Resolution of rectal bleeding by day 7 in acute severe ulcerative colitis is prognostic for post-discharge corticosteroid free clinical remission and endoscopic improvement.

This study assesses two different disease activity measures, the MTWSI and the partial Mayo score, in hospitalized acute severe UC patients for prediction of post-discharge corticosteroid-free clinical remission and endoscopic improvement to help guide future considerations for disease activity assessment. In this post-hoc analysis from the TRIUMPH trial, these results suggest resolution of Mayo rectal bleeding sub-score may have high prognostic utility and could be considered as a primary endpoint for hospitalized UC trials. The study underscores the need for further research on patient-reported outcomes and endoscopic indices in larger populations for inpatient UC trials.

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.

Tissue-specific reprogramming leads to angiogenic neutrophil specialization and tumor vascularization in colorectal cancer.

Neutrophil (PMN) tissue accumulation is an established feature of ulcerative colitis (UC) lesions and colorectal cancer (CRC). To assess the PMN phenotypic and functional diversification during the transition from inflammatory ulceration to CRC we analyzed the transcriptomic landscape of blood and tissue PMNs. Transcriptional programs effectively separated PMNs based on their proximity to peripheral blood, inflamed colon, and tumors. In silico pathway overrepresentation analysis, protein-network mapping, gene signature identification, and gene-ontology scoring revealed unique enrichment of angiogenic and vasculature development pathways in tumor-associated neutrophils (TANs). Functional studies utilizing ex vivo cultures, colitis-induced murine CRC, and patient-derived xenograft models demonstrated a critical role for TANs in promoting tumor vascularization. Spp1 (OPN) and Mmp14 (MT1-MMP) were identified by unbiased -omics and mechanistic studies to be highly induced in TANs, acting to critically regulate endothelial cell chemotaxis and branching. TCGA data set and clinical specimens confirmed enrichment of SPP1 and MMP14 in high-grade CRC but not in patients with UC. Pharmacological inhibition of TAN trafficking or MMP14 activity effectively reduced tumor vascular density, leading to CRC regression. Our findings demonstrate a niche-directed PMN functional specialization and identify TAN contributions to tumor vascularization, delineating what we believe to be a new therapeutic framework for CRC treatment focused on TAN angiogenic properties.

Crohn's Patient Serum Proteomics Reveals Response Signature for Infliximab but not Vedolizumab.

BACKGROUND: Crohn's disease is a chronic inflammatory bowel disease that affects the gastrointestinal tract. Common biologic families used to treat Crohn's are tumor necrosis factor (TNF)-α blockers (infliximab and adalimumab) and immune cell adhesion blockers (vedolizumab). Given their differing mechanisms of action, the ability to monitor response and predict treatment efficacy via easy-to-obtain blood draws remains an unmet need. METHODS: To investigate these gaps in knowledge, we leveraged 2 prospective cohorts (LOVE-CD, TAILORIX) and profiled their serum using high-dimensional isobaric-labeled proteomics before treatment and 6 weeks after treatment initiation with either vedolizumab or infliximab. RESULTS: The proportion of patients endoscopically responding to treatment was comparable among infliximab and vedolizumab cohorts; however, the impact of vedolizumab on patient sera was negligible. In contrast, infliximab treatment induced a robust response including increased blood-gas regulatory response proteins, and concomitant decreases in inflammation-related proteins. Further analysis comparing infliximab responders and nonresponders revealed a lingering innate immune enrichments in nonresponders and a unique protease regulation signature related to clotting cascades in responders. Lastly, using samples prior to infliximab treatment, we highlight serum protein biomarkers that potentially predict a positive response to infliximab treatment. CONCLUSIONS: These results will positively impact the determination of appropriate patient treatment and inform the selection of clinical trial outcome metrics.

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.

Integrating Evidence to Guide Use of Biologics and Small Molecules for Inflammatory Bowel Diseases.

Advances in science have led to the development of multiple biologics and small molecules for the treatment of inflammatory bowel diseases (IBDs). This growth in advanced medical therapies has been accompanied by an increase in methodological innovation to study and compare therapies. Guidelines provide an evidence-based approach to integrating therapies into routine practice, but they are often unable to provide timely recommendations as new therapies come to market, and they have limited incorporation of real-world evidence when making recommendations. This limits the scope and usability of guidelines, and a gap remains in defining how best to position and integrate advanced medical therapies for IBD. In this review, we provide a framework for clinicians and researchers to understand key differences in sources of evidence, how different methodologies are applied to study the comparative effectiveness of advanced medical therapies in IBD, and considerations for how these sources of evidence can be used to better integrate current guideline recommendations. Over time, we anticipate this framework will allow for a transition to living guidelines and/or practice recommendations.

Trends of inflammatory bowel disease from the Global Burden of Disease Study (1990-2019).

BACKGROUND: The global burden of inflammatory bowel disease (IBD) is reportedly increasing. Methodologies and datasets are routinely updated, allowing for more accurate estimates to guide healthcare policy. METHODS: The Global Burden of Diseases, Injuries and Risk Factors Study (GBD) dataset was accessed and the trends in IBD at the global and regional levels from 1990 to 2019 were estimated for incidence, prevalence, deaths, years of life lost (YLL), years lived with disability (YLD) and disability-adjusted life-years (DALYs) per 100,000 population. The three decadal trends of the disease measures were calculated. RESULTS: In 2019, there were 4.9 million (95% Uncertainty Interval [UI] 4.3-5.5) cases of IBD globally. The age-standardized prevalence and incidence rates decreased from 73.23 (95% UI 63.8-83.6) and 6.1 (95% UI 5.3-6.9) in 1990 to 59.2 (95% UI 52.7-66.4) and 4.9 (95% UI 4.4-5.6) in 2019, respectively. Like prior estimates, the highest age-standardized prevalence and incidence rates occurred in North America, but the lowest rates were reported in Oceania (209.5 [195.4-224.4] and 24.5 [22.6-26.7] and 3.87 [3.1-4.7] and 0.5 [0.5-0.7], respectively) and not the Caribbean, as previously reported. High socio-demographic index (SDI) locations had the highest age-standardized prevalence rate, though the rates declined in 2019 compared to 1990. The age-standardized prevalence and incidence rates increased in middle, low middle and low SDI quintiles over the three decades. The age-standardized rates for deaths, DALYs, YLD and YLL decreased globally from 1990 to 2019. Between 1990 and 2019 the total number of patients with IBD in India doubled from 0.13 million (95% UI 0.10-0.16) to 0.27 million (95% UI 0.21-0.33) with age-standardized incidence rate increasing from 2.23 (95% UI 1.85-2.73) to 2.34 (95% UI 1.95-2.86). CONCLUSION: This analysis of the GBD 2019 database demonstrates that the overall global burden of IBD is lower than previously estimated, but an increasing disease burden is observed in the middle and low-SDI locations.

Safety and Effectiveness of Vedolizumab in Elderly Patients with Inflammatory Bowel Disease: A Systematic Review & Meta-Analysis.

BACKGROUND: There is limited data on Vedolizumab utilization in elderly patients. Our study aims to assess the effectiveness and safety of Vedolizumab in this subset population. MATERIALS AND METHODS: Databases including Cochrane Central, Embase, Medline (via Ovid), Scopus, and Web of Science were searched in August 2022 to identify studies that assessed Vedolizumab therapy in elderly patients. Pooled proportion and risk ratios (RR) were calculated. RESULTS: Total 11 studies with 3546 IBD patients (1314 elderly and 2232 young) were included in the final analysis. Pooled rate of overall and serious infections in the elderly cohort was 8.45% (95% CI=6.27-11.29; I 2 23%) and 2.59% (95% CI=0.78-8.29; I 2 76%), respectively. However, there was no difference in overall infection rates between elderly and young patients. Pooled rate of endoscopic, clinical, and steroid-free remission for elderly IBD patients was 38.45% (95% CI=20.74-59.56; I 2 93%), 37.95% (95% CI=33.08-43.06; I 2 13%), and 38.8% (95% CI=31.6-46.4; I 2 77%), respectively. Elderly patients had lower steroid-free remission rates [RR 0.85, 95% CI=0.74-0.99; I 2 0%, P =0.03]; however, there was no difference in rates of clinical (RR 0.86, 95% CI=0.72-1.03; I 2 0%, P =0.10) or endoscopic remission (RR 1.06, 95% CI=0.83-1.35; I 2 0%, P =0.63) compared with younger patients. Pooled rate of IBD-related surgery and IBD-related hospitalizations was 9.76% (95% CI=5.81-15.92; I 2 78%) and 10.54% (95% CI=8.37-13.2; I 2 0%), respectively for the elderly cohort. There was no statistical difference in IBD-related surgeries between elderly and young IBD patients, RR 1.20 (95% CI=0.79-1.84; I 2 16%), P =0.4. CONCLUSIONS: Vedolizumab is equally safe and effective for clinical and endoscopic remission in elderly and younger populations.

The importance of predicting patient responses to monoclonal antibodies for Crohn's disease.

INTRODUCTION: Crohn's disease (CD) is a chronic immune-mediated inflammatory bowel disease that results in relapsing and remitting symptoms but progressive transmural bowel damage leading to significant morbidity. CD results from dysregulation of the immune system related to genetic and environmental factors. While the use of monoclonal antibodies targeting cytokines and adhesion molecules has been shown to improve outcomes in CD patients, their widespread use has been limited due to high costs as well as variable access. Here, we summarize the factors that have been shown to correlate with responsiveness to biologic agents for use in practice. AREAS COVERED: We summarize the current literature regarding factors that have been shown to influence patient response to various biologic agents including: patient-related factors (e.g. age, gender, weight smoking history); disease-specific factors (e.g. disease duration, location/extension, behavior/phenotype, severity); genetic markers; transcription factors, and the gut microbiome. Finally, we review the utility of prediction models and present data supporting the use of recently developed decision support tools. EXPERT OPINION: Clinical decision support tools developed by machine learning are currently available for the selection of biologic agents in CD patients. We expect these models to become an integral tool for clinicians in the treatment of CD in the coming years.

Efficacy of biologic and small molecule agents as second-line therapy after exposure to TNF inhibitors in patients with ulcerative colitis: A propensity-matched cohort study.

BACKGROUND: There is limited real-world data on comparative effectiveness of different biologic or small molecule agents as second-line therapies in patients with ulcerative colitis (UC) with prior exposure to a tumour necrosis factor inhibitor (TNFi). METHODS: We conducted a retrospective cohort study using TriNetX, a multi-institutional database to assess the efficacy of tofacitinib, vedolizumab and ustekinumab in patients with ulcerative colitis (UC) with prior exposure to a TNFi. Failure of medical therapy was defined as a composite outcome of intravenous steroids or colectomy within 2 years. One-to-one propensity score matching was performed for demographics, disease extent, mean haemoglobin, C-reactive protein, albumin and calprotectin, prior IBD medications and steroid use between cohorts. RESULTS: Among 2141 patients with UC and prior exposure to TNFi, 348 (16.2%), 716 (33.4%) and 1077 (50.3%) were switched to tofacitinib, ustekinumab and vedolizumab, respectively. After propensity-score matching, there was no difference in the composite outcome (aOR: 0.77, 95% CI: 0.55-1.07) but higher risk of colectomy (aOR: 2.69, 95% CI: 1.31-5.50) in the tofacitinib cohort than the vedolizumab cohort. There was no difference in the risk of composite outcome (aOR: 1.29, 95% CI: 0.89-1.86) but higher risk of colectomy (aOR: 2.63, 95% CI: 1.24-5.58) in the tofacitinib cohort than the ustekinumab cohort. The vedolizumab cohort had a higher risk of composite outcome (aOR: 1.67, 95% CI: 1.29-2.16) than the ustekinumab cohort. CONCLUSION: Ustekinumab might be the preferred second-line therapy over tofacitinib and vedolizumab in patients with UC that were previously exposed to a TNFi.

Role of hyperbaric oxygen therapy in patients with inflammatory bowel disease.

PURPOSE OF REVIEW: Hypoxia is a known contributor to inflammation in inflammatory bowel diseases (IBD), and a growing interest has emerged in pharmacologically targeting hypoxia response pathways to treat IBD. The most basic form of treatment for hypoxia is delivering higher amounts of oxygen to the intestinal mucosa. In this review, we summarize the evidence in support of hyperbaric oxygen therapy (HBOT), a mechanism to deliver high amounts of oxygen to tissue, for treating IBD. RECENT FINDINGS: Two phase 2 clinical trials in hospitalized ulcerative colitis patients suffering from moderate-to-severe flares have demonstrated that HBOT improves responsiveness to steroids and avoidance of rescue medical and surgical therapy. Outpatient cohort studies in perianal fistulizing Crohn's disease and fistulizing complications of the pouch have demonstrated improved healing, particularly for complex fistulae. Several systematic reviews have now been completed, and HBOT has been observed to be well tolerated with low rates of adverse events. SUMMARY: HBOT may be considered as an adjunctive treatment for hospitalized ulcerative colitis flares and Crohn's disease-related fistulae. Higher quality trials are needed to confirm efficacy.

Correlations Between Gastrointestinal Symptoms and Endoscopic-Histologic Disease Activity in Adults with Ulcerative Colitis.

INTRODUCTION: Discordance between gastrointestinal (GI) symptoms and endoscopic inflammation in patients with ulcerative colitis (UC) is known. However, the correlations between symptoms and endoscopic and histologic (endo-histologic) mucosal healing and remains unknown. METHODS: We performed a secondary analysis of prospectively collected clinical, endoscopic, and histologic data on 254 colonoscopies from 179 unique adults at a tertiary referral center from 2014 to 2021. Spearman's rank was used to assess the correlation between patient reported outcomes and objective assessments of disease activity, as measured by validated instruments: Two-item patient-reported outcome measure (PRO-2) for stool frequency and rectal bleeding, the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) for endoscopic inflammation, and the Geboes score for histologic inflammation. The predictive value of objective assessments of inflammation and clinical symptoms was described using sensitivity, specificity, and positive/negative predictive value. RESULTS: One-quarter (28%, 72/254) of cases were in endo-histologic remission; of these, 25% (18/72) report GI symptoms (22% diarrhea; 6% rectal bleeding). Endo-histologically active disease had higher sensitivity (95% rectal bleeding; 87% diarrhea) and negative predictive value (94% rectal bleeding, 78% diarrhea) for clinically active disease compared to active disease on endoscopic (77%) or histologic assessment only (80%). The specificity of endo/histologic inflammation for GI symptoms was < 65%. PRO-2 was positively correlated with endoscopic disease activity (Spearman's rank 0.57, 95% CI 0.54-0.60, p < 0.0001) and histologic disease activity (Spearman's rank 0.49, 0.45-0.53, p < 0.0001). CONCLUSION: One-quarter of patients with ulcerative colitis in endo-histologic (deep) remission have gastrointestinal symptoms, more commonly with diarrhea than rectal bleeding. Endo-histologic inflammation has high sensitivity (≥ 87%) for diarrhea/rectal bleeding.

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.

Macrophage-endothelial cell crosstalk orchestrates neutrophil recruitment in inflamed mucosa.

Neutrophil (PMN) mobilization to sites of insult is critical for host defense and requires transendothelial migration (TEM). TEM involves several well-studied sequential adhesive interactions with vascular endothelial cells (ECs); however, what initiates or terminates this process is not well-understood. Here, we describe what we believe to be a new mechanism where vessel-associated macrophages through localized interactions primed EC responses to form ICAM-1 "hot spots" to support PMN TEM. Using real-time intravital microscopy of LPS-inflamed intestines in CX3CR1-EGFP macrophage-reporter mice, complemented by whole-mount tissue imaging and flow cytometry, we found that macrophage vessel association is critical for the initiation of PMN-EC adhesive interactions, PMN TEM, and subsequent accumulation in the intestinal mucosa. Anti-colony stimulating factor 1 receptor Ab-mediated macrophage depletion in the lamina propria and at the vessel wall resulted in elimination of ICAM-1 hot spots impeding PMN-EC interactions and TEM. Mechanistically, the use of human clinical specimens, TNF-α-KO macrophage chimeras, TNF-α/TNF receptor (TNF-α/TNFR) neutralization, and multicellular macrophage-EC-PMN cocultures revealed that macrophage-derived TNF-α and EC TNFR2 axis mediated this regulatory mechanism and was required for PMN TEM. As such, our findings identified clinically relevant mechanisms by which macrophages regulate PMN trafficking in inflamed mucosa.

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.

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.