Endoscopic, Histologic, and Composite Endpoints in Patients with Ulcerative Colitis Treated with Etrasimod [106/120 characters, including spaces].

BACKGROUND & AIMS: Histologic remission, a potentially important treatment target in ulcerative colitis (UC), is associated with favorable long-term outcomes. Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active UC. This post-hoc analysis of the ELEVATE UC program evaluated the efficacy of etrasimod according to histologic and composite (histologic/endoscopic/symptomatic) endpoints and examined their prognostic value. METHODS: Patients with moderately to severely active UC were randomized 2:1 to once-daily oral etrasimod 2 mg or placebo. Histologic and composite endpoints, including disease clearance (endoscopic/histologic/symptomatic remission), were assessed at Weeks 12 (ELEVATE UC 52; ELEVATE UC 12) and 52 (ELEVATE UC 52). Logistic regressions examined associations between baseline and Week 12 histologic/composite endpoints and Week 52 outcomes. RESULTS: At Weeks 12 and 52, significant improvements with etrasimod vs placebo were observed in histologic/composite outcomes, including endoscopic improvement-histologic remission (EIHR) and disease clearance. The proportion of patients treated with etrasimod achieving clinical remission (CR) at Week 52 was higher among those with disease clearance at Week 12 vs those without disease clearance (73.9% [17/23] vs 28.3% [71/251]). Histologic improvement and endoscopic improvement (EI) at Week 12 were moderately and strongly associated with CR at Week 52, odds ratio (OR) (95% confidence interval [CI]): 2.37 (1.27, 4.41) and 6.36 (3.47, 11.64), respectively. Histologic remission and EI at Week 12 were strongly associated with EIHR at Week 52, OR (95% CI): 3.21 (1.70, 6.06) and 5.47 (2.89, 10.36), respectively. CONCLUSIONS: Etrasimod was superior to placebo for achievement of stringent histologic and composite endpoints; NCT03945188, NCT03996369.

Long-term safety and efficacy of filgotinib for the treatment of moderately to severely active ulcerative colitis: Interim analysis from up to 4 years of follow-up in the SELECTION open-label long-term extension study.

BACKGROUND: Filgotinib, an oral, once-daily, Janus kinase 1 preferential inhibitor, is an approved treatment for moderately to severely active ulcerative colitis. AIMS: The aim of this study is to assess the safety and efficacy of continued filgotinib therapy over ~4 years in the long-term extension of the phase 2b/3 SELECTION trial (SELECTIONLTE; NCT02914535). METHODS: In this interim analysis of SELECTIONLTE, SELECTION completers (week 10 responders to filgotinib who completed the maintenance study) continued their assigned treatment (double-blind filgotinib 200 mg [FIL200] or filgotinib 100 mg) and SELECTION week 10 non-responders received open-label FIL200. We assessed safety by adverse events (AEs), and efficacy by partial Mayo Clinic Score (pMCS), inflammatory biomarkers and health-related quality of life (HRQoL). We compared safety and efficacy between achievers and non-achievers of a multi-component endpoint, comprehensive disease control (CDC), comprising symptomatic, endoscopic, inflammatory biomarker and HRQoL improvements. RESULTS: Data for completers (n = 250) and non-responders (n = 372) were reported for ≤202 weeks. AE occurrences were low and consistent with previous analyses. The as-observed proportion of FIL200-treated patients in pMCS, biomarker and HRQoL remission during SELECTIONLTE remained high among completers (week 144: 80.0%, 86.4% and 86.0%, respectively) and increased among non-responders (week 192: 62.1%, 76.7% and 59.3%, respectively). Significantly higher proportions of CDC achievers at SELECTION week 58 achieved pMCS, IBDQ and corticosteroid-free pMCS remission than non-achievers, up to LTE week 96. CONCLUSIONS: Filgotinib induced and maintained symptomatic remission and improved HRQoL over 4 years. Safety results showed a proven long-term benefit-risk profile. FIL200-treated CDC achievers had better long-term outcomes than non-achievers.

Mucosal Healing With Vedolizumab in Patients with Chronic Pouchitis: EARNEST, a Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND & AIMS: Vedolizumab is indicated for the treatment of chronic pouchitis in the EU. We assessed whether vedolizumab induced mucosal healing (MH) and if MH was associated with clinical improvements. METHODS: EARNEST, a randomized, double-blind, placebo-controlled study, evaluated vedolizumab efficacy and safety in adults with chronic pouchitis. Centrally read endoscopic and histological evaluation was performed at baseline, week (W)14, and W34. Ulcer count, adapted Simple Endoscopic Score for Crohn's Disease (SES-CD) in the pouch, and Pouchitis Disease Activity Index (PDAI) histological component were evaluated. PDAI and Inflammatory Bowel Disease Questionnaire (IBDQ) remission at W14 and W34 were compared by MH status at W14. RESULTS: Following treatment, mean (SD) number of ulcers in vedolizumab-treated patients reduced from 15.1 (16.4) to 5.0 (4.9) at W14 and 2.7 (3.2) at W34 vs placebo-treated patients with corresponding values of 11.8 (11.3), 13.4 (18.4), and 9.7 (13.8) (vedolizumab vs placebo difference [95% CI]: W14:-8.4 [-14.3,-2.6]; W34:-7.0 [-12.0,-2.0]). More patients receiving vedolizumab vs placebo achieved reduction in ulcerated pouch surface area (W14: 52.4% vs 20.0%; difference 32.4p.p [9.7, 51.4]; W34: 52.1% vs 12.9%; difference 40.2p.p [15.6, 60.3]), absence of ulceration (W14: 23.8% vs 7.5%; difference 16.3p.p [1.1, 31.6]; W34: 34.4% vs 15.6%; difference 18.8p.p [-2.0, 39.5]), SES-CD remission (W14: 23.8% vs 7.5%; difference 16.3p.p [1.1, 31.6]; W34: 34.4% vs 15.6%; difference 18.8p.p [-2.0, 39.5]) and MH (W14: 16.7% vs 2.5%; difference 14.2p.p [1.9, 26.4]). Patients with MH at W14 had higher rates of PDAI and IBDQ remission at W14 and W34 than those without. CONCLUSION: Vedolizumab induced endoscopic improvements in patients with chronic pouchitis, which was associated with improved outcomes at W34, particularly in patients achieving MH at W14. CLINICALTRIALS: gov number, NCT02790138.

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.

Systematic review: effectiveness and safety of switching between originator infliximab and biosimilar infliximab in patients with inflammatory bowel disease.

INTRODUCTION: Infliximab (IFX) biosimilars are available to treat inflammatory bowel disease (IBD), offering cost reductions versus originator IFX in some jurisdictions. However, concerns remain regarding the efficacy and safety of originator-to-biosimilar switching. This systematic literature review evaluated safety and effectiveness of switching between IFX products in patients with IBD, including multiple switchers. METHODS: Embase, PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials were searched to capture studies (2012-2022) including patients with IBD who switched between approved IFX products. Effectiveness outcomes: disease activity; disease severity; response to treatment; patient-reported outcomes (PROs). Safety outcomes: incidence and rate of adverse events (AEs); discontinuations due to AEs, failure rate; hospitalizations; surgeries. Immunogenicity outcomes (n, %): anti-drug antibodies; patients receiving concomitant immunomodulatory medication. RESULTS: Data from 85 publications (81 observational, two randomized controlled trials) were included. Clinical effectiveness outcomes were consistent with the known profile of originator IFX with no difference after switching. There were no unexpected/serious AEs after switching, and rates of AEs were generally consistent with the known profile of IFX. CONCLUSIONS: Most studies reported that clinical, PROs, and safety outcomes for originator-to-biosimilar switching were clinically equivalent to originator responses. Limited data are available regarding multiple switches. PROTOCOL REGISTRATION: www.crd.york.ac.uk/prospero identifier is CRD42021289144.

Impact of upadacitinib induction and maintenance therapy on health-related quality of life, fatigue, and work productivity in patients with moderately-to-severely active Crohn's disease.

BACKGROUND AND AIMS: Quality of life in patients with active Crohn's disease may be significantly reduced. We evaluated the effects of upadacitinib induction and maintenance therapy on fatigue, quality of life, and work productivity in the phase 3 trials U-EXCEL, U-EXCEED, and U-ENDURE. METHODS: Clinical responders to upadacitinib 45 mg in U-EXCEL and U-EXCEED induction trials were re-randomized 1:1:1 to upadacitinib 30 mg, 15 mg, or placebo for 52 weeks of maintenance in U-ENDURE. Clinically meaningful improvements in Inflammatory Bowel Disease Questionnaire (IBDQ) response, IBDQ remission, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and Work Productivity and Activity Impairment were evaluated. Percentages of patients achieving clinically meaningful improvements were assessed at induction Weeks 4 and 12 and maintenance Week 52. RESULTS: Analysis included 1021 and 502 patients assessed at induction and maintenance, respectively. In U-EXCEL, greater improvements (all p≤0.001) in IBDQ response (71.0% vs 50.2%), IBDQ remission (44.2% vs 23.7%), and FACIT-Fatigue (42.0% vs 27.0%) were observed in upadacitinib-treated patients versus placebo at Week 4. Improvements in IBDQ response, IBDQ remission, and FACIT-Fatigue were similar or greater at Week 12. Clinically meaningful improvement in overall work impairment (52.1% vs 38.1%, p≤0.05) was demonstrated at Week 12. Similar results were observed in U-EXCEED. Improvements were sustained through 52 weeks of upadacitinib maintenance treatment. CONCLUSIONS: In patients with active Crohn's disease, upadacitinib treatment relative to placebo significantly improved fatigue, quality of life, and work productivity as early as Week 4. These effects were sustained through 52 weeks of maintenance.

Diagnosis of Inflammatory Bowel Disease-Associated Peripheral Arthritis: A Systematic Review.

BACKGROUND: Inflammatory bowel disease (IBD)-associated peripheral spondyloarthritis (pSpA) decreases quality of life and remains poorly understood. Given the prevalence of this condition and its negative impact, it is surprising that evidence-based disease definitions and diagnostic strategies are lacking. This systematic review summarizes available data to facilitate development and validation of diagnostics, patient-reported outcomes, and imaging indices specific to this condition. METHODS: A literature search was conducted. Consensus or classification criteria, case series, cross-sectional studies, cohort studies, and randomized controlled trials related to diagnosis were included. RESULTS: A total of 44 studies reporting data on approximately 1500 patients with pSpA were eligible for analysis. Data quality across studies was only graded as fair to good. Due to large heterogeneity, meta-analysis was not possible. The majority of studies incorporated patient-reported outcomes and a physical examination. A total of 13 studies proposed or validated screening tools, consensus, classification, or consensus criteria. A total of 28 studies assessed the role of laboratory tests, none of which were considered sufficiently accurate for use in diagnosis. A total of 17 studies assessed the role of imaging, with the available literature insufficient to fully endorse any imaging modality as a robust diagnostic tool. CONCLUSIONS: This review highlights existing inconsistency and lack of a clear diagnostic approach for IBD-associated pSpA. Given the absence of an evidence-based approach, a combination of existing criteria and physician assessment should be utilized. To address this issue comprehensively, our future efforts will be directed toward pursuit of a multidisciplinary approach aimed at standardizing evaluation and diagnosis of IBD-associated pSpA.

This systematic review highlights the lack of an evidence-based approach to the diagnosis of inflammatory bowel disease­associated peripheral spondyloarthritis and the need to standardize evaluation and diagnosis via multidisciplinary collaboration with development of patient-reported outcomes and imaging indices.

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.

Impact of Prior Biologic or Janus Kinase Inhibitor Therapy on Efficacy and Safety of Etrasimod in the ELEVATE UC 52 and ELEVATE UC 12 Trials.

BACKGROUND AND AIMS: Etrasimod is an oral, once daily, selective sphingosine 1-phosphate [S1P]1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis [UC]. This subgroup analysis evaluated the efficacy and safety of etrasimod 2 mg once daily vs placebo by prior biologic/Janus kinase inhibitor [bio/JAKi] exposure in ELEVATE UC 52 and ELEVATE UC 12. METHODS: Pre-defined efficacy endpoints were assessed at Weeks 12 and 52 in ELEVATE UC 52 and Week 12 in ELEVATE UC 12 in bio/JAKi-naïve and -experienced patients, and at Week 12 [pooled] based on prior advanced therapy exposure mechanism. RESULTS: In the ELEVATE UC 52 and ELEVATE UC 12 analysis populations, 80/274 [29.2%] and 74/222 [33.3%] patients receiving etrasimod and 42/135 [31.1%] and 38/112 [33.9%] patients receiving placebo, respectively, were bio/JAKi-experienced. In both bio/JAKi-naïve and -experienced patients, a significantly greater proportion receiving etrasimod vs placebo achieved clinical remission (p<0.05) in ELEVATE UC 52 at Weeks 12 [naïve: 30.9% vs 9.7%; experienced: 17.5% vs 2.4%] and 52 [naïve: 36.6% vs 7.5%; experienced: 21.3% vs 4.8%]; in ELEVATE UC 12, this was observed only for bio/JAKi-naïve patients [naïve: 27.7% vs 16.2%, p=0.033; experienced: 18.9% vs 13.2%, p=0.349]. Similar patterns were observed for most efficacy endpoints. Among patients with prior anti-integrin exposure [N=90], a significantly greater proportion achieved clinical response [54.1% vs 27.6%, p=0.030], but not clinical remission [9.8% vs 3.4%, p=0.248], with etrasimod vs placebo. CONCLUSIONS: Bio/JAKi-naïve and -experienced patients had clinically meaningful induction and maintenance treatment benefits with etrasimod vs placebo.

Qualitative and Psychometric Evaluation of 29-Item Patient-Reported Outcomes Measurement Information System® to Assess General Health-Related Quality of Life in Patients With Moderately to Severely Active Inflammatory Bowel Disease.

OBJECTIVES: To evaluate content validity and psychometric properties of the 29-item Patient-Reported Outcomes Measurement Information System (PROMIS-29) to determine its suitability in inflammatory bowel disease (IBD) clinical trials. METHODS: Content validity of PROMIS-29 was evaluated using qualitative interviews, including concept elicitation and cognitive debriefing, among patients living with Crohn's disease (Crohn's disease n = 20) or ulcerative colitis (UC, n = 19). PROMIS-29 validity, reliability, and responsiveness were assessed using data from phase II clinical trials of Crohn's disease (N = 360) and UC (N = 518). RESULTS: Common (≥74%) symptoms reported in qualitative interviews were increased stool frequency, fatigue, abdominal pain/cramping, blood/mucus in stool, bowel urgency, and diarrhea. Disease impact aligned with PROMIS-29 content (depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles/activities). Cognitive debriefing indicated that PROMIS-29 instructions were easily understood, items were relevant, and the recall period was appropriate. Psychometric evaluations demonstrated that PROMIS-29 scores indicating worse symptoms/functioning were associated with lower health-related quality of life and greater disease activity and severity. PROMIS-29 domain scores correlated (rs ≥ 0.40) with IBD Questionnaire domains and EuroQol-5-Dimension-5-Level dimensions measuring similar concepts. Test-retest reliability among patients with stable disease was moderate-to-excellent (0.64-0.94) for nearly all domains in all studies. PROMIS-29 was responsive to change in disease status from baseline to week 12. Thresholds for clinically meaningful improvement ranged from ≥3 to ≥8, depending on domain. CONCLUSIONS: PROMIS-29 is valid, reliable, and responsive for assessing general health-related quality of life and treatment response in IBD clinical trials.

A global consensus on the definitions, diagnosis and management of fibrostenosing small bowel Crohn's disease in clinical practice.

Fibrostenosis of the small bowel is common in patients with Crohn's disease. No consensus recommendations on definition, diagnosis and management in clinical practice are currently available. In this Consensus Statement, we present a clinical practice RAND/UCLA appropriateness study on the definition, diagnosis and clinical management of fibrostenosing Crohn's disease. It was conducted by a panel of 28 global experts and one patient representative. Following a systematic literature review, 526 candidate items grouped into 136 questions were generated and subsequently evaluated for appropriateness. Strictures are best defined as wall thickening, luminal narrowing and prestenotic dilation. Cross-sectional imaging is required for accurate diagnosis of fibrostenosing Crohn's disease, and it is recommended before making treatment decisions. It should also assess the degree of inflammation in the bowel wall. Multiple options for medical anti-inflammatory, endoscopic and surgical therapies were suggested, including follow-up strategies following therapy. This Consensus Statement supports clinical practice through providing guidance on definitions, diagnosis and therapeutic management of patients with fibrostenosing small bowel Crohn's disease.

Serum Extracellular Matrix Molecules and Their Fragments as Biomarkers of Inflammation and Fibrosis in Inflammatory Bowel Diseases - A Systematic Review.

BACKGROUND AND AIM: Contemporary techniques to assess disease activity or bowel damage in patients with inflammatory bowel disease (IBD), such as endoscopy and imaging, are either invasive or lack accuracy. Non-invasive biomarkers for this purpose remain an unmet medical need. Herein, we provide a comprehensive systematic review of studies evaluating blood extracellular matrix (ECM) biomarkers and their relevance in IBD. METHODS: We conducted a systematic review of PubMed, EMBASE, Web of Science, and Scopus to identify citations pertaining ECM biomarkers of IBD up to March 1, 2024. Studies were categorized based on marker subtype and clinical use. RESULTS: Thirty-one ECM markers were identified, 28 of these demonstrated the ability to differentiate IBD disease activity. Collagen III emerged as the most extensively investigated (1212 IBD patients), with the degradation marker C3M and deposition marker PRO-C3 being associated with IBD and subtypes. Collagen V markers C5M and PRO-C5 emerged as the most accurate single markers for diagnosis of IBD, with an area under the curves of 0.91 and 0.93, respectively. Overall, studies were characterized by variable endpoints. None of the studies included histological grading of intestinal damage, repair, or fibrosis formation as the primary outcome in relation to the ECM blood markers. CONCLUSIONS: Multiple ECM markers are linked with IBD and its phenotypes. However, more rigorous study designs and clearly defined endpoints are needed to ensure reproducibility and develop reliable and accurate biomarkers. ECM markers hold promise as they provide a 'window' into transmural tissue remodeling and fibrosis burden, warranting further investigation.

Efficacy and Safety of Etrasimod in Patients with Moderately to Severely Active Isolated Proctitis: Results From the Phase 3 ELEVATE UC Clinical Programme.

BACKGROUND AND AIMS: Pivotal trials in ulcerative colitis have historically excluded patients with isolated proctitis. Etrasimod is an oral, oncedaily, selective sphingosine 1phosphate1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis. This post hoc analysis assessed efficacy and safety of etrasimod 2 mg once daily in patients with isolated proctitis (centrally read) from the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials. METHODS: Patients, including those with isolated proctitis (<10 cm rectal involvement) who met all other inclusion criteria in ELEVATE UC 52 and ELEVATE UC 12, were randomised 2:1 to receive etrasimod or placebo. Primary, secondary and other identified efficacy endpoints and safety were assessed. RESULTS: We analysed data from 64 and 723 patients at Week 12 (both trials pooled), and 36 and 397 patients at Week 52 (ELEVATE UC 52 only) with isolated proctitis and more extensive colitis (≥10 cm rectal involvement), respectively. Patients with isolated proctitis receiving etrasimod demonstrated significant improvements versus placebo, including clinical remission rates at Weeks 12 (42.9% vs 13.6%) and 52 (44.4% vs 11.1%), endoscopic improvement (52.4% vs 22.7%) at Week 12 and bowel urgency numerical rating scale score at Week 12 (all p<0.01). Generally similar trends were observed in patients with more extensive colitis. Safety was consistent across subgroups, with no new findings. CONCLUSIONS: Etrasimod demonstrated significant improvements versus placebo in patients with isolated proctitis, and those with more extensive disease, in most efficacy endpoints at Week 12 and 52.

Ozanimod Differentially Impacts Circulating Lymphocyte Subsets in Patients with Moderately to Severely Active Crohn's Disease.

BACKGROUND: Ozanimod showed efficacy and safety in the phase 2 STEPSTONE study conducted in patients with moderately to severely active Crohn's disease. AIMS: This analysis assessed the effects of ozanimod on circulating lymphocytes in Crohn's disease. METHODS: Patients received ozanimod 0.92 mg for 12 weeks. Lymphocyte subtypes were evaluated using multicolor flow analysis on blood samples collected before treatment and on Week 12. Absolute lymphocyte count changes were analyzed by Wilcoxon signed rank tests. Disease activity changes and efficacy outcomes were evaluated at Week 12, and associations with lymphocyte subtype levels were assessed using Spearman's correlation and logistic regression. RESULTS: Reductions in median total T, Th, and cytotoxic T cells occurred at Week 12 (45.4%-76.8%), with reductions in most subtypes of 47.5% to 91.3% (P < 0.001). CD8+ terminally differentiated effector memory cells were largely unaffected (median change, - 19%; P = 0.44). Reductions in median total B cells occurred at Week 12 (76.7%), with reductions in subtypes of 71.4% to 81.7% (P < 0.001). Natural killer and monocyte cell counts were unchanged. Greater baseline levels and changes in nonswitched memory B cells were significantly associated with clinical, endoscopic, and histologic efficacy (P < 0.05, all comparisons). CONCLUSIONS: Ozanimod reduced circulating levels of all B-cell and most T-cell subsets but not monocytes or natural killer cells. Key subsets relevant to immune surveillance were not reduced, supporting the low risk of infection and malignancy with ozanimod in chronic inflammatory diseases. Levels of nonswitched memory B cells were associated with efficacy, providing a potential marker for ozanimod response. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02531113, EudraCT: 2015-002025-19.

Incidence of Total Knee Arthroplasty After Arthroscopic Surgery for Knee Osteoarthritis: A Secondary Analysis of a Randomized Clinical Trial.

Importance: It is unclear whether arthroscopic resection of degenerative knee tissues among patients with osteoarthritis (OA) of the knee delays or hastens total knee arthroplasty (TKA); opposite findings have been reported. Objective: To compare the long-term incidence of TKA in patients with OA of the knee after nonoperative management with or without additional arthroscopic surgery. Design, Setting, and Participants: In this ad hoc secondary analysis of a single-center, assessor-blinded randomized clinical trial performed from January 1, 1999, to August 31, 2007, 178 patients were followed up through March 31, 2019. Participants included adults diagnosed with OA of the knee referred for potential arthroscopic surgery in a tertiary care center specializing in orthopedics in London, Ontario, Canada. All participants from the original randomized clinical trial were included. Data were analyzed from June 1, 2021, to October 20, 2022. Exposures: Arthroscopic surgery (resection or debridement of degenerative tears of the menisci, fragments of articular cartilage, or chondral flaps and osteophytes that prevented full extension) plus nonoperative management (physical therapy plus medications as required) compared with nonoperative management only (control). Main Outcomes and Measures: Total knee arthroplasty was identified by linking the randomized trial data with prospectively collected Canadian health administrative datasets where participants were followed up for a maximum of 20 years. Multivariable Cox proportional hazards regression models were used to compare the incidence of TKA between intervention groups. Results: A total of 178 of 277 eligible patients (64.3%; 112 [62.9%] female; mean [SD] age, 59.0 [10.0] years) were included. The mean (SD) body mass index was 31.0 (6.5). With a median follow-up of 13.8 (IQR, 8.4-16.8) years, 31 of 92 patients (33.7%) in the arthroscopic surgery group vs 36 of 86 (41.9%) in the control group underwent TKA (adjusted hazard ratio [HR], 0.85 [95% CI, 0.52-1.40]). Results were similar when accounting for crossovers to arthroscopic surgery (13 of 86 [15.1%]) during follow-up (HR, 0.88 [95% CI, 0.53-1.44]). Within 5 years, the cumulative incidence was 10.2% vs 9.3% in the arthroscopic surgery group and control group, respectively (time-stratified HR for 0-5 years, 1.06 [95% CI, 0.41-2.75]); within 10 years, the cumulative incidence was 23.3% vs 21.4%, respectively (time-stratified HR for 5-10 years, 1.06 [95% CI, 0.45-2.51]). Sensitivity analyses yielded consistent results. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial of arthroscopic surgery for patients with OA of the knee, a statistically significant association with delaying or hastening TKA was not identified. Approximately 80% of patients did not undergo TKA within 10 years of nonoperative management with or without additional knee arthroscopic surgery. Trial Registration: ClinicalTrials.gov Identifier: NCT00158431.

Reliability and Responsiveness of Clinical and Endoscopic Outcome Measures in Crohn's Disease.

BACKGROUND: Regulatory guidance for Crohn's disease trials recommends coprimary efficacy end points that evaluate both symptoms and mucosal inflammation. We aimed to characterize the operating properties of commonly used disease activity assessments alone and in combination. METHODS: Endoscopic and clinical data were available for 129 participants from the Study of Biologic and Immunomodulator Naïve Patients in Crohn's Disease trial. Readers scored the Simple Endoscopic Score for Crohn's Disease and the Crohn's Disease Endoscopic Index of Severity using standardized conventions. Index reliability was determined using intraclass correlation coefficients. Index responsiveness was assessed using standardized effect sizes based upon treatment assignment. Outcomes were evaluated for optimal sensitivity to treatment effect. RESULTS: Substantial inter-rater reliability was observed when the Simple Endoscopic Score for Crohn's Disease and Crohn's Disease Endoscopic Index of Severity were used as continuous measures (intraclass correlation coefficient, 0.64; 95% confidence interval [CI], 0.50-0.73; and 0.62 95% CI, 0.36-0.77) compared with moderate reliability when dichotomized (0.46; 95% CI, 0.26-0.65; and 0.51; 95% CI, 0.00-0.78). The Simple Endoscopic Score for Crohn's Disease, Crohn's Disease Endoscopic Index of Severity, patient-reported outcome-2, and Crohn's Disease Activity Index were similarly responsive (standardized effect size, 0.43, 95% CI, 0.05-0.81; 0.38, 95% CI, 0.0-0.76; 0.53, 95% CI, 0.15-0.91). A composite outcome of Crohn's Disease Activity Index score <150 and Crohn's Disease Endoscopic Index of Severity score <6 was most sensitive to treatment effect (28.9%; 95% CI, 11.0%-46.8%; P = .003). CONCLUSION: Endoscopic indices were more reliable as continuous measures. Composite outcomes including endoscopy improved sensitivity to treatment effect.

This study largely supports current regulatory guidance for Crohn's disease trials recommending coprimary efficacy end points evaluating both symptoms and mucosal inflammation. Continuous endoscopic measures are most reliable and improve sensitivity to treatment effect when employed in composite outcomes.

Systematic review: Defining, diagnosing and monitoring small bowel strictures in Crohn's disease on intestinal ultrasound.

BACKGROUND: Stricturing Crohn's disease (CD) occurs most commonly in the terminal ileum and poses a clinical problem. Cross-sectional imaging modalities such as intestinal ultrasound (IUS), computed tomography enterography (CTE), and magnetic resonance enterography (MRE) allow for assessment of the entire bowel wall and associated peri-enteric findings. Radiologic definitions of strictures have been developed for CTE and MRE; their reliability and responsiveness are being evaluated in index development programs. A comprehensive assessment strategy for strictures using IUS is needed. AIMS: To provide a detailed summary of definitions, diagnosis and monitoring of strictures on IUS as well as technical aspects of image acquisition. METHODS: We searched four databases up to 6 January 2024. Two-stage screening was done in duplicate. We assessed risk of bias using QUADAS-2. RESULTS: There were 56 studies eligible for inclusion. Definitions for strictures on IUS are heterogeneous, but the overall accuracy for diagnosis of strictures is high. The capability of IUS for characterising inflammation versus fibrosis in strictures is not accurate enough to be used in clinical practice or trials. We summarise definitions for improvement of strictures on IUS, and discuss parameters for image acquisition and standardisation. CONCLUSIONS: This systematic review is the first step for a structured program to develop a stricture IUS index for CD.

Exposure-efficacy relationship of vedolizumab subcutaneous and intravenous formulations in Crohn's disease and ulcerative colitis.

BACKGROUND AND AIMS: This posthoc analysis of the GEMINI and VISIBLE studies in ulcerative colitis (UC) and Crohn's Disease (CD) assessed exposure-efficacy of vedolizumab intravenous (IV) and subcutaneous (SC). METHODS: A previously described population pharmacokinetic model was used to predict average serum and trough concentrations at steady state (Cav,ss, Ctrough,ss) and simulate the transition from vedolizumab IV to SC. Efficacy was defined as clinical remission at week 52: complete Mayo score ≤ 2 points and no individual subscore > 1 point (UC), and CD activity index score ≤ 150 points (CD). RESULTS: Data were from 1968 patients (GEMINI 1 [n = 334], VISIBLE 1 [n = 216], GEMINI 2 [n = 1009], VISIBLE 2 [n = 409]) who received maintenance treatment with vedolizumab IV-Q8W, IV-Q4W, SC-Q2W, or placebo. Model-predicted Cav,ss for IV-Q8W and SC-Q2W was similar in UC and CD. Cav,ss was higher for IV-Q4W than IV-Q8W and SC-Q2W. Ctrough,ss values from IV and SC aligned well with pooled observed Ctrough by treatment group in UC and CD. Cav,ss was equivalent for SC and IV. For UC and CD, efficacy rates were greater in patients in the highest quartiles of vedolizumab exposure for both formulations. CONCLUSION: Exposure-efficacy relationships for IV and SC vedolizumab administration were comparable, confirming that both are equally effective during maintenance treatment.

Combination Therapy With Guselkumab and Golimumab in Patients With Moderately to Severely Active Ulcerative Colitis: Pharmacokinetics, Immunogenicity and Drug-Drug Interactions.

A proof-of-concept study with the combination of guselkumab and golimumab in patients with ulcerative colitis (UC) has shown that the combination therapy resulted in greater efficacy than the individual monotherapies. The current analysis evaluated the pharmacokinetics (PK) and immunogenicity of guselkumab and golimumab in both the combination therapy and individual monotherapies. Blood samples were collected to evaluate serum concentrations and immunogenicity of guselkumab and golimumab. Population PK (PopPK) models were developed to assess the effects of combination therapy and other potential covariates on the PK of guselkumab and golimumab. The guselkumab PK was comparable between monotherapy and combination therapy, whereas golimumab concentrations were slightly higher with combination therapy. The anti-guselkumab antibody incidence was low with both monotherapy and combination therapy, and guselkumab immunogenicity did not impact the clearance. Conversely, the anti-golimumab antibody incidence with combination therapy was lower than that for monotherapy. PopPK analysis suggested that the slightly higher golimumab concentrations with combination therapy were partially due to lower immunogenicity and thus lower clearance with combination therapy. C-reactive protein (CRP) was also a significant covariate on golimumab clearance. The greater improvement of inflammation with combination therapy, as shown by reductions in CRP, may have also contributed to the higher golimumab concentrations. Combination therapy slightly decreased the clearance of golimumab, but not guselkumab clearance, in patients with UC. Lower immunogenicity and greater improvement of inflammation with combination therapy were potential mechanisms for slightly increased golimumab concentrations with combination therapy as compared with golimumab monotherapy.

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.