Reliability and Responsiveness of Histologic Indices for the Assessment of Crohn's Disease Activity.

BACKGROUND & AIMS: The operating properties of histologic indices for evaluating Crohn's disease (CD) activity are poorly characterized. We assessed the reliability and responsiveness of existing histologic indices/items used in CD and ulcerative colitis (UC), in addition to 3 novel items, and developed exploratory ileal, colonic, and colonic-ileal CD instruments. METHODS: Blinded central readers independently reviewed paired baseline and week 12 image sets from the EXTEND trial. Disease activity was scored using 4 indices (the Global Histologic Activity Score, Geboes Score, Nancy Histological Index, and Robarts Histopathology Index) and 3 items identified by an expert panel (mucin depletion, basal plasmacytosis, and ileal pyloric gland metaplasia). Reliability and responsiveness were quantified using the intraclass correlation coefficient (ICC) and area under the receiver operating curve (AUC), respectively. Exploratory indices were developed using backward stepwise linear regression analysis. Candidate independent variables were items with an inter-rater ICC ≥0.40 and AUC ≥0.56. The dependent variable was histologic disease activity measured by a 100-mm visual analogue scale. RESULTS: Paired image sets were available from 55 patients. Substantial to almost perfect inter-rater reliability (ICC, 0.63-0.87) and some responsiveness (AUC, 0.57-0.94) were observed for all existing indices regardless of whether individual colonic and ileal segments, combined colonic segments, or combined colonic and ileal segments were assessed and the calculation method used. Five items were tested as candidate items, and exploratory colonic, ileal, and colonic-ileal indices were developed. CONCLUSIONS: CD and UC indices were similarly reliable and responsive in measuring histologic CD activity. Exploratory index development did not offer benefit over current histologic instruments.

CORE-IBD: A Multidisciplinary International Consensus Initiative to Develop a Core Outcome Set for Randomized Controlled Trials in Inflammatory Bowel Disease.

BACKGROUND & AIMS: End points to determine the efficacy and safety of medical therapies for Crohn's disease (CD) and ulcerative colitis (UC) are evolving. Given the heterogeneity in current outcome measures, harmonizing end points in a core outcome set for randomized controlled trials is a priority for drug development in inflammatory bowel disease. METHODS: Candidate outcome domains and outcome measures were generated from systematic literature reviews and patient engagement surveys and interviews. An iterative Delphi process was conducted to establish consensus: panelists anonymously voted on items using a 9-point Likert scale, and feedback was incorporated between rounds to refine statements. Consensus meetings were held to ratify the outcome domains and core outcome measures. Stakeholders were recruited internationally, and included gastroenterologists, colorectal surgeons, methodologists, and clinical trialists. RESULTS: A total of 235 patients and 53 experts participated. Patient-reported outcomes, quality of life, endoscopy, biomarkers, and safety were considered core domains; histopathology was an additional domain for UC. In CD, there was consensus to use the 2-item patient-reported outcome (ie, abdominal pain and stool frequency), Crohn's Disease Activity Index, Simple Endoscopic Score for Crohn's Disease, C-reactive protein, fecal calprotectin, and co-primary end points of symptomatic remission and endoscopic response. In UC, there was consensus to use the 9-point Mayo Clinic Score, fecal urgency, Robarts Histopathology Index or Geboes Score, fecal calprotectin, and a composite primary end point including both symptomatic and endoscopic remission. Safety outcomes should be reported using the Medical Dictionary for Regulatory Activities. CONCLUSIONS: This multidisciplinary collaboration involving patients and clinical experts has produced the first core outcome set that can be applied to randomized controlled trials of CD and UC.

Efficacy and Safety of IL-12/23 and IL-23 Inhibitors for Crohn's Disease: Systematic Review and Meta-Analysis.

BACKGROUND: Targeting interleukin-23 (IL-23) is an important therapeutic strategy for Crohn's disease (CD). AIMS: This systematic review and meta-analysis assessed the efficacy and safety of selective IL-23p19 and IL-12/23p40 inhibitors in patients with moderate-to-severe CD. METHODS: MEDLINE, Embase, and the Cochrane library (CENTRAL) were searched from inception to May 24, 2023, for randomized, placebo- or active comparator-controlled induction and/or maintenance trials of selective IL-23p19 and IL-12/23p40 inhibitors in pediatric and adult patients with CD. The primary outcome was the proportion of patients in clinical remission. Secondary outcomes were clinical response, endoscopic remission, endoscopic response, and safety. Data were pooled using a random-effects model. Risk of bias and certainty of evidence were assessed using the Cochrane risk of bias tool and the GRADE criteria, respectively. RESULTS: Eighteen trials (n = 5561) were included. Most studies were rated as low risk of bias. Targeting IL-23 was significantly superior to placebo for inducing clinical (risk ratio [RR] = 1.87, 95% confidence interval [CI] 1.58-2.21) and endoscopic (RR = 3.20, 95%CI 2.17-4.70) remission and maintaining clinical remission (RR = 1.39, 95%CI 1.10-1.77) (GRADE high certainty evidence for all outcomes). Subgroup analysis showed that targeting IL-23 was superior to placebo for inducing clinical remission in biologic-naïve (RR = 2.20, 95%CI 1.46-3.32, I2 = 0%, p = 0.39) and biologic-experienced patients (RR = 1.82, 95%CI 1.27-2.60, I2 = 56.5%, p = 0.01). Targeting IL-23 was associated with a decreased risk of serious adverse events in induction (RR = 0.55, 95%CI 0.44-0.73) and maintenance (RR = 0.72, 95%CI 0.53-0.98) trials compared to placebo (high certainty evidence). CONCLUSION: Targeting IL-23 is effective and safe for inducing and maintaining clinical and endoscopic remission in patients with moderate-to-severe CD.

International consensus to standardise histopathological scoring for small bowel strictures in Crohn's disease.

OBJECTIVE: Effective medical therapy and validated trial outcomes are lacking for small bowel Crohn's disease (CD) strictures. Histopathology of surgically resected specimens is the gold standard for correlation with imaging techniques. However, no validated histopathological scoring systems are currently available for small bowel stricturing disease. We convened an expert panel to evaluate the appropriateness of histopathology scoring systems and items generated based on panel opinion. DESIGN: Modified RAND/University of California Los Angeles methodology was used to determine the appropriateness of 313 candidate items related to assessment of CD small bowel strictures. RESULTS: In this exercise, diagnosis of naïve and anastomotic strictures required increased bowel wall thickness, decreased luminal diameter or internal circumference, and fibrosis of the submucosa. Specific definitions for stricture features and technical sampling parameters were also identified. Histopathologically, a stricture was defined as increased thickness of all layers of the bowel wall, fibrosis of the submucosa and bowel wall, and muscularisation of the submucosa. Active mucosal inflammatory disease was defined as neutrophilic inflammation in the lamina propria and any crypt or intact surface epithelium, erosion, ulcer and fistula. Chronic mucosal inflammatory disease was defined as crypt architectural distortion and loss, pyloric gland metaplasia, Paneth cell hyperplasia, basal lymphoplasmacytosis, plasmacytosis and fibrosis, or prominent lymphoid aggregates at the mucosa/submucosa interface. None of the scoring systems used to assess CD strictures were considered appropriate for clinical trials. CONCLUSION: Standardised assessment of gross pathology and histopathology of CD small bowel strictures will improve clinical trial efficiency and aid drug development.

Modeling Endoscopic Improvement after Induction Treatment With Mesalamine in Patients With Mild-to-Moderate Ulcerative Colitis.

BACKGROUND & AIMS: Endoscopic improvement is an important treatment target for mild-to-moderate ulcerative colitis (UC). However, early endoscopic evaluation is not always feasible. We aimed to develop a clinical decision support tool to discriminate patients who have achieved endoscopic improvement from those with more severe inflammation following mesalamine induction therapy. METHODS: We performed a post-hoc analysis of data from a phase 3 non-inferiority trial of 726 adults with mild-to-moderate UC treated with mesalamine. Multivariable logistic regression modeling determined associations between candidate variables and endoscopic improvement (Mayo endoscopic subscore=0-1 according to blinded central reading) at Week 8. Internal model validation was performed using bootstrap resampling. A clinical decision support tool was developed to stratify patients into low, intermediate, and high probability groups for endoscopic improvement. RESULTS: Variables associated with endoscopic improvement at Week 8 included 50% reduction in fecal calprotectin from baseline (odds ratio [OR] 2.64, 95% CI:, 1.81, 3.85), reduction in rectal bleeding (OR 1.79 per point reduction, 95% CI: 1.35, 2.39), and improvement in physician global assessment (OR 2.32 per point improvement, 95% CI: 1.88, 2.85). The baseline Geboes score (OR 0.74 per grade, 95% CI: 0.65, 0.85) and prolonged disease duration (OR 0.95 per year, 95% CI: 0.92, 0.98) were negatively associated with endoscopic improvement. This model strongly discriminated endoscopic improvement in the development dataset (area under the curve [AUC] 0.84, 95% CI: 0.81, 0.87) and during validation (AUC 0.83). CONCLUSIONS: We developed and validated a clinical decision support tool that has good discriminative performance for induction of endoscopic improvement in patients with mild-to-moderate UC treated with mesalamine. ClinicalTrials.gov Registration: NCT01903252.

An International Consensus to Standardize Integration of Histopathology in Ulcerative Colitis Clinical Trials.

BACKGROUND & AIMS: Histopathology is an emerging treatment target in ulcerative colitis (UC) clinical trials. Our aim was to provide guidance on standardizing biopsy collection protocols, identifying optimal evaluative indices, and defining thresholds for histologic response and remission after treatment. METHODS: An international, interdisciplinary expert panel of 19 gastroenterologists and gastrointestinal pathologists was assembled. A modified RAND/University of California, Los Angeles appropriateness methodology was used to address relevant issues. A total of 138 statements were derived from a systematic review of the literature and expert opinion. Each statement was anonymously rated as appropriate, uncertain, or inappropriate using a 9-point scale. Survey results were reviewed and discussed before a second round of voting. RESULTS: Histologic measurements collected using a uniform biopsy strategy are important for assessing disease activity and determining therapeutic efficacy in UC clinical trials. Multiple biopsy strategies were deemed acceptable, including segmental biopsies collected according to the endoscopic appearance. Biopsies should be scored for architectural change, lamina propria chronic inflammation, basal plasmacytosis, lamina propria and epithelial neutrophils, epithelial damage, and erosions/ulcerations. The Geboes score, Robarts Histopathology Index, and Nancy Index were considered appropriate for assessing histologic activity; use of the modified Riley score and Harpaz Index were uncertain. Histologic activity at baseline should be required for enrollment, recognizing this carries operational implications. Achievement of histologic improvement or remission was considered an appropriate and realistic therapeutic target. Current histologic indices require validation for pediatric populations. CONCLUSIONS: These recommendations provide a framework for standardized implementation of histopathology in UC trials. Additional work is required to address operational considerations and areas of uncertainty.

Increased Risk of Infections with Anti-TNF Agents in Patients with Crohn's Disease After Elective Surgery: Meta-Analysis.

BACKGROUND: Postoperative complication rates in patients with inflammatory bowel disease (IBD) receiving preoperative biologics have been analyzed without considering the surgical context. Emergency surgery may be associated with an increased risk of infectious complications, compared to elective operations. AIMS: To conduct a systematic review and meta-analysis investigating the relationship between preoperative biologic therapy and postoperative outcomes in Crohn's disease (CD) and ulcerative colitis (UC), focusing on elective surgery. METHODS: Electronic databases were searched up to February 12, 2020, for studies of patients with IBD undergoing elective abdominal surgery receiving biologic therapy within 3 months before surgery compared to no therapy, or another biologic therapy. Certainty of evidence was evaluated using GRADE. The primary outcomes were the rate of infections and total complications within 30 days. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: Thirty-three studies were included. Preoperative treatment with anti-tumor necrosis factor (TNF) therapy in patients with CD undergoing elective surgery was associated with increased odds of infection (OR 2.05; 95% CI 1.40-3.01), but not total complications (OR 1.03; 95% CI 0.71-1.51). In elective surgery for UC, preoperative anti-TNF therapy was not associated with infectious (OR 1.03; 95% CI 0.34-3.07) or total complications (OR 0.67; 95% CI 0.29-1.58). Limited data indicate that emergency surgery did not significantly affect the rate of complications. CONCLUSIONS: Anti-TNF therapy prior to elective surgery may increase the odds of postoperative infection in CD, although the certainty of evidence is very low. More evidence is needed, particularly for newer biologics.

Histopathology Scoring Systems of Stenosis Associated With Small Bowel Crohn's Disease: A Systematic Review.

BACKGROUND & AIMS: Stenosis is a common complication of Crohn's disease (CD) that has no effective medical therapy. Development of antifibrotic agents will require testing in randomized controlled trials. Computed tomography enterography- and magnetic resonance enterography-based technologies might be used to measure outcomes in these trials. These approaches have been validated in studies of patients with symptomatic strictures who underwent imaging evaluations followed by resection with histopathologic grading of the intestinal tissue for inflammation and/or fibrosis (the reference standard). Imaging findings have correlated with findings from quantitative or semiquantitative histologic evaluation of the degree of fibromuscular stenosis and/or inflammation on the resection specimen. However, it is not clear whether histologic findings are an accurate reference standard. We performed a systematic review of all published histologic scoring systems used to assess stenosing CD. METHODS: We performed a comprehensive search of Embase and MEDLINE of studies through March 13, 2019, that used a histologic scoring system to characterize small bowel CD and assessed inflammatory and fibrotic alterations within the same adult individual. All scores fitting the criteria were included in our analysis, independent of the presence of stricturing disease, as long as inflammation and fibrosis were evaluated separately but in the same scoring system. RESULTS: We observed substantial heterogeneity among the scoring systems, which were not derived from modern principles for evaluative index development. None had undergone formal validity or reliability testing. None of the existing indices had been constructed according to accepted methods for the development of evaluative indices. Basic knowledge regarding their operating properties were lacking. Specific indices for evaluating the important pathologic component of myofibroblast hypertrophy or hyperplasia have not been proposed. CONCLUSIONS: In a systematic review of publications, we found a lack of validated histopathologic scoring systems for assessment of fibromuscular stenosis. Data that describe the operating properties of existing cross-sectional imaging techniques for stenosing CD should be questioned. Development and validation of a histopathology index is an important research priority.

Reliability of Endoscopic Evaluation of Postoperative Recurrent Crohn's Disease.

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

Response to Placebo, Measured by Endoscopic Evaluation of Crohn's Disease Activity, in a Pooled Analysis of Data From 5 Randomized Controlled Induction Trials.

BACKGROUND & AIMS: Endoscopy is used to measure activity of Crohn's disease (CD) and determine eligibility and outcomes of participants in randomized controlled trials of therapeutic agents. We aimed to estimate the rate of response to placebo in trials, based on endoscopic evaluation of CD activity, and identify factors that affect this response. METHODS: We collected patient-level data from randomized, double-blind, placebo-controlled trials of therapeutic agents for CD that included centrally-read endoscopic assessments with validated scoring indices. We analyzed data from induction trials of eldelumab, filgotinib, risankizumab, and ustekinumab (from 188 patients given placebo). The primary outcome was the rate of response to placebo, based on endoscopic assessment of CD activity (>50% reduction in the simple endoscopic score for CD). Rate of remission, based on endoscopic score, was a secondary outcome. Overall rates of response to placebo were calculated using the inverse variance-weighted average method and presented with 95% CIs. We performed a multi-variable meta-regression analysis to identify determinants of response to placebo, assessed endoscopically, using patient-level data from the filgotinib and ustekinumab trials. RESULTS: The pooled rate of response among patients given placebo was 16.2% (95% CI, 10.5%-22.0%) and the rate of remission in this group was 5.2% (95% CI, 1.7%-8.8%). Prior exposure to tumor necrosis factor antagonists (odds ratio, 0.31; 95% CI, 0.10-0.93; P = .036) and increased concentration of C-reactive protein at baseline (odds ratio, 0.93; 95% CI, 0.87-0.98; P = .014 per 10 mg/L increase) were independently associated with lower rates of response to placebo. CONCLUSIONS: Rates of response and remission to placebo, determined by centrally-read endoscopy, in induction trials of therapies for CD are low. These estimates are important for sample size calculations for randomized placebo-controlled trials that use the Simple Endoscopic Score for CD as an endpoint. They also provide a benchmark to interpret findings from non-placebo controlled, prospective, randomized, unblinded trials.

Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.

BACKGROUND: Oral 5-aminosalicylic acid (5-ASA; also known as mesalazine or mesalamine) preparations were intended to avoid the adverse effects of sulfasalazine (SASP) while maintaining its therapeutic benefits. In an earlier version of this review, we found that 5-ASA drugs were more effective than placebo for maintenance of remission of ulcerative colitis (UC), but had a significant therapeutic inferiority relative to SASP. In this version, we have rerun the search to bring the review up to date. OBJECTIVES: To assess the efficacy, dose-responsiveness, and safety of oral 5-ASA compared to placebo, SASP, or 5-ASA comparators for maintenance of remission in quiescent UC and to compare the efficacy and safety of once-daily dosing of oral 5-ASA with conventional (two or three times daily) dosing regimens. SEARCH METHODS: We performed a literature search for studies on 11 June 2019 using MEDLINE, Embase, and the Cochrane Library. In addition, we searched review articles and conference proceedings. SELECTION CRITERIA: We included randomized controlled trials with a minimum treatment duration of six months. We considered studies of oral 5-ASA therapy for treatment of participants with quiescent UC compared with placebo, SASP, or other 5-ASA formulations. We also included studies that compared once-daily 5-ASA treatment with conventional dosing of 5-ASA and 5-ASA dose-ranging studies. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. The primary outcome was the failure to maintain clinical or endoscopic remission. Secondary outcomes were adherence, adverse events (AE), serious adverse events (SAE), withdrawals due to AEs, and withdrawals or exclusions after entry. Trials were separated into five comparison groups: 5-ASA versus placebo, 5-ASA versus SASP, once-daily dosing versus conventional dosing, 5-ASA (balsalazide, Pentasa, and olsalazine) versus comparator 5-ASA formulation (Asacol and Salofalk), and 5-ASA dose-ranging. We calculated the risk ratio (RR) and 95% confidence interval (CI) for each outcome. We analyzed data on an intention-to-treat basis, and used GRADE to assess the overall certainty of the evidence. MAIN RESULTS: The search identified 44 studies (9967 participants). Most studies were at low risk of bias. Ten studies were at high risk of bias. Seven of these studies were single-blind and three were open-label. 5-ASA is more effective than placebo for maintenance of clinical or endoscopic remission. About 37% (335/907) of 5-ASA participants relapsed at six to 12 months compared to 55% (355/648) of placebo participants (RR 0.68, 95% CI 0.61 to 0.76; 8 studies, 1555 participants; high-certainty evidence). Adherence to study medication was not reported for this comparison. SAEs were reported in 1% (6/550) of participants in the 5-ASA group compared to 2% (5/276) of participants in the placebo group at six to 12 months (RR 0.60, 95% CI 0.19 to 1.84; 3 studies, 826 participants; low-certainty evidence). There is probably little or no difference in AEs at six to 12 months' follow-up (RR 0.93, 95% CI 0.73 to 1.18; 5 studies, 1132 participants; moderate-certainty evidence). SASP is more effective than 5-ASA for maintenance of remission. About 48% (416/871) of 5-ASA participants relapsed at six to 18 months compared to 43% (336/784) of SASP participants (RR 1.14, 95% CI 1.03 to 1.27; 12 studies, 1655 participants; high-certainty evidence). Adherence to study medication and SAEs were not reported for this comparison. There is probably little or no difference in AEs at six to 12 months' follow-up (RR 1.07, 95% CI 0.82 to 1.40; 7 studies, 1138 participants; moderate-certainty evidence). There is little or no difference in clinical or endoscopic remission rates between once-daily and conventionally dosed 5-ASA. About 37% (717/1939) of once-daily participants relapsed over 12 months compared to 39% (770/1971) of conventional-dosing participants (RR 0.94, 95% CI 0.88 to 1.01; 10 studies, 3910 participants; high-certainty evidence). There is probably little or no difference in medication adherence rates. About 10% (106/1152) of participants in the once-daily group failed to adhere to their medication regimen compared to 8% (84/1154) of participants in the conventional-dosing group (RR 1.18, 95% CI 0.72 to 1.93; 9 studies, 2306 participants; moderate-certainty evidence). About 3% (41/1587) of participants in the once-daily group experienced a SAE compared to 2% (35/1609) of participants in the conventional-dose group at six to 12 months (RR 1.20, 95% CI 0.77 to 1.87; moderate-certainty evidence). There is little or no difference in the incidence of AEs at six to 13 months' follow-up (RR 0.98, 95% CI 0.92 to 1.04; 8 studies, 3497 participants; high-certainty evidence). There may be little or no difference in the efficacy of different 5-ASA formulations. About 44% (158/358) of participants in the 5-ASA group relapsed at six to 18 months compared to 41% (142/349) of participants in the 5-ASA comparator group (RR 1.08, 95% CI 0.91 to 1.28; 6 studies, 707 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: There is high-certainty evidence that 5-ASA is superior to placebo for maintenance therapy in UC. There is high-certainty evidence that 5-ASA is inferior compared to SASP. There is probably little or no difference between 5-ASA and placebo, and 5-ASA and SASP in commonly reported AEs such as flatulence, abdominal pain, nausea, diarrhea, headache, and dyspepsia. Oral 5-ASA administered once daily has a similar benefit and harm profile as conventional dosing for maintenance of remission in quiescent UC.

Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis.

BACKGROUND: Oral 5-aminosalicylic acid (5-ASA) preparations were intended to avoid the adverse effects of sulfasalazine (SASP) while maintaining its therapeutic benefits. It was previously found that 5-ASA drugs in doses of at least 2 g/day were more effective than placebo but no more effective than SASP for inducing remission in ulcerative colitis (UC). This review is an update of a previously published Cochrane Review. OBJECTIVES: To assess the efficacy, dose-responsiveness and safety of oral 5-ASA compared to placebo, SASP, or 5-ASA comparators (i.e. other formulations of 5-ASA) for induction of remission in active UC. A secondary objective was to compare the efficacy and safety of once-daily dosing of oral 5-ASA versus conventional dosing regimens (two or three times daily). SEARCH METHODS: We searched MEDLINE, Embase and the Cochrane Library on 11 June 2019. We also searched references, conference proceedings and study registers to identify additional studies. SELECTION CRITERIA: We considered randomized controlled trials (RCTs) including adults (aged 18 years or more) with active UC for inclusion. We included studies that compared oral 5-ASA therapy with placebo, SASP, or other 5-ASA formulations. We also included studies that compared once-daily to conventional dosing as well as dose-ranging studies. DATA COLLECTION AND ANALYSIS: Outcomes include failure to induce global/clinical remission, global/clinical improvement, endoscopic remission, endoscopic improvement, adherence, adverse events (AEs), serious adverse events (SAEs), withdrawals due to AEs, and withdrawals or exclusions after entry. We analyzed five comparisons: 5-ASA versus placebo, 5-ASA versus sulfasalazine, once-daily dosing versus conventional dosing, 5-ASA (e.g. MMX mesalamine, Ipocol, Balsalazide, Pentasa, Olsalazine and 5-ASA micropellets) versus comparator 5-ASA (e.g. Asacol, Claversal, Salofalk), and 5-ASA dose-ranging. We calculated the risk ratio (RR) and 95% confidence interval (95% CI) for each outcome. We analyzed data on an intention-to-treat basis, and used GRADE to assess the overall certainty of the evidence. MAIN RESULTS: We include 54 studies (9612 participants). We rated most studies at low risk of bias. Seventy-one per cent (1107/1550) of 5-ASA participants failed to enter clinical remission compared to 83% (695/837) of placebo participants (RR 0.86, 95% CI 0.82 to 0.89; 2387 participants, 11 studies; high-certainty evidence). We also observed a dose-response trend for 5-ASA. There was no difference in clinical remission rates between 5-ASA and SASP. Fifty-four per cent (150/279) of 5-ASA participants failed to enter remission compared to 58% (144/247) of SASP participants (RR 0.90, 95% CI 0.77 to 1.04; 526 participants, 8 studies; moderate-certainty evidence). There was no difference in remission rates between once-daily dosing and conventional dosing. Sixty per cent (533/881) of once-daily participants failed to enter clinical remission compared to 61% (538/880) of conventionally-dosed participants (RR 0.99, 95% CI 0.93 to 1.06; 1761 participants, 5 studies; high-certainty evidence). Eight per cent (15/179) of participants dosed once daily failed to adhere to their medication regimen compared to 6% (11/179) of conventionally-dosed participants (RR 1.36, 95% CI 0.64 to 2.86; 358 participants, 2 studies; low-certainty evidence). There does not appear to be any difference in efficacy among the various 5-ASA formulations. Fifty per cent (507/1022) of participants in the 5-ASA group failed to enter remission compared to 52% (491/946) of participants in the 5-ASA comparator group (RR 0.94, 95% CI 0.86 to 1.02; 1968 participants, 11 studies; moderate-certainty evidence). There was no evidence of a difference in the incidence of adverse events and serious adverse events between 5-ASA and placebo, once-daily and conventionally-dosed 5-ASA, and 5-ASA and comparator 5-ASA formulation studies. Common adverse events included flatulence, abdominal pain, nausea, diarrhea, headache and worsening UC. SASP was not as well tolerated as 5-ASA. Twenty-nine per cent (118/411) of SASP participants experienced an AE compared to 15% (72/498) of 5-ASA participants (RR 0.48, 95% CI 0.36 to 0.63; 909 participants, 12 studies; moderate-certainty evidence). AUTHORS' CONCLUSIONS: There is high-certainty evidence that 5-ASA is superior to placebo, and moderate-certainty evidence that 5-ASA is not more effective than SASP. Considering relative costs, a clinical advantage to using oral 5-ASA in place of SASP appears unlikely. High-certainty evidence suggests 5-ASA dosed once daily appears to be as efficacious as conventionally-dosed 5-ASA. There may be little or no difference in efficacy or safety among the various 5-ASA formulations.

Oral Janus kinase inhibitors for maintenance of remission in ulcerative colitis.

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.

Adalimumab for maintenance of remission in Crohn's disease.

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.

Assessment of Crohn's disease-associated small bowel strictures and fibrosis on cross-sectional imaging: a systematic review.

Patients with Crohn's disease commonly develop ileal and less commonly colonic strictures, containing various degrees of inflammation and fibrosis. While predominantly inflammatory strictures may benefit from a medical anti-inflammatory treatment, predominantly fibrotic strictures currently require endoscopic balloon dilation or surgery. Therefore, differentiation of the main components of a stricturing lesion is key for defining the therapeutic management. The role of endoscopy to diagnose the nature of strictures is limited by the superficial inspection of the intestinal mucosa, the lack of depth of mucosal biopsies and by the risk of sampling error due to a heterogeneous distribution of inflammation and fibrosis within a stricturing lesion. These limitations may be in part overcome by cross-sectional imaging techniques such as ultrasound, CT and MRI, allowing for a full thickness evaluation of the bowel wall and associated abnormalities. This systematic literature review provides a comprehensive summary of currently used radiologic definitions of strictures. It discusses, by assessing only manuscripts with histopathology as a gold standard, the accuracy for diagnosis of the respective modalities as well as their capability to characterise strictures in terms of inflammation and fibrosis. Definitions for strictures on cross-sectional imaging are heterogeneous; however, accuracy for stricture diagnosis is very high. Although conventional cross-sectional imaging techniques have been reported to distinguish inflammation from fibrosis and grade their severity, they are not sufficiently accurate for use in routine clinical practice. Finally, we present recent consensus recommendations and highlight experimental techniques that may overcome the limitations of current technologies.

Identifying Outcomes in Clinical Trials of Fistulizing Crohn's Disease for the Development of a Core Outcome Set.

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.

Identifying Outcomes in Clinical Trials of Pouchitis for the Development of a Core Outcome Set.

Treatment targets in both randomized controlled trials (RCTs) and daily practice have evolved for patients with ulcerative colitis (UC), motivated by changing regulatory requirements and efforts to alter the disease's natural history. Substantial heterogeneity in outcome definitions has been identified in UC RCTs.1 To harmonize treatment outcomes that should be reported, we proposed the collaborative development of a core outcome set (COS).2 A COS is an agreed minimum set of outcomes that should be measured and reported in all clinical trials to facilitate reporting consistency, reduce selective reporting bias, and improve quality of evidence synthesis.3.

Histologic Healing Rates of Medical Therapies for Ulcerative Colitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: Histologic remission is a potentially valuable means of assessing disease activity and treatment response in ulcerative colitis (UC). However, the efficacy of existing therapies to achieve this outcome is unclear. We performed a systematic review and meta-analysis of histologic outcomes in UC randomized controlled trials and examined the relationship between histologic and endoscopic outcomes. METHODS: MEDLINE, EMBASE, CENTRAL, and the Cochrane IBD Register were searched for randomized controlled trials of aminosalicylates, corticosteroids, immunosuppressives, biologics, and small molecules. Histologic and endoscopic remission and response data were independently extracted and pooled using binomial-normal random-effect or fixed-effect models. Pooled efficacy estimates were calculated as risk ratios (RRs) using the Mantel-Haenszel method. Univariable and multivariable random-effect meta-regression models examined factors associated with histologic remission. RESULTS: Seventy-four studies (68 induction and 7 maintenance) were identified. Topical aminosalicylate enemas [37.2%, 95% confidence interval (CI), 29.0-46.3] and suppositories (44.9%, 95% CI, 28.9-62.3) had the highest induction of histologic remission rates. Aminosalicylate enemas (RR = 4.14, 95% CI, 2.35-7.31), aminosalicylate suppositories (RR = 3.94, 95% CI, 1.26-12.32), and budesonide multimatrix (RR = 1.47, 95% CI 1.08-1.99) had higher histologic remission rates than placebo. Data were lacking for biologics and immunosuppressives. The pooled histologic remission rate for placebo in induction studies was 10.4% (95% CI, 7.1-15.2). Histologic and endoscopic remission correlated strongly (r = 0.66; 95% CI, 0.50-0.78). In multivariate analysis of placebo-arm data, less severe clinical disease activity and corticosteroid use were associated with higher histologic remission rates. Similarly, mild clinical disease activity was associated with higher histologic remission rates when active-arm data were analyzed. CONCLUSIONS: Histologic remission rates for current UC treatments ranged from 15.0% to 44.9% according to drug class and patient population with the highest rates observed for topical aminosalicylates. Placebo remission rates were low with relatively narrow CIs. These data provide benchmarks to inform future trial design. Histologic remission is a potential treatment target in clinical practice.

Anti-IL-12/23p40 antibodies for maintenance of remission in Crohn's disease.

BACKGROUND: Ustekinumab and briakinumab are monoclonal antibodies that target the standard p40 subunit of cytokines interleukin-12 and interleukin-23 (IL-12/23p40), which are involved in the pathogenesis of Crohn's disease (CD). A significant proportion of people with Crohn's disease fail conventional therapy or therapy with biologics (e.g. infliximab) or develop significant adverse events. Anti-IL-12/23p40 antibodies such as ustekinumab may be an effective alternative for these individuals. OBJECTIVES: The objectives of this review were to assess the efficacy and safety of anti-IL-12/23p40 antibodies for maintenance of remission in CD. SEARCH METHODS: We searched the Cochrane IBD Group Specialized Register, CENTRAL, MEDLINE, Embase, and trials registers from inception to 17 September 2019. We searched references and conference abstracts for additional studies. SELECTION CRITERIA: We considered for inclusion randomized controlled trials in which monoclonal antibodies against IL-12/23p40 were compared to placebo or another active comparator in participants with quiescent CD. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies for inclusion, extracted data, and assessed bias using the Cochrane 'Risk of bias' tool. The primary outcome measure was failure to maintain clinical remission, defined as a Crohn's disease activity index (CDAI) of < 150 points. Secondary outcomes included failure to maintain clinical response, adverse events (AE), serious adverse events (SAE), and withdrawals due to AEs. Clinical response was defined as a decrease in CDAI score of ≥ 100 points from baseline score. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each outcome. We analyzed all data on an intention-to-treat basis. We used GRADE to evaluate the overall certainty of the evidence supporting the outcomes. MAIN RESULTS: Three randomized controlled trials (646 participants) met the inclusion criteria. Two trials assessed the efficacy of ustekinumab (542 participants), and one study assessed the efficacy of briakinumab (104 participants). We assessed all of the included studies as at low risk of bias. One study (N = 145) compared subcutaneous ustekinumab (90 mg) administered at 8 and 16 weeks compared to placebo. Fifty-eight per cent (42/72) of ustekinumab participants failed to maintain clinical remission at 22 weeks compared to 73% (53/73) of placebo participants (RR 0.80, 95% CI 0.63 to 1.02; moderate-certainty evidence). Failure to maintain clinical response at 22 weeks was seen in 31% (22/72) of ustekinumab participants compared to 58% (42/73) of placebo participants (RR 0.53, 95% CI 0.36 to 0.79; moderate-certainty evidence). One study (N = 388) compared subcutaneous ustekinumab (90 mg) administered every 8 weeks or every 12 weeks to placebo for 44 weeks. Forty-nine per cent (126/257) of ustekinumab participants failed to maintain clinical remission at 44 weeks compared to 64% (84/131) of placebo participants (RR 0.76, 95% CI 0.64 to 0.91; moderate-certainty evidence). Forty-one per cent (106/257) of ustekinumab participants failed to maintain clinical response at 44 weeks compared to 56% (73/131) of placebo participants (RR 0.74, 95% CI 0.60 to 0.91; moderate-certainty evidence). Eighty per cent (267/335) of ustekinumab participants had an AE compared to 84% (173/206) of placebo participants (RR 0.94, 95% CI 0.87 to 1.03; high-certainty evidence). Commonly reported adverse events included infections, injection site reactions, CD event, abdominal pain, nausea, arthralgia, and headache. Eleven per cent of ustekinumab participants had an SAE compared to 16% (32/206) of placebo participants (RR 0.74, 95% CI 0.48 to 1.15; moderate-certainty evidence). SAEs included serious infections, malignant neoplasm, and basal cell carcinoma. Seven per cent (5/73) of ustekinumab participants withdrew from the study due to an AE compared to 1% (1/72) of placebo participants (RR 4.93, 95% CI 0.59 to 41.18; low-certainty evidence). Worsening CD was the most common reason for withdrawal due to an AE. One study compared intravenous briakinumab (200 mg, 400 mg, or 700 mg) administered at weeks 12, 16, and 20 with placebo. Failure to maintain clinical remission at 24 weeks was seen in 51% (32/63) of briakinumab participants compared to 61% (22/36) of placebo participants (RR 0.84, 95% CI 0.58 to 1.20; low-certainty evidence). Failure to maintain clinical response at 24 weeks was seen in 33% (21/63) of briakinumab participants compared to 53% (19/36) of placebo participants (RR 0.64, 95% CI 0.40 to 1.02; low-certainty evidence). Sixty-six per cent (59/90) of briakinumab participants had an AE compared to 64% (9/14) of placebo participants (RR 1.02, 95% CI 0.67 to 1.55; low-certainty evidence). Common AEs included upper respiratory tract infection, nausea, abdominal pain, headache, and injection site reaction. Two per cent (2/90) of briakinumab participants had an SAE compared to 7% (1/14) of placebo participants (RR 0.31, 95% CI 0.03 to 3.21; low-certainty evidence). SAEs included small bowel obstruction, deep vein thrombosis, and respiratory distress. Withdrawal due to an AE was noted in 2% of briakinumab participants compared to 0% (0/14) of placebo participants (RR 0.82, 95% CI 0.04 to 16.34; low-certainty evidence). The AEs leading to study withdrawal were not described. AUTHORS' CONCLUSIONS: Moderate-certainty evidence suggests that ustekinumab is probably effective for the maintenance of clinical remission and response in people with moderate to severe CD in remission without an increased risk of adverse events (high-certainty evidence) or serious adverse events (moderate-certainty evidence) relative to placebo. The effect of briakinumab on maintenance of clinical remission and response in people with moderate to severe Crohn's disease in remission was uncertain as the certainty of the evidence was low. The effect of briakinumab on adverse events and serious adverse events was also uncertain due to low-certainty evidence. Further studies are required to determine the long-term efficacy and safety of subcutaneous ustekinumab maintenance therapy in Crohn's disease and whether it should be used by itself or in combination with other agents. Future research comparing ustekinumab with other biologic medications will help to determine when treatment with ustekinumab in CD is most appropriate. Currently, there is an ongoing study that compares ustekinumab with adalimumab. This review will be updated when the results of this study become available. The manufacturers of briakinumab have stopped production of this medication, thus further studies of briakinumab are unlikely.

Adalimumab for induction of remission in Crohn's disease.

BACKGROUND: Adalimumab is an IgG1 monoclonal antibody that targets and blocks tumor necrosis factor-alpha, a pro-inflammatory cytokine involved in the pathogenesis of Crohn's disease (CD). A significant proportion of people with CD fail conventional therapy or therapy with biologics or develop significant adverse events. Adalimumab may be an effective alternative for these individuals. OBJECTIVES: The objectives of this review were to assess the efficacy and safety of adalimumab for the induction of remission in CD. SEARCH METHODS: We searched MEDLINE, Embase, CENTRAL, the Cochrane IBD Group Specialized Register, ClinicalTrials.Gov and the World Health Organization trial registry (ICTRP) from inception to 16 April 2019. References and conference abstracts were searched to identify additional studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing any dose of adalimumab to placebo or an active comparator in participants with active CD were included. DATA COLLECTION AND ANALYSIS: Two authors independently screened studies, extracted data and assessed bias using the Cochrane 'Risk of bias' tool. The primary outcome was the failure to achieve clinical remission, as defined by the original studies. Clinical remission was defined as a Crohn's Disease Activity Index (CDAI) score of less than 150 points. Secondary outcomes included failure to achieve clinical response (defined as a decrease in CDAI of > 100 points or > 70 points from baseline), failure to achieve endoscopic remission and response, failure to achieve histological remission and response, failure to achieve steroid withdrawal, adverse events (AEs) and serious adverse events (SAEs), withdrawal from study due to AEs and quality of life measured by a validated instrument. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for dichotomous outcomes. Data were pooled for analysis if the participants, interventions, outcomes and time frame were similar. Data were analyzed on an intention-to-treat basis. The overall certainty of the evidence was assessed using GRADE. MAIN RESULTS: Three placebo-controlled RCTs (714 adult participants) were included. The participants had moderate to severely active CD (CDAI 220 to 450). Two studies were rated as at low risk of bias and one study was rated as at unclear risk of bias. Seventy-six per cent (342/451) of adalimumab participants failed to achieve clinical remission at four weeks compared to 91% (240/263) of placebo participants (RR 0.85, 95% CI 0.79 to 0.90; high-certainty evidence). Forty-four per cent (197/451) of adalimumab participants compared to 66% (173/263) of placebo participants failed to achieve a 70-point clinical response at four weeks (RR 0.68, 95% CI 0.59 to 0.79; high-certainty evidence). At four weeks, 57% (257/451) of adalimumab participants failed to achieve a 100-point clinical response compared to 76% (199/263) of placebo participants (RR 0.77, 95% CI 0.69 to 0.86; high-certainty evidence). Sixty-two per cent (165/268) of adalimumab participants experienced an AE compared to 72% (188/263) of participants in the placebo group (RR 0.90, 95% CI 0.74 to 1.09; moderate-certainty evidence). Two percent (6/268) of adalimumab participants experienced a SAE compared to 5% (13/263) of participants in the placebo group (RR 0.44, 95% CI 0.17 to 1.15; low-certainty evidence). Lastly, 1% (3/268) of adalimumab participants withdrew due to AEs compared to 3% (8/268) of participants in the placebo group (RR 0.38, 95% CI 0.11 to 1.30; low-certainty evidence). Commonly reported adverse events included injection site reactions, abdominal pain, fatigue, worsening CD and nausea. Quality of life data did not allow for meta-analysis. Three studies reported better quality of life at four weeks with adalimumab (measured with either Inflammatory Bowel Disease Questionnaire or Short-Form 36; moderate-certainty evidence). Endoscopic remission and response, histologic remission and response, and steroid withdrawal were not reported in the included studies. AUTHORS' CONCLUSIONS: High-certainty evidence suggests that adalimumab is superior to placebo for induction of clinical remission and clinical response in people with moderate to severely active CD. Although the rates of AEs, SAEs and withdrawals due to AEs were lower in adalimumab participants compared to placebo, we are uncertain about the effect of adalimumab on AEs due to the low number of events. Therefore, no firm conclusions can be drawn regarding the safety of adalimumab in CD. Futher studies are required to look at the long-term effectiveness and safety of using adalimumab in participants with CD.