Cost Effectiveness of Sequencing Vedolizumab as First-Line Biologic in Ulcerative Colitis and Crohn's Disease in Canada: An Analysis Using Real-World Evidence from the EVOLVE Study.

INTRODUCTION: Vedolizumab is a gut-selective anti-lymphocyte trafficking biologic indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD) in Canada. OBJECTIVE: The objective of this study was to evaluate the cost effectiveness of treatment sequencing for UC and CD from a public healthcare payer perspective, leveraging new real-world evidence from the literature and the EVOLVE study, a retrospective chart review. METHODS: Using separate decision tree/Markov models to assess cost effectiveness for UC and CD, two sequencing approaches were estimated for adult patients (≥ 18 years) diagnosed with UC or CD who were biologic-naïve: vedolizumab as first-line biologic followed by anti-tumor necrosis factor (TNF)-α versus first-line anti-TNFα followed by vedolizumab. Treatment effectiveness (response and remission), surgery rates, dose escalation and regain of response and safety inputs were estimated from EVOLVE, a retrospective chart review of real-world data, and evidence synthesis from the literature, whereas costs and utilities were estimated from health technology assessment reports, clinical trials, and the literature. Biosimilar costs were used for anti-TNFα. Both models simulated a 5-year time horizon and discounted costs and outcomes at 1.5%. Probabilistic base-case analyses (n = 10,000) reported total costs (2023 Canadian dollars) and quality-adjusted life-years (QALYs). Several scenario analyses were conducted to explore robustness of results. RESULTS: In UC, vedolizumab as a first-line biologic followed by anti-TNFα resulted in an incremental gain of 0.09 QALYs (2.46 vs. 2.55) and saved $7179 ($134,028 vs. $126,848), making this a dominant strategy compared with first-line anti-TNFα followed by vedolizumab. In CD, use of vedolizumab as a first-line biologic resulted in an incremental gain of 0.04 QALYs (3.35 vs. 3.39) at an incremental cost of $50,631 ($89,850 vs. $140,381) versus first-line anti-TNFα followed by vedolizumab (incremental cost-effectiveness ratio of $1,265,775 per QALY). CONCLUSIONS: Based on this analysis, sequencing vedolizumab as a first-line biologic prior to anti-TNFα in UC and CD provided additional clinical benefit to patients. In UC, vedolizumab as a first-line biologic also saved healthcare system costs compared with anti-TNFα, whereas in CD, vedolizumab provided incremental benefit at an incremental cost, which was not considered cost effective at a threshold of $50,000/QALY.

Outcomes of patients with prior biologic intolerance are better than those with biologic failure in clinical trials of inflammatory bowel disease.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) trials often stratify patients by prior biologic exposure, including prior biologic failure or intolerance. This study aimed to assess clinical outcomes in IBD patients with prior biologic failure versus intolerance treated with ustekinumab or vedolizumab. METHODS: A post-hoc analysis of ulcerative colitis (UC) and Crohn's disease (CD) clinical trials for ustekinumab (UNITI, UNIFI) and vedolizumab (GEMINI-1, GEMINI-2) was performed. Clinical response, clinical remission, and endoscopic improvement (for UC) were compared among biologic naïve, biologic-failure, and biologic intolerant patients. Statistical analyses, including chi-square tests and logistic regression, were performed. RESULTS: 1178 UC and 1439 CD patients received either ustekinumab or vedolizumab. In UC, biologic intolerant patients exhibited higher clinical response (54.7% vs. 38.8%, aOR 1.87 [95% CI 0.93-3.73]), clinical remission (25.0% vs. 11.0%, aOR 2.84 [95% CI 1.47-5.49]), and endoscopic improvement (40.6% vs. 24.8%, aOR 2.76 [95% CI 1.28-5.94]) compared to biologic failure, with outcomes similar to biologic naïve patients. In biologic-intolerant CD patients, clinical response was similar between prior biologic failure and intolerance (34.2% vs 32.8%), but after adjustment for potential confounders, biologic intolerance was associated with higher odds of clinical response (aOR: 1.67, 95% CI 1.09-2.55), with no significant difference observed for clinical remission (aOR: 1.48, 95% CI 0.88-2.49). CONCLUSION: Improved treatment outcomes were generally observed in patients with biologic intolerance compared to failure, especially in UC, where outcomes were similar to biologic naïve patients. Future clinical trials should meticulously differentiate prior biologic failure versus intolerance to mitigate potential bias.

Healthy First-Degree Relatives From Multiplex Families vs Simplex Families Have a Higher Subclinical Intestinal Inflammation, a Distinct Fecal Microbial Signature, and Harbor a Higher Risk of Developing Crohn's Disease.

BACKGROUND & AIMS: Unaffected first-degree relatives (FDRs) from families with ≥2 affected FDRs with Crohn's disease (CD, multiplex families) have a high risk of developing CD, although the underlying mechanisms driving this risk are poorly understood. We aimed to identify differences in biomarkers between FDRs from multiplex vs simplex families and investigate the risk of future CD onset accounting for potential confounders. METHODS: We assessed the Crohn's and Colitis Canada Genetic Environmental Microbial cohort of healthy FDRs of patients with CD. Genome-wide CD-polygenic risk scores, urinary fractional excretion of lactulose-to-mannitol ratio, fecal calprotectin (FCP), and fecal 16S ribosomal RNA microbiome were measured at recruitment. Associations between CD multiplex status and baseline biomarkers were determined using generalized estimating equations models. Cox models were used to assess the risk of future CD onset. RESULTS: There were 4051 participants from simplex families and 334 from CD multiplex families. CD multiplex status was significantly associated with higher baseline FCP (P = .026) but not with baseline CD-polygenic risk scores or the lactulose-to-mannitol ratio. Three bacterial genera were found to be differentially abundant between both groups. CD multiplex status at recruitment was independently associated with an increased risk of developing CD (adjusted hazard ratio, 3.65; 95% confidence interval, 2.18-6.11, P < .001). CONCLUSION: Within FDRs of patients with CD, participants from multiplex families had a 3-fold increased risk of CD onset, a higher FCP, and an altered bacterial composition, but not genetic burden or altered gut permeability. These results suggest that putative environmental factors might be enriched in FDRs from multiplex families.

The relationship among vedolizumab drug concentrations, biomarkers of inflammation, and clinical outcomes in a Canadian real-world study.

Background and Aims: Therapeutic drug monitoring is used to optimize anti-tumour necrosis factor biologic effectiveness in inflammatory bowel disease, but its role with other biological classes is unclear. This study explores relationships between post-induction vedolizumab trough concentrations and biochemical outcomes in a real-world study of individuals with inflammatory bowel disease. Methods: This retrospective analysis of data from a national patient support program between 2018 and 2020, included 436 individuals with Crohn's disease or ulcerative colitis receiving vedolizumab. Optimal vedolizumab concentration thresholds (at weeks 6 and 14) were determined based on their ability to predict biochemical normalization (week 30 faecal calprotectin [<250 µg/g], C-reactive protein [<5 mg/l]). Thresholds best associated with each outcome were evaluated in multivariate analyses. Results: Among patients with Crohn's disease, week 6 serum vedolizumab concentrations (>41.65 µg/ml) predicted normalization defined by C-reactive protein: Spearman correlation coefficient [ρ] = -0.26, P = 0.002 and multivariate analysis (MVA)-OR: 3.22, 95% CI: 1.32-7.87, P = 0.01, and at week 14 (>22.25 µg/ml): ρ = -0.38, P < 0.0001, and MVA-OR: 3.21, 95% CI: 1.26-8.17 but not faecal calprotectin. Similarly, among patients with ulcerative colitis, week 6 vedolizumab concentrations (>39.65 g/ml) predicted normalization defined by C-reactive protein: ρ = -0.26, P = 0.005 and MVA-OR: 4.03, 95% CI: 1.30-12.52, P = 0.016, and at week 14 (>17.35 µg/ml): ρ = -0.39, P = 0.0001 and MVA-OR: 6.95, 95% CI: 1.81-26.77, P = 0.005, but not faecal calprotectin. Conclusions: Induction and post-induction serum vedolizumab were not consistently associated with biochemical normalization. As such, proactive therapeutic drug monitoring for vedolizumab should not be routinely incorporated in a treat to target strategy for inflammatory bowel disease. Clinical Trial Registration Number: NCT04567628.

Using Diet to Treat Inflammatory Bowel Disease: A Systematic Review.

INTRODUCTION: To review the efficacy of various dietary interventions for induction of clinical remission in inflammatory bowel disease (IBD) and provide healthcare providers with a practical reference for recommending suitable diets for managing patients with IBD. METHODS: PubMed, Medline(R), and Cochrane were searched from inception up to February 17, 2023, to identify all studies reporting information on using diet to treat IBD. Studies investigating the role of dietary interventions in adult patients with a confirmed diagnosis of active IBD for improvement or remission of IBD symptoms were rigorously considered. Sample meal plans, with a list of included and excluded foods, were also generated to provide clinicians with practical tools for advising patients on dietary intake. RESULTS: Eleven included studies provided data on 10 distinct diets: autoimmune protocol diet, high-fiber diet, 4-strategies-to-SUlfide-Reduction diet, highly restricted diet, McMaster elimination diet for Crohn's disease, specific carbohydrate diet, Mediterranean diet, Crohn's disease exclusion diet, individualized elimination diet, and the food-specific IgG4-guided exclusion diet. A total of 9 studies provided data on clinical remission. Many of these diets share common elements, such as an initial elimination phase with subsequent reintroduction of dietary components, inclusion of whole foods, and exclusion of highly or ultraprocessed foods. DISCUSSION: Currently, there is limited evidence to support the use of specific diets to treat adult patients with mildly to moderately active IBD. Larger, randomized studies with standardized methodologies and outcome measures, rigorous adherence assessment, and an emphasis on endoscopic assessment outcome measures are required to validate most diets that have been studied for IBD. The included sample diet plans and dietary recommendations may prove helpful in the interim as part of a holistic strategy to manage patients with IBD.

Adaptive steroid tapering impedes corticosteroid-free remissions compared to forced tapering in clinical trials of ulcerative colitis.

INTRODUCTION: It is unclear if steroid tapering protocols can impact clinical trial outcomes in ulcerative colitis (UC), particularly fixed versus adaptive steroid tapering. Fixed steroid tapering involves incremental dose decreases at prespecified intervals and adaptive steroid tapering utilizes investigator discretion as determined by the patient's response. METHODS: In this post-hoc analysis from six clinical trials of UC (VARSITY, ACT 1, PURSUIT, GEMINI1, OCTAVE and ULTRA2), responders to induction therapy with baseline corticosteroid use were considered as the primary population of interest. Adjustments were made to account for treat-through versus re-randomization designs and multivariate regression was performed to account for other potential confounding variables. The primary outcome was corticosteroid-free clinical remission (CR) at one-year and secondary outcomes were CR and endoscopic improvement. RESULTS: There was a total of 861 patients who had achieved clinical response after induction and were using corticosteroids. Within multivariate analysis, patients using adaptive steroid tapering regimens were less likely to achieve corticosteroid-free CR at one year (odds ratio [OR] 0.66 [95% CI 0.48-0.92], p=0.015) but had increased odds for achieving CR at one year (OR 1.9 [95% CI 1.43-2.52], p<0.001). The steroid tapering regimen was not associated with achievement of endoscopic improvement at one year. CONCLUSIONS: Among patients with UC on corticosteroids in clinical trials, patients using adaptive steroid weaning regimens were less likely to achieve corticosteroid-free CR at one year but more likely to achieve CR at one year. Consideration should be given to implementing mandatory fixed steroid weaning protocols in future clinical trials of UC.

Environmental Factors Associated With Risk of Crohn's Disease Development in the Crohn's and Colitis Canada - Genetic, Environmental, Microbial Project.

BACKGROUND & AIMS: To date, it is unclear how environmental factors influence Crohn's disease (CD) risk and how they interact with biological processes. This study investigates the association between environmental exposures and CD risk and evaluates their association with pre-disease biomarkers. METHODS: We studied 4289 healthy first-degree relatives (FDRs) of patients with CD from the Crohn's and Colitis Canada - Genetic, Environmental, Microbial (CCC-GEM) project. Regression models identified environmental factors associated with future CD onset and their association with pre-disease biological factors, including altered intestinal permeability measured by urinary fractional excretion of lactulose to mannitol ratio (LMR); gut inflammation via fecal calprotectin (FCP) levels; and fecal microbiome composition through 16S rRNA sequencing. RESULTS: Over a 5.62-year median follow-up, 86 FDRs developed CD. Living with a dog between ages 5 and 15 (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.40-0.96; P = .034), and living with a large family size in the first year of life (HR, 0.43; 95% CI, 0.21-0.85; P = .016) were associated with decreased CD risk, whereas having a bird at the time of recruitment (HR, 2.78; 95% CI, 1.36-5.68; P = .005) was associated with an increased CD risk. Furthermore, living with a dog was associated with reduced LMR, altered relative abundance of multiple bacterial genera, and increased Chao1 diversity, whereas bird owners had higher FCP levels. Large family during participants' first year of life was associated with altered microbiota composition without affecting FCP or LMR. CONCLUSION: This study identifies environmental variables associated with CD risk. These variables were also associated with altered barrier function, subclinical inflammation, and gut microbiome composition shifts, suggesting potential roles in CD pathogenesis.

Defining Endoscopic Remission in Crohn's Disease: MM-SES-CD and SES-CD Thresholds Associated With Low Risk of Disease Progression.

BACKGROUND & AIMS: We assessed Modified Multiplier Simple Endoscopic Score for Crohn's Disease (MM-SES-CD) and Simple Endoscopic Score for Crohn's Disease (SES-CD) thresholds that are best associated with low likelihood of long-term disease progression. METHODS: Data from 61 patients with early Crohn's disease (CD) who participated in the CALM long-term extension study were used as the derivation cohort and validated using the McMaster inflammatory bowel disease database (n = 99). The primary outcome was disease progression (new internal fistula/abscess, stricture, perianal fistula or abscess, CD-related hospitalization or surgery) since the end of the CALM trial. Optimal MM-SES-CD and SES-CD thresholds were determined using the maximum Youden index. Receiver operating characteristic curve analyses compared threshold scores of remission definitions on disease progression. RESULTS: In the derivation cohort, based on the maximum Youden index, the optimal thresholds associated with a low likelihood of disease progression were MM-SES-CD <22.5 and SES-CD <4. A significantly greater proportion of patients with a MM-SES-CD ≥22.5 had disease progression as compared with patients in the derivation cohort with MM-SES-CD <22.5 (10/17 [58.8%] vs 3/44 [6.8%]; P < .001). Similarly, a significantly greater number of patients with SES-CD ≥ 4 had disease progression compared with those with a SES-CD <4 (11/25 [44.0%] vs 2/36 [5.6%]; P < .001). Compared with other clinical or endoscopic remission definitions, which demonstrated poor to fair accuracy, MM-SES-CD <22.5 performed the best for predicting disease progression (area under the curve = 0.81; 95% confidence interval, 0.68-0.94; P < .001). These thresholds were confirmed in the validation cohort. CONCLUSION: Achievement of MM-SES-CD <22.5 or SES-CD <4 in patients with ileocolonic or colonic CD is associated with low risk of disease progression and may be suitable targets in clinical trials and practice for endoscopic healing.

Delayed Ustekinumab and Adalimumab Responders Have Similar Outcomes as Early Responders in Biologic-Naïve Crohn's Disease.

INTRODUCTION: Differences in 1-year outcomes among early and delayed responders have been demonstrated with some therapies in ulcerative colitis. However, it is unclear whether similar differences exist in patients with Crohn's disease (CD) treated with biologic therapies. METHODS: This was a post hoc analysis of patient-level data from the SEAVUE clinical trial program. Ustekinumab-treated and adalimumab-treated patients with clinical response at week 8, defined as a reduction in Crohn's Disease Activity Index (CDAI) score of at least 100 points from baseline or CDAI score <150, were deemed early responders and their outcomes were compared with delayed responders (week 8 nonresponders who subsequently responded at week 16) and nonresponders (no response at week 8 or 16). The primary outcome assessed was clinical remission at week 56, defined as CDAI <150. RESULTS: A total of 373 participants (187 treated with ustekinumab and 186 treated with adalimumab) were included in this analysis. The overall rate of delayed clinical response was low in the SEAVUE clinical trial program (13.1%). No differences were observed for week 56 clinical remission among early vs delayed responders to ustekinumab or adalimumab nor were there significant differences for secondary outcomes assessed. Delayed responders to ustekinumab and adalimumab had a significant decline in C-reactive protein by week 8 when compared with nonresponders. DISCUSSION: Among patients with moderate-to-severe CD, early and delayed responders to adalimumab and ustekinumab have similar 1-year clinical outcomes. Biomarker decline can be observed through the initial 8 weeks of therapy in patients who will eventually be delayed responders, which may help differentiate from nonresponders.

Predicting Endoscopic Improvement in Ulcerative Colitis Using the Ulcerative Colitis Severity Index.

INTRODUCTION: We developed and internally validated a prognostic scoring index for ulcerative colitis (UC) patients that includes baseline patient-reported outcomes (PROs), biomarkers, endoscopy, and histology for achieving 1-year endoscopic improvement (EI). METHODS: This post hoc analysis included 644 patients treated with ustekinumab induction therapy. Data were randomly split to obtain a 70% training and 30% testing cohort. Multivariate analyses assessed baseline variables and those with P < .05 were assigned weights based on their relative prognostic value from logistic regression modeling for predicting 1-year EI (Mayo endoscopic score ≤1). A cutoff was obtained by calculating the maximum Youden index and validated in the testing cohort. RESULTS: Prior biologic failure, albumin <40 g/L, C-reactive protein >5 mg/L, Mayo stool frequency subscore, endoscopic erosions/ulcerations, and chronic histologic structural/architectural changes demonstrated significant associations with 1-year EI and were included in the final model. The Ulcerative Colitis Severity Index (UCSI) had acceptable discriminative ability for 1-year EI in the training (area under the curve [AUC], 0.78; 95% confidence interval, 0.70-0.86) and testing cohort (AUC, 0.76; 95% CI, 0.68-0.85). Compared with the UCSI, the Mayo Clinic score demonstrated poor accuracy (AUC, 0.49; 95% CI, 0.40-0.58) for predicting 1-year EI (P = .0006). The UCSI predicted 1-year endoscopic healing (Mayo endoscopic score = 0), clinical remission (total Mayo Clinic score ≤2 and no subscore >1), partial Mayo score remission <2, and 2-item Patient-Reported Outcome score (Mayo stool frequency and rectal bleeding subscore = 0) with significantly greater accuracy compared with the Mayo Clinic score. DISCUSSION: The UCSI is an internally validated prognostic scoring tool that accurately predicts 1-year EI at baseline among moderate-to-severe UC patients initiating therapy. Further validation with additional datasets is needed.

Predictors of histologic response to mepolizumab in pediatric eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic, allergic disease of the esophagus. Current treatment options are limited. One experimental therapy is antibodies against interleukin-5 (IL-5). However, it is unknown why some patients respond to anti-IL-5 treatment whereas others do not. We sought to delineate predictors of histologic response to anti-IL-5 therapy in pediatric EoE. METHODS: This post hoc analysis of a multicenter, double-blind clinical trial (ClinicalTrial.gov identifier: NCT00358449) evaluated mepolizumab for the treatment of EoE in pediatric patients. Predictors were assessed for their association with a histologic response at week 12 of treatment. A histologic response was defined as either <15 eosinophils per hpf or a reduction in peak eosinophil counts by ≥50%. Predictors on univariate analysis with P < 0.10 were included in multivariate logistic regression models. Statistical significance for multivariate comparisons was set at P < 0.05. RESULTS: Patients with a higher BMI were more likely to attain histologic response at week 12, defined as <15 eosinophils per hpf [aOR, 1.31; 95% confidence interval (CI), 1.07-1.60; P = 0.008]. Higher BMI (aOR, 1.70; 95% CI, 1.06-2.74; P = 0.029) and signs of exudate plaques on endoscopy (aOR, 18.30; 95% CI, 2.11-158.53; P = 0.008) were significant predictors of histologic response at week 12 where a histologic response was defined as a reduction in peak eosinophil counts by ≥50. CONCLUSION: Higher BMI and signs of exudative plaques on endoscopy may be predictors of histologic response in pediatric EoE patients treated with antibodies against IL-5. Further studies are needed to validate our findings.

Real-World Persistence of Ustekinumab in the Treatment of Inflammatory Bowel Disease.

INTRODUCTION: There is an urgent need to understand the long-term real-world effectiveness of ustekinumab (UST) in the treatment of Crohn's disease (CD), fistulizing CD (FCD), and ulcerative colitis (UC). Persistence on treatment is commonly used as a surrogate measure of real-world treatment response. This study aims to estimate the long-term real-world persistence of UST in adult patients with CD, FCD, and UC. METHODS: A retrospective study was conducted in patients with CD, FCD, and UC treated with UST through a national patient support program in Canada. Treatment persistence was described using the Kaplan-Meier method, and the impact of patient characteristics on persistence was explored through stratified analyses and multivariable Cox proportional hazards models. RESULTS: Persistence rates for 8724 patients with CD were 82.9%, 71.4%, 64.1%, and 59.7% at 1, 2, 3, and 4 years, respectively. Similarly, persistence rates for 276 patients with FCD were 84.1%, 70.9%, 64.9%, and 63.1% at 1, 2, 3, and 4 years, respectively. Persistence rates for 1291 patients with UC were 76.5% at 1 year and 69.5% at 1.5 years. When stratified by prior IBD-indicated biologic experience, persistence was numerically higher in biologic-naïve patients across all disease cohorts. A Cox proportional hazards model confirmed that this difference was significant in patients with CD (hazard ratio: 0.72; confidence interval: [0.65-0.79]). CONCLUSIONS: This study estimated long-term persistence in a large population of patients with IBD. At 1 year, over three-fourths of patients remained on UST treatment in all disease cohorts, and over half of patients remained on treatment at 4 years in CD and FCD patients. Biologic-naïve status was significantly associated with higher persistence in patients with CD.

Inflammatory bowel disease is a term that refers to a group of disorders where the tissues of the gastrointestinal tract are chronically inflamed and may become damaged; it includes Crohn's disease and ulcerative colitis. While there is no cure, treatments are available to help patients manage their disease. Patients must typically continue treatment to ensure ongoing control. As such, the length of time a patient continues using a specific treatment can be suggestive of its success in the real-world. Ustekinumab is a biologic therapy that is used to treat both Crohn's disease and ulcerative colitis. Although ustekinumab has been evaluated in clinical trials, understanding how patients respond to treatment in the real world is valuable to physicians. This study was able to look at patients with inflammatory bowel disease who received treatment with ustekinumab through a patient support program in Canada and assess the length of time they continued treatment. After 1 year, over three-fourths of all patients with inflammatory bowel disease were still using ustekinumab; and after 4 years, more than half of patients with Crohn's disease were still using ustekinumab. This study was also able to look at whether certain factors affected the likelihood of a patient continuing treatment with ustekinumab. Patients that had never received a biologic therapy before were more likely to continue ustekinumab treatment than those who had received a different biologic therapy beforehand.

Delayed Ustekinumab Responders in Ulcerative Colitis Have Greater Inflammatory Burden but Similar Outcomes as Early Responders.

BACKGROUND & AIMS: Differences in 1-year outcomes among early compared with delayed responders to vedolizumab have been shown in ulcerative colitis. However, it is unclear whether similar differences exist with ustekinumab, and what factors differentiate delayed responders from nonresponders. METHODS: This study was a post hoc analysis of patient-level data from the UNIFI clinical trial. Ustekinumab-treated patients with clinical response, defined as a reduction in total Mayo score of 30% or more and 3 or more points from baseline with a reduction in their rectal bleeding subscore of 1 or more or a rectal bleeding subscore of 1 or less, at week 8 were deemed early responders and their outcomes were compared with delayed responders (week 8 nonresponders who subsequently responded at week 16). The primary outcome assessed was 1-year clinical remission, defined as a total Mayo score of 2 or less and no subscore greater than 1. RESULTS: We included 642 ustekinumab-treated patients, including 321 (50%) early responders, 115 (17.9%) delayed responders, and 205 (32.1%) nonresponders. No differences were observed for 1-year clinical remission among early vs delayed responders (132 of 321 [41.1%] vs 40 of 115 [34.8%]; P = .233), or for other outcomes assessed regardless of induction dose. Compared with early responders, delayed responders had more severe baseline Mayo endoscopic disease (88 of 115 [76.5%] vs 206 of 321 [64.2%]; P = .015) and abnormal baseline C-reactive protein level greater than 3 mg/L (83 of 115 [72.2%] vs 183 of 321 [57%]; P = .004). Compared with nonresponders, delayed responders had a significant decrease in C-reactive protein level (F-value [degrees of freedom, mean squares] [4, 844]; P < .0001) and fecal calprotectin level (F[4, 818]; P < .0001) through week 16. CONCLUSIONS: Compared with early ustekinumab responders, delayed responders had a greater inflammatory burden at baseline. Early and delayed responders had similar 1-year outcomes. Biomarker decline observed in delayed responders can help differentiate them from nonresponders.

Gut Microbiome Composition Is Associated With Future Onset of Crohn's Disease in Healthy First-Degree Relatives.

BACKGROUND & AIMS: The cause of Crohn's disease (CD) is unknown, but the current hypothesis is that microbial or environmental factors induce gut inflammation in genetically susceptible individuals, leading to chronic intestinal inflammation. Case-control studies of patients with CD have cataloged alterations in the gut microbiome composition; however, these studies fail to distinguish whether the altered gut microbiome composition is associated with initiation of CD or is the result of inflammation or drug treatment. METHODS: In this prospective cohort study, 3483 healthy first-degree relatives (FDRs) of patients with CD were recruited to identify the gut microbiome composition that precedes the onset of CD and to what extent this composition predicts the risk of developing CD. We applied a machine learning approach to the analysis of the gut microbiome composition (based on 16S ribosomal RNA sequencing) to define a microbial signature that associates with future development of CD. The performance of the model was assessed in an independent validation cohort. RESULTS: In the validation cohort, the microbiome risk score (MRS) model yielded a hazard ratio of 2.24 (95% confidence interval, 1.03-4.84; P = .04), using the median of the MRS from the discovery cohort as the threshold. The MRS demonstrated a temporal validity by capturing individuals that developed CD up to 5 years before disease onset (area under the curve > 0.65). The 5 most important taxa contributing to the MRS included Ruminococcus torques, Blautia, Colidextribacter, an uncultured genus-level group from Oscillospiraceae, and Roseburia. CONCLUSION: This study is the first to demonstrate that gut microbiome composition is associated with future onset of CD and suggests that gut microbiome is a contributor in the pathogenesis of CD.

Comparative Efficacy of Infliximab Versus Tofacitinib for Inducing Remission in Biologic Naive Ulcerative Colitis: A Propensity Matched Study.

OBJECTIVE: In the absence of head-to-head clinical trials, indirect comparative studies are needed to help position therapies in ulcerative colitis (UC). We aimed to compare the efficacy of infliximab vs. tofacitinib for moderate-severe UC among biologic-naïve participants at post-induction. METHODS: This was a post-hoc analysis of patient-level data from four clinical trials including 659 biologic-naïve UC participants. We compared proportions of patients achieving week 8 clinical remission (CR), endoscopic improvement, and endoscopic remission. Clinical response at week 2 was also assessed. Multiple logistic regression models were adjusted for potential confounders identified as having an association with the outcome of interest on univariate analysis. Propensity scores were calculated to create a cohort of participants with similar distribution of baseline co-variates. RESULTS: Patients treated with infliximab had significantly greater odds of CR at week 8 compared to tofacitinib [88/242 (36.4%) vs. 100/417 (24.0%), aOR: 1.65 (95% CI 1.11-2.44), p = 0.013]. Endoscopic improvement at week 8 was also significantly greater among infliximab-treated patients [149/242 (61.6%) vs. 159/417 (38.1%), aOR: 2.12 (95% CI 1.45-3.10), p < 0.001]. Similar findings were observed with week 8 endoscopic remission [61/242 (25.2%) vs. 43/417 (10.3%); aOR: 2.72 (95% CI 1.66-4.46), p < 0.001]. A similar proportion of participants attained clinical response at week 2 [205/242 (84.7%) vs. 334/417 (80.1%), aOR: 1.48 (95% CI 0.93-2.37), p = 0.101]. Similar results were observed among the propensity score matched cohort. CONCLUSION: Based on the efficacy observed in this post-hoc analysis, consideration should be given to use of infliximab over tofacitinib for treatment of moderate to severe biologic-naïve UC. However, baseline characteristic mismatches persisted despite propensity score matching, and further studies are needed to confirm our findings.

Combined Histological and Endoscopic Endpoints at Post-induction Lack Additional Prognostic Value Compared with Endoscopic Improvement Alone in Ulcerative Colitis: A Post hoc Analysis of the VARSITY study.

BACKGROUND AND AIMS: Evaluating histological outcomes in ulcerative colitis [UC] has become common in recent clinical trials. In this study, we explored the additional value of the combined endpoint of histo-endoscopic mucosal improvement [HEMI] compared with endoscopic improvement [EI] at post-induction [Week 14] and post-maintenance [1 year]. METHODS: This post hoc analysis included 620 UC participants with available data from the VARSITY trial. Participants achieving post-induction and post-maintenance HEMI [Mayo endoscopic subscore ≤1 and Geboes score <3.2] were compared across clinical outcomes, patient-reported outcomes [PROs], and inflammatory markers. Univariate analyses were performed to identify variables associated with the outcome of interest. Multivariate analyses included covariates with a p <0.05 on univariate analyses. RESULTS: Among the 468 patients with 1-year data available, a total of 166 [35.5%] attained HEMI and 209 [44.7%] attained EI at post-induction. No difference in achievement of clinical remission [CR] at 1 year was observed among those who attained post-induction HEMI vs EI (121/166 [72.9%] vs 147/209 [70.3%], p = 0.903). Similar findings were observed for the outcome of 1-year treatment failure (45/166 [27.1%] vs 55/209 [26.3%], p = 0.781). Patients who achieved HEMI at post-induction had lower total and partial Mayo scores and had the largest improvement from baseline. Faecal calprotectin and C-reactive protein [CRP] were also significantly lower among HEMI achievers at post-induction [p <0.001]. Similar findings were observed at post-maintenance. CONCLUSIONS: In this post hoc analysis, at post-induction, HEMI did not demonstrate additional prognostic value in predicting 1-year outcomes over EI. However, HEMI was associated with lower clinical disease activity at post-induction and at 1 year compared with endoscopic or histological outcomes in isolation.

Vedolizumab and Adalimumab in Biologic-Naïve Ulcerative Colitis: Comparison of Patient-Level Clinical Trial Data and VARSITY for Week 6 Clinical Remission.

BACKGROUND: Indirect treatment comparisons using patient-level data are increasing in popularity within inflammatory bowel disease research. We compared the efficacy of adalimumab and vedolizumab for biologic-naïve moderate-severe ulcerative colitis (UC) using indirect comparisons of phase 3 clinical trials and compared the results to the RCT VARSITY. DESIGN: Pooled analysis of patient-level data from 518 biologic-naïve patients with UC was performed using GEMINI-1 and ULTRA-1. Proportions of patients achieving week 6 clinical remission and clinical response were compared, and propensity score matching and multivariate logistic regression were used to account for potential confounders. These results were compared to those derived from VARSITY. RESULTS: A numerically greater proportion of vedolizumab-treated patients from GEMINI-1 achieved week 6 clinical remission compared to those treated with adalimumab [136/388 (35.1%) vs. 38/130 (29.2%)]. Similar findings were observed among the propensity score matched cohort [33/110 (30.0%) vs. 25/110 (22.7%), adjusted OR (aOR) 1.56 (95% confidence interval (CI) 0.81-3.02), p = 0.187]. A similar magnitude for absolute difference in the proportions of patients achieving week 6 clinical remission was observed from VARSITY in vedolizumab compared to adalimumab [131/305 (43.0%) vs. 114/307 (37.1%), OR 1.27 (95% CI 0.92-1.76), p = 0.142]. CONCLUSIONS: In this post hoc analysis, a similar magnitude in the absolute difference of efficacy at week 6 among biologic-naïve patients was observed using indirect comparisons of phase 3 clinical trial data as was observed in VARSITY. Indirect comparisons using patient-level clinical trial data could be used to inform drug choices for future head-to-head trials and guide positioning of drugs in the absence of head-to-head trials.

Associations of Antibiotics, Hormonal Therapies, Oral Contraceptives, and Long-Term NSAIDS With Inflammatory Bowel Disease: Results From the Prospective Urban Rural Epidemiology (PURE) Study.

BACKGROUND & AIMS: Several medications have been suspected to contribute to the etiology of inflammatory bowel disease (IBD). This study assessed the association between medication use and the risk of developing IBD using the Prospective Urban Rural Epidemiology cohort. METHODS: This was a prospective cohort study of 133,137 individuals between the ages of 20 and 80 from 24 countries. Country-specific validated questionnaires documented baseline and follow-up medication use. Participants were followed up prospectively at least every 3 years. The main outcome was the development of IBD, including Crohn's disease (CD) and ulcerative colitis (UC). Short-term (baseline but not follow-up use) and long-term use (baseline and subsequent follow-up use) were evaluated. Results are presented as adjusted odds ratios (aORs) with 95% CIs. RESULTS: During a median follow-up period of 11.0 years (interquartile range, 9.2-12.2 y), there were 571 incident IBD cases (143 CD and 428 UC). Incident IBD was associated significantly with baseline antibiotic (aOR, 2.81; 95% CI, 1.67-4.73; P = .0001) and hormonal medication use (aOR, 4.43; 95% CI, 1.78-11.01; P = .001). Among females, previous or current oral contraceptive use also was associated with IBD development (aOR, 2.17; 95% CI, 1.70-2.77; P < .001). Nonsteroidal anti-inflammatory drug users also were observed to have increased odds of IBD (aOR, 1.80; 95% CI, 1.23-2.64; P = .002), which was driven by long-term use (aOR, 5.58; 95% CI, 2.26-13.80; P < .001). All significant results were consistent in direction for CD and UC with low heterogeneity. CONCLUSIONS: Antibiotics, hormonal medications, oral contraceptives, and long-term nonsteroidal anti-inflammatory drug use were associated with increased odds of incident IBD after adjustment for covariates.

Predictors of Clinical Remission to Placebo in Clinical Trials of Crohn's Disease.

BACKGROUND: In placebo-controlled clinical trials for Crohn's disease (CD), some placebo-treated patients demonstrate improvement. However, it is unclear what factors contribute to placebo response and remission. METHODS: This was a post hoc analysis of 3 placebo-controlled clinical trial programs (GEMINI-2, UNITI-1/2, and CLASSIC-1) of moderate-severe CD evaluating the efficacy of vedolizumab, ustekinumab, and adalimumab. Baseline predictors of clinical remission at the end of induction (week 4/6), defined as Crohn's Disease Activity Index <150 were evaluated among placebo-treated patients. Clinical response (decrease in Crohn's Disease Activity Index ≥100 points from baseline) at the end of induction was also evaluated. Univariate analyses were performed and predictors with P < .10 were included in multivariable analyses. RESULTS: A total of 683 patients (148 from GEMINI-2, 470 from UNITI-1/2, and 65 from CLASSIC-1) treated with placebo were included. Of the predictors evaluated, C-reactive protein <5 mg/L (odds ratio [OR], 1.66; 95% confidence interval [CI], 1.04-2.67; P = .035), albumin >40 g/L (OR, 1.57; 95% CI, 1.05-2.93; P = .023), and disease duration <5 years (OR, 1.70; 95% CI, 1.05-2.75; P = .032) were included in the multivariable model for clinical remission. Disease duration <5 years was the only variable that retained significance on multivariable analysis (adjusted OR, 1.67; 95% CI, 1.02-2.73; P = .040). For clinical response, isolated ileal disease and disease duration <1 year were included in the multivariable model, of which only the latter retained significance (adjusted OR, 1.84; 95% CI, 1.04-3.24; P = .035). CONCLUSIONS: Strategies that reduce placebo response rates in clinical trials of CD should be considered, including stratification or exclusion of subjects by disease duration and mild disease severity as measured by objective biomarkers.

Disease duration <5 years was independently associated with clinical remission at the end of induction. To reduce the placebo response rates in clinical trials, consideration should be given to stratification or exclusion of subjects by disease duration and mild disease severity as measured by objective biomarkers.