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Background and Aims Despite increasing interest in histologic remission as a treatment target in ulcerative colitis (UC), the accuracy of histologic findings in left colon in detecting pancolonic histologic remission is unknown. Methods In a retrospective cohort study of patients with endoscopically active pancolitis undergoing treat-to-target interventions, we evaluated the diagnostic accuracy of left-sided (distal to splenic flexure) histologic and endoscopic findings on colonoscopy for detecting histologic and endoscopic healing elsewhere in the colon. Results Of 86 patients with moderate to severely active pancolitis who underwent 2 consecutive colonoscopies during treat-to-target interventions, 38% and 51% achieved histologic and endoscopic remission, respectively. Substantial agreement (kappa, 0.67; 95% confidence interval (CI), 0.51-0.83) was observed in histologic findings between left and right colon on follow-up colonoscopy. Histologic, and endoscopic, findings in left colon showed excellent accuracy in detecting pancolonic histologic remission (area under the curve (AUC), 0.96 [95% CI, 0.93-1.0]; misclassification rate, 5.9%), histologic normalization (AUC, 1.0, 0%), endoscopic improvement (AUC, 0.95 [0.96-1.0], 3.5%) and endoscopic remission (AUC, 0.98 [0.96-1.00], 5.8%), respectively. Conclusions In patients with active pancolitis undergoing treat-to-target interventions, histologic and endoscopic findings in the left colon on colonoscopy have excellent accuracy for detecting pancolonic histologic remission, histologic normalization, endoscopic improvement, and endoscopic remission. Flexible sigmoidoscopy may suffice for monitoring histologic and endoscopic activity in patients with pancolitis.

Background: Mirikizumab is a humanized monoclonal antibody targeting interleukin 23p19 with demonstrated efficacy in psoriasis and ulcerative colitis. We investigated the safety and efficacy of mirikizumab in patients with moderate-to-severe Crohn's disease (CD). Methods: Patients (N = 191) were randomized (2:1:1:2) to receive placebo (PBO), 200, 600, or 1000 mg mirikizumab, administered intravenously (IV) every 4 weeks. Patients who received mirikizumab and achieved ≥1 point improvement in Simple Endoscopic Score-CD at Week 12 (rerandomized maintenance cohort) were rerandomized to continue their induction IV treatment (combined IV groups [IV-C]) or receive 300 mg mirikizumab subcutaneously (SC) every 4 weeks. Nonrandomized maintenance cohort included endoscopic nonimprovers (1000 mg) and PBO patients (PBO/1000 mg) who received 1000 mg mirikizumab IV from Week 12. The primary objective was to evaluate superiority of mirikizumab to PBO in inducing endoscopic response (50% reduction from baseline in Simple Endoscopic Score-CD) at Week 12. Results: At Week 12, endoscopic response was significantly higher by the predefined 2-sided significance level of 0.1 for all mirikizumab groups compared with PBO (200 mg: 25.8%, 8/31, 95% confidence interval [CI], 10.4–41.2, P = .079; 600 mg: 37.5%, 12/32, 95% CI, 20.7–54.3, P = .003; 1000 mg: 43.8%, 28/64, 95% CI, 31.6–55.9, P < .001; PBO: 10.9 %, 7/64, 95% CI, 3.3–18.6). Endoscopic response at Week 52 was 58.5% (24/41) and 58.7% (27/46) in the IV-C and SC groups, respectively. Frequencies of adverse events (AE) in the mirikizumab groups were similar to PBO. Through Week 52, frequencies of treatment-emergent AEs were similar across all groups. Frequencies of serious AE and discontinuations due to AE were higher in the nonrandomized maintenance cohort. Conclusion: Mirikizumab effectively induced endoscopic response after 12 weeks in patients with moderate-to-severe CD and demonstrated durable efficacy to Week 52. A detailed summary can be found in the Video Abstract. ClinicalTrials.gov, Number: NCT02891226

Background & Aims We aimed to compare safety and effectiveness of vedolizumab to tumor necrosis factor (TNF)-antagonist therapy in ulcerative colitis in routine practice. Methods A multicenter, retrospective, observational cohort study (May 2014 to December 2017) of ulcerative colitis patients treated with vedolizumab or TNF-antagonist therapy. Propensity score weighted comparisons for development of serious adverse events and achievement of clinical remission, steroid-free clinical remission, and steroid-free deep remission. A priori determined subgroup comparisons in TNF-antagonist–naive and –exposed patients, and for vedolizumab against infliximab and subcutaneous TNF-antagonists separately. Results A total of 722 (454 vedolizumab, 268 TNF antagonist) patients were included. Vedolizumab-treated patients were more likely to achieve clinical remission (hazard ratio [HR], 1.651; 95% confidence interval [CI], 1.229-2.217), steroid-free clinical remission (HR, 1.828; 95% CI, 1.135-2.944), and steroid-free deep remission (HR, 2.819; 95% CI, 1.496-5.310) than those treated with TNF antagonists. Results were consistent across subgroup analyses in TNF-antagonist–naive and −exposed patients, and for vedolizumab vs infliximab and vs subcutaneous TNF-antagonist agents separately. Overall, there were no statistically significant differences in the risk of serious adverse events (HR, 0.899; 95% CI, 0.502-1.612) or serious infections (HR, 1.235; 95% CI, 0.608-2.511) between vedolizumab-treated and TNF-antagonist−treated patients. However, in TNF-antagonist−naive patients, vedolizumab was less likely to be associated with serious adverse events than TNF antagonists (HR, 0.192; 95% CI, 0.049-0.754). Conclusions Treatment of ulcerative colitis with vedolizumab is associated with higher rates of remission than treatment with TNF-antagonist therapy in routine practice, and lower rates of serious adverse events in TNF-antagonist−naive patients.

High placebo response rates in clinical trials of ulcerative colitis (UC) have been reported previously. However, data from patient-level analyses are lacking. We assessed factors associated with clinical and endoscopic placebo response among placebo-treated patients in clinical trials of UC.We performed a post hoc analysis of pooled clinical trial data from GEMINI-1, ACT-1, ACT-2, PURSUIT, ULTRA-2, OCTAVE-1, and OCTAVE-2. Predictors were assessed in placebo-treated patients for their association with end of induction (week 6 of 8) clinical response (reduction in total Mayo score of ≥3 and ≥30% from baseline with ≥1 point decrease in rectal bleeding subscore [RBS] or absolute RBS ≤1); clinical remission (total Mayo score ≤2 and no subscore1); endoscopic healing (Mayo endoscopic subscore ≤1); partial Mayo score of 0; patient-reported outcome 2-item remission (RBS of 0 and stool frequency ≤1), resolution of rectal bleeding, and stool frequency normalization. Predictors on univariate analyses with P.05 were included in multivariate logistic regression models.Placebo-treated patients with normal serum C-reactive protein and albumin levels were more likely to attain clinical response (71 of 437 [16.3%] vs 49 of 660 [7.4%]; adjusted odds ratio, 2.76; 95% confidence interval, 1.19-5.41; P = .018). Compared with patients with a Mayo endoscopic score of 2, patients with a Mayo endoscopic score of 3 were less likely to attain clinical response (105 of 556 [18.8%] vs 179 of 675 [25.9%]; adjusted odds ratio, 0.33; 95% confidence interval, 0.16-0.68; P = .003). Similar findings were observed for clinical remission and resolution of rectal bleeding.Biomarkers such as normal serum C-reactive protein and albumin and baseline endoscopic severity were found to affect placebo response rates in clinical trials of UC. These findings have implications for clinical trial design in UC.

Crohn's disease and ulcerative colitis are heterogeneous conditions which may manifest with 1 or more of a constellation of abnormal symptoms, elevated biomarkers, and/or objective evidence of inflammation on endoscopic or cross-sectional evaluation. Whilst resolution of symptoms and restoration of quality of life is the primary goal for patients following a disease flare, there may be discordance between resolution of symptoms, biomarkers, and endoscopy. Increased emphasis is placed on the achievement of endoscopic remission, given it is associated with improved outcomes and reduction in hospitalization and surgeries. As the therapeutic armamentarium for inflammatory bowel disease does not achieve remission in all patients, there is greater emphasis on repetitive interval-based assessment of disease activity with sequential algorithmic treatment adjustments until endoscopic remission is achieved, in a so-called treat-to-target approach. We review the role of symptoms, biomarkers, imaging and endoscopy within treat-to-target algorithms and provide a practical guidance to their use in clinical practice.

Background & Aims Adenoma detection rate (ADR) is an important quality assurance measure for colonoscopy. Some studies suggest that narrow-band imaging (NBI) may be more effective at detecting adenomas than white-light endoscopy (WLE) when bowel preparation is optimal. We conducted a meta-analysis of data from individual patients in randomized controlled trials that compared the efficacy of NBI to WLE in detection of adenomas. Methods We searched MEDLINE, EMBASE, and Cochrane Library databases through April 2017 for randomized controlled trials that assessed detection of colon polyps by high-definition WLE vs NBI and from which data on individual patients were available. The primary outcome measure was ADR adjusted for bowel preparation quality. Multilevel regression models were used with patients nested within trials, and trial included as a random effect. Results We collected data from 11 trials, comprising 4491 patients and 6636 polyps detected. Adenomas were detected in 952 of 2251 (42.3%) participants examined by WLE vs 1011 of 2239 (45.2%) participants examined by NBI (unadjusted odds ratio [OR] for detection of adenoma by WLE vs NBI, 1.14; 95% CI, 1.01–1.29; P = .04). NBI outperformed WLE only when bowel preparation was best: adequate preparation OR, 1.07 (95% CI, 0.92–1.24; P = .38) vs best preparation OR, 1.30 (95% CI, 1.04–1.62; P = .02). Second-generation bright NBI had a better ADR than WLE (second-generation NBI OR, 1.28; 95% CI, 1.05–1.56; P = .02), whereas first-generation NBI did not. NBI detected more non-adenomatous polyps than WLE (OR, 1.24; 95% CI, 1.06–1.44; P = .008) and flat polyps than WLE (OR, 1.24; 95% CI, 1.02–1.51; P = .03). Conclusions In a meta-analysis of data from individual patients in randomized controlled trials, we found NBI to have a higher ADR than WLE, and that this effect is greater when bowel preparation is optimal.

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.

Objectives To evaluate whether noninferiority trials are designed to adequately preserve the historical treatment effect of their active comparators. Study Design and Setting We reviewed 162 noninferiority trials published in high-impact medical journals. We assessed whether trials were designed to ensure that interventions could only be declared noninferior if they preserved at least 50% of the active comparator's historical treatment effect. Results Only 25 of 162 trials (15%) were designed so that interventions could only be declared noninferior if they preserved at least 50% of the active comparator's historical treatment effect. Most trials did not provide evidence that the active comparator was effective (n = 101), provided inadequate evidence (n = 18), or used a noninferiority margin that was too wide (n = 18). In a subset of 61 noninferiority trials which referenced a prior randomized trial or meta-analysis evaluating the active comparator, only 25 (41%) used a noninferiority margin small enough to preserve at least 50% of the active comparator's treatment effect. Overall, 14 of 162 noninferiority trials (9%) would have allowed the intervention to be declared noninferior even if it was worse than either placebo or another historical control. Conclusion Most noninferiority trials published in major medical journals could allow erroneous declarations of noninferiority.

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

International audience; Background and aims: Inflammatory bowel diseases (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), are chronic and disabling disorders. Prospective disease-modification trials to prevent disease progression are eagerly awaited. However, disease progression is not clearly defined. The objective of the Selecting End PoInts foR Disease-ModIfication Trials (SPIRIT) initiative was to achieve international expert consensus on the endpoints to be used in future IBD-disease modification trials.Methods: This initiative under the auspices of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) began with a systematic literature search to evaluate the current evidence on the definition of disease progression in IBD. On October 22, 2019, a consensus meeting took place during the United European Gastroenterology Week (UEGW) Congress in Barcelona, during which predefined proposed statements were discussed in a plenary session and voted on anonymously. Agreement was defined as at least 75% of participants voting for any one statement.Results: The group agreed that the ultimate therapeutic goal in both CD and UC is to prevent disease impact on patient's life (health-related quality of life, disability, fecal incontinence), midterm complications (encompass bowel damage in CD, IBD-related surgery and hospitalizations, disease extension in UC, extraintestinal manifestations, permanent stoma, short bowel syndrome), and long-term complications (gastrointestinal and extraintestinal dysplasia or cancer, mortality).Conclusions: Recommendations on which goals to achieve in disease-modification trials for preventing disease progression in patients with IBD are proposed by the SPIRIT consensus. However, these recommendations will require validation in actual clinical studies before implementation in disease-modification trials.

Objectives Results from randomized trials can depend on the statistical analysis approach used. It is important to prespecify the analysis approach in the trial protocol to avoid selective reporting of analyses based on those which provide the most favourable results. We undertook a review of published trial protocols to assess how often the statistical analysis of the primary outcome was adequately prespecified. Methods We searched protocols of randomized trials indexed in PubMed in November 2016. We identified whether the following aspects of the statistical analysis approach for the primary outcome were adequately prespecified: (1) analysis population; (2) analysis model; (3) use of covariates; and (4) method of handling missing data. Results We identified 99 eligible protocols. Very few protocols adequately prespecified the analysis population (8/99, 8%), analysis model (27/99, 27%), covariates (40/99, 40%), or approach to handling missing data (10/99, 10%). Most protocols did not adequately predefine any of these four aspects of their statistical analysis approach (39%) or predefined only one aspect (36%). No protocols adequately predefined all four aspects of the analysis. Conclusion The statistical analysis approach is rarely prespecified in published trial protocols. This may allow selective reporting of results based on different analyses.

Background & aimsWe conducted a systematic review with meta-analysis to estimate rates and trends of colectomy in patients with ulcerative colitis (UC), and of primary and re-resection in patients with Crohn's disease (CD), focusing on contemporary risks.MethodsThrough a systematic review until September 3, 2019, we identified population-based cohort studies that reported patient-level cumulative risk of surgery in patients with UC and CD. We evaluated overall and contemporary risk (after 2000) of surgery and analyzed time trends through mixed-effects meta-regression.ResultsIn patients with UC (26 studies), the overall 1-, 5-, and 10-year risks of colectomy was 4.0% (95% CI, 3.3-5.0), 8.8% (95% CI, 7.7-10.0), and 13.3% (95% CI, 11.3-15.5), respectively, with a decrease in risk over time (P < .001). Corresponding contemporary risks were 2.8% (95% CI, 2.0-3.9), 7.0% (95% CI, 5.7-8.6), and 9.6% (95% CI, 6.3-14.2), respectively. In patients with CD (22 studies), the overall 1-, 5-, and 10-year risk of surgery was 18.7% (95% CI, 15.0-23.0), 28.0% (95% CI, 24.0-32.4), and 39.5% (95% CI, 33.3-46.2), respectively, with a decrease in risk over time (P < .001). Corresponding contemporary risks were 12.3% (95% CI, 10.8-14.0), 18.0% (95% CI, 15.4-21.0), and 26.2% (95% CI, 23.4-29.4), respectively. In a meta-analysis of 8 studies in patients with CD with prior resection, the cumulative risk of a second resection at 5 and 10 years after the first resection was 17.7% (95% CI, 13.5-22.9) and 31.3% (95% CI, 24.1-39.6), respectively.ConclusionsPatient-level risks of surgery have decreased significantly over time, with a 5-year cumulative risk of surgery of 7.0% in UC and 18.0% in CD in contemporary cohorts. This decrease may be related to early detection and/or better treatment.

Ustekinumab (UST) targets the common subunit (p40) of interleukins-12/23,1,2 approved for intravenous (IV) induction of remission in moderate-to-severe Crohn's disease (CD), followed by subcutaneous (SC) doses for maintenance of remission.3,4 The role of IV reinduction of UST in patients already on every-4-week (Q4) maintenance with partial response or loss of response (LOR) is unclear.5 The aim was to assess response and remission rates for UST IV reinduction in patients with CD with partial response or LOR who already were on Q4 SC dosing and had failed prior biological therapies.

Background & Aims Infliximab is an effective treatment for moderate to severe ulcerative colitis (UC). Little is known about patient-related factors that might be used to predict endoscopic healing with infliximab therapy. Methods We analyzed data from 484 patients included in the randomized trials of the effects of infliximab therapy for patients with UC (Active Ulcerative Colitis Trials [ACT]-1 and ACT-2). We used a 2-compartment population pharmacokinetic model to calculate baseline infliximab clearance. Two multivariable regression models were derived and validated for their ability to identify patients with endoscopic healing (Mayo endoscopic score, ≤1) at weeks 8 and 30, using only baseline variables. We developed a clinical decision support tool (CDST) and calculator to determine the probability of endoscopic healing in patients starting infliximab. Results Higher baseline infliximab clearance, stool frequency, and rectal bleeding scores were associated negatively with endoscopic healing at week 8. In the validation set, a CDST score of 9 points or fewer identified patients without endoscopic healing at week 8 with 82% sensitivity (95% CI, 76%–88%), whereas a CDST score of 16 points or more identified patients with endoscopic healing at week 8 with 87% specificity (95% CI, 81%–94%). Higher baseline infliximab clearance, stool frequency score, white blood cell count, and lower body weight were associated negatively with endoscopic healing at week 30. In the validation set, CDST scores of 17 points or fewer identified patients without endoscopic healing at week 30 with 90% sensitivity (95% CI, 85%–95%), whereas scores greater than 22 points identified patients with endoscopic healing at week 30 with 80% specificity (95% CI, 73%–87%). External validation models had a modest predictive value, with an area under of the curve of 0.67 (95% CI, 0.61–0.74). Patient-level probabilities of endoscopic healing at weeks 8 or 30 can be calculated online ( www.premedibd.com ). Conclusions Using data from 2 clinical trials of patients receiving infliximab therapy for UC, we developed and validated the CDST, which uses data on infliximab clearance and baseline patient and disease measures to identify patients most likely to have endoscopic healing. This tool will facilitate therapy decision making and precision medicine.

Summary Background Acute lower gastrointestinal bleeding is a common reason for emergency hospital admission, and identification of patients at low risk of harm, who are therefore suitable for outpatient investigation, is a clinical and research priority. We aimed to develop and externally validate a simple risk score to identify patients with lower gastrointestinal bleeding who could safely avoid hospital admission. Methods We undertook model development with data from the National Comparative Audit of Lower Gastrointestinal Bleeding from 143 hospitals in the UK in 2015. Multivariable logistic regression modelling was used to identify predictors of safe discharge, defined as the absence of rebleeding, blood transfusion, therapeutic intervention, 28 day readmission, or death. The model was converted into a simplified risk scoring system and was externally validated in 288 patients admitted with lower gastrointestinal bleeding (184 safely discharged) from two UK hospitals (Charing Cross Hospital, London, and Hammersmith Hospital, London) that had not contributed data to the development cohort. We calculated C statistics for the new model and did a comparative assessment with six previously developed risk scores. Findings Of 2336 prospectively identified admissions in the development cohort, 1599 (68%) were safely discharged. Age, sex, previous admission for lower gastrointestinal bleeding, rectal examination findings, heart rate, systolic blood pressure, and haemoglobin concentration strongly discriminated safe discharge in the development cohort (C statistic 0·84, 95% CI 0·82–0·86) and in the validation cohort (0·79, 0·73–0·84). Calibration plots showed the new risk score to have good calibration in the validation cohort. The score was better than the Rockall, Blatchford, Strate, BLEED, AIMS65, and NOBLADS scores in predicting safe discharge. A score of 8 or less predicts a 95% probability of safe discharge. Interpretation We developed and validated a novel clinical prediction model with good discriminative performance to identify patients with lower gastrointestinal bleeding who are suitable for safe outpatient management, which has important economic and resource implications. Funding Bowel Disease Research Foundation and National Health Service Blood and Transplant.

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.

Summary Background The burden of inflammatory bowel disease (IBD) is rising globally, with substantial variation in levels and trends of disease in different countries and regions. Understanding these geographical differences is crucial for formulating effective strategies for preventing and treating IBD. We report the prevalence, mortality, and overall burden of IBD in 195 countries and territories between 1990 and 2017, based on data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017. Methods We modelled mortality due to IBD using a standard Cause of Death Ensemble model including data mainly from vital registrations. To estimate the non-fatal burden, we used data presented in primary studies, hospital discharges, and claims data, and used DisMod-MR 2.1, a Bayesian meta-regression tool, to ensure consistency between measures. Mortality, prevalence, years of life lost (YLLs) due to premature death, years lived with disability (YLDs), and disability-adjusted life-years (DALYs) were estimated. All of the estimates were reported as numbers and rates per 100 000 population, with 95% uncertainty intervals (UI). Findings In 2017, there were 6·8 million (95% UI 6·4–7·3) cases of IBD globally. The age-standardised prevalence rate increased from 79·5 (75·9–83·5) per 100 000 population in 1990 to 84·3 (79·2–89·9) per 100 000 population in 2017. The age-standardised death rate decreased from 0·61 (0·55–0·69) per 100 000 population in 1990 to 0·51 (0·42–0·54) per 100 000 population in 2017. At the GBD regional level, the highest age-standardised prevalence rate in 2017 occurred in high-income North America (422·0 [398·7–446·1] per 100 000) and the lowest age-standardised prevalence rates were observed in the Caribbean (6·7 [6·3–7·2] per 100 000 population). High Socio-demographic Index (SDI) locations had the highest age-standardised prevalence rate, while low SDI regions had the lowest age-standardised prevalence rate. At the national level, the USA had the highest age-standardised prevalence rate (464·5 [438·6–490·9] per 100 000 population), followed by the UK (449·6 [420·6–481·6] per 100 000). Vanuatu had the highest age-standardised death rate in 2017 (1·8 [0·8–3·2] per 100 000 population) and Singapore had the lowest (0·08 [0·06–0·14] per 100 000 population). The total YLDs attributed to IBD almost doubled over the study period, from 0·56 million (0·39–0·77) in 1990 to 1·02 million (0·71–1·38) in 2017. The age-standardised rate of DALYs decreased from 26·5 (21·0–33·0) per 100 000 population in 1990 to 23·2 (19·1–27·8) per 100 000 population in 2017. Interpretation The prevalence of IBD increased substantially in many regions from 1990 to 2017, which might pose a substantial social and economic burden on governments and health systems in the coming years. Our findings can be useful for policy makers developing strategies to tackle IBD, including the education of specialised personnel to address the burden of this complex disease. Funding Bill & Melinda Gates Foundation.

Background & aimsWe created and validated a clinical decision support tool (CDST) to predict outcomes of vedolizumab therapy for ulcerative colitis (UC).MethodsWe performed logistic regression analyses of data from the GEMINI 1 trial, from 620 patients with UC who received vedolizumab induction and maintenance therapy (derivation cohort), to identify factors associated with corticosteroid-free remission (full Mayo score of 2 or less, no subscore above 1). We used these factors to develop a model to predict outcomes of treatment, which we called the vedolizumab CDST. We evaluated the correlation between exposure and efficacy. We validated the CDST in using data from 199 patients treated with vedolizumab in routine practice in the United States from May 2014 through December2017.ResultsAbsence of exposure to a tumor necrosis factor (TNF) antagonist (+3 points), disease duration of 2 y or more (+3 points), baseline endoscopic activity (moderate vs severe) (+2 points), and baseline albumin concentration (+0.65 points per 1 g/L) were independently associated with corticosteroid-free remission during vedolizumab therapy. Patients in the derivation and validation cohorts were assigned to groups of low (CDST score, 26 points or less), intermediate (CDST score, 27-32 points), or high (CDST score, 33 points or more) probability of vedolizumab response. We observed a statistically significant linear relationship between probability group and efficacy (area under the receiver operating characteristic curve, 0.65), as well as drug exposure (P < .001) in the derivation cohort. In the validation cohort, a cutoff value of 26 points identified patients who did not respond to vedolizumab with high sensitivity (93%); only the low and intermediate probability groups benefited from reducing intervals of vedolizumab administration due to lack of response (P = .02). The vedolizumab CDST did not identify patients with corticosteroid-free remission during TNF antagonist therapy.ConclusionsWe used data from a trial of patients with UC to develop a scoring system, called the CDST, which identified patients most likely to enter corticosteroid-free remission during vedolizumab therapy, but not anti-TNF therapy. We validated the vedolizumab CDST in a separate cohort of patients in clinical practice. The CDST identified patients most likely to benefited from reducing intervals of vedolizumab administration due to lack of initial response. ClinicalTrials.gov no: NCT00783718.

BACKGROUND: Patients with inflammatory bowel diseases (IBD) require repeated healthcare encounters, although the focus of care differs when patients are seen in ambulatory, emergency department (ED), or inpatient settings. We examined contemporary trends and disparities in IBD-related healthcare visits. METHODS: We used data from the National Ambulatory Medical Care Survey, Nationwide Emergency Department Sample, and National Inpatient Sample to estimate the total number of annual IBD-related visits from 2005 through 2016. We performed logistic regression analyses to test temporal linear trends. Slope and differences in distributions of patient demographics were compared across time and treatment settings. RESULTS: From 2005 through 2016, approximately 2.2 million IBD-related ambulatory visits (95 CI, 1.9–2.5 million IBD-related ambulatory visits) occurred annually on average, increasing by 70.3% from the time period of 2005–2007 through the time period of 2008–2010, and decreasing by 19.8% from the time period of 2011–2013 through the time period of 2014–2016. An average of 115,934 IBD-related ED visits (95% CI, 113,758–118,111 IBD-related ED visits) and 89,111 IBD-related hospital discharges (95% CI, 87,416–90,807 IBD-related hospital discharges) occurred annually. Significant increases in the rate of IBD-related ED visits (3.2 visits/10,000 encounters, P

Background & Aims Clinical remission, defined by a composite of patient reported outcomes and Mayo endoscopy subscore (MES) 0 or 1 is a recommended treatment target in patients with ulcerative colitis (UC). We estimated whether incorporating more rigorous remission definitions, of endoscopic remission (MES 0) and histologic remission, affects risk of relapse. Methods Through a systematic review, we identified cohort studies in adults with UC in clinical remission that reported a minimum 12-month risk of clinical relapse, based on MES (0 vs 1) and/or histologic disease activity, in patients with endoscopic remission. Using random effects meta-analysis, we calculated relative and absolute risk of clinical relapse in patients with UC achieving different treatment targets. Results In a meta-analysis of 17 studies that included 2608 patients with UC in clinical remission, compared to patients achieving MES 1, patients achieving MES 0 had a 52% lower risk of clinical relapse (relative risk, 0.48; 95% CI, 0.37–0.62). The median 12-month risk of clinical relapse in patients with MES 1 was 28.7%; the estimated annual risk of clinical relapse in patients with MES 0 was 13.7% (95% CI, 10.6–17.9). In a meta-analysis of 10 studies in patients in endoscopic remission (MES 0), patients who achieved histologic remission had a 63% lower risk of clinical relapse vs patients with persistent histologic activity (relative risk, 0.37; 95% CI, 0.24–0.56). Estimated annual risk of clinical relapse in who achieved achieving histologic remission was 5.0% (95% CI, 3.3–7.7). CONCLUSIONS In a systematic review and meta-analysis of patients with UC in clinical remission, we observed that patients achieving more rigorous treatment endpoints (endoscopic and histologic remission) have a substantially lower risk of clinical relapse compared with patients achieving clinical remission.

Background & Aims Little is known about the association between rectal bleeding and increased stool frequency with endoscopic findings in patients with mild to moderate ulcerative colitis (UC). We evaluated the associations between rectal bleeding or stool frequency and endoscopic remission in this population. Methods We performed a post-hoc analysis of data from a phase 3 non-inferiority trial of 817 adults with mild to moderate UC who received treatment with mesalazine. We obtained information on rectal bleeding, stool frequency, and Mayo endoscopic subscores (MESs) at weeks 0, 8, and 38. The sensitivity, specificity, and positive and negative predictive values with which rectal bleeding and stool frequency identified patients with MESs of 0 and/or 1 were calculated at weeks 8 and 38 of treatment. The associations between change in rectal bleeding and stool frequency and change in MES after treatment were quantified using the Spearman's rank correlation coefficient. Results Among patients with a MES of 0, 7/82 patients (9%) had a rectal bleeding score of 1 or more and 40/82 patients (49%) had a stool frequency score of 1 or more at week 8; at week 38, 6/167 patients (4%) had a rectal bleeding score of 1 or more and 63/167 patients (38%) had a stool frequency score of 1 or more. Among patients with MESs of 0 or 1, 50/310 patients (16%) had a rectal bleeding score of 1 or more and 162/310 patients (52%) had had a stool frequency score of 1 or more at week 8; at week 38, 18/363 patients (5%) had a rectal bleeding score of 1 or more and 141/363 patients (39%) had a stool frequency score of 1 or more. The Spearman rank correlation coefficients for change in rectal bleeding and stool frequency with change in MES at week 8 were 0.39 (95% CI, 0.32–0.45) and 0.34 (95% CI, 0.27–0.40), respectively. In patients with reduced MESs at week 8, 39/389 patients (10%) had unchanged or worsening rectal bleeding and 81/389 patients (21%) had unchanged or increasing stool frequencies. Conclusions In a post-hoc analysis of data from a phase 3 trial of adults with mild to moderate UC treated with mesalazine, we found absence of rectal bleeding to identify patients in endoscopic remission. However, many patients in remission still have increased stool frequency, indicating that it may not be a sensitive marker of disease activity in patients with mild to moderate UC.

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.