Endoscopic assessment of the J pouch in ulcerative colitis: A narrative review.

Patients with ulcerative colitis sometimes need a total colectomy with ileal pouch-anal anastomosis due to medically refractory disease or colitis-associated neoplasia. Up to 50% of patients with ulcerative colitis postoperatively develop pouchitis and the rate of chronic inflammatory pouch conditions requiring pouch excision or diverting ileostomy is reported to be 10%. In order to diagnose and monitor pouchitis, pouchoscopy is essential to assess endoscopic inflammatory findings of the J pouch and to survey neoplasia development, particularly in the remnant distal rectum. However, endoscopic protocols for the evaluation of the pouch may not be standardized worldwide and the reliability of existing disease activity indices for pouchitis has been questioned due to the lack of validation. Recently, reliable endoscopic scoring systems based on an observation of the anatomical location of the J pouch were reported and a significant association between the distribution pattern of endoscopic inflammation (i.e., endoscopic phenotype) and pouch outcomes was also uncovered. In this review, we discuss how to survey the J pouch using pouchoscopy, endoscopic indices for pouchitis disease activity, endoscopic phenotypes and classification, and the pathological mechanisms of pouchitis phenotype in patients with ulcerative colitis.

Management of colorectal neoplasia in IBD patients: current practice and future perspectives.

Inflammatory bowel disease (IBD) patients are at increased risk of developing colorectal neoplasia (CRN). In this review, we aim to provide an up-to-date overview and future perspectives on CRN management in IBD. Advances in endoscopic surveillance and resection techniques have resulted in a shift towards endoscopic management of neoplastic lesions in place of surgery. Endoscopic treatment is recommended for all CRN if complete resection is feasible. Standard (cold snare) polypectomy, endoscopic mucosal resection and endoscopic submucosal dissection should be performed depending on lesion complexity (size, delineation, morphology, surface architecture, submucosal fibrosis/invasion) to maximize the likelihood of complete resection. If complete resection is not feasible, surgical treatment options should be discussed by a multidisciplinary team. While (sub)total and proctocolectomy play an important role in management of endoscopically unresectable CRN, partial colectomy may be considered in a subgroup of patients in endoscopic remission with limited disease extent without other CRN risk factors. High synchronous and metachronous CRN rates warrant careful mucosal visualization with shortened intervals for at least 5 years after treatment of CRN.

Impact of a health-system specialty pharmacy on time to upadacitinib initiation.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: Upadacitinib has been found to improve symptoms as early as day 1 in patients with inflammatory bowel disease. As a result, early and timely initiation of upadacitinib is paramount to prevent hospital admission for an acute flare. The purpose of this study was to identify the time to initiation of upadacitinib, comparing external specialty pharmacies (ESPs) to a health-system specialty pharmacy (HSSP). METHODS: This was a single-center, retrospective study at the University of Chicago Medicine (UCM) Inflammatory Bowel Disease Center and included patients initiated on upadacitinib between March 1, 2022, and April 1, 2023. Data collected included demographics, prior authorization information, appeal information, insurance type, date the prescription was sent, and date the patient initiated therapy (patients were called to confirm the date). The primary outcome evaluated was the days from prescribing to patient initiation. Secondary outcomes included the total time to initiation and the time to notification from insurance regarding determination of a prior authorization or appeal. Patients were excluded if they were lost to follow-up, initiated therapy through alternative means, or had previously initiated upadacitinib. RESULTS: A total of 107 patients were initiated on upadacitinib during the study period (n = 18 through the UCM HSSP, n = 89 through an ESP). The median number of days to patient initiation was 3 days (interquartile range, 3-6 days) for the UCM specialty pharmacy vs 9 days (interquartile range, 4-13 days) for ESPs (P = 0.003). A total of 88.9% of patients filling through the UCM specialty pharmacy initiated upadacitinib within 7 days, compared to 47.2% of patients filling through an ESP (P = 0.001). Seven patients needed earlier initiation of therapy to prevent hospital admission. CONCLUSION: This study validates the ability of HSSPs to initiate therapies earlier than ESPs with a particular focus on upadacitinib.

Patient and Health Care Professional Perceptions of the Experience and Impact of Symptoms of Moderate-to-Severe Crohn's Disease in US and Europe: Results from the Cross-Sectional CONFIDE Study.

BACKGROUND: Crohn's disease (CD) significantly affects patients' health-related quality of life and well-being. AIMS: Communicating Needs and Features of IBD Experiences (CONFIDE) survey explores the experience and impact of moderate-to-severe CD symptoms on patients' lives and identifies communication gaps between patients and health care professionals (HCPs). METHODS: Online, quantitative, cross-sectional surveys of patients, and HCPs were conducted in the United States (US), Europe (France, Germany, Italy, Spain, United Kingdom), and Japan. Criteria based on previous treatment, steroid use, and/or hospitalization defined moderate-to-severe CD. US and Europe data are presented as descriptive statistics. RESULTS: Surveys were completed by 215 US and 547 European patients and 200 US and 503 European HCPs. In both patient groups, top three symptoms currently (past month) experienced were diarrhea, bowel urgency, and increased stool frequency, with more than one-third patients wearing diaper/pad/protection at least once a week in past 3 months due to fear of bowel urgency-related accidents. HCPs ranked diarrhea, blood in stool, and increased stool frequency as the most common symptoms. Although 34.0% US and 27.2% European HCPs ranked bowel urgency among the top five symptoms affecting patient lives, only 12.0% US and 10.9% European HCPs ranked it among top three most impactful symptoms on treatment decisions. CONCLUSION: Bowel urgency is common and impactful among patients with CD in the US and Europe. Differences in patient and HCP perceptions of experiences and impacts of bowel urgency exist, with HCPs underestimating its burden. Proactive communication between HCPs and patients in clinical settings is crucial for improving health outcomes in patients with CD.

Ultrasound remission after biologic induction and long-term endoscopic remission in Crohn's disease: a prospective cohort study.

Background: The Bowel Ultrasound Score (BUSS) accurately detects therapy-related changes by using the Simple Endoscopic Score for Crohn's disease (SES-CD) as the reference standard. We aimed to evaluate ultrasound remission as a treatment target and its prediction for long-term endoscopic remission. Methods: This single-centre prospective observational study, based at a tertiary referral centre in Milan, Italy, enrolled, between March 1, 2018, and January 31, 2021, adult patients with active CD (SES-CD >2) who were starting biologics. Colonoscopy and IUS was performed at baseline and at 12 months (mean 12.8 ± 4.2). The primary outcome was the predictive value of ultrasound remission at week 12 (BUSS ≤3.52) for long-term endoscopic remission at 12 months. The International Bowel Ultrasound Segmental Activity Score (IBUS-SAS) was also calculated and optimal cut-point to detect endoscopic remission was identified through ROC analysis. Findings: 93 patients with CD were included. Of these, 22 patients (24%) achieved endoscopic remission. Week 12 ultrasound remission predicted endoscopic remission (59% compared with 41% of the patients who were not in ultrasound remission; OR 9.93, 95% CI 3.10-31.80; p < 0.001), while week 12 calprotectin values (<50, <100, <250 µg/g) did not. Week 12 ultrasound activity was associated with failure to achieve long-term endoscopic remission (NPV 87%, PPV 54%). IBUS-SAS cut-off to discriminate endoscopic remission was 22.8 (AUC 0.906). ROC curve comparison showed no-significant difference between BUSS and IBUS-SAS (p = 0.46) for detecting endoscopic remission. Interpretation: Early ultrasound remission predicts long-term endoscopic remission, making it a valuable early treatment target for clinical practice and in clinical trials. Larger multicentre validation studies are warranted to confirm these findings. Funding: None.

Upadacitinib Achieves Clinical and Endoscopic Outcomes in Crohn's Disease Regardless of Prior Biologic Exposure.

BACKGROUND & AIMS: Upadacitinib, an oral Janus kinase inhibitor, achieved significantly higher rates of clinical remission and endoscopic response vs placebo during induction (U-EXCEL [NCT03345849], U-EXCEED [NCT03345836]) and maintenance (U-ENDURE [NCT03345823]) treatment in patients with moderate-to-severe Crohn's disease. Prior biologic failure is often associated with reduced responses to subsequent therapies. This post hoc analysis assessed upadacitinib efficacy by prior biologic failure status. METHODS: Patients were randomized to placebo or upadacitinib 45 mg (UPA45) for 12 weeks (induction). UPA45 clinical responders were enrolled in U-ENDURE and rerandomized to placebo, upadacitinib 15 mg, or upadacitinib 30 mg (UPA30) for 52 weeks. Assessments were by prior biologic failure. RESULTS: Of 1021 patients, 733 (71.8%) had prior biologic failure. Across outcomes and subgroups, upadacitinib-treated patients achieved higher rates vs placebo. During induction, upadacitinib had higher rates vs placebo for clinical remission based on stool frequency/abdominal pain score (without failure: 54.0% vs 28.3%; with failure: 42.2% vs 14.1%) and endoscopic response (without failure: 52.0% vs 16.2%; with failure: 35.7% vs 5.3%). In maintenance, the greatest treatment effect (upadacitinib vs placebo) was among patients with prior biologic failure treated with UPA30 (clinical remission without failure: 58.5% vs 32.7%; with failure: 42.5% vs 8.7%; endoscopic response without failure: 43.9% vs 17.9%; with failure: 38.9% vs 4.0%). Patients without vs with prior biologic failure had fewer adverse events. CONCLUSIONS: Upadacitinib led to higher absolutes rates of clinical and endoscopic outcomes in patients without vs with prior biologic failure. Patients treated with upadacitinib achieved greater rates of clinical and endoscopic improvements vs placebo, regardless of prior biologic exposure. CLINICALTRIALS: gov: NCT03345849, NCT03345836, NCT03345823.

The evolving understanding of histology as an endpoint in ulcerative colitis.

A therapeutic goal for patients with ulcerative colitis (UC) is deep remission including clinical remission and mucosal healing. Mucosal healing was previously defined by endoscopic appearance, but recent studies demonstrate that histological improvements can minimize the risks of experiencing clinical relapse after achieving endoscopic remission, and there is growing interest in the value and feasibility of histological targets of treatment in inflammatory bowel disease, and specifically UC. In this review article, we identify remaining challenges and discuss an evolving role of histology in the management of UC.

Association Between Smoking Status and the Efficacy and Safety of Tofacitinib in Patients with Ulcerative Colitis.

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). This analysis assessed the impact of cigarette smoking on tofacitinib efficacy and safety in the UC clinical program. Methods: Efficacy endpoints and adverse events (AEs) were evaluated by smoking status (ever smokers [current and ex-smokers] and never smokers) in the phase (P)2 induction study (baseline demographics and safety only), P3 studies (OCTAVE Induction 1&2, OCTAVE Sustain, OCTAVE Open), and P3/4b RIVETING study. Results: This post hoc analysis included 1156 patients (ever smokers, n = 416 [36.0%; current smokers, n = 59 (5.1%); ex-smokers, n = 357 (30.9%)]; never smokers, n = 740 [64.0%]; median [range] treatment duration 654 [1-2712] and 615.5 [1-2850] days, respectively). Similar proportions of ever smokers and never smokers achieved efficacy endpoints. AEs were reported in 88.7% of ever smokers and 83.8% of never smokers. Overall, 60.6% of ever smokers had an infection (serious infections, 5.5%; herpes zoster [nonserious and serious], 10.8%; Clostridioides difficile infection, 12.0%; lower respiratory tract infection, 19.5%: corresponding values among never smokers were 53.1%, 3.9%, 6.8%, 8.5%, and 11.4%). Major adverse cardiovascular events were reported in 1.0% of ever smokers and 0.7% of never smokers and thromboembolism events (venous and arterial) in 1.0% of ever smokers and 0.9% never smokers. Deaths, malignancies (excluding non-melanoma skin cancer [NMSC]), and NMSC occurred infrequently in ever smokers (0.5%, 2.5%, and 3.7%, respectively) and never smokers (0.1%, 1.5%, and 1.0%, respectively). Colorectal cancer was reported in 0.6% of never smokers; no cases occurred in ever smokers. Conclusions: Efficacy and safety of tofacitinib were generally similar in ever smokers and never smokers. Overall, serious AEs and, as expected, infections were more frequent in ever smokers versus never smokers. This may inform treatment selection and monitoring strategies. ClinicalTrialsgov: NCT00787202;NCT01465763;NCT01458951;NCT01458574;NCT01470612;NCT03281304.

Continuous Monitoring of CRP, IL-6, and Calprotectin in Inflammatory Bowel Disease Using a Perspiration-Based Wearable Device.

BACKGROUND: Wearable sensor devices represent a noninvasive technology to continuously track biomarkers linked to inflammatory bowel disease (IBD). We assessed the inflammatory markers associated with IBD in human perspiration. METHODS: Participants with IBD were monitored for 40 to 130 minutes with a proprietary wearable sensor device used to measure C-reactive protein, interleukin-6, and calprotectin. Sensor response using electrochemical impedance spectroscopy and serum samples were measured on the same day. The Mann-Whitney test was used to analyze the relationship between active and remission IBD in serum and perspiration, classified according to endoscopic reports and serum biomarker levels. Asynchronously collected fecal calprotectin from a subset of the population was similarly analyzed. RESULTS: A total of 33 subjects were enrolled. Expression of calprotectin was significantly elevated in the active cohort compared with the remission cohort in perspiration (P < .05; median = 906.69 ng/mL; active 95% confidence interval [CI], 466.0-1833 ng/mL; remission 95% CI, 328.4-950.8 ng/mL), serum (median = 1860.82 ng/mL; active 95% CI, 1705-2985 ng/mL; remission 95% CI, 870.2-1786 ng/mL), and stool (P < .05; median = 126.74 µg/g; active 95% CI, 77.08-347.1 µg/g; remission 95% CI, 5.038-190.4 µg/g). Expression of CRP in perspiration and serum was comparable between the active and remission cohorts (perspiration: P > .05; median = 970.83 pg/mL; active 95% CI, 908.7-992 pg/mL; remission 95% CI, 903.3-991.9 pg/mL; serum: median = 2.34 µg/mL; active 95% CI, 1.267-4.492 µg/mL; remission 95% CI, 1.648-4.287 µg/mL). Expression of interleukin-6 in perspiration was nonsignificant in the active cohort compared with the remission cohort and was significantly elevated in serum (perspiration: P < .05; median = 2.13 pg/mL; active 95% CI, 2.124-2.44 pg/mL; remission 95% CI, 1.661-2.451 pg/mL; serum: median = 1.15 pg/mL; active 95% CI, 1.549-3.964 pg/mL; remission 95% CI, 0.4301-1.257 pg/mL). Analysis of the linear relationship between perspiration and serum calprotectin (R2 = 0.7195), C-reactive protein (R2 = 0.615), and interleukin-6 (R2 = 0.5411) demonstrated a strong to moderate relationship across mediums. CONCLUSIONS: We demonstrate the clinical utility of perspiration as a noninvasive medium for continuous measurement of inflammatory markers in IBD and find that the measures correlate with serum and stool markers across a range of disease activity.

This work establishes the clinical utility of perspiration as a noninvasive, continuous marker for gut inflammation and demonstrates the ability to distinguish between active and inactive inflammatory bowel disease across perspiration, serum, and stool.

Extensive Disease and Exposure to Multiple Biologics Precolectomy Is Associated with Endoscopic Cuffitis Post-Ileal Pouch-Anal Anastomosis in Patients With Ulcerative Colitis.

INTRODUCTION: To better inform the risk of cuffitis in patients with ulcerative colitis (UC), we aimed to identify its occurrence and associated precolectomy factors in a large multicenter cohort of patients who underwent restorative proctocolectomy (RPC) with stapled ileal pouch-anal anastomosis (IPAA). METHODS: This study was a retrospective cohort analysis of individuals diagnosed with UC or indeterminate colitis who underwent RPC with IPAA for refractory disease or dysplasia at Mount Sinai Hospital or the University of Chicago followed by at least 1 pouchoscopy with report of the pouch-anal anastomosis. The primary outcome was cuffitis defined as ulceration of the cuff as reported in each pouchoscopy report. RESULTS: The pouch-anal anastomosis was mentioned in the pouchoscopy reports of 674 patients, of whom 525 (77.9%) had a stapled anastomosis. Among these, cuffitis occurred in 313 (59.6%) patients a median of 1.51 (interquartile range 0.59-4.17) years after final surgical stage. On multivariable analysis, older age (hazard ratio [HR], 1.01; 95% confidence interval [CI], 1.01-1.02), extensive disease (HR, 1.34; 95% CI, 1.01-1.78), exposure to biologics before colectomy (HR, 2.51; 95% CI, 1.93-3.27), and exposure to at least 2 or more biologics before colectomy (HR, 2.18; 95% CI, 1.40-3.39) were significantly associated with subsequent cuffitis. CONCLUSIONS: In this multicenter study of patients who underwent RPC with stapled IPAA and at least 1 follow-up pouchoscopy, cuffitis occurred in approximately 60% and was significantly associated with extensive disease and exposure to multiple biologics precolectomy.

In this multicenter study of patients who underwent restorative proctocolectomy with stapled ileal pouch­anal anastomosis and at least 1 subsequent pouchoscopy, endoscopic cuffitis occurred in 60% and was significantly associated with extensive disease and exposure to multiple biologics.

Risk of Common Neurological Disorders in Adult Patients with Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

BACKGROUND: Several studies investigated the risks of neurological conditions in patients with inflammatory bowel disease (IBD), with some variability in findings. We aimed to perform a systematic review and meta-analysis of available evidence to elucidate the association between IBD and the risks of common neurological disorders. METHODS: We conducted a literature search through Embase, PubMed, Scopus, and ProQuest databases from inception to June 30, 2023, to identify cohort studies assessing the risk of developing stroke, all-cause dementia, Parkinson's disease (PD), multiple sclerosis (MS), seizure/epilepsy, and peripheral neuropathy in adult IBD patients compared with non-IBD population. We combined hazard ratios (HRs) with 95% confidence intervals (CIs) to compute pooled estimates using a random-effects model. RESULTS: In total, 22 cohort studies were included, of which 9 studies reported 7074 stroke events in 202 460 IBD patients, 5 studies reported 3783 all-cause dementia diagnoses in 109 602 IBD patients, 7 studies reported 932 PD diagnoses in 354 792 IBD patients, and 1 study reported 6 MS events in 35 581 IBD patients. We observed increased risks of incident stroke (pooled HR = 1.19; 95% CI, 1.06-1.31), all-cause dementia (pooled HR = 1.22; 95% CI, 1.05-1.38), PD (pooled HR = 1.39; 95% CI, 1.20-1.58), and MS (HR = 2.89; 95% CI, 1.02-8.42). No eligible studies were found on peripheral neuropathy and seizure/epilepsy. CONCLUSIONS: Inflammatory bowel disease may be modestly associated with increased risks of stroke, all-cause dementia, and PD. Further longitudinal studies are warranted to investigate potential links with MS, seizure/epilepsy, and peripheral neuropathy, as well as their clinical significance.

This systematic review and meta-analysis of cohort studies aimed to clarify association between inflammatory bowel disease and risks of common neurological disorders. Based on analyses, inflammatory bowel disease may modestly increase risks of stroke, all-cause dementia, and Parkinson's disease vs the healthy population.

Increasing Exposure to Inflammatory Bowel Diseases Education in Gastroenterology Fellowship: The Pilot IBD 101 Experience.

BACKGROUND: Inflammatory bowel disease (IBD) management has become increasingly complex, and education varies across fellowship programs. IBD 101 was designed to introduce first-year gastroenterology (GI) fellows to IBD care and training. METHODS: In 2019, a cohort of fellows participated in a 1-day course with small group learning and group observed structured clinical examinations. Pre- and postcourse surveys were administered to evaluate the course. To assess the long-term impact, surveys were emailed in May 2022 to all third-year fellows from previously participating programs. The primary outcome was comfort managing IBD scenarios and information regarding each fellow's exposure to IBD education. RESULTS: Fifty-five fellows from 32 programs participated. A total of 49 (89%) of 55 completed pre- and postcourse surveys. All fellows agreed that the course content was appropriate. In the postcourse survey, all fellows reported increased comfort managing IBD patients. Ninety-six percent of attendees stated that they would strongly recommend this course. Thirty-six fellows completed surveys in 2022, 21 (58%) attendees and 15 (42%) nonattendees. Attendees reported equivalent or higher levels of comfort compared with nonattendees. Higher global competence was noted among attendees (odds ratio, 5.21; 95% confidence interval, 0.91-29.9; P = .06) after adjusting for presence of a local IBD specialist, number of IBD patients seen monthly (≤5 vs >5), and rotation through an IBD service. CONCLUSIONS: IBD 101, an introductory course for first-year GI trainees, was associated with increased comfort managing IBD with a durable benefit independent of individual access to IBD education. Continuation of this program will further enhance the IBD education of future GI fellows.

IBD 101 was created to increase exposure for first-year gastroenterology fellows to inflammatory bowel disease. The program was well received by attendees and showed increased comfort and sustained benefit in discussing inflammatory bowel disease diagnosis and management with patients.

Clinical Application of Intestinal Ultrasound in Inflammatory Bowel Disease.

PURPOSE OF REVIEW: Intestinal ultrasound (IUS) is a non-invasive, accurate, and well-tolerated tool that provides real-time assessment of inflammatory bowel disease (IBD) activity and is therefore an ideal monitoring tool. This review describes the evolving role of IUS in each phase of clinical management of IBD. RECENT FINDINGS: Accumulating evidence has demonstrated that IUS is an excellent tool for the assessment of suspected IBD, with a very high negative predictive value. It accurately assesses disease activity, disease complications, and in the pre-treatment phase, provides a benchmark for subsequent follow-up. IUS can detect early therapeutic response and correlates well with other established monitoring modalities with arguably superior predictive capabilities and ability to assess a deeper degree of remission, transmural healing (TH). IUS has a crucial role in the management of IBD and has ushered in a new era of monitoring with more rapid evaluation and the opportunity for early optimization, deeper therapeutic targets, and improved outcomes.

Real World Clinical Effectiveness and Safety of Ozanimod in the Treatment of Ulcerative Colitis: 1-Year Follow-Up from a Tertiary Center.

BACKGROUND: Ozanimod is a first-in-class Sphingosine-1-phosphate (S1P) receptor modulator approved for the treatment of moderately to severely active ulcerative colitis (UC). Real world data describing use of ozanimod are limited. AIM: To provide 1-year follow-up results of our UC patient cohort treated with ozanimod. METHODS: This prospective, observational cohort study includes consecutive patients who initiated ozanimod at the University of Chicago IBD Center between 5/2021 and 12/2022. We collected demographic, clinical, and laboratory data. Clinical disease activity was prospectively assessed using the Simple Clinical Colitis Activity Index. RESULTS: Forty-five patients with UC initiated ozanimod therapy and were included in the effectiveness analysis. The median age was 35 years (interquartile range (IQR) 28-52), median disease duration of 6 years (IQR 3-13), 26 (58%) were male, 23 (51%) had extensive colitis, 34 (76%) had previous advanced therapy exposure. Thirty-four patients had clinically active UC at the time of ozanimod initiation; week 10 clinical response and remission rates were 58% and 53%, respectively. By week 52, the rates were 25% for both clinical response and remission. In the 12 (39%) patients with a > 75% reduction in absolute lymphocyte count, numerically greater induction clinical response and remission rates were observed (80% vs 54%, p = 0.4 and 75% vs 53%, p = 0.4, respectively). There were no episodes of symptomatic bradycardia and no other new safety signals. CONCLUSION: Ozanimod effectively induced clinical response and remission patients with largely treatment refractory UC, however, had modest long-term effectiveness. The safety profile was favorable with no new signals.

Long-Term Safety Outcomes of Fecal Microbiota Transplantation: Real-World Data Over 8 Years From the Hong Kong FMT Registry.

BACKGROUND AND AIMS: Prospective long-term real-world safety data after fecal microbiota transplantation (FMT) remain limited. We reported long-term outcomes of FMT from a population-based FMT registry in Hong Kong. METHODS: We recruited patients undergoing FMT for recurrent Clostridioides difficile infection (CDI) and non-CDI indications from clinical trials, from June 2013 to April 2022 in Hong Kong. We captured data on demographics, FMT indications and procedures, clinical outcomes and short- to long-term safety. New medical diagnoses were obtained from electronic medical records and independently adjudicated by clinicians. Long-term safety in patients with recurrent CDI was compared with a control group treated with antibiotics. RESULTS: Overall, 123 subjects (median age 53 years, range 13-90 years; 52.0% male) underwent 510 FMTs and were prospectively followed up for a median of 30.3 (range, 1-57.9) months. The most common indication for FMT was type 2 diabetes mellitus. The most common short-term adverse events within 1 month of FMT included diarrhea and abdominal pain. At long-term follow-up beyond 12 months, 16 patients reported 21 new-onset medical conditions confirmed by electronic medical records. All were adjudicated to be unlikely to be related to FMT. There was no new case of inflammatory bowel disease, irritable bowel syndrome, allergy, diabetes mellitus, or psychiatric disorder. In a subgroup of patients with recurrent CDI, FMT was associated with a significantly higher cumulative survival probability compared with matched control subjects. CONCLUSIONS: This prospective real-world data from Asia's first FMT registry demonstrated that FMT has an excellent long-term safety profile. The risk of developing new medical conditions beyond 12 months after FMT is low.

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.

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.

Dual-Targeted Therapy with Upadacitinib and Ustekinumab in Medically Complex Crohn's Disease.

BACKGROUND AND AIMS: Ongoing efforts to break the therapeutic ceiling in inflammatory bowel disease include combination therapy approaches. Dual-targeted therapy (DTT) has been reported in case reports and small case series. This report describes our experience with ustekinumab (UST) and upadacitinib (UPA) as DTT in patients with Crohn's disease (CD). METHODS: In this retrospective, observational study, we reviewed medical records of patients with CD treated with combined UST and UPA between April 2021 and July 2022. Clinical remission was defined as Harvey-Bradshaw Index (HBI) ≤ 4, and clinical response was defined as decrease in HBI ≥ 3 or physician's assessment of clinical response. RESULTS: We identified 10 CD patients treated with UST/UPA, with median follow-up period of 10 months (interquartile range (IQR) 7.3-12). Median age was 35.5 years (IQR 28.3-43.8) and median number of prior biologic treatment exposures was 4 (IQR 4-5). Indications for UST/UPA were active CD (n = 6), extraintestinal manifestations (EIM) (n = 2), and both active CD and EIM (n = 2). Five of six patients with active CD achieved clinical remission with UST/UPA. Two patients with active EIM (joint pain) achieved resolution of their symptoms. One patient exhibited improvement in both conditions. Three patients developed mild respiratory symptoms and one experienced bowel obstruction. Two patients developed nausea resulting in de-escalation of treatment interval or discontinuation altogether. CONCLUSION: Based on our case series, combination therapy with UST and UPA may be effective and appears safe in refractory Crohn's disease and for patients with co-existing extraintestinal manifestations.