US National Estimates of Contemporary Mortality Rates in Patients with Ulcerative Colitis Undergoing Colectomy.

OBJECTIVE: Despite a growing armamentarium of medical therapies for ulcerative colitis (UC), colectomy remains an important therapeutic option. To better inform shared decision-making about surgery, we estimated the contemporary risk of mortality post-colectomy. METHODS: Mortality rates were estimated using the National Inpatient Sample (2016-2020). Factors associated with post-colectomy death were evaluated in multivariable regression. RESULTS: Post-colectomy mortality occurred in 1.2% [95% CI: 0.8%, 1.9%] of hospitalizations. Comorbidity burden, emergent laparotomy, and delays to surgery >5 days after admission were associated with mortality. CONCLUSIONS: Colectomy may be associated with mortality; however, this risk is heterogeneous based on patient- and procedural-related factors.

Comparative Efficacy of Biologics and Small Molecule Therapies in Improving Patient-Reported Outcomes in Ulcerative Colitis: Systematic Review and Network Meta-Analysis.

BACKGROUND: Ulcerative colitis (UC) is a chronic disorder with a considerable negative impact on health-related quality of life (HRQoL), which has been recently recognized as an important treatment target. The purpose of this study is to compare the efficacy of different biologics and small molecule therapies in achieving better patient-reported outcomes and HRQoL in patients with UC. METHODS: We performed a systematic review and network meta-analysis of the EMBASE, MEDLINE, and Cochrane Central databases from inception until February 1, 2024. The primary endpoint was clinical remission in the patient-reported outcome (PRO-2) score in UC patients who were treated with different biologics or small molecules during induction and maintenance phases. PRO-2 score is the sum of both stool frequency and rectal bleeding subscores. The secondary outcome was improvement of HRQoL defined as an increase in Inflammatory Bowel Disease Questionnaire score of ≥16 points from baseline or any change in total score from baseline. A random effects model was used, and outcomes were reported as odds ratio with 95% confidence interval. Interventions were ranked per the SUCRA (surface under the cumulative ranking curve) score. RESULTS: A total of 54 studies were included in the primary outcome analysis and 15 studies were included in the secondary outcome analysis. The primary analysis showed that during the induction phase all of included drugs were better than placebo in improving the PRO-2 score. Interestingly, upadacitinib was found to be superior to most medications in improving PRO-2 scores. The secondary analysis showed that guselkumab ranked first in the improvement of the Inflammatory Bowel Disease Questionnaire score, followed by upadacitinib during the induction phase. CONCLUSION: Upadacitinib ranked first in PRO-2 clinical remission during the induction and maintenance phases. Guselkumab, mirikizumab, tofacitinib, and upadacitinib were the only novel medications that were superior to placebo in improving HRQoL in UC, with guselkumab ranking the highest, followed by tofacitinib and upadacitinib. During maintenance of remission, tofacitinib ranked highest in improving HRQoL.

Patient-reported outcome (PRO-2) and disease impact on health-related quality of life (HRQoL) have been recognized as important treatment targets in ulcerative colitis. In this systematic review and network meta-analysis, we compared different biologics and small molecules in achieving these outcomes. We found that upadacitinib ranked first in PRO-2 clinical remission during induction and maintenance phases. Guselkumab, tofacitinib, and upadacitinib were the only novel medications that were superior to placebo in improving HRQoL during induction in ulcerative colitis, with guselkumab ranking the highest, followed by tofacitinib and upadacitinib. During maintenance of remission, tofacitinib ranked highest in improving HRQoL.

Comparative Efficacy and Safety of Upadacitinib vs. Vedolizumab, Ustekinumab, and Tofacitinib After Induction and Maintenance for Ulcerative Colitis: Three Matching-Adjusted Indirect Comparisons.

INTRODUCTION: Evidence on the comparative efficacy and safety of approved therapies for ulcerative colitis (UC) during induction and maintenance, including upadacitinib (UPA), vedolizumab (VEDO), ustekinumab (UST), and tofacitinib (TOFA), is limited. METHODS: Using data from phase 3 trials, three placebo (PBO)-anchored matching-adjusted indirect comparisons of the efficacy and safety of UPA versus VEDO, UST, and TOFA (U-ACHIEVE and U-ACCOMPLISH, GEMINI-1, UNIFI, and OCTAVE induction and maintenance trials) have been conducted. Baseline characteristics from UPA trials were weighted separately to match each comparator trial. Induction responders were re-randomized to oral UPA 15 or 30 mg, VEDO 300 mg intravenously every 8 weeks (Q8W), UST 90 mg SC Q8W, or oral TOFA 5 mg, or PBO in maintenance. Treat-through efficacy outcomes at weeks 44(UST)/46(VEDO)/52(UPA/TOFA) were adjusted by the likelihood of induction response and included clinical response, clinical remission, and endoscopic improvement. Safety outcomes included adverse events (AEs), serious AEs (SAEs), and AEs leading to discontinuation (except UPA vs. VEDO). Benefit-risk was assessed by numbers needed to treat (NNT)/harm, calculated as the inverse of the difference in proportions of patients achieving each efficacy/safety outcome for UPA versus comparator. RESULTS: The proportions of patients who demonstrated clinical response or endoscopic improvement was greater with UPA 15 mg versus VEDO and TOFA (p < 0.05). The proportions of patients demonstrating all treat-through efficacy outcomes were significantly greater with UPA 30 mg versus VEDO, UST, or TOFA with NNTs 3.2-8.7. No significant differences in proportions of AEs, SAEs, and AEs leading to discontinuation were observed between the two doses of UPA and comparators. CONCLUSION: In patients with active UC, greater clinical efficacy, and similar safety after 1 year of maintenance were observed with UPA versus VEDO, UST, and TOFA, suggesting a favorable benefit-risk profile for UPA. Despite matched baseline characteristics, differences in trial design and endpoints may persist.

Performance of bowel preparation quality scales in patients with Crohn's disease.

BACKGROUND: The performance of bowel preparation (BP) in patients with Crohn's disease (CD) is unknown. AIMS: To evaluate the operating properties of instruments used to assess BP quality in patients with CD. METHODS: We used the Boston Bowel Preparation Scale, modified Boston Bowel Preparation Scale, Harefield Cleansing Scale, Food and Drug Administration Bowel Cleansing Assessment Scale (BCAS), and a 100-mm visual analogue scale of bowel cleanliness to assess BP quality in 50 videos from 40 patients with CD. We assessed endoscopic activity with the Simple Endoscopic Score for CD (SES-CD). Assessments were on endoscope insertion and withdrawal. Reliability was quantified using the intraclass correlation coefficient (ICC). We assessed validity by within-patient correlation between instruments and the visual analogue scale using mixed-effect models. The correlation between BP quality and SES-SD scores was assessed using Spearman's rho. RESULTS: Inter- and intra-rater reliability for all BP quality instruments was substantial (ICC ≥0.61) except for the Food and Drug Administration BCAS on insertion (inter-rater reliability ICC ≥0.41). The visual analogue scale had substantial inter- and almost perfect (ICC ≥0.81) intra-rater reliability. Correlation coefficients for the validity of the instruments exceeded 0.58. BP quality and endoscopic disease activity scores in the colon were negatively correlated. CONCLUSION: Most existing instruments reliably assess BP quality in patients with CD. These results support the use of these instruments in clinical practice, provide a framework for scoring BP quality in CD clinical trials, and support evaluation of novel BP agents in patients with CD.

Reliability of CT Enterography for Describing Fibrostenosing Crohn Disease.

Background Standardized methods to measure and describe Crohn disease strictures at CT enterography are needed to guide clinical decision making and for use in therapeutic studies. Purpose To assess the reliability of CT enterography features to describe Crohn disease strictures and their correlation with stricture severity. Materials and Methods A retrospective study was conducted in 43 adult patients with symptomatic terminal ileal Crohn disease strictures who underwent standard-of-care CT enterography at a tertiary care center at the Cleveland Clinic between January 2008 and August 2016. After training on standardized definitions, four abdominal radiologists blinded to all patient information assessed imaging features (seven continuous measurements and nine observations) of the most distal ileal stricture in two separate sessions (separated by ≥2 weeks) in random order. Features with an interrater intraclass correlation coefficient (ICC) of 0.41 or greater (ie, moderate reliability or better) were considered reliable. Univariable and multivariable linear regression analysis identified reliable features associated with a visual analog scale of overall stricture severity. Significant reliable features were assessed as components of a CT enterography-based model to quantitate stricture severity. Results Examinations in 43 patients (mean age, 52 years ± 16 [SD]; 23 female) were evaluated. Five continuous measurements and six observations demonstrated at least moderate interrater reliability (interrater ICC range, 0.42 [95% CI: 0.25, 0.57] to 0.80 [95% CI: 0.67, 0.88]). Of these, 10 were univariably associated with stricture severity, and three continuous measurements-stricture length (interrater ICC, 0.64 [95% CI: 0.42, 0.81]), maximal associated small bowel dilation (interrater ICC, 0.80 [95% CI: 0.67, 0.88]), and maximal stricture wall thickness (interrater ICC, 0.50 [95% CI: 0.34, 0.62])-were independently associated (P value range, <.001 to .003) with stricture severity in a multivariable model. These three measurements were used to derive a well-calibrated (optimism-adjusted calibration slope = 1.00) quantitative model of stricture severity. Conclusion Standardized CT enterography measurements and observations can reliably describe terminal ileal Crohn disease strictures. Stricture length, maximal associated small bowel dilation, and maximal stricture wall thickness are correlated with stricture severity. © RSNA, 2024 Supplemental material is available for this article. See also the article by Rieder et al in this issue. See also the editorial by Galgano and Summerlin in this issue.

Reliability of MR Enterography Features for Describing Fibrostenosing Crohn Disease.

Background Clinical decision making and drug development for fibrostenosing Crohn disease is constrained by a lack of imaging definitions, scoring conventions, and validated end points. Purpose To assess the reliability of MR enterography features to describe Crohn disease strictures and determine correlation with stricture severity. Materials and Methods A retrospective study of patients with symptomatic terminal ileal Crohn disease strictures who underwent MR enterography at tertiary care centers (Cleveland Clinic: September 2013 to November 2020; Mayo Clinic: February 2008 to March 2019) was conducted by using convenience sampling. In the development phase, blinded and trained radiologists independently evaluated 26 MR enterography features from baseline and follow-up examinations performed more than 6 months apart, with no bowel resection performed between examinations. Follow-up examinations closest to 12 months after baseline were selected. Reliability was assessed using the intraclass correlation coefficient (ICC). In the validation phase, after five features were redefined, reliability was re-estimated in an independent convenience sample using baseline examinations. Multivariable linear regression analysis identified features with at least moderate interrater reliability (ICC ≥0.41) that were independently associated with stricture severity. Results Ninety-nine (mean age, 40 years ± 14 [SD]; 50 male) patients were included in the development group and 51 (mean age, 45 years ± 16 [SD]; 35 female) patients were included in the validation group. In the development group, nine features had at least moderate interrater reliability. One additional feature demonstrated moderate reliability in the validation group. Stricture length (ICC = 0.85 [95% CI: 0.75, 0.91] and 0.91 [95% CI: 0.75, 0.96] in development and validation phase, respectively) and maximal associated small bowel dilation (ICC = 0.74 [95% CI: 0.63, 0.80] and 0.73 [95% CI: 0.58, 0.87] in development and validation group, respectively) had the highest interrater reliability. Stricture length, maximal stricture wall thickness, and maximal associated small bowel dilation were independently (regression coefficients, 0.09-3.97; P < .001) associated with stricture severity. Conclusion MR enterography definitions and scoring conventions for reliably assessing features of Crohn disease strictures were developed and validated, and feature correlation with stricture severity was determined. © RSNA, 2024 Supplemental material is available for this article. See also the article by Rieder and Ma et al in this issue. See also the editorial by Galgano and Summerlin in this issue.

Differences Between the 2016 and 2022 Food and Drug Administration Guidance-Implications for Design and Interpretation of Clinical Trials in Ulcerative Colitis.

Background: In 2022, the Food and Drug Administration (FDA) updated its draft guidance for drug development in ulcerative colitis, replacing the version from 2016. Several changes from the 2016 version merit further discussion as they impact clinical trial design and the interpretation of trial results. Methods: We compared both documents and critically appraised the changes and implications for future clinical trials. Results: The 2022 guidance recommends full colonoscopy, rather than flexible sigmoidoscopy, to document disease activity in all involved segments of the colon. The concordance between the findings of the 2 procedures is very high and there is little evidence to support colonoscopy over sigmoidoscopy. The use of colonoscopy, rather than sigmoidoscopy, is also associated with a higher burden to trial participants who must undergo full bowel preparation, cost, and a potential for more adverse events. The definition of the Mayo endoscopic score of 0 was changed from the original publication to "normal appearance of mucosa," which suggests that endoscopic signs of prior disease, such as pseudopolyps and scarring, are incompatible with a score 0, even though they are not associated with active disease. The term "mucosal healing" has been abolished and histologic outcomes defined as exploratory. A welcome change is that shorter washout periods than 5 half-lives will be considered to reduce patient exposure to corticosteroids as bridging therapy. Conclusions: The 2022 FDA draft guidance includes changes which for the most part are not informed by empirical evidence, which may ultimately complicate interpretation of future trials and preclude comparisons with past trials.

Re-evaluating Methods for Assessing Differences in Response in Ileal vs. Colonic Crohn's Disease: A Post-hoc Analysis of the FITZROY Trial.

BACKGROUND AND AIMS: The ileum is the most commonly affected segment of the gastrointestinal tract in Crohn's disease (CD). We aimed to determine whether disease location affects response to filgotinib, a Janus kinase (JAK) inhibitor, in patients with moderate-to-severely active Crohn's disease (CD) and applying appropriate methods to account for differences in measuring disease activity in the ileum compared to the colon. METHODS: This post-hoc analysis of data from the FITZROY phase 2 trial (NCT02048618) compared changes in the Crohn's Disease Activity Index (CDAI) and Simple Endoscopic Score for Crohn's Disease (SES-CD) amongst patients with ileal-dominant and isolated colonic CD treated with 10 weeks of filgotinib 200 mg daily or placebo. A mixed effects model for repeated measures was used to test whether ileal disease responded differently than colonic disease, by evaluating for effect modification using the interaction term of treatment assignment-by-disease location. RESULTS: Numerically greater proportions of patients with isolated colonic disease compared to ileal-dominant CD achieved clinical remission (CDAI <150, 75.9% vs. 41.6%) and endoscopic response (SES-CD reduction by 50%, 52.5% vs. 15.5%) at Week 10. However, after adjusting for baseline disease activity by disease location and within-patient clustering effects, there was no significant difference in treatment response by disease location (mean difference in ΔCDAI between ileal-dominant vs. isolated colonic disease +9.24 [95% CI: -87.19, +105.67], p=0.85; mean difference in ΔSES-CD -1.93 [95% CI: -7.03, +3.44], p=0.48). CONCLUSIONS: Filgotinib demonstrated similar efficacy in ileal-dominant and isolated colonic CD when controlling for baseline disease activity and clustering effects.

The Future of Clinical Trials in Inflammatory Bowel Disease.

The medical management of inflammatory bowel disease (IBD) has been transformed over the past few decades by the approval of multiple classes of advanced therapies and the integration of more targeted treatment strategies for Crohn's disease and ulcerative colitis. These changes have been driven by an increasing number of pivotal randomized controlled trials, which have grown in size and complexity over time. Several landmark studies that are anticipated to change current IBD management paradigms have recently been completed or are on-going, including the first head-to-head biologic trials, advanced combination treatment trials, therapeutic strategy and treatment target trials, and multiple phase 3 registrational programs of novel compounds. Despite these advances, the future of IBD trials also faces major challenges with respect to cost, feasibility, and recruitment. Accordingly, innovative methods for early and late phase randomized controlled trials must be adopted. In this review, we provide a comprehensive overview of the evolution of modern IBD trials, discuss methods for improving trial efficiency in early and late phase development, and provide insights into the interpretation and implications of these data for clinical care.

Endoscopic scoring indices for assessing disease severity in familial adenomatous polyposis: Systematic review.

Background and study aims There is limited consensus on the optimal method for measuring disease severity in familial adenomatous polyposis (FAP). We aimed to systematically review the operating properties of existing endoscopic severity indices for FAP. Methods We searched MEDLINE, EMBASE, and the Cochrane Library from inception to February 2023 to identify randomized controlled trials (RCTs) that utilized endoscopic outcomes or studies that evaluated the operating properties of endoscopic disease severity indices in FAP. Results A total of 134 studies were included. We evaluated scoring indices and component items of scoring indices, such as polyp count, polyp size, and histology. Partial validation was observed for polyp count and size. The most commonly reported scoring index was the Spigelman classification system, which was used for assessing the severity of duodenal involvement. A single study reported almost perfect interobserver and intra-observer agreement for this system. The InSIGHT polyposis staging system, which was used for assessing colorectal polyp burden, has been partially validated. It showed substantial interobserver reliability; however, the intra-observer reliability was not assessed. Novel criteria for high-risk gastric polyps have been developed and assessed for interobserver reliability. However, these criteria showed a poor level of agreement. Other scoring indices assessing the anal transition zone, duodenal, and colorectal polyps have not undergone validation. Conclusions There are no fully validated endoscopic disease severity indices for FAP. Development and validation of a reliable and responsive endoscopic disease severity instrument will be informative for clinical care and RCTs of pharmacological therapies for FAP.

Protocol for the development of a core outcome set for clinical trials in primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a progressive immune-mediated liver disease, for which no medical therapy has been shown to slow disease progression. However, the horizon for new therapies is encouraging, with several innovative clinical trials in progress. Despite these advancements, there is considerable heterogeneity in the outcomes studied, with lack of consensus as to what outcomes to measure, when to measure and how to measure. Furthermore, there has been a paradigm shift in PSC treatment targets over recent years, moving from biochemistry-based endpoints to histological assessment of liver fibrosis, imaging-based biomarkers and patient-reported outcome measures. The abundance of new interventional trials and evolving endpoints pose opportunities for all stakeholders involved in evaluating novel therapies. To this effect, there is a need to harmonise measures used in clinical trials through the development of a core outcome set (COS). METHODS AND ANALYSIS: Synthesis of a PSC-specific COS will be conducted in four stages. Initially, a systematic literature review will be performed to identify outcomes previously used in PSC trials, followed by semistructured qualitative interviews conducted with key stakeholders. The latter may include patients, clinicians, researchers, pharmaceutical industry representatives and healthcare payers and regulatory agencies, to identify additional outcomes of importance. Using the outcomes generated from the literature review and stakeholder interviews, an international two-round Delphi survey will be conducted to prioritise outcomes for inclusion in the COS. Finally, a consensus meeting will be convened to ratify the COS and disseminate findings for application in future PSC trials. ETHICS AND DISSEMINATION: Ethical approval has been granted by the East Midlands-Leicester Central Research Ethics Committee (Ref: 24/EM/0126) for this study. The COS from this study will be widely disseminated including publication in peer-reviewed journals, international conferences, promotion through patient-support groups and made available on the Core Outcomes Measurement in Effectiveness Trials (COMET) database. TRIAL REGISTRATION NUMBER: 1239.

Differential efficacy of medical therapies for ulcerative colitis according to disease extent: patient-level analysis from multiple randomized controlled trials.

Background: Disease extent in Ulcerative Colitis (UC) has prognostic implications for disease course. It is unclear whether the efficacy of medical therapies for moderate to severely active UC vary according to disease extent at enrollment. Methods: We analyzed patient level data from 11 Phase 2 and 3 clinical trials of advanced therapies in patients with moderate-to-severe UC to assess modifications of advanced therapy effects by disease extent. Primary outcome was clinical response and secondary outcomes were clinical remission, endoscopic response/remission and endoscopic improvement, and Mayo clinic subscore for both induction and maintenance studies. Binary and continuous outcomes were analyzed using the modified Poisson regression model and the mixed-effects model, respectively, adjusting for age, sex, disease duration, concomitant steroid use and prior anti-TNF use. Effect modifications with binary outcomes were quantified by ratios of risk ratio for left-sided to that for extensive colitis while effect modifications with the Mayo subscores were quantified by differences of the differences between mean scores of the left-sided and extensive colitis. Results were presented with point estimates and 95% confidence intervals as well as p-values. Findings: Eleven clinical trials enrolling 5450 UC patients (infliximab = 2, adalimumab = 2, golimumab = 2, vedolizumab = 2, tofacitinib = 3) were included. In induction trials, there was evidence to suggest effect modification by disease extent for clinical response with tofacitinib (the ratio of RRs 0.67, 95% CI [0.45, 0.99], p = 0.049) and clinical remission with infliximab (ratio of RRs 0.33, 95% CI [0.13, 0.85], p = 0.020) favoring patients with extensive colitis. There was no evidence to suggest effect modification for endoscopic improvement and clinical outcomes. There was evidence to suggest effect modification by disease extent for clinical remission with tofacitinib (ratio of RRs 0.44, 95% CI [0.22, 0.89], p = 0.020) favoring patients with extensive colitis. For symptom subscores from the Mayo Clinic score, tofacitinib was associated with a greater reduction in both stool frequency (difference of differences 0.37, 95% CI [0.08, 0.65], p = 0.012) and rectal bleeding scores (difference of differences 0.25, 95% CI [0.03, 0.47], p = 0.026) in patients with extensive colitis compared to left sided. Interpretation: These findings underscore the possibility of differential efficacy of medical therapies according to disease distribution. These results warrant further exploration in forthcoming trials to better inform treatment strategies and consideration of disease distribution as a baseline stratification factor in clinical trials. Funding: This study did not receive any financial support.

Healthcare resource utilization following ustekinumab initiation among bio-naïve Canadian patients with moderately-to-severely active Crohn's disease.

BACKGROUND/AIMS: Real-world healthcare resource utilization (HCRU) of bio-naïve patients with Crohn's disease (CD) receiving ustekinumab was assessed. METHODS: A multicentre, retrospective chart review study of bio-naïve Canadian adult patients with moderately-to-severely active CD treated with ustekinumab was conducted. CD-related HCRU (i.e., surgery, hospitalization, or emergency room [ER] visits) was evaluated at Months 4, 6, and 12 post-ustekinumab initiation, and associated costs were sourced from a provincial database. Proportion of patients with HCRU events and ustekinumab persistence were summarized at each timepoint. Paired analysis compared HCRU events and associated costs incurred by the same patient whilst in remission vs. when not in remission. RESULTS: By Month 12, 11.1 % (17/153) of patients had record(s) of any CD-related HCRU event, with ER visits being the most common (7.7 %; 12/155). Hospitalization had the highest average cost (CAD $436.10; SD $2,089.25) across all patients, accounting for 82.2 % of the mean total annual cost/patient (CAD $530.47; SD $2,229.92). While in remission, ≤5 % of patients experienced some healthcare encounter, compared with 7 % when not in remission (P = 0.289). Finally, 93.5 % of patients persisted on ustekinumab at Month 12. CONCLUSIONS: HCRU rates and associated total annual costs were lower for bio-naïve CD patients receiving ustekinumab, and when patients were in remission. Most patients continued with ustekinumab at Month 12.

Experiences of community pharmacists in the United Kingdom on the provision of travel health services and associated educational requirements.

BACKGROUND: Travel health services play a critical role in public health. Previously, travel services were provided solely through GPs or private specialist clinics. In recent years, they have been available from community pharmacists in the UK. This study sought to understand the types of travel health services provided by community pharmacists and to establish the educational needs. METHOD: Qualitative interviews and focus groups explored current practices and educational needs in travel medicine. Thematic analysis of transcribed interviews and focus groups was conducted to understand how travel services are provided and the training undertaken by community pharmacists in delivering these services. RESULTS: Nine individual interviews and one focus group of seven additional pharmacists was conducted. Pharmacists considered that they provided a comprehensive service and undertook the necessary training for safe delivery. Pharmacists described a 'vaccine centric' approach to travel services, with aspects, such as management of chronic conditions, fitness/preparedness for travel, prevention and self-management of travel-related conditions considered to be of lower priority. This was reflected in the travel medicine education that they had received and their perception of future requirements. CONCLUSION: Whilst vaccination is a critical aspect of travel health medicine, taking a 'vaccine centric' approach represents a missed opportunity in public health. Future educational opportunities for pharmacists could include training that encourages a broader approach to travel health consultations, to include a co-created, structured, and holistic risk assessment for travellers and recommendations for appropriate prevention and management strategies for travellers prior to, during and after travel.

A practical guide to combination advanced therapy in inflammatory bowel disease.

PURPOSE OF REVIEW: To provide an overview of the current literature regarding the use of advanced combination therapy (ACT) in patients with inflammatory bowel disease (IBD). Although the treatment of IBD has come a long way, many patients do not respond or will lose response to currently available treatments over time. ACT has been proposed as a model to create sustained remission in difficult-to-treat IBD patient populations. This review discusses the available literature supporting the use of ACT, followed by practical tips for applying this model of treatment to clinical practice. RECENT FINDINGS: Both observational and controlled evidence have demonstrated that there may be an increased benefit of ACT in specific IBD patient populations compared to advanced targeted immunomodulator (TIM) monotherapy. Additional data is required to understand how to best use combination TIMs and the long-term risks associated with this strategy. SUMMARY: While the literature has demonstrated the potential for benefit in both Crohn's disease and ulcerative colitis, the use of ACT is currently off-label and long-term controlled data is needed. The successful application of ACT requires careful consideration of both patient and disease profiles as well as close monitoring of treatment response and adverse events.

Operating Properties of Disease Activity Indices in Pediatric Inflammatory Bowel Disease: A Systematic Review.

BACKGROUND: Accurate, reliable, and responsive disease activity indices are important to streamline drug approval and treatment modalities for pediatric inflammatory bowel disease (pIBD). We aimed to identify all scoring indices used in pIBD randomized controlled trials (RCTs) and to evaluate their operating properties. METHODS: MEDLINE, EMBASE, and CENTRAL were searched on December 6, 2022, to identify studies evaluating clinical, endoscopic, imaging, or patient-reported outcome measures (PROMs) in pIBD including Crohn's disease (CD) and ulcerative colitis (UC). Validity, reliability, responsiveness, and feasibility were summarized. RESULTS: Seventy RCTs evaluating pIBD indices were identified. Forty-one studies reported on the operating properties of 14 eligible indices (n = 9 CD, n = 5 UC). The Pediatric Crohn's Disease Activity Index (PCDAI) varied widely in terms of validity and reliability and was less feasible overall. In contrast, the Mucosal Inflammation Noninvasive Index, which includes fecal calprotectin, had better operating properties than the PCDAI. The Simplified Endoscopic Mucosal Assessment of Crohn's Disease appears more feasible and had similar operating properties than the longer Simple Endoscopic Score for Crohn's Disease. The Pediatric Ulcerative Colitis Activity Index was feasible, valid, and reliable, but responsiveness needs to be evaluated further. The Endoscopic Mayo score and the Ulcerative Colitis Endoscopic Index of Severity were reliable, but validity and responsiveness need to be evaluated further. Imaging and PROMs/quality of life indices need further evaluation. CONCLUSIONS: The operating properties of pIBD clinical trial end points varied widely. These results highlight the need for further validation and development of novel indices.

The operating properties of pediatric inflammatory bowel disease clinical trial end points varied widely. These results highlight the need for further validation and development of novel indices in this population.

Upadacitinib for the treatment of moderate-to-severe Crohn's disease.

Despite an increasing number of therapies for Crohn's disease (CD), half of patients do not respond to initial treatment or lose response over time, highlighting the need for novel therapies. Inhibition of Janus kinases (JAKs) has emerged as an important therapeutic target for CD. Upadacitinib is an orally administered selective JAK1 inhibitor, which is effective for the induction and maintenance of remission in moderately-to-severely active CD, including in patients with prior failure of biological therapy. Nonselective JAK inhibition has been associated with thromboembolic disease, cardiovascular events and malignancy in patients older than 50 years with rheumatoid arthritis and pre-existing cardiovascular risk factors, which should be considered upon prescription. Upadacitinib is the first and currently only oral advanced therapy for CD.

Not all patients with Crohn's disease (CD) get better with treatment. Blocking Janus kinases (JAKs), enzymes that promote inflammation in the gut, could help these patients. The treatment upadacitinib blocks JAK1 (an enzyme transmitting inflammatory signals) and decreases inflammation in the gut. It eases symptoms. It also resolves gut inflammation in patients with CD. Regarding side effects, JAK inhibitors can cause blood clots in veins, and in the lungs, heart attacks, cancer and infections. Further studies are needed, but caution is advised. Upadacitinib is the first advanced therapy for CD given by mouth.

Determining the optimal treatment target in patients with ulcerative colitis: rationale, design, protocol and interim analysis for the randomised controlled VERDICT trial.

INTRODUCTION: Symptoms, endoscopy and histology have been proposed as therapeutic targets in ulcerative colitis (UC). Observational studies suggest that the achievement of histologic remission may be associated with a lower risk of complications, compared with the achievement of endoscopic remission alone. The actiVE ulcerative colitis, a RanDomIsed Controlled Trial (VERDICT) aims to determine the optimal treatment target in patients with UC. METHODS AND ANALYSIS: In this multicentre, prospective randomised study, 660 patients with moderate to severe UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2) are randomly assigned to three treatment targets: corticosteroid-free symptomatic remission (Mayo RBS=0) (group 1); corticosteroid-free endoscopic remission (MES ≤1) and symptomatic remission (group 2); or corticosteroid-free histologic remission (Geboes score <2B.0), endoscopic remission and symptomatic remission (group 3). Treatment is escalated using vedolizumab according to a treatment algorithm that is dependent on the patient's baseline UC therapy until the target is achieved at weeks 16, 32 or 48. The primary outcome, the time from target achievement to a UC-related complication, will be compared between groups 1 and 3 using a Cox proportional hazards model. ETHICS AND DISSEMINATION: The study was approved by ethics committees at the country level or at individual sites as per individual country requirements. A full list of ethics committees is available on request. Study results will be disseminated in peer-reviewed journals and at scientific meetings. TRIAL REGISTRATION NUMBER: EudraCT: 2019-002485-12; NCT04259138.