of inflammatory bowel disease with low treatment-related risks. Given the high therapeutic index of this gut-specific agent, it can be used as either a first- or second-line biologic therapy for UC and CD.

Persons with inflammatory bowel disease (IBD) make up more than 0.75% of the Canadian population in 2021. Early in the COVID-19 pandemic, individuals with IBD, particularly those on immunosuppressive therapies, were concerned that their health status may place them at higher risk of contracting COVID-19 or experiencing more severe disease course if infected with SARS-CoV-2. In response, Crohn’s and Colitis Canada developed the COVID-19 and IBD Taskforce in March 2020 to rapidly synthesize the evolving knowledge of COVID-19 as relevant to Canadians with IBD. The Taskforce communicated expert information directly to the Canadian IBD community through online tools and a webinar series. In order to understand the full impact of COVID-19 on the IBD community, Crohn’s and Colitis Canada commissioned a policy report that was informed through a systematic literature review and synthesized across working groups along the following domains: Epidemiology, Children and Expectant Mothers with IBD, Seniors with IBD, Mental Health, Risk Factors and Medications, Vaccines, and Healthcare Delivery during the Pandemic and the Future Model of IBD Care. This report from Canadian physicians, researchers, and IBD community representatives highlights the physical, mental, and health systems impact of COVID-19 on the entire spectrum of the IBD community, including children, adolescents, adults, seniors, and pregnant people with IBD. This executive summary provides an overview of the crucial information from each of the chapters of the policy report, supplemented with additional information made available through Crohn’s and Colitis Canada’s webinar-based knowledge translation platform.

Background We assessed whether differential efficacy of early combined immunosuppression (ECI) in comparison with conventional management (CM) is present in patients with Crohn disease (CD) according to disease location. Methods In this posthoc analysis of the Randomized Evaluation of an Algorithm for Crohn’s Treatment trial, the effect of ECI vs CM modified by disease location (isolated-colonic vs ileal-dominant) in terms of time to first complication (hospitalization, surgery, or disease-related complications—presence of a new abscess, fistula, or stricture; serious worsening of disease activity; extraintestinal manifestations) was analyzed using a marginal Cox proportional hazard model to account for cluster randomization. Factors adjusted included practice size, country, and other covariates selected in a backward logistic regression analysis with the first composition as outcome and P < 0.10. Results Of the 1969 patients with CD, 435 had isolated colonic CD (ECI n = 257, CM n = 178) and 1534 had ileal CD (ECI n = 817, CM n = 717). Over 24 months there was a significant differential impact for ECI vs CM for reducing the risk of a CD-related complication between patients with colonic CD and ileal CD (colonic CD hazard ratio [HR] = 0.51; 95% CI, 0.30-0.85 vs ileal CD HR = 0.79; 95% CI, 0.57-1.10; P = 0.033). No difference was identified between ECI vs CM for reducing the risk of surgery (colonic HR = 0.52 vs ileal HR = 0.74; P = 0.468) or hospitalization (colonic HR = 0.77 vs ileal HR = 0.83; P = 0.806). Conclusions In this posthoc analysis of the Randomized Evaluation of an Algorithm for Crohn’s Treatment trial, symptom-based ECI was associated with greater efficacy for reducing the risk of CD-related complications in patients with colonic disease location relative to ileal disease location.

BACKGROUND: Conventional medications for Crohn's disease (CD) include anti‐inflammatory drugs, immunosuppressants and corticosteroids. If an individual does not respond, or loses response to first‐line treatments, then biologic therapies such as tumour necrosis factor‐alpha (TNF‐α) antagonists such as adalimumab are considered for treating CD. Maintenance of remission of CD is a clinically important goal, as disease relapse can negatively affect quality of life. OBJECTIVES: To assess the efficacy and safety of adalimumab for maintenance of remission in people with quiescent CD. SEARCH METHODS: We searched the Cochrane IBD Group Specialized Register, CENTRAL, MEDLINE, Embase, and clinicaltrials.gov from inception to April 2019. SELECTION CRITERIA: We considered for inclusion randomized controlled trials (RCTs) comparing adalimumab to placebo or to an active comparator. DATA COLLECTION AND ANALYSIS: We analyzed data on an intention‐to‐treat basis. We calculated risk ratios (RRs) and corresponding 95% confidence intervals (95% CI) for dichotomous outcomes. The primary outcome was failure to maintain clinical remission. We define clinical remission as a Crohn's Disease Activity Index (CDAI) score of < 150. Secondary outcomes were failure to maintain clinical response, endoscopic remission, endoscopic response, histological remission and adverse events (AEs). We assessed biases using the Cochrane 'Risk of bias' tool. We used GRADE to assess the overall certainty of evidence supporting the primary outcome. MAIN RESULTS: We included six RCTs (1158 participants). We rated four trials at low risk of bias and two trials at unclear risk of bias. All participants had moderate‐to‐severe CD that was in clinical remission. Four studies were placebo‐controlled (1012 participants). Two studies (70 participants) compared adalimumab to active medication (azathioprine, mesalamine or 6‐mercaptopurine) in participants who had an ileocolic resection prior to study enrolment. Adalimumab versus placebo Fifty‐nine per cent (252/430) of participants treated with adalimumab failed to maintain clinical remission at 52 to 56 weeks, compared with 86% (217/253) of participants receiving placebo (RR 0.70, 95% CI 0.64 to 0.77; 3 studies, 683 participants; high‐certainty evidence). Among those who received prior TNF‐α antagonist therapy, 69% (129/186) of adalimumab participants failed to maintain clinical or endoscopic response at 52 to 56 weeks, compared with 93% (108/116) of participants who received placebo (RR 0.76, 95% CI 0.68 to 0.85; 2 studies, 302 participants; moderate‐certainty evidence). Fifty‐one per cent (192/374) of participants who received adalimumab failed to maintain clinical remission at 24 to 26 weeks, compared with 79% (149/188) of those who received placebo (RR 0.66, 95% CI 0.52 to 0.83; 2 studies, 554 participants; moderate‐certainty evidence). Eighty‐seven per cent (561/643) of participants who received adalimumab reported an AE compared with 85% (315/369) of participants who received placebo (RR 1.01, 95% CI 0.94 to 1.09; 4 studies, 1012 participants; high‐certainty evidence). Serious adverse events were seen in 8% (52/643) of participants who received adalimumab and 14% (53/369) of participants who received placebo (RR 0.56, 95% CI 0.39 to 0.80; 4 studies, 1012 participants; moderate‐certainty evidence) and withdrawal due to AEs was reported in 7% (45/643) of adalimumab participants compared to 13% (48/369) of placebo participants (RR 0.59, 95% CI 0.38 to 0.91; 4 studies, 1012 participants; moderate‐certainty evidence). Commonly‐reported AEs included CD aggravation, arthralgia, nasopharyngitis, urinary tract infections, headache, nausea, fatigue and abdominal pain. Adalimumab versus active comparators No studies reported failure to maintain clinical remission. One study reported on failure to maintain clinical response and endoscopic remission at 104 weeks in ileocolic resection participants who received either adalimumab, azathioprine or mesalamine as post‐surgical maintenance therapy. Thirteen per cent (2/16) of adalimumab participants failed to maintain clinical response compared with 54% (19/35) of azathioprine or mesalamine participants (RR 0.23, 95% CI 0.06 to 0.87; 51 participants). Six per cent (1/16) of participants who received adalimumab failed to maintain endoscopic remission, compared with 57% (20/35) of participants who received azathioprine or mesalamine (RR 0.11, 95% CI 0.02 to 0.75; 51 participants; very low‐certainty evidence). One study reported on failure to maintain endoscopic response at 24 weeks in ileocolic resection participants who received either adalimumab or 6‐mercaptopurine (6‐MP) as post‐surgical maintenance therapy. Nine per cent (1/11) of adalimumab participants failed to maintain endoscopic remission compared with 50% (4/8) of 6‐MP participants (RR 0.18, 95% CI 0.02 to 1.33; 19 participants). AUTHORS' CONCLUSIONS: Adalimumab is an effective therapy for maintenance of clinical remission in people with quiescent CD. Adalimumab is also effective in those who have previously been treated with TNF‐α antagonists. The effect of adalimumab in the post‐surgical setting is uncertain. More research is needed in people with recent bowel surgery for CD to better determine treatment plans following surgery. Future research should continue to explore factors that influence initial and subsequent biologic selection for people with moderate‐to‐severe CD. Studies comparing adalimumab to other active medications are needed, to help determine the optimal maintenance therapy for CD.

'Treat-to-target' paradigms in Crohn's disease (CD) directed at suppressing intestinal inflammation require accurate and reliable measures of disease activity. Although endoscopy has traditionally been considered a gold standard, cost, complexity, resource limitations, and invasiveness are important limitations. Hence, substantial interest exists for non-invasive serum and fecal biomarkers, namely C-reactive protein (CRP) and fecal calprotectin (FC), in the diagnosis, monitoring, and treatment of CD. Areas covered: We review the evidence for using serum CRP and FC in distinguishing patients with CD from those with irritable bowel syndrome, categorizing disease activity among patients with an established diagnosis of CD, predicting the likelihood of treatment response, identifying asymptomatic patients in medically or surgically induced remission who are at risk for disease relapse, and as treatment targets. Expert commentary: Accurate interpretation of CRP and FC is dependent on several factors including the clinical context, the performance characteristics of the assay, the specified test cut-offs, and the pre-test probability of disease. Emerging evidence indicates that CRP and FC are valuable adjuncts for the management of CD in specific circumstances described in this review.

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

In patients with Crohn's disease and ulcerative colitis, poor correlation between symptoms and active luminal inflammation has been well established. As a result, the field has moved towards the use of endoscopic assessment to evaluate inflammatory activity. Numerous endoscopic indices have been used for this purpose although none are completely validated. The Simple Endoscopic Score for Crohn's Disease and the Crohn's Disease Endoscopic Index of Severity have been used most frequently; however in addition to incomplete validation, they have important limitations for clinical use, including complexity of scoring and poor reliability of items such as stenosis. The Rutgeerts' score for postoperative Crohn's disease was developed primarily as a prognostic rather than evaluative tool and also requires additional validation. In ulcerative colitis, the Mayo endoscopic subscore has been used as the regulatory standard, although the Ulcerative Colitis Endoscopic Index of Severity may provide a more granular assessment of individual components of disease activity. The use of combined outcomes with patient reported outcomes (PROs) and endoscopic indices has received favor by regulatory bodies but require further validation. This review describes the indications for endoscopic assessment in trials, the indices most frequently utilized for these purposes, and potential future approaches to assessment of disease activity.

Prokinetics are recommended for the treatment of functional dyspepsia (FD) but systematic reviews give conflicting results on the efficacy of these agents. We have therefore conducted an updated systematic review to support the 2017 joint ACG/CAG dyspepsia guidelines. Electronic databases, including MEDLINE, EMBASE, and CENTRAL, were searched until September 2017 for randomized controlled trials (RCTs) comparing either prokinetics and placebo or two types of prokinetics to improve FD symptoms. The primary outcome was absence or improvement of dyspeptic symptoms at the end of treatment. Double-blind eligibility assessment and data extraction was performed. Pooled risk ratios of symptoms persisting or adverse events occurring, and standardized mean difference of quality-of-life (QoL) scores with 95% CI, using a random effects model, were calculated. Quality of evidence was assessed using GRADE. The search identified 1388 citations; 38 studies in 35 papers were included. Of these, 29 trials comparing prokinetics with placebo were found. There was a statistically significant effect of prokinetic treatment in reducing global symptoms of FD (RR 0.81, 95% CI 0.74 to 0.89; I2 91%; NNT 7), regardless of FD subtype or ethnicity. When comparing two types of prokinetic, the most commonly used comparator was domperidone. There was no difference in reducing global symptoms (RR 0.94, 95% CI 0.83 to 1.07). QoL was not improved with prokinetic treatment. The adverse events with individual prokinetics were not different from placebo, except for cisapride. The GRADE assessment rated the quality of the evidence in each outcome as very low. From the current evidence, prokinetics may be effective for the treatment in all subtypes of FD, with very low quality of evidence. There was no difference between prokinetics for dyspeptic symptom improvement. High-quality RCTs with large sample sizes of FD patients are needed to verify the efficacy of prokinetics.

ObjectiveWe evaluated the reliability and responsiveness of available but incompletely validated UC histological disease activity indices using standardised rules for centralised assessment.DesignDisease activity was assessed in biopsies collected in a phase II placebo-controlled ozanimod trial by four blinded pathologists using the Geboes (GS) and modified Riley (MRS) scores, the Robarts Histopathology (RHI) and Nancy Histological (NHI) indices and a Visual Analogue Scale. Reliability was assessed with intraclass correlation coefficients (ICCs). Index responsiveness was evaluated by assessing longitudinal validity (Pearson correlations of changes in index scores and other disease measures), and effect size estimates (standardised effect size (SES)) using two criteria for change (treatment assignment and >2 point decrease in total Mayo Clinic score). Area under the receiver operating characteristic (AUROC) curve estimates evaluated the probability of the indices to discriminate between treatment and placebo.ResultsInter-rater reliability of the histological indices was substantial to almost perfect (ICC>0.61), and responsiveness was moderate to large (SES estimates>0.5); 0.81 (0.52, 1.10), 0.87 (0.58, 1.17), 0.57 (0.30, 0.84) and 0.81 (0.52, 1.09) when treatment assignment was the criterion for change and 1.05 (0.80, 1.31), 1.13 (0.87, 1.39), 0.88 (0.64, 1.12) and 1.06 (0.80, 1.31) for the change in Mayo score criterion for the GS, MRS, RHI and NHI, respectively. The indices had similar drisciminative ability based on AUROC estimates (range 0.608–0.649).ConclusionAll four existing histological indices were similarly reliable and responsive based on this dataset.

Introduction: Medical therapy for Crohn’s disease (CD) is directed at controlling intestinal inflammation to prevent development of disease-related complications. Not all patients will respond to c...

Background & Aims Crohn’s disease (CD) is a lifelong illness with substantial morbidity, although new therapies and treatment paradigms have been developed. We provide guidance for treatment of ambulatory patients with mild to severe active luminal CD. Methods We performed a systematic review to identify published studies of the management of CD. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a group of specialists. Results The consensus includes 41 statements focused on 6 main drug classes: antibiotics, 5-aminosalicylate, corticosteroids, immunosuppressants, biologic therapies, and other therapies. The group suggested against the use of antibiotics or 5-aminosalicylate as induction or maintenance therapies. Corticosteroid therapies (including budesonide) can be used as induction, but not maintenance therapies. Among immunosuppressants, thiopurines should not be used for induction, but can be used for maintenance therapy for selected low-risk patients. Parenteral methotrexate was proposed for induction and maintenance therapy in patients with corticosteroid-dependent CD. Biologic agents, including tumor necrosis factor antagonists, vedolizumab, and ustekinumab, were recommended for patients failed by conventional induction therapies and as maintenance therapy. The consensus group was unable to clearly define the role of concomitant immunosuppressant therapies in initiation of treatment with a biologic agent. Conclusions Optimal management of CD requires careful patient assessment, acknowledgement of patient preferences, evidence-based use of existing therapies, and thorough assessment to define treatment success.

In patients with Crohn's disease (CD) and ulcerative colitis (UC), the use of therapeutic drug monitoring (TDM) with TNF-α antagonists has led to a personalized approach to optimize treatment and has been shown to be cost-effective. The utility of this TDM-based personalized approach for novel biologic agents, which target different inflammatory pathways, is unclear. Commercial assays for ustekinumab (UST) and vedolizumab (VDZ) are available, but there is little available guidance for clinicians regarding the use of TDM with these drugs. Although there is limited evidence for definitive threshold concentrations for UST and VDZ, this review highlights the available literature on the pharmacokinetics of these medications, the association of clinical and endoscopic outcomes with drug concentrations, and the clinical utility of TDM to guide treatment decisions.

Background: Regulatory requirements for claims of mucosal healing in ulcerative colitis (UC) will require demonstration of both endoscopic and histologic healing. Quantifying these rates is essential for future drug development. Aims: To meta-analyse endoscopic and histologic placebo response and remission rates in UC randomised controlled trials (RCTs) and identify factors influencing these rates. Methods: MEDLINE, EMBASE and the Cochrane Library were searched from inception to March 2017 for placebo-controlled trials of pharmacological interventions for UC. Endoscopic and histologic placebo rates were pooled by random effects. Mixed effects univariable and multivariable meta-regression was used to evaluate the influence of patient, intervention and trial-related study-level covariates on these rates. Results: Fifty-six induction (placebo n = 4171) and 8 maintenance trials (placebo n = 1011) were included. Pooled placebo endoscopic remission and response rates for induction trials were 23% [95 confidence interval (CI) 19-28%] and 35% [95% CI 27-42%] respectively, and 20% [95% CI 16-24%] for maintenance of remission. The pooled histologic placebo remission rate was 14% [95% CI 8-22%] for induction trials. High heterogeneity was observed for all outcomes (I2 56.2%-88.3%). On multivariable meta-regression, central endoscopy reading was associated with significantly lower endoscopic placebo remission rates (16% vs 25%; OR = 0.52, [95% CI 0.29-0.92], P = 0.03). On univariable meta-regression, higher histologic placebo remission was associated with concomitant corticosteroids (OR = 1.17 [95% CI 1.08-1.26], P

Recently in Gut , Gottlieb et al summarised considerations for endoscopy central reading in IBD clinical trials.1 Achieving endoscopic remission is an important measure of therapeutic efficacy, and most Crohn’s disease (CD) trials now require video-recorded ileocolonoscopy at screening and for evaluation of the primary outcome. While the Crohn’s Disease Endoscopic Index of Severity (CDEIS)2 and the Simplified Endoscopic Score for Crohn’s Disease (SES-CD)3 are commonly used instruments, Gottlieb et al correctly highlight that these scores are sensitive to missing data if one or more of the five ileocolonic segments are not examined. Bowel segments may not be visualised if there is an impassable stricture, when the bowel preparation is poor or if there are technical challenges precluding procedure completion. In these situations, appropriately handling missing data is essential because the total endoscopic score may not be reflective of the actual disease burden. We empirically evaluated the effect of different methods for handling missing data from non-visualised segments on the SES-CD and CDEIS. Ileocolonoscopy videos from baseline and week 12 in the Extend the Safety and Efficacy of Adalimumab through Endoscopic Healing (EXTEND) trial were used.4 EXTEND was a randomised, placebo-controlled trial evaluating adalimumab in patients with moderate-to-severe CD. Six methods of handling missing segments were applied: 1. No imputation: non-visualised segments ignored. 2. Worst …

Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak, also known as COVID-19, initially began in a small cluster of patients in Wuhan, China and was declared a worldwide pandemic in March of 2020. Since the onset of the pandemic, the focus of many healthcare systems has shifted toward limiting non-essential visits to the hospital in order to prioritize and allocate resources toward treating those affected by COVID-19. While the effect of COVID-19 has been felt amongst many patient populations, those with Inflammatory Bowel Disease (IBD) have been particularly impacted. We aimed to determine how changes to the provision of IBD care due to the COVID-19 pandemic has affected IBD patients. Methods A retrospective cohort study was carried out in patients with an IBD diagnosis comparing patients admitted to two tertiary care centres affiliated with Western University in London, Canada between March 17 and August 31 2019 (2019 cohort or pre-pandemic), to patients admitted between March 17 and August 31 2020 (2020 cohort or pandemic). Patients were reviewed to assess any differences in care utilization and IBD-related outcomes such as hospitalization, need for surgery, length of stay in hospital and in-patient drug therapy during the defined time periods. Results A total of 863 patients were reviewed in 2019, and 554 in 2020. Of those, 184 (CD, n= 125; UC, n= 59) and 172 (CD, n= 109; UC, n= 62) encounters met the inclusion criteria for 2019 and 2020 respectively. Patient demographics were similar between 2019 and 2020 cohort with the exception of age (2019, mean age = 44.76 years ± 16.78; 2020, mean age=50.36 years ± 17.82, p=0.002). The length of stay in hospital was shorter in 2020 (6.88 days vs 9.63, p=0.045). Significantly fewer patients were initiated on Infliximab in hospital in 2020 (2020, 3.50 per month; 2019, 6.83 per month, p=0.001). Fewer in-patient surgeries were performed in 2020 (2019, 76; 2020, 57; p=0.112). Conclusion Preliminary data demonstrate during the COVID-19 pandemic there was a significant reduction in the length of stay for patients with IBD as well as fewer patients initiated on infliximab while in hospital. There was also a decrease in the number of surgeries performed in 2020. These differences may reflect an effort to minimize contact between patients and health care facilities as well as reduce the introduction of further immunosuppression. Further research will be to determine whether if more ER visits became hospitalizations and any delays in appointment times or endoscopies, or compliance issues with medications may have led to these aforementioned outcomes.

Background We aim to explore the impact of COVID-19 pandemic-related restrictions on gastroenterologists providing care to inflammatory bowel disease (IBD) patients in Canada. Methods We invited 28 Canadian gastroenterology societies, 14 academic centres and 101 community hospitals and private clinics to have their gastroenterologists engage in an online mixed methods survey from December 2020 - March 2021. The survey explored the impact of pandemic-related restrictions on gastroenterologists managing IBD patients and the impact on clinical decision-making, rates of consultation, investigations and endoscopies conducted before and during the pandemic. Results 59 gastroenterologists (59.3% male) participated in our study with 40.7% having completed additional training in IBD. Respondents mean age was 43.7 years with 30.5% practising independently for a duration of less than or equal to 5 years. The majority of respondents were from Ontario (43.1%), Quebec (31%) and British Columbia (13.8%) with 62.7% practising primarily at an academic centre. 93.2% of respondents reported that their practice was affected by the pandemic. 44.6% note a reduction in the number of total consultations completed. Only 60% were able to arrange endoscopies for patients in an active IBD flare at an appropriate time interval compared to their pre-COVID practice. During the pandemic, 87.3% reported a reduction in the total endoscopies performed, with 43.8% of those individuals noting a minimum reduction of 25% of previous volumes. The following barriers attributed to the decrease in endoscopies performed during the pandemic: institutional-imposed restriction on daily allowed endoscopies (97.9%), indication for endoscopy was non-urgent (68.8%) and patient-requested cancellation due to a fear of contracting COVID-19 (87.5%). 63.6% of respondents were able to arrange outpatient laboratory investigations in less than 1-week prior to the pandemic vs. 41.8% arranging similar tests in 1–2 weeks during the pandemic. 50.9% were able to arrange diagnostic investigations in 1–2 months before the pandemic vs. 65% arranging similar tests in 3-months or more during the pandemic. When advancing drug therapy in IBD patients before versus during the pandemic, respondents reported the following factors as playing a crucial role in clinical decision making: patient symptomatology (87% vs. 79.3%), laboratory investigations (94.8% vs. 96.6%), diagnostic imaging (89.7% vs. 81%) and endoscopy findings (89.7% vs 72.4%). Conclusion We illustrate that Canadian gastroenterologists have been affected by the pandemic, with decreases in endoscopy performance related to access and patient preference and less decision-making guided by endoscopy. Outpatient access to urgent investigations was reduced.

Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak, also known as COVID-19, was declared a worldwide pandemic in March of 2020. Since the onset of the pandemic, the focus of many healthcare systems has shifted toward limiting non-essential visits to hospitals in order to prioritize and allocate resources toward treating those affected by COVID-19, and preventing further exposures. While the effect of COVID-19 has been felt amongst many patient populations, those with inflammatory bowel disease (IBD) have been particularly impacted through delayed appointments and endoscopy, which is critical in disease monitoring. Aims We aimed to determine how changes to the provision of IBD care due to the COVID-19 pandemic have affected IBD patients. Methods A retrospective cohort study was conducted using administrative data comparing IBD patients admitted to the gastroenterology ward from March 17 to August 31 2019, with IBD patients admitted from March 17 to August 31 2020 at a tertiary care centre in London, Ontario. Patients were reviewed to assess differences in care utilization and IBD-related outcomes such as hospitalization, surgery and length of stay and in-patient drug therapy. Results A total of 538 patients (259 in 2019 cohort and 279 in 2020 cohort) were reviewed with 48 and 60 IBD patients meeting the inclusion criteria for 2019 and 2020 respectively. Patient demographics were similar between 2019 and 2020 cohort for age, sex, rurality, disease type, and biologic exposure. A greater proportion of patients were admitted with IBD flares in 2020 (86.7% vs 75%, p=0.03). Furthermore, the 2020 cohort also had a 45% increase in in-patient surgical consultations (p=0.07), a 50% increase in in-patient IBD-related surgeries (p=0.39), a 69% increase in inpatient Remicade prescription (p=0.13) and a 70% increase in infectious complications at presentation to hospital (p=0.21). A shorter median length of stay was reported for patients in the 2020 cohort (4 days IQR 3.95 vs 5.85 IQR 4.65, p=0.09). Conclusions Preliminary data suggest that during the COVID-19 pandemic, we have seen more deleterious outcomes in our IBD patients such as increased flares necessitating hospital admission. There was also a non-significant trend toward increased infectious complications as well as in-patient surgeries and need for in-patient Remicade. Though these results cannot be fully interpreted due to the need for further sampling, they suggest that IBD patients may be at-risk for poor outcomes in the current climate of medical care. Completion of this study will help define the full impact of care shifts related to reducing the spread of the novel coronavirus on IBD patients and highlight areas of care that need careful assessment and consideration to protect IBD patient health. Funding Agencies None

Despite advances in care, most patients with Crohn's disease (CD) develop complications, such as fistulas, or require surgery. Given the recent advances in drug therapy, an opportunity exists to optimize the management of this chronic disease through early use of effective therapies, clear definition of treatment targets, and application of the principles of personalized medicine. In this article, the authors discuss the evolution of treatment algorithms for CD to incorporate these strategies.

Intracellular adhesion molecule-1 (ICAM-1), is a transmembrane glycoprotein of the immunoglobulin family, constitutively expressed on vascular endothelial cells and upregulated in inflamed colonic tissue. Alicaforsen, a 20 base ICAM-1 anti-sense oligonucleotide and highly selective ICAM-1 inhibitor, down-regulates ICAM-1 mRNA. Areas covered: We review mechanism of action, pharmacokinetics, pre-clinical, clinical and safety data of alicaforsen for the treatment of ulcerative colitis (UC), pouchitis and Crohn's disease (CD). Expert opinion: After 6 weeks of treatment, topical alicaforsen was significantly more effective than placebo in inducing remission in patients with moderate-severe distal UC, with treatment effects lasting up to 30 weeks. No difference was observed in head-head comparison with mesalamine topical enema, although alicaforsen appeared to have more durable treatment effect. Clinical trials of an intravenous formulation in Crohn's disease showed no significant treatment effect compared to placebo. An open-label trial in alicaforsen for pouchitis demonstrated encouraging results, now being assessed in a multi-national phase 3 trial. No major safety signals have been observed in UC patients treated with alicaforsen enemas. The potential as a novel therapy for pouchitis has led to orphan designation for this indication by the FDA and European Medicines Agency.

Background and aims The prevalence and incidence of inflammatory bowel disease (IBD) in North America is among the highest in the world and imparts substantial direct and indirect medical costs. The Choosing Wisely Campaign was launched in wide variety of medical specialties and disciplines to reduce unnecessary or harmful tests or treatment interventions. Methods The Choosing Wisely list for IBD was developed by the Canadian IBD Network for Research and Growth in Quality Improvement (CINERGI) in collaboration with Crohn's and Colitis Canada (CCC) and the Canadian Association of Gastroenterology (CAG). Using a modified Delphi process, 5 recommendations were selected from an initial list of 30 statements at a face-to-face consensus meeting. Results The 5 things physicians and patients should question: (1) Don't use steroids (e.g., prednisone) for maintenance therapy in IBD; (2) Don't use opioids long-term to manage abdominal pain in inflammatory bowel disease (IBD); (3) Don't unnecessarily prolong the course of intravenous corticosteroids in patients with acute severe ulcerative colitis (UC) in the absence of clinical response; (4) Don't initiate or escalate long-term medical therapies for the treatment of IBD based only on symptoms; and (5) Don't use abdominal computed tomography (CT) scan to assess IBD in the acute setting unless there is suspicion of a complication (obstruction, perforation, abscess) or a non-IBD etiology for abdominal symptoms. Conclusions The Choosing Wisely recommendations will foster patient-physician discussions to optimize IBD therapy, reduce adverse effects from testing and treatment, and reduce medical expenditure.

Ulcerative colitis (UC) is a relapsing-remitting chronic inflammatory disorder affecting the mucosal surface in a continuous manner from the rectum through part of, or the entire, colon. Patients with severe disease and those who become refractory or intolerant to corticosteroids and/or immunosuppressants, require treatment with biologic agents that target tumor necrosis factor-α (TNF). Golimumab, a fully human monoclonal antibody, is the latest TNF antagonist to get approved for the treatment of moderate-to-severe UC. Subcutaneously administered golimumab induces and maintains clinical response, remission, and mucosal healing. Serum concentrations of golimumab are associated with response to therapy, as patients with higher drug exposure are more likely to achieve these outcomes. Since various patient and disease-related factors were shown to influence the pharmacokinetics of TNF antagonists, drug exposure may be variable over time and between patients, affecting success of therapy. A major contributing factor is immunogenicity, with development of anti-drug antibodies (ADAb) and an accelerated clearance of drug as a result. Although there is a growing body of evidence to support therapeutic drug monitoring (TDM) for infliximab and adalimumab, two other TNF antagonists, only limited data is available for golimumab. In addition, the clinically important drug exposure thresholds are not widely known, which has limited the use of TDM for golimumab in clinical practice. This review summarizes available data regarding the use of golimumab for UC, with emphasis on the pharmacokinetics, exposure-response relationship, and the role of TDM in optimizing therapy.

Vedolizumab is a humanized monoclonal antibody to the α4β7-integrin that blocks lymphocyte trafficking to the gut and is approved for treatment of patients with moderate-to-severe ulcerative colitis (UC). The gut-selective mechanism of action has the potential to improve vedolizumab's safety profile compared to other approved biologic drugs. Areas covered: We review the mechanism of action, efficacy and safety of vedolizumab treatment for UC. The positioning of vedolizumab in management algorithms is also discussed. Expert opinion: The highly selective mechanism of action of vedolizumab restricts immunosuppressive effects to the gut. Vedolizumab is efficacious as induction and maintenance therapy in UC patients who are naive or refractory to tumor necrosis factor antagonists. No clinically important safety signals have been identified. Infusion reactions are reported in

Background Tofacitinib is an oral Janus kinase (JAK) inhibitor which blocks cytokine signaling involved in the pathogenesis of autoimmune diseases including ulcerative colitis (UC). The etiology of UC is poorly understood, however research suggests the development and progression of the disease is due to a dysregulated immune response leading to inflammation of the colonic mucosa in genetically predisposed individuals. Additional medications are currently required since some patients do not respond to the available medications and some medications are associated with serious adverse events (SAEs). JAK inhibitors have been widely studied in diseases including rheumatoid arthritis and Crohn's disease and may represent a promising and novel therapeutic option for the treatment of UC. Objectives The primary objective was to assess the efficacy and safety of oral JAK inhibitors for the maintenance of remission in participants with quiescent UC. Search methods We searched the following databases from inception to 20 September 2019: MEDLINE, Embase, CENTRAL, and the Cochrane IBD Group Specialized Register, WHO trials registry and clinicaltrials.gov. References and conference abstracts were searched to identify additional studies. Selection criteria Randomized control trial (RCTs) in which an oral JAK inhibitor was compared with placebo or active comparator in the treatment of quiescent UC were eligible for inclusion. Data collection and analysis Two review authors independently screened studies for inclusion and extraction. Bias was assessed using the Cochrane 'Risk of bias' tool. The primary outcome was the proportion of participants who failed to maintain remission as defined by any included studies. Secondary outcomes included failure to maintain clinical response, failure to maintain endoscopic remission, failure to maintain endoscopic response, disease-specific quality of life, adverse events (AEs), withdrawal due to AEs and SAEs. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each dichotomous outcome. Data were analyzed on an intention-to-treat basis. The overall certainty of the evidence supporting the outcomes was evaluated using the GRADE criteria. Main results One RCT (593 participants) including patients with moderately to severely active UC met the inclusion criteria. Patients were randomly assigned in a 1:1:1 ratio to receive maintenance therapy with tofacitinib at 5 mg twice daily, 10 mg twice daily or placebo for 52 weeks. The primary endpoint was remission at 52 weeks and the secondary endpoints included mucosal healing at 52 weeks, sustained remission at 24 and 52 weeks and glucocorticosteroid-free remission. This study was rated as low risk of bias. The study reported on most of the pre-specified primary and secondary outcomes for this review including clinical remission, clinical response, endoscopic remission, AEs, SAEs and withdrawal due to AEs. However, the included study did not report on endoscopic response or disease-specific quality of life. Sixty-three per cent (247/395) of tofacitinib participants failed to maintain clinical remission at 52 weeks compared to 89% (176/198) of placebo participants (RR 0.70, 95% CI 0.64 to 0.77; high-certainty evidence). Forty-three per cent (171/395) of tofacitinib participants failed to maintain clinical response at 52 weeks compared to 80% (158/198) of placebo participants (RR 0.54, 95% CI 0.48 to 0.62; high-certainty evidence). Eighty-four per cent (333/395) of tofacitinib participants failed to maintain endoscopic remission at 52 weeks compared to 96% (190/198) of placebo participants (RR 0.88, 95% CI 0.83 to 0.92; high-certainty evidence). AEs were reported in 76% (299/394) of tofacitinib participants compared with 75% (149/198) of placebo participants (RR 1.01, 95% CI 0.92 to 1.11; high-certainty evidence). Commonly reported AEs included worsening UC, nasopharyngitis, arthralgia (joint pain)and headache. SAEs were reported in 5% (21/394) of tofacitinib participants compared with 7% (13/198) of placebo participants (RR 0.81, 95% CI 0.42 to 1.59; low-certainty evidence). SAEs included non-melanoma skin cancers, cardiovascular events, cancer other than non-melanoma skin cancer, Bowen's disease, skin papilloma and uterine leiomyoma (a tumour in the uterus). There was a higher proportion of participants who withdrew due to an AE in the placebo group compared to the tofacitinib group. Nine per cent (37/394) of participants taking tofacitinib withdrew due to an AE compared to 19% (37/198) of participants taking placebo (RR 0.50, 95% CI 0.33 to 0.77; moderate-certainty evidence). The most common reason for withdrawal due to an AE was worsening UC. The included study did not report on endoscopic response or on mean disease-specific quality of life scores. Authors' conclusions High-certainty evidence suggests that tofacitinib is superior to placebo for maintenance of clinical and endoscopic remission at 52 weeks in participants with moderate-to-severe UC in remission. The optimal dose of tofacitinib for maintenance therapy is unknown. High-certainty evidence suggests that there is no increased risk of AEs with tofacitinib compared to placebo. However, we are uncertain about the effect of tofacitinib on SAEs due to the low number of events. Further studies are required to look at the long-term effectiveness and safety of using tofacitinib and other oral JAK inhibitors as maintenance therapy in participants with moderate-to-severe UC in remission.

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Background Patient-reported outcome (PRO) measures historically used in inflammatory bowel disease have been considered inadequate to support future drug labelling claims by regulatory agencies. Aims To develop PRO tools for use in Crohn's disease (CD) and ulcerative colitis (UC) following guidance issued by the US FDA and the ISPOR (International Society for Pharmacoeconomics and Outcomes Research). Methods Concept elicitation and cognitive interviews were conducted in adult patients (≥18 years) across the United States and Canada. Semi-structured interview guides were used to collect data, and interview transcripts were coded and analysed. Concept elicitation results were considered alongside existing literature and clinical expert opinion to identify candidate PRO items. Cognitive interviews evaluated concept relevance, interpretability and structure, and facilitated instrument refinement. Concept elicitation participants, except those with an ostomy, underwent centrally read endoscopy to assess inflammatory status. Results In all, 54 participants (mean age: 46.2 years; 66.7% female) were included in the CD concept elicitation interviews. In total, 80 symptom concepts and 61 impact concepts were identified. After three waves of cognitive interviews, the 31-item Symptoms and Impacts Questionnaire for CD (SIQ-CD) was developed. In the UC concept elicitation phase, 53 participants were interviewed (mean age: 41.4 years; 49.1% female). In total, 79 symptoms concepts and 49 impact concepts were identified. Following two waves of cognitive interviews, the 29-item Symptoms and Impacts Questionnaire for UC (SIQ-UC) was developed. Both instruments include four symptom and six impact domains. Conclusions We developed PROs to support CD and UC drug labelling claims. Psychometric validation studies to evaluate instrument reliability and responsiveness are ongoing.

Background Patients with inflammatory bowel disease (IBD) post–liver transplant (LT) may have bowel inflammation requiring biologic therapy. We aimed to evaluate the safety of combination biologic and antirejection therapy in IBD patients after LT from a tertiary center case series and an updated literature review. Methods Inflammatory bowel disease patients undergoing LT between 1985 and 2018 and requiring combination biologic and antirejection therapy post-LT were identified from the London Health Sciences Transplant Registry (Ontario, Canada). Safety outcomes were extracted by medical chart review. For an updated literature review, EMBASE, Medline, and CENTRAL were searched to identify studies evaluating the safety of combination biologic and antirejection therapy in IBD patients. Results In the case series, 19 patients were identified. Most underwent LT for primary sclerosing cholangitis (PSC; 14/19, 74%) treated with anti-integrins (8/19, 42%) or tumor necrosis factor α (TNF) antagonists (6/19, 32%). Infections occurred in 11/19 (58%) patients, most commonly Clostridium difficile (4/19, 21%). Two patients required colectomy, and 1 patient required re-transplantation. In the literature review, 13 case series and 8 case reports reporting outcomes for 122 IBD patients treated with biologic and antirejection therapy post-LT were included. PSC was the indication for LT in 97/122 (80%) patients, and 91/122 (75%) patients were treated with TNF antagonists. Infections occurred in 32/122 (26%) patients, primarily Clostridium difficile (7/122, 6%). Conclusions Inflammatory bowel disease patients receiving combination biologic and antirejection therapy post-LT appeared to be at increased risk of Clostridium difficile. Compared with the general liver transplant population in the published literature, there was no increased risk of serious infection.

Background: The appropriate location for biopsy procurement relative to an ulcer in active Crohn's disease is unknown. Aim: To explore the relationship between biopsy location, histological disease activity, proinflammatory gene expression and the presence of inflammatory cells. Methods: Fifty-one patients with Crohn's disease and ulcers >0.5 cm diameter in the colon and/or ileum were prospectively enrolled at three centres. Biopsies were obtained from 0 mm, 7 to 8 mm and 21 to 24 mm from the edge of the largest ulcer. Histological activity was blindly assessed with the Global Histological Disease Activity Score, the Robarts Histopathology and Nancy Histological indices. Messenger ribonucleic acid (mRNA) levels for interleukins-6, -8 and -23 (p19 and p40 subunits), CD31 and S100A9 were measured using quantitative polymerase chain reaction. The number of CD3+, CD68+ and myeloperoxidase-positive cells was quantified by immunohistochemistry. Data were analysed using mixed models with location and segment as fixed effects and patients as random effect to account for correlation among segments within a patient. Results: Histological disease activity scores (P

BACKGROUND: Maintenance of remission of Crohn’s disease (CD) is a clinically important goal, as disease relapse can negatively affect quality of life. AIMS: The objective of this systematic review was to assess the efficacy and safety of adalimumab for maintenance of remission in patients with quiescent CD. METHODS: EMBASE, MEDLINE, CENTRAL and the Cochrane IBD Group Specialized Register were searched from inception to April 2018. Randomized controlled trials (RCTs) comparing adalimumab to placebo or an active comparator were considered for inclusion. Data were analyzed on an intention-to-treat basis. Risk ratios (RR) and corresponding 95% confidence intervals (95% CI) were calculated for dichotomous outcomes. The primary outcome was the number of patients who relapsed. Secondary outcomes were failure to maintain clinical response, endoscopic remission, endoscopic response, histological remission and adverse events. Bias was assessed using the Cochrane risk of bias tool. GRADE was used to assess the overall quality of evidence supporting the primary outcome. RESULTS: Seven RCTs (n=1229) were included. Five trials were rated low risk of bias and two trials were rated as unclear risk of bias. Three studies comprising 683 patients included relapse at 52–56 weeks as an endpoint. Fifty-nine percent (252/430) of patients treated with adalimumab relapsed compared with 86% (217/253) of patients receiving placebo (RR 0.69, 95% CI 0.63–0.76, P

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

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