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.

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.

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.

Safety of Ustekinumab in Inflammatory Bowel Disease: Pooled Safety Analysis Through 5 Years in Crohn's Disease and 4 Years in Ulcerative Colitis.

BACKGROUND AND AIMS: Previously published long-term safety data reported a favorable ustekinumab safety treatment profile for treatment of inflammatory bowel disease (IBD). We present the final cumulative safety data from pooled ustekinumab IBD phase 2/3 clinical studies through 5 years in Crohn's disease (CD) and 4 years in ulcerative colitis (UC). METHODS: In phase 3 studies, patients received a single IV placebo or ustekinumab (130mg or ~6mg/kg) induction dose followed by subcutaneous maintenance doses of placebo or ustekinumab (90mg q8w or q12w). Analyses included all patients who received one dose of study treatment and included patients who were biologic-naïve and patients with a history of biologic failure. Safety outcomes are summarized and presented using number of events per 100 patient-years of follow-up and corresponding 95% confidence interval. RESULTS: In this final pooled safety analysis, 2575 patients were treated with ustekinumab with 4826 patient-years of follow-up. Rates of key safety events, including MACE and malignancies, were similar between placebo and ustekinumab or not higher for ustekinumab.Opportunistic infections, including tuberculosis, and malignancies were reported infrequently. Rates of key safety events in the IBD group were no higher in the ustekinumab group than in the placebo group for both patients who were biologic naïve or who had previously failed a biologic. No lymphomas or cases of posterior reversible encephalopathy syndrome (PRES; formerly known as reversible posterior leukoencephalopathy syndrome [RPLS] were reported. CONCLUSION: The final cumulative ustekinumab safety data through 5 years in CD and 4 years in UC demonstrated favorable safety compared to placebo and continues to support the well-established safety profile across all approved indications.

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.

Standardizing Randomized Controlled Trials in Celiac Disease: An International Multidisciplinary Appropriateness Study.

BACKGROUND & AIMS: There is a need to develop safe and effective pharmacologic options for the treatment of celiac disease (CeD); however, consensus on the appropriate design and configuration of randomized controlled trials (RCTs) in this population is lacking. METHODS: A 2-round modified Research and Development/University of California Los Angeles Appropriateness Method study was conducted. Eighteen gastroenterologists (adult and pediatric) and gastrointestinal pathologists voted on statements pertaining to the configuration of CeD RCTs, inclusion and exclusion criteria, gluten challenge, and trial outcomes. Two RCT designs were considered, representing the following distinct clinical scenarios for which pharmacotherapy may be used: trials incorporating a gluten challenge to simulate exposure; and trials evaluating reversal of histologic changes, despite attempted adherence to a gluten-free diet. Each statement was rated as appropriate, uncertain, or inappropriate, using a 9-point Likert scale. RESULTS: For trials evaluating prevention of relapse after gluten challenge, participants adherent to a gluten-free diet for 12 months or more with normal or near-normal-sized villi should be enrolled. Gluten challenge should be FODMAPS (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) free, and efficacy evaluated using histology with a secondary patient-reported outcome measure. For trials evaluating reversal of villus atrophy, the panel voted it appropriate to enroll participants with a baseline villus height to crypt depth ratio ≤2 and measure efficacy using a primary histologic end point. Guidance for measuring histologic, endoscopic, and patient-reported outcomes in adult and pediatric patients with CeD are provided, along with recommendations regarding the merits and limitations of different end points. CONCLUSIONS: We developed standardized recommendations for clinical trial design, eligibility criteria, outcome measures, gluten challenge, and disease evaluations for RCTs in patients with CeD.

Endoscopic and Histological Placebo Rates in Crohn's Disease Clinical Trials: A Systematic Review and Meta-analysis.

BACKGROUND: Precise estimates of placebo response rates help efficient clinical trial design. In this systematic review and meta-analysis, we assessed contemporary placebo endoscopic and histological response rates in Crohn's disease (CD) clinical trials. METHODS: MEDLINE, EMBASE, and Cochrane CENTRAL were searched from inception to April 2022 to identify placebo-controlled studies of pharmacological interventions for CD. Endoscopic response, remission, and mucosal healing rates for participants assigned to placebo in induction and maintenance studies were pooled using a random-effects model. Point estimates and associated 95% confidence intervals (CIs) were calculated. RESULTS: In total, 16 studies (11 induction, 3 maintenance, 2 induction and maintenance) that randomized 1646 participants to placebo were eligible. For induction trials, the pooled placebo endoscopic response, endoscopic remission, and mucosal healing rates in participants assigned to placebo were 13% (95% CI, 10-16; I2 = 14.1%; P = .14), 6% (95% CI, 3-11; I2 = 74.7%; P < .001), and 6% (95% CI, 4-9; I2 = 26.9%; P = .29), respectively. The pooled endoscopic remission rate in patients who were bio-naïve was 10% (95% CI, 4-23) compared with only 4% (95% CI, 3-7) in bio-experienced patients. For maintenance trials, the pooled endoscopic response, remission, and mucosal healing rates were 7% (95% CI, 1-31; I2 = 78.2%; P = .004), 11% (95% CI, 4-27; I2 = 70.8%; P = .06), and 7% (95% CI, 3-15; I2 = 29.7; P = .23), respectively. Only 3 trials assessed histological outcomes. CONCLUSIONS: Endoscopic placebo rates vary according to trial phase and prior biologic exposure. These contemporary data will serve to inform CD trial design, sample size calculation, and end point selection for future trials.

Recommendations for Standardizing MRI-based Evaluation of Perianal Fistulizing Disease Activity in Pediatric Crohn's Disease Clinical Trials.

BACKGROUND: Perianal fistulas and abscesses occur commonly as complications of pediatric Crohn's disease (CD). A validated imaging assessment tool for quantification of perianal disease severity and activity is needed to evaluate treatment response. We aimed to identify magnetic resonance imaging (MRI)-based measures of perianal fistulizing disease activity and study design features appropriate for pediatric patients. METHODS: Seventy-nine statements relevant to MRI-based assessment of pediatric perianal fistulizing CD activity and clinical trial design were generated from literature review and expert opinion. Statement appropriateness was rated by a panel (N = 15) of gastroenterologists, radiologists, and surgeons using modified RAND/University of California Los Angeles appropriateness methodology. RESULTS: The modified Van Assche Index (mVAI) and the Magnetic Resonance Novel Index for Fistula Imaging in CD (MAGNIFI-CD) were considered appropriate instruments for use in pediatric perianal fistulizing disease clinical trials. Although there was concern regarding the use of intravascular contrast material in pediatric patients, its use in clinical trials was considered appropriate. A clinically evident fistula tract and radiologic disease defined as at least 1 fistula or abscess on pelvic MRI were considered appropriate trial inclusion criteria. A coprimary clinical and radiologic end point and inclusion of a patient-reported outcome were also considered appropriate. CONCLUSION: Outcomes of treatment of perianal fistulizing disease in children must include MRI. Existing multi-item measures, specifically the mVAI and MAGNIFI-CD, can be adapted and used for children. Further research to assess the operating properties of the indices when used in a pediatric patient population is ongoing.

Efficacy and safety of 48 weeks of guselkumab for patients with Crohn's disease: maintenance results from the phase 2, randomised, double-blind GALAXI-1 trial.

BACKGROUND: Many patients with moderately to severely active Crohn's disease do not respond to available therapies or lose response over time. The GALAXI-1 study previously found that three intravenous guselkumab dosages showed superior clinical and endoscopic outcomes over placebo at week 12 in patients with moderately to severely active Crohn's disease. We report the safety and efficacy of subcutaneous guselkumab maintenance regimens to week 48 in the GALAXI-1 study. METHODS: We did a phase 2, randomised, multicentre, double-blind trial. Adult patients with moderately to severely active Crohn's disease were randomly allocated with a computer-generated randomisation schedule to receive one of five treatment groups, with regimens consisting of an intravenous induction phase transitioning to a subcutaneous maintenance phase starting at week 12 in a treat-through design: (1) guselkumab 200→100 mg group (200 mg intravenous at weeks 0, 4, and 8, then 100 mg subcutaneous every 8 weeks; (2) guselkumab 600→200 mg group (600 mg intravenous at weeks 0, 4, and 8, then 200 mg subcutaneous every 4 weeks); (3) guselkumab 1200→200 mg group (1200 mg intravenous at weeks 0, 4, and 8, then 200 mg subcutaneous every 4 weeks); (4) ustekinumab group (approximately 6 mg/kg intravenous at week 0, then 90 mg subcutaneous every 8 weeks); or (5) placebo group (placebo induction followed by either placebo maintenance [for those with CDAI clinical response at week 12] or crossover to ustekinumab [for those without CDAI clinical response at week 12]). Endpoints assessed at week 48 included CDAI remission (CDAI score <150), endoscopic response (≥50% improvement from baseline in SES-CD or SES-CD score ≤2), and endoscopic remission (SES-CD score ≤2) in the primary efficacy analysis population of all randomised patients who received at least one dose of study drug, excluding those discontinued during a temporary study pause. Safety analyses included all randomised patients who received at least one study drug dose. This trial is registered at Clinical Trials.gov (NCT03466411) and is active but not recruiting. FINDINGS: Among 700 patients screened, 309 (112 biologic-naive; 197 biologic-experienced) were included in the primary efficacy analysis population: 61 in the guselkumab 200→100 mg group, 63 in the guselkumab 600→200 mg group, 61 in the guselkumab 1200→200 mg group, 63 in the ustekinumab group, and 61 in the placebo group. 126 (41%) women and 183 (59%) men were included, with median age 36·0 years (IQR 28·0-49·0). At week 48, the numbers of patients with CDAI clinical remission were 39 (64%) in the guselkumab 200→100 mg group, 46 (73%) in the guselkumab 600→200 mg group, 35 (57%) in the guselkumab 1200→200 mg group, and 37 (59%) in the ustekinumab group. The corresponding numbers of patients with endoscopic response were 27 (44%), 29 (46%), 27 (44%), and 19 (30%), respectively, and endoscopic remission was seen in 11 (18%), 11 (17%), 20 (33%), and four (6%) patients, respectively. In the placebo group, 15 patients were in CDAI clinical response at week 12 and continued placebo; of these, nine (60%) were in clinical remission at week 48. 44 patients in the placebo group were not in CDAI clinical response at week 12 and crossed over to ustekinumab; of these, 26 (59%) were in clinical remission at week 48. Up to week 48, adverse events frequencies in the safety population (n=360) were 46 (66%) of 70 patients (464·9 events per 100 patient-years of follow-up) in the placebo group, 163 (74%) of 220 patients (353·1 per 100 patient-years) in the three guselkumab groups combined, and 60 (85%) of 71 patients (350·7 per 100 patient-years) in the ustekinumab group. Among patients treated with guselkumab or ustekinumab, the most frequently reported infections up to week 48 were nasopharyngitis (25 [11%] of 220 guselkumab recipients, 12 [11%] of 114 ustekinumab recipients) and upper respiratory infections (13 [6%] guselkumab recipients, eight [7%] ustekinumab recipients). After week 12, one patient who responded to placebo induction and two guselkumab-treated patients had serious infections. No active tuberculosis, opportunistic infections, or deaths occurred. INTERPRETATION: Patients receiving guselkumab intravenous induction and subcutaneous maintenance treatment achieved high rates of clinical and endoscopic efficacy up to week 48. No new safety concerns were identified. FUNDING: Janssen Research & Development.

Reliability and Responsiveness of Histologic Indices for the Assessment of Crohn's Disease Activity.

BACKGROUND & AIMS: The operating properties of histologic indices for evaluating Crohn's disease (CD) activity are poorly characterized. We assessed the reliability and responsiveness of existing histologic indices/items used in CD and ulcerative colitis (UC), in addition to 3 novel items, and developed exploratory ileal, colonic, and colonic-ileal CD instruments. METHODS: Blinded central readers independently reviewed paired baseline and week 12 image sets from the EXTEND trial. Disease activity was scored using 4 indices (the Global Histologic Activity Score, Geboes Score, Nancy Histological Index, and Robarts Histopathology Index) and 3 items identified by an expert panel (mucin depletion, basal plasmacytosis, and ileal pyloric gland metaplasia). Reliability and responsiveness were quantified using the intraclass correlation coefficient (ICC) and area under the receiver operating curve (AUC), respectively. Exploratory indices were developed using backward stepwise linear regression analysis. Candidate independent variables were items with an inter-rater ICC ≥0.40 and AUC ≥0.56. The dependent variable was histologic disease activity measured by a 100-mm visual analogue scale. RESULTS: Paired image sets were available from 55 patients. Substantial to almost perfect inter-rater reliability (ICC, 0.63-0.87) and some responsiveness (AUC, 0.57-0.94) were observed for all existing indices regardless of whether individual colonic and ileal segments, combined colonic segments, or combined colonic and ileal segments were assessed and the calculation method used. Five items were tested as candidate items, and exploratory colonic, ileal, and colonic-ileal indices were developed. CONCLUSIONS: CD and UC indices were similarly reliable and responsive in measuring histologic CD activity. Exploratory index development did not offer benefit over current histologic instruments.

Qualitative and psychometric evaluation of the PROMIS®-Fatigue SF-7a scale to assess fatigue in patients with moderately to severely active inflammatory bowel disease.

BACKGROUND: This study evaluated the content validity and psychometric properties of the Patient-Reported Outcomes Measurement Information System® (PROMIS)-Fatigue Short Form 7a (SF-7a) v1.0 scale to determine its suitability in clinical trials to assess fatigue in patients with moderately to severely active Crohn's disease (CD) and ulcerative colitis (UC). METHODS: A qualitative interview assessed patients' experience living with CD (N = 20) and UC (N = 19). The contents of the SF-7a scale were cognitively debriefed to evaluate content validity. A psychometric evaluation was performed using data from clinical trials of patients with CD (N = 360) and UC (N = 214). Correlations with Inflammatory Bowel Disease Questionnaire (IBDQ), Crohn's Disease Activity Index (CDAI; CD only), and Mayo score (UC only) determined validity. The Patient Global Impression of Change (PGIC) was used to evaluate reliability and responsiveness to change. Using PGIC as an anchor, a preliminary threshold for clinically meaningful change was identified to define fatigue response in both CD and UC patients. RESULTS: All patients reported fatigue as a common symptom. Patients confirmed SF-7a items were relevant to assessing fatigue, instructions and response options were clear, and its 7-day recall period was appropriate. Higher SF-7a scores were associated with higher disease activity (CDAI and Mayo score) and lower health-related quality of life (IBDQ), confirming known groups validity. The correlation of the SF-7a scale was higher with fatigue-related items. (rs ≥ -0.70) than with items not directly associated with fatigue. Test-retest reliability was moderate to good (0.54-0.89) among patients with stable disease, and responsiveness to change in disease severity was demonstrated from baseline to Week 12. A ≥7point decrease was identified as a reasonable threshold to define clinically meaningful improvement. CONCLUSION: The SF-7a scale is a valid, reliable, and sensitive measure of fatigue in patients with moderately to severely active IBD and can be used to evaluate treatment response.

Efficacy and Safety of IL-12/23 and IL-23 Inhibitors for Crohn's Disease: Systematic Review and Meta-Analysis.

BACKGROUND: Targeting interleukin-23 (IL-23) is an important therapeutic strategy for Crohn's disease (CD). AIMS: This systematic review and meta-analysis assessed the efficacy and safety of selective IL-23p19 and IL-12/23p40 inhibitors in patients with moderate-to-severe CD. METHODS: MEDLINE, Embase, and the Cochrane library (CENTRAL) were searched from inception to May 24, 2023, for randomized, placebo- or active comparator-controlled induction and/or maintenance trials of selective IL-23p19 and IL-12/23p40 inhibitors in pediatric and adult patients with CD. The primary outcome was the proportion of patients in clinical remission. Secondary outcomes were clinical response, endoscopic remission, endoscopic response, and safety. Data were pooled using a random-effects model. Risk of bias and certainty of evidence were assessed using the Cochrane risk of bias tool and the GRADE criteria, respectively. RESULTS: Eighteen trials (n = 5561) were included. Most studies were rated as low risk of bias. Targeting IL-23 was significantly superior to placebo for inducing clinical (risk ratio [RR] = 1.87, 95% confidence interval [CI] 1.58-2.21) and endoscopic (RR = 3.20, 95%CI 2.17-4.70) remission and maintaining clinical remission (RR = 1.39, 95%CI 1.10-1.77) (GRADE high certainty evidence for all outcomes). Subgroup analysis showed that targeting IL-23 was superior to placebo for inducing clinical remission in biologic-naïve (RR = 2.20, 95%CI 1.46-3.32, I2 = 0%, p = 0.39) and biologic-experienced patients (RR = 1.82, 95%CI 1.27-2.60, I2 = 56.5%, p = 0.01). Targeting IL-23 was associated with a decreased risk of serious adverse events in induction (RR = 0.55, 95%CI 0.44-0.73) and maintenance (RR = 0.72, 95%CI 0.53-0.98) trials compared to placebo (high certainty evidence). CONCLUSION: Targeting IL-23 is effective and safe for inducing and maintaining clinical and endoscopic remission in patients with moderate-to-severe CD.

Efficacy and Safety of Advanced Oral Small Molecules for Inflammatory Bowel Disease: Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: Oral small-molecule drugs [SMDs] are expanding the therapeutic landscape for inflammatory bowel disease [IBD]. This systematic review and meta-analysis summarizes the efficacy and safety of JAK inhibitor [JAKi] and sphingosine-1-phosphate [S1P] receptor modulator treatments for ulcerative colitis [UC] and Crohn's disease [CD]. METHODS: MEDLINE, Embase, and CENTRAL were searched from inception to May 30, 2022. Randomized controlled trials [RCTs] of JAKi and S1P receptor modulators in adults with UC or CD were eligible. Clinical, endoscopic, histological, and safety data were pooled and analysed using a random-effects model. RESULTS: Thirty-five RCTs [26 UC, nine CD] were included. In UC, JAKi therapy was associated with induction of clinical (risk ratio [RR] 3.16, 95% confidence interval [CI] 2.03-4.92; I2 = 65%) and endoscopic [RR 3.99, 95% CI 2.36-6.75; I2 = 36%] remission compared to placebo. Upadacitinib was associated with histological response [RR 2.63, 95% CI 1.97-3.53]. S1P modulator therapy was associated with induction of clinical [RR 2.52, 95% CI 1.88-3.39; I2 = 1%] and endoscopic [RR 2.39, 95% CI 1.07-5.33; I2 = 0%] remission relative to placebo. Ozanimod was superior to placebo for inducing histological remission in UC [RR 2.20, 95% CI 1.43-3.37; I2 = 0%], while etrasimod was not [RR 2.36, 95% CI 0.71-7.88; I2 = 0%]. In CD, JAKi therapy was superior to placebo for induction of clinical remission [RR 1.53, 95% CI 1.19-1.98; I2 = 31%], and endoscopic remission [RR 4.78, 95% CI 1.63-14.06; I2 = 43%] compared to placebo. The risk of serious infections was similar for oral SMDs and placebo. CONCLUSION: JAKi and S1P receptor modulator therapies are effective in IBD for inducing clinical and endoscopic remission and, in some circumstances, histological response.

Targeting IL-23 for IBD: Rationale and Progress to Date.

Inflammatory bowel disease, including Crohn's disease and ulcerative colitis, comprises multiple complex immune-mediated disorders. Early diagnosis and prompt disease control may prevent long-term complications and hospitalization. The therapeutic options have expanded in the last two decades, with the development of biologics and small molecules targeting specific pathways implicated in inflammatory bowel disease pathogenesis. The interleukin (IL)-23/Th-17 axis is one such example. Targeting IL-12/23 is effective for the treatment of both moderate-to-severe Crohn's disease and ulcerative colitis, and ustekinumab (an IL-12/23p40 antagonist) is approved for both indications. In patients with psoriasis, improved clinical outcomes were observed with agents that more selectively targeted IL-23 (IL-23p19 antagonists) compared with those that target both IL-12 and IL-23. Many specific IL-23p19 antagonists are currently being investigated in Crohn's disease and ulcerative colitis, and risankizumab has been recently approved for moderate-to-severely active Crohn's disease. In this review, we summarize the mechanisms of action and the evidence from clinical trials supporting the efficacy and safety of IL-23p19 antagonists for the treatment of inflammatory bowel disease.

Standardizing Scoring Conventions for Crohn's Disease Endoscopy: An International RAND/UCLA Appropriateness Study.

BACKGROUND AND AIMS: Endoscopic assessment of disease activity is integral for evaluating treatment response in patients with Crohn's disease (CD). We aimed to define appropriate items for evaluating endoscopic activity and conventions for consistent endoscopic scoring rules in CD. METHODS: A 2-round modified RAND/University of California at Los Angeles Appropriateness Method study was conducted. A panel of 15 gastroenterologists used a 9-point Likert scale to rate the appropriateness of statements pertaining to the Simple Endoscopic Score for CD, Crohn's Disease Endoscopic Index of Severity, and additional items relevant to endoscopy scoring in CD. Each statement was voted as appropriate, uncertain, or inappropriate based on the median panel rating and presence of disagreement. RESULTS: Panelists voted that it is appropriate for all ulcers to contribute to endoscopic scoring in CD, including aphthous ulcers, ulcerations at a surgical anastomosis, and anal canal ulcers (scored in the rectum). Endoscopic healing should reflect an absence of ulcers. Narrowing should be defined as a clear decrease in luminal diameter; stenosis should be defined by an impassable narrowing, and if occurring at the junction of 2 segments, scored in the distal segment. Scarring and inflammatory polyps were considered inappropriate for including in the affected area score. The optimal method for defining ulcer depth remains uncertain. CONCLUSIONS: We outlined scoring conventions for the Simple Endoscopic Score for CD and Crohn's Disease Endoscopic Index of Severity, noting that both scores have limitations. Therefore, we identified priorities for future research and steps for developing and validating a more representative endoscopic index in CD.

Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies.

BACKGROUND: Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P2,3, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these two phase 3 trials, we aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis. METHODS: In two independent randomised, multicentre, double-blind, placebo-controlled, phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12, adults with active moderate-to-severe ulcerative colitis and an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients in ELEVATE UC 52 were enrolled from 315 centres in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centres in 37 countries. Randomisation was stratified by previous exposure to biologicals or Janus kinase inhibitor therapy (yes vs no), baseline corticosteroid use (yes vs no), and baseline disease activity (modified Mayo score [MMS]; 4-6 vs 7-9). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 independently assessed induction at week 12. The primary efficacy endpoints were the proportion of patients with clinical remission at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. Safety was evaluated in both trials. ELEVATE UC 52 and ELEVATE UC 12 were registered with ClinicalTrials.gov, NCT03945188 and NCT03996369, respectively. FINDINGS: Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and Jan 28, 2021. Patients in ELEVATE UC 12 were enrolled between Sept 15, 2020, and Aug 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment. The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo. In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74 [27%] of 274 patients vs ten [7%] of 135 patients; p<0·0001) and at week 52 (88 [32%] of 274 patients vs nine [7%] of 135 patients; p<0·0001). In ELEVATE UC 12, 55 (25%) of 222 patients in the etrasimod group had clinical remission compared with 17 (15%) of 112 patients in the placebo group at the end of the 12-week induction period (p=0·026). Adverse events were reported in 206 (71%) of 289 patients in the etrasimod group and 81 (56%) of 144 patients in the placebo group in ELEVATE UC 52 and 112 (47%) of 238 patients in the etrasimod group and 54 (47%) of 116 patients in the placebo group in ELEVATE UC 12. No deaths or malignancies were reported. INTERPRETATION: Etrasimod was effective and well tolerated as an induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Etrasimod is a treatment option with a unique combination of attributes that might address the persistent unmet needs of patients with ulcerative colitis. FUNDING: Arena Pharmaceuticals.

Efficacy of Filgotinib in Patients with Ulcerative Colitis by Line of Therapy in the Phase 2b/3 SELECTION Trial.

BACKGROUND AND AIMS: The efficacy of new therapies for ulcerative colitis [UC] is usually influenced by previous biologic use. These post hoc analyses of SELECTION, a placebo-controlled phase 2b/3 trial in patients with moderately to severely active UC, evaluated the efficacy of filgotinib, an oral Janus 1 kinase preferential inhibitor, with respect to prior biologic failure. METHODS: The effect of filgotinib 200 mg (FIL200) relative to placebo was compared in biologic-naïve and biologic-failed patient groups, and in further subgroups by number of failed biologics [1 or >1], biologic mechanism of action [MoA] classes [1 or 2] and tumour necrosis factor [TNF] antagonists [1 or >1]. Odds ratios [ORs] for clinical remission at week 10 [induction] and hazard ratios [HRs] for protocol-specific disease worsening [PSDW] from week 11 to week 58 [maintenance] were calculated. RESULTS: At week 10, FIL200-treated patients were more likely to achieve clinical remission than placebo-treated patients in the biologic-naïve (OR [95% confidence interval, CI]: 1.98 [1.14-3.44]) and biologic-failed (3.91 [1.33-11.48]) groups. During maintenance, FIL200-treated patients had a reduced risk of PSDW in the biologic-naïve (HR [95% CI]: 0.22 [0.11-0.44]) and biologic-failed (0.22 [0.12-0.40]) groups, and in all biologic-failed subgroups (except >1 TNF antagonist failure). The data suggest that the likelihood of PSDW at week 58 increased with increasing numbers of failed biologics. CONCLUSIONS: FIL200 induced and maintained benefits relative to placebo regardless of previous biologic use; however, the estimated therapeutic benefit was greatest in biologic-naïve patients and patients previously treated with one biologic or biologic MoA class. [ClinicalTrials.gov: NCT02914522].

A Phase 2b, Randomised, Double-blind, Placebo-controlled, Parallel-arm, Multicenter Study Evaluating the Safety and Efficacy of Tesnatilimab in Patients with Moderately to Severely Active Crohn's Disease.

BACKGROUND AND AIMS: Tesnatilimab, a monoclonal antibody targeting NKG2D, was evaluated in Crohn's disease [CD] patients who had failed or were intolerant to biologic or conventional therapy. METHODS: TRIDENT was a phase 2b, two-part, randomised, double-blind, placebo-controlled, parallel-arm, multicenter study. In Part 1 [proof of concept], 145 patients who were biologic intolerant or refractory [Bio-IR] or had not failed biologic therapy [Bio-NF] were randomised in a 1:1 ratio to placebo subcutaneously [SC] or tesnatilimab 400 mg SC. In Part 2 [dose ranging], 243 Bio-IR and Bio-NF patients were randomised in a 1:1:1:1:1 ratio to placebo, tesnatilimab [50 mg, 150 mg, 400 mg], or intravenous infusion of ustekinumab ~6 mg/kg at Week 0 and 90 mg SC at Weeks 8 and 16. The primary endpoint was mean change from baseline in Crohn's Disease Activity Index [CDAI] at Week 8 [Part 1] and Week 12 [Part 2]. Clinical and endoscopic remission/response were evaluated. Efficacy analyses were also assessed by NKG2D and MICB single nucleotide polymorphism [SNP] status [SNP-positive means positive in at least one of two SNPs]. Safety events were summarised. RESULTS: In Part 1, mean change from baseline in CDAI score was significantly greater with tesnatilimab vs placebo at Week 8 [-103.6 vs -60.0; p < 0.01]. In Part 2, no dose-response signal was detected. Mean changes from baseline in CDAI at Week 12 were -93.2, -72.2, and -84.3 for low, middle, and high doses of tesnatilimab, respectively, vs -59.2 for placebo and -148.8 for ustekinumab. Similar reductions from baseline in CDAI score were observed in patients receiving tesnatilimab, regardless of SNP status. Clinical remission rates were greater with tesnatilimab than placebo in Parts 1 and 2, whereas endoscopic response rates were greater with tesnatilimab only in Part 1. No unexpected safety events occurred. CONCLUSIONS: Tesnatilimab was well tolerated. The efficacy of tesnatilimab in patients with CD was significant for the primary endpoint in Part 1; however, no dose-response signal was detected for the primary endpoint in Part 2. Based on these inconsistent findings, tesnatilimab was not considered an effective treatment for patients with CD and no further development is planned. CLINICALTRIALS.GOV IDENTIFIER: NCT02877134.

Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trial.

BACKGROUND: Despite the introduction of new monoclonal antibodies and oral therapies for the treatment of ulcerative colitis, clinical remission rates remain low, underscoring the need for innovative treatment approaches. We assessed whether guselkumab plus golimumab combination therapy was more effective for ulcerative colitis than either monotherapy. METHODS: We did a randomised, double-blind, controlled, proof-of-concept trial at 54 hospitals, academic medical centres, or private practices in nine countries. Eligible adults (aged ≥18 to 65 years) had a confirmed diagnosis of ulcerative colitis at least 3 months before screening and moderately-to-severely active ulcerative colitis (Mayo score 6-12) with a centrally-read baseline endoscopy subscore of 2 or higher. Patients were randomly assigned (1:1:1) using a computer-generated randomisation schedule to combination therapy (subcutaneous golimumab 200 mg at week 0, subcutaneous golimumab 100 mg at weeks 2, 6, and 10, and intravenous guselkumab 200 mg at weeks 0, 4, and 8, followed by subcutaneous guselkumab monotherapy 100 mg every 8 weeks for 32 weeks), golimumab monotherapy (subcutaneous golimumab 200 mg at week 0 followed by subcutaneous golimumab 100 mg at week 2 and every 4 weeks thereafter for 34 weeks), or guselkumab monotherapy (intravenous guselkumab 200 mg at weeks 0, 4, and 8, followed by subcutaneous guselkumab 100 mg every 8 weeks thereafter for 32 weeks). The primary endpoint was clinical response at week 12 (defined as a ≥30% decrease from baseline in the full Mayo score and a ≥3 points absolute reduction with either a decrease in rectal bleeding score of ≥1 point or a rectal bleeding score of 0 or 1). Efficacy was analysed in the modified intention-to-treat population up to week 38, which included all randomly assigned patients who received at least one (partial or complete) study intervention dose. Safety was analysed up to week 50, according to study intervention received among all patients who received at least one (partial or complete) dose of study intervention. This trial is complete and is registered with ClinicalTrials.gov, NCT03662542. FINDINGS: Between Nov 20, 2018, and Nov 15, 2021, 358 patients were screened for eligibility, of whom 214 patients were randomly assigned to combination therapy (n=71), golimumab monotherapy (n=72), or guselkumab monotherapy (n=71). Of the 214 patients included, 98 (46%) were women and 116 (54%) were men and the mean age was 38·4 years (SD 12·0). At week 12, 59 (83%) of 71 patients in the combination therapy group had achieved clinical response compared with 44 (61%) of 72 patients in the golimumab monotherapy group (adjusted treatment difference 22·1% [80% CI 12·9 to 31·3]; nominal p=0·0032) and 53 (75%) of 71 patients in the guselkumab monotherapy group (adjusted treatment difference 8·5% [-0·2 to 17·1; nominal p=0·2155). At week 50, 45 (63%) of 71 patients in the combination therapy group, 55 (76%) of 72 patients in the golimumab monotherapy group, and 46 (65%) of 71 patients in the guselkumab monotherapy group had reported at least one adverse event. The most common adverse events were ulcerative colitis, upper respiratory tract infection, headache, anaemia, nasopharyngitis, neutropenia, and pyrexia. No deaths, malignancies, or cases of tuberculosis were reported during the combination induction period. One case of tuberculosis was reported in the combination therapy group and one case of colon adenocarcinoma was reported in the guselkumab monotherapy group; both occurred after week 12. Two deaths were reported after the final dose of study intervention (poisoning in the combination therapy group and COVID-19 in the guselkumab monotherapy group). INTERPRETATION: Data from this proof-of-concept study suggest that combination therapy with guselkumab and golimumab might be more effective for ulcerative colitis than therapy with either drug alone. These findings require confirmation in larger trials. FUNDING: Janssen Research and Development.