Practical management of mild-to-moderate ulcerative colitis: an international expert consensus.

INTRODUCTION: Although there are well-defined guidelines for the management of mild-to-moderate ulcerative colitis (UC), there are still unmet needs. For this reason, we conducted an international expert consensus to standardize the management of patients with mild-to-moderate UC and provide practical guidance to clinicians. AREAS COVERED: Based on Delphi methodology, 15 statements were approved after two rounds of voting, addressing several aspects of disease management from sequencing to treatment duration, from monitoring to optimization techniques and safety profile. EXPERT OPINION: Growing knowledge of mild-to-moderate UC has led to the development of new ambitious outcomes such as histological remission and disease clearance. Furthermore, noninvasive tools for patient monitoring such as fecal calprotectin and intestinal ultrasound are now available. Their implementation in clinical practice will allow clinicians to tightly monitor disease activity and promptly adapt treatment, avoiding complications and disease progression and targeting better disease control.

Achievement of Endoscopic Remission After Induction Reduces Hospitalization Burden in Crohn's Disease: Findings From a Pooled Post Hoc Analysis of Risankizumab and Upadacitinib Phase III Trials.

BACKGROUND: Endoscopic remission has emerged as an important treatment target in Crohn's disease (CD) and has been associated with improvement in long-term outcomes. We examined the relationship between achievement of endoscopic remission and hospitalizations using pooled 52-week Phase III risankizumab and upadacitinib maintenance trials for patients with moderate-to-severely active CD. METHODS: Included patients received maintenance therapy after achieving a clinical response following a 12-week induction with risankizumab or upadacitinib. Endoscopic remission defined as a Simple Endoscopic Score for CD no greater than 4 with at least a 2-point reduction versus induction baseline and no subscore greater than 1. All subsequent hospitalization events were recorded until completion of the maintenance trial or discontinuation. Exposure-adjusted negative binomial regression models were estimated to assess the relationship between post-induction endoscopic remission and long-term hospitalization, controlling for demographics, clinical variables, and treatment arm. RESULTS: Post-induction hospitalization rates were lower in patients who achieved endoscopic remission at the end of the induction period. In multivariable models, post-induction endoscopic remission was independently associated with an IRR of 0.45 (95% CI [0.22-0.95], p=0.036) and 0.71 (95% CI [0.44-1.14], p=0.156) for long-term disease-related and all-cause hospitalizations, respectively. CONCLUSIONS: Week 12 endoscopic remission is independently associated with reducing 52-week disease-related hospitalizations. However, achieving this stringent endpoint within 12 weeks of therapy may be challenging. Endoscopic response may be a more realistic early endoscopic target in the post-induction timeframe. Additional research is needed to evaluate early achievement of alternative endoscopic endpoints in CD.

Mucosal and Transmural Healing and Long-term Outcomes in Crohn's Disease.

BACKGROUND: Healing in Crohn's disease is complex and difficult to measure due to incongruencies between clinical symptoms and disease states. Mucosal healing (MH) and transmural healing (TH) are increasingly used to measure clinical improvement in Crohn's disease, but definitions of MH and TH can vary across studies, and their relationship to long-term outcomes is not clear. To address this knowledge gap, we performed a systematic literature review (SLR) to examine studies measuring MH and TH in Crohn's disease. METHODS: Database records from 2012 to 2022 were searched for real-world evidence and interventional studies that reported the association of MH or TH with clinical, economic, or quality of life outcomes of adult patients with Crohn's disease. RESULTS: A total of 46 studies were identified in the systematic literature review, representing a combined patient population of 5530. Outcomes of patients with MH were reported by 39 studies; of these, 14 used validated scales for endoscopic assessment. Thirteen studies reported outcomes of patients with TH. Among studies that examined the outcomes of patients with and without MH or TH, patients with healing generally experienced improved clinical outcomes and reduced healthcare resource utilization, including fewer hospitalizations and surgeries and improved rates of clinical remission. This was especially true for patients with TH. CONCLUSIONS: Mucosal and transmural healing are associated with positive long-term outcomes for adult patients with Crohn's disease. The adoption of standardized measures and less invasive assessment tools will maximize the benefits of patient monitoring.

Inflammation of the bowel wall is a key component of Crohn's disease (CD). A systematic literature review (SLR) showed bowel wall healing was associated with positive long-term outcomes in CD, supporting healing as an indicator of disease control.

Filgotinib induction-study baseline characteristics of patients with ulcerative colitis who achieve sustained corticosteroid-free remission: post hoc analysis of the phase 2b/3 SELECTION study.

Background/Aims: Obtaining and maintaining corticosteroid-free remission are important goals of treatment for ulcerative colitis (UC). Characteristics associated with achieving corticosteroid-free remission were assessed in filgotinib-treated patients in SELECTION, a 58-week, phase 2b/3 trial in moderately to severely active UC. Methods: This post hoc analysis used data from filgotinib-treated patients receiving corticosteroids at maintenance baseline in SELECTION. Univariate logistic regression was performed to assess induction baseline characteristics associated with 6 months of corticosteroid-free remission at week 58, defined as clinical remission without using corticosteroids for at least 6 months. Results: At maintenance baseline, 92 and 81 patients were receiving corticosteroids in the filgotinib 200 mg and filgotinib 100 mg groups, respectively. Age, body mass index, history of pancolitis, disease duration, fecal calprotectin levels, C-reactive protein levels, Mayo Clinic Score, concomitant corticosteroids, immunomodulators, and aminosalicylates had no statistically significant effect on the likelihood of achieving corticosteroid-free remission. Baseline characteristics associated with increased odds of corticosteroid-free remission were Mayo Clinic Endoscopic Subscore of 2 (vs. 3) in the filgotinib 200 mg and filgotinib 100 mg groups, and female (vs. male) sex, current (vs. former or never) smoking, and being biologic­naive (vs. experienced) in the filgotinib 200 mg group. Conclusions: Steroid tapering can be achieved in patients with UC receiving filgotinib 200 mg independently of baseline characteristics such as clinical activity and duration of illness. However, the likelihood of achieving corticosteroid-free remission was higher among patients who were biologic-naive, current smokers, had low endoscopic inflammatory burden and who were female.

Early and Sustained Symptom Control with Mirikizumab in Patients with Ulcerative Colitis in the Phase 3 LUCENT Program.

BACKGROUND AND AIMS: Ulcerative colitis (UC), a chronic inflammatory bowel disease, may manifest with symptoms of increased stool frequency (SF), rectal bleeding (RB), bowel urgency (BU), abdominal pain (AP), and fatigue. Mirikizumab, an anti-IL-23p19 antibody, demonstrated efficacy and safety in patients with moderately to severely active UC in the LUCENT Phase 3 trials. We evaluated mirikizumab's efficacy in achieving symptom control and time to symptom improvement during induction, maintenance of sustained symptom control, "comprehensive symptom control", defined according to a combination of individual patient-reported outcomes, and prognostic baseline indicators of early symptomatic remission at week 4. METHODS: The results of LUCENT-1/-2 have previously been reported. Treatment differences for symptomatic endpoints were compared over 52 weeks versus placebo (PBO) and comprehensive symptomatic endpoints at 12 and 52 weeks of continuous treatment. Subgroup analyses were conducted for prior biologic or tofacitinib treatment failure. Prognostic analyses were run using regression analysis. RESULTS: By Week (W)2, mirikizumab-treated patients achieved greater reductions in SF, RB, BU, and fatigue versus PBO. At W4, there was a higher rate of AP improvement. At W12, a greater proportion of mirikizumab-treated patients achieved symptomatic remission, RB remission, SF remission, and BU remission/clinically meaningful improvement. Mirikizumab-treated patients sustained symptom control versus placebo patients in maintenance until W52. This treatment effect was shown in patients regardless of prior biologic or tofacitinib failure. Additionally, mirikizumab achieved comprehensive symptom control versus PBO at W12 and W52. CONCLUSIONS: Mirikizumab demonstrated efficacy in achieving and sustaining symptom control and comprehensive symptom control over 52 weeks. [NCT03518086; NCT03524092].

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.

Proportion of inflammatory bowel diseases patients with suboptimal disease control in daily clinical practice-Real-world evidence from the inflammatory bowel diseases-podcast study.

BACKGROUND: Crohn's disease and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by a progressive nature of the disease resulting in subsequent intestinal damage, limited efficacy of current treatments and suboptimal disease management and a significant burden for patients. OBJECTIVES: The IBD-PODCAST study aims to estimate the proportion of Crohn's disease and UC patients with suboptimal disease control (SDC) in a real-world setting. METHODS: A non-interventional and cross-sectional study was conducted across 103 sites in 10 countries (Austria, Belgium, Canada, Germany, Greece, Italy, Portugal, Spain, Turkey, and UK). Criteria for SDC were based on STRIDE-II criteria and adapted by an expert panel. RESULTS: 2185 patients (Crohn's disease: n = 1,108, UC: n = 1077) with a mean (SD) age of 44.0 (14.8) years and mean (SD) disease duration of 12.4 (9.2) years were included (52.2% male). Ileal involvement was present in 39.1% of Crohn's disease patients, 35.3% of UC patients had extensive colitis. 77.3% of Crohn's disease and 65.3% of UC patients were on targeted immunomodulators and, according to STRIDE-II-based treatment phases, 85.6% of Crohn's disease and 85.4% of UC patients were assigned to the long-term treatment phase. SDC was detected in 52.2% of Crohn's disease and 44.3% of UC patients predominantly due to impaired quality of life (QoL), clinically significant extraintestinal manifestations, steroid overuse, signs of active inflammation in UC and Crohn's disease, and active fistulas in Crohn's disease. More than one criterion was seen in 37% of patients with SDC. Opportunities for on-label treatment optimization were observed in 49% of Crohn's disease and 61% of UC patients on advanced therapy. CONCLUSION: The high percentage of SDC in this global, real-world cohort suggests a large disease burden and high unmet medical need in IBD patients. Future analysis should focus on monitoring and responding to SDC in this cohort and on patients' QoL.

Preventing and managing cardiovascular events in patients with inflammatory bowel diseases treated with small-molecule drugs, an international Delphi consensus.

Janus kinase (JAK) inhibitors and sphingosine 1 phosphate (S1P) receptor modulators are small molecule drugs (SMDs) approved for IBD treatment. Their use in clinical practice might be limited due to cardiovascular concerns. We aimed to provide guidance on risk assessment, monitoring, and management strategies, aiming to minimize potential cardiovascular risks of SMDs and to facilitate an adequate shared decision-making. A systematic literature search was conducted, and proposed statements were prepared. A virtual consensus meeting was held, in which eleven IBD physicians and two cardiovascular specialists from ten countries attended. Proposed statements were voted upon in an anonymous manner. Agreement was defined as at least 75 % of participants voting as 'agree' with each statement. Consensus was reached for eighteen statements. Available evidence does not show a higher risk of cardiovascular events with JAK inhibitors in the overall IBD population, although it might be increased in patients with an unfavorable cardiovascular profile. S1P receptor modulators may be associated with a risk of bradycardia, atrioventricular blocks, and hypertension. Cardiovascular risk stratification should be done before initiation of SMDs. Although the risk of cardiovascular events in patients with IBD on SMDs appears to be low overall, caution should still be taken in certain scenarios.

Upadacitinib in Crohn's disease.

INTRODUCTION: The small molecule and oral selective and reversible Janus kinase (JAK) inhibitor upadacitinib has been approved for the treatment of moderate to severe active Crohn's disease (CD) in adult patients since April 2023 by EMA/FDA. AREAS COVERED: The approval is based on the two induction studies a maintenance study showing that upadacitinib induction and maintenance therapy was superior to placebo. The approval of upadacitinib in CD expands the therapeutic armamentarium for the management of inflammatory bowel diseases (IBD). Upadacitinib is the first and only JAK inhibitor approved in patients with CD and provides a novel mechanism of action and the first advanced oral treatment option for patients with CD. Upadacitinib is approved for the treatment of other immunologically mediated disorders, including ulcerative colitis, rheumatoid arthritis, psoriasis arthritis, axial spondylarthritis, ankylosing spondylitis, and atopic dermatitis. Treatment of atopic dermatitis has been approved from the age of 12 years. EXPERT OPINION: Upadacitinib may cause relevant changes of our current treatment algorithms for Crohn's disease. Further real-world studies and head-to-head comparisons are needed to position upadacitinib in our current treatment algorithms for CD.

Two-Year Efficacy and Safety of Mirikizumab Following 104 Weeks of Continuous Treatment for Ulcerative Colitis: Results From the LUCENT-3 Open-Label Extension Study.

BACKGROUND: Mirikizumab, a p19-directed interleukin-23 monoclonal antibody, is efficacious in inducing clinical remission at week 12 (W12) and maintaining clinical remission at W52 in patients with moderately to severely active ulcerative colitis. Results are presented from the open-label extension study through W104. METHODS: Clinical, symptomatic, quality-of-life, and adverse event outcomes are reported for mirikizumab induction responders and extended induction responders, including biologic-failed patients, who entered LUCENT-3, with data shown for W52 maintenance responders or remitters. Discontinuations or missing data were handled by nonresponder imputation (NRI), modified NRI (mNRI), and observed case (OC). RESULTS: Among W52 mirikizumab responders, clinical response at W104 was 74.5%, 87.2%, and 96.7% and clinical remission was 76.6%, 89.0%, and 98.3% for NRI, mNRI, and OC, respectively. Among W52 mirikizumab remitters, clinical response at W104 was 54.0%, 62.8%, and 70.1% and clinical remission was 65.6%, 76.1%, and 84.2%. Using mNRI, remission rates at W104 for W52 clinical remitters were 74.7% corticosteroid-free, 79.5% endoscopic, 63.9% histologic-endoscopic mucosal remission, 85.9% symptomatic, 59.8% bowel urgency, 80.5% Inflammatory Bowel Disease Questionnaire (using NRI), 71.2% histologic-endoscopic mucosal improvement, and 77.5% bowel urgency improvement. Previous biologic-failed vs not-biologic-failed patient data were generally similar. Extended induction mNRI clinical response was 81.9%. Serious adverse events were reported in 5.2% of patients; 2.8% discontinued treatment due to adverse events. CONCLUSIONS: Endoscopic, histologic, symptomatic, and quality-of-life outcomes support the long-term benefit of mirikizumab treatment up to 104 weeks in patients with ulcerative colitis, including biologic-failed patients, with no new safety concerns.

Long-term clinical response/remission, endoscopic, histologic, and symptomatic data from an open-label study in patients with moderately to severely active ulcerative colitis demonstrate that 2-year continuous mirikizumab treatment maintained clinical remission in a majority of induction clinical responders, regardless of previous biologic failure status.

Primary Tumor Resection Before Systemic Therapy in Patients With Colon Cancer and Unresectable Metastases: Combined Results of the SYNCHRONOUS and CCRe-IV Trials.

PURPOSE: Chemotherapy is established as primary treatment in patients with stage IV colorectal cancer and unresectable metastases. Data from nonrandomized clinical trials have fueled persistent uncertainty if primary tumor resection (PTR) before chemotherapy prolongs survival. We investigated the prognostic value of PTR in patients with newly diagnosed stage IV colon cancer who were not amenable to curative treatment. PATIENTS AND METHODS: Patients enrolled in the multicenter, randomized SYNCHRONOUS and CCRe-IV trials were included in the analysis. Patients with colon cancer with synchronous unresectable metastases were randomly assigned at 100 sites in Austria, Germany, and Spain to undergo PTR or up-front chemotherapy (No PTR group). The chemotherapy regimen was left at discretion of the local team. Patients with tumor-related symptoms, inability to tolerate surgery and/or systemic chemotherapy, and history of another cancer were excluded. The primary end point was overall survival (OS), and the analyses were performed with intention-to-treat. RESULTS: A total of 393 patients were randomly assigned to undergo PTR (n = 187) or no PTR (n = 206) between November 2011 and March 2017. Chemotherapy was not administered to 6.4% in the No PTR group and 24.1% in the PTR group. The median follow-up time was 36.7 months (95% CI, 36.6 to 37.3). The median OS was 16.7 months (95% CI, 13.2 to 19.2) in the PTR group and 18.6 months (95% CI, 16.2 to 22.3) in the No PTR group (P = .191). Comparable OS between the study groups was further confirmed on multivariate analysis (hazard ratio, 0.944 [95% CI, 0.738 to 1.209], P = .65) and across all subgroups. Patients with serious adverse events were more common in the No PTR group (10.2% v 18.0%; P = .027). CONCLUSION: Among patients with colon cancer and synchronous unresectable metastases, PTR before systemic chemotherapy was not associated with prolonged OS.

Efficacy and safety of biologics in primary sclerosing cholangitis with inflammatory bowel disease: A systematic review and meta-analysis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is an immune-mediated, chronic cholestatic liver disease. Currently, liver transplantation is the only established life-saving treatment. Several studies have evaluated the effect of different biologic therapies on PSC with inconclusive findings. We conducted a systematic review and meta-analysis to assess the effects of biologics in PSC and associated inflammatory bowel disease (IBD). METHODS: MEDLINE, Scopus, and Embase were searched up to July 31, 2023, for studies reporting the effects of biologics in patients with PSC-IBD. Effects of biologic therapy on alkaline phosphatase, total bilirubin, ulcerative colitis response score, and adverse events were calculated and expressed as standardized difference of means (SMD), proportions, and 95% CI using a random-effects model. RESULTS: Six studies, including 411 PSC-IBD patients who received biologics, were included. Biologic treatment was associated with no change in alkaline phosphatase (SMD: 0.1, 95% CI: -0.07 -0.17, p=0.43), but a small and statistically significant increase in total bilirubin (SMD: 0.2, 95% CI: 0.05-0.35, p<0.01). 31.2% (95% CI: 23.8-39.7) of patients with IBD achieved endoscopic response, and there was a significant improvement in ulcerative colitis response score (SMD: -0.6,95% CI: -0.88 to 0.36, p<0.01). Furthermore, 17.6% (95% CI: 13.0-23.5) of patients experienced adverse events severe enough to discontinue therapy, and 29.9% (95% CI: 25.2-34.8) had a loss of response to biologics. CONCLUSIONS: Treatment of patients with PSC-IBD with biologics (vedolizumab, infliximab, and adalimumab) was not associated with improvement of biochemical markers of cholestasis. Biologics are effective in treating the colitis associated with PSC. Vedolizumab was associated with worsening liver enzymes in contrast to other biologics, a finding that warrants further study.

Efficacy and Safety of Approximately 3 Years of Continuous Ozanimod in Moderately to Severely Active Ulcerative Colitis: Interim Analysis of the True North Open-label Extension.

BACKGROUNDS AND AIMS: This interim analysis from the True North open-label extension [OLE] study examines efficacy and safety of approximately 3 years of continuous ozanimod treatment in patients with moderately to severely active ulcerative colitis. METHODS: Clinical responders after 52 weeks of ozanimod during the phase 3 True North study, who continued treatment in the OLE, were evaluated. Efficacy, including endoscopic and histological endpoints, was assessed during the OLE for approximately 2 additional years through OLE Week 94, using observed case [OC] and nonresponder imputation [NRI] analyses. Adverse events were monitored from True North baseline through OLE data cutoff and expressed as exposure-adjusted incidence rates. RESULTS: This analysis included 131 patients; 54% had achieved corticosteroid-free remission at True North Week 52. In OC analyses, clinical response, clinical remission, and corticosteroid-free remission were achieved by 91.4%, 69.1%, and 67.9% of patients, respectively, at OLE Week 94 [146 weeks of total treatment]. Similarly, endoscopic improvement, histological remission, and mucosal healing were achieved by 73.3%, 67.3%, and 56.3% of patients, respectively, at OLE Week 94. Efficacy rates were lower using NRI analyses, but maintenance of efficacy was demonstrated through OLE Week 94. No new safety signals emerged from this analysis. Serious infections, malignancy, cardiovascular events, and hepatic events occurred infrequently. CONCLUSIONS: Among patients who achieved clinical response after 1 year of ozanimod treatment during True North, a high percentage sustained clinical and mucosal efficacy over 2 additional years in the OLE. No new safety signals were observed with long-term ozanimod use.

Modified-Release Phosphatidylcholine (LT-02) for Ulcerative Colitis: Two Double-Blind, Randomized, Placebo-Controlled Trials.

BACKGROUND & AIMS: The aim of this study was to evaluate the efficacy of LT-02, a novel modified-release phosphatidylcholine (PC) formulation, for induction and maintenance of remission in patients with mild to moderate ulcerative colitis (UC) and inadequate response to mesalamine. METHODS: LT-02 was evaluated in a multicenter double-blind, randomized, placebo-controlled study comprising a 12-week induction trial (PCG-2), followed by a 48-week maintenance trial (PCG-4). In PCG-2, patients were randomized 1:1:1 to treatment with 0.8 g LT-02 4 times daily (QID), 1.6 g LT-02 twice daily (BID), or placebo, respectively. All patients continued to take a standard dose of oral mesalamine (≥2.4 g/day). The primary end point in PCG-2 was deep remission. Patients achieving remission at week 12 were randomly assigned 2:1:1 to 1.6 g LT-02 BID, placebo, or 500 mg mesalamine (3 times daily), respectively, in PCG-4; the primary end point was remission at 48 weeks. RESULTS: PCG-2 was terminated early for futility after a prespecified interim analysis; 466 patients (of 762 planned) were randomized. There was no statistically significant difference in deep remission at week 12 (placebo, 13.5%; LT-02 BID, 14.2%; LT-02 QID, 9.7%). In PCG-4, 150 patients (of approximately 400 planned) were randomized. There was no statistically significant difference in remission rates at week 48 (LT-02 BID, 49.3%; mesalamine, 50.0%; placebo, 43.2%). LT-02 was safe. CONCLUSIONS: Despite prior evidence of beneficial effects of PC in phase 2 trials, our induction study with LT-02 in patients with mild to moderate UC was terminated prematurely for futility. Signals of efficacy in maintenance therapy require confirmation in an adequately powered maintenance trial. LT-02 was safe and well-tolerated. CLINICALTRIALS: gov: NCT02280629, NCT02142725.

Defining Comprehensive Disease Control for Use as a Treatment Target for Ulcerative Colitis in Clinical Practice: International Delphi Consensus Recommendations.

BACKGROUND AND AIMS: Treatment of ulcerative colitis [UC] requires a patient-centric definition of comprehensive disease control that considers improvements in aspects not typically captured by classical landmark trial endpoints. In an international initiative, we reviewed aspects of UC that affect patients and/or indicate mucosal inflammation, to achieve consensus on which aspects to combine in a definition of comprehensive disease control, using a modified Delphi process. METHODS: The Delphi panel comprised 12 gastroenterologists and one patient advocate. Two gastroenterologists were elected as chairs and did not vote. To inform statements, we asked 18 patients and the panel members about their experiences of remission and reviewed published literature. Panel members voted on statements anonymously in three rounds, with a live discussion before Round 3. Consensus was met if ≥67% of the panel agreed. Statements without consensus in Rounds 1 and 2 were revised or discarded after Round 3. RESULTS: The panel agreed to measure individual patient benefit using a definition of comprehensive disease control that combines aspects currently measured in trials [rectal bleeding, stool frequency, disease-related quality of life, endoscopy, histological inflammatory activity, inflammatory biomarkers, and corticosteroid use] with additional patient-reported symptoms [bowel urgency, abdominal pain, extraintestinal manifestations, fatigue, and sleep disturbance]. The panel agreed on scoring systems and thresholds for many aspects. CONCLUSIONS: Using a robust methodology, we defined comprehensive disease control in UC. Next, we will combine the measurement and scoring of these aspects into a multicomponent tool and will adopt comprehensive disease control as a treatment target in clinical practice and trials.

Clinical trial: Clinical and endoscopic outcomes with ustekinumab in patients with Crohn's disease: Results from the long-term extension period of STARDUST.

BACKGROUND: STARDUST, a phase 3b randomised trial, compared ustekinumab therapeutic strategies in patients with Crohn's disease (CD) using early endoscopic assessment and treat-to-target (T2T) versus standard of care (SoC). AIM: To assess the efficacy of ustekinumab extended treatment in a long-term extension (LTE) of up to 104 weeks with dosing adapted according to clinical, biomarker and endoscopy outcomes. METHODS: Adults with moderately-to-severely active CD received intravenous ustekinumab approximating 6 mg/kg at Week 0 and subcutaneous ustekinumab 90 mg at Week 8. At Week 16, 440 ≥70-point responders were randomised to T2T or SoC and 323 entered the LTE. At Week 48, a unified, protocol-defined ustekinumab dose frequency escalation/de-escalation was applied based on achieving endoscopic remission and corticosteroid-free clinical remission. Achieving corticosteroid-free clinical remission and biomarker remission at consecutive visits determined ustekinumab dosing frequency. Dichotomous variables were analysed using non-responder imputation. RESULTS: Among patients who entered the LTE, 7.7%, 48.6% and 43.7% received doses every 4, 8 and 12 weeks, respectively. Ustekinumab dose frequency was escalated in 23.5% and de-escalated in 19.7%. Endoscopic response and remission rates were 28.9% and 10.73% (all randomised) and 39.3% and 14.6% (patients entering the LTE), respectively, at Week 104. Clinical remissiona rates at week 104 were 50.2% (all randomised) and 68.4% (patients entering the LTE). There were no new safety signals. CONCLUSION: STARDUST LTE is the first interventional ustekinumab efficacy study to show a favourable benefit-risk profile with preservation of clinical and endoscopic outcomes through Week 104 using flexible, algorithm-driven dose adjustment including de-escalation.

Outcomes and Endpoints of Postoperative Recurrence in Crohn's Disease: Systematic Review and Consensus Conference.

BACKGROUND: Outcomes after ileocolonic resection in Crohn's disease [CD] are heterogeneous, and a clear definition of postoperative recurrence remains to be determined. Our Endpoints Working Group of the International Organization for the study of Inflammatory Bowel Disease [IOIBD] aimed to standardise postoperative outcomes, to discuss which endpoints should be used for postoperative clinical trials, and to define those which could be used in trials or registries. METHODS: Based on a systematic review of the literature, recommendations and statements were drafted and sent to all IOIBD members for a first round of voting. Recommendations and statements were revised based on the voters' comments during a consensus hybrid conference open to all IOIBD members. If no agreement was reached after two rounds of voting, the statement was excluded. RESULTS: In the systematic review, 3071 manuscripts were screened of which 434 were included. Sixteen recommendations were identified, of which 11 were endorsed. Recommendations and statements include that endoscopy remains the gold standard and should be used as a short-term primary endpoint in both observational cohorts and randomised controlled trials. Clinical symptoms classically used in clinical trials for luminal CD are not reliable in this specific situation. For that reason, longer-term endpoints should be based on the evidence of macroscopic inflammation assessed by imaging techniques, endoscopy, or as reflected by the presence of complications. CONCLUSIONS: Agencies recommend the use of clinical evaluations, as in the case of luminal CD, and do not recognise primary endpoints based solely on endoscopy. This consensus has led to agreement on the need to define postoperative endoscopy-based and/or imaging-based endpoints.