Background:The modified Mayo score (mMS) is a measure for ulcerative colitis (UC) disease activity. Recent US Food and Drug Administration guidance for moderately to severely active UC trials suggests that patients should have baseline mMS of 5-9 including an endoscopy score of at least 2, as opposed to the previous range of 4-9. This disclosure reports results from patients with UC with baseline mMS of 5-9 who received mirikizumab, a monoclonal antibody directed against the interleukin-23 p19 subunit, or placebo in the phase 3 LUCENT trials. Methods:Mirikizumab was evaluated in the randomized, double-blind, placebo-controlled LUCENT-1 (NCT03518086) and LUCENT-2 (NCT03524092) trials, and the ongoing long-term LUCENT-3 (NCT03519945) trial, which use mMS 4-9. Analyses for patients with baseline mMS of 5-9 (excluding patients with mMS of 4) were conducted according to LUCENT trial statistical analysis plans. Categorical efficacy endpoints were summarized using proportions and confidence intervals. Continuous efficacy endpoints are presented as least-squares mean (standard error) changes from baseline. Results:Mirikizumab demonstrated efficacy for the primary endpoint of clinical remission and major secondary endpoints including clinical response, endoscopic improvement, histologic-endoscopic mucosal improvement/remission, bowel urgency remission, and corticosteroid-free remission. Importantly, mirikizumab exhibited greater improvements versus placebo in the Inflammatory Bowel Disease Questionnaire, fatigue, symptomatic remission, and work productivity. Finally, mirikizumab demonstrated long-term (104-week) sustained, durable efficacy across all studied endpoints. No new safety signals were identified during the 2-year follow-up. Conclusions:Mirikizumab delivered significant clinical benefit for patients with baseline mMS of 5-9 and demonstrated a favorable safety profile.

INTRODUCTION:Ulcerative colitis (UC) is a chronic immune-mediated disease requiring ongoing treatment to maintain remission. This report presents the 2-year safety outcomes of mirikizumab, a humanized immunoglobulin G4 anti-interleukin-23p19 monoclonal antibody, in moderately to severely active UC from phase 3 studies LUCENT-1 (NCT03518086), LUCENT-2 (NCT03524092), and LUCENT-3 (NCT03519945). METHODS:Patients who underwent induction (LUCENT-1) and maintenance (LUCENT-2), and entered long-term maintenance (LUCENT-3) were assessed in 2 cohorts: induction responders and extended-induction responders. Both cohorts underwent up to 104 weeks of continuous treatment with mirikizumab. Adverse events (AEs) were assessed in these 2 cohorts and within subsets of patients aged 60 years or older and patients using corticosteroids, immunomodulators, or both at baseline. RESULTS:Safety was generally consistent across induction responders (N = 333) and extended-induction responders (N = 149) and across patient subsets. Nasopharyngitis, COVID-19, arthralgia, UC (worsening/reoccurrence of symptoms), and headache were the most common AEs. Serious AEs were reported in less than 10% of both cohorts. Infections (mostly mild), cerebrocardiovascular events, and malignancies occurred in 47.4% and 49.7%, 0.9% and 1.3%, and 0% and 3.4% of induction responders and extended-induction responders, respectively. Injection-site reactions (induction responders: 10.2% and extended-induction responders: 8.1%) declined over time. Safety profiles in patient subsets and in the whole population were similar, except for hypertension, which was more frequent in patients aged 60 years or older. DISCUSSION:The mirikizumab 2-year integrated safety profile in patients with moderately to severely active UC was consistent across subgroups and with previous findings, without new significant safety concerns.

Background An increasing incidence of pediatric-onset inflammatory bowel disease (PIBD) has been reported in many countries. However, the global burden and distribution of this disease remain less understood. We aimed to examine the global epidemiology and trends of PIBD from 1990 to 2019.Methods Data from the 2019 Global Burden of Disease Study, covering 204 countries, were analyzed. We assessed key measures like incidence, prevalence, mortality, and disability-adjusted life years (DALYs) using linear regression to calculate annual percentage changes and assess trends.Results Between 1990 and 2019, the PIBD incidence rate increased and the DALY rate and mortality rate declined. The incidence rate was notably elevated in the high Socio-demographic Index (SDI) quintile, reaching 6.3 per 100 000 person-years, corresponding to 13 914 new cases in 2019. Incidence and prevalence of PIBD positively correlated with the SDI, while higher death and DALY burdens were observed in lower-SDI countries. In 2019, the top 5 countries with the highest PIBD incidence rates were Canada (19.9 per 100 000 population), Denmark (12.4 per 100 000 population), Hungary (8.5 per 100 000 population), Austria (8.1 per 100 000 population), and the United States (7.4 per 100 000 population). Several countries experienced significant increases in incidence rates from 1990 to 2019, led by Taiwan (annual percent change 4.2%), followed by China (2.8%), Japan (2.1%), Australia (1.8%), and Hungary (1.6%).Discussion PIBD incidence has significantly increased since 1990. High-SDI countries face higher incidence, while lower-SDI countries experience higher mortality and DALY burdens. The study underscores the need for ongoing monitoring and research to address this emerging public health issue. This study analyzed global pediatric-onset inflammatory bowel disease trends from 1990 to 2019. Findings show an increased incidence, especially in high Socio-demographic Index countries, highlighting a growing public health concern and the need for continued monitoring and investigation.

Introduction: Plasmablastic lymphoma (PBL) is rare and aggressive with a survival rate less than 14 months. There have been 9 documented cases of PBL in Crohn's disease (CD) and 2 in ulcerative colitis (UC). Here we present the third case of PBL in UC and the first while on ustekinumab. Case Description/Methods: A 45-year-old man with treatment-refractory ulcerative colitis on ustekinumab for 8 months presented to the emergency department for 1 month of fever, night sweats, fatigue, weight loss and 1-day of severe abdominal pain. His prior UC history included prior treatment failure to azathioprine, infliximab, adalimumab, golimumab, and tofacitinib. He had been treated with prednisone at varying doses for >20 years. He was started on ustekinumab with partial clinical response and successfully tapered off budesonide and to a minimal dose of prednisone. Fecal calprotectin improved from 4800ug/g to 735ug/g but follow-up colonoscopy remained Mayo score 3 with minimal improvement in inflammation (Figure 1A,B). Based on his refractory disease and presence of low grade dysplasia on biopsies, he underwent a total abdominal colectomy. Surgical pathology was consistent with stage IV PBL. Histologic examination showed the malignancy was isolated to the submucosa without mucosal infiltration (Figure 1F,G). Despite a course of EPOCH therapy, he had recurrence of his disease and subsequently died 10 months after his initial diagnosis. Discussion: There are 2 previously reported cases of PBL in UC. To our knowledge this is the first definite case of PBL in UC without a defined mass limited to the submucosa and the first patient with UC on ustekinumab to develop PBL. While our patient had clinical improvement after starting ustekinumab, he had long-standing severe and refractory disease. Although ustekinumab has not been associated with PBL, we suspect this patient’s long history on anti-TNFs and steroid use increased his risk of developing PBL. This case represents an unusual malignant complication of long-standing immunosuppressive therapy that can be seen in patients with IBD.Figure 1.: A and B. Representative Colonoscopy Images. C, D and E. Representative Coronal CT Images. F. Plasmablastic Lymphoma at Low Magnification. G. Plasmablastic Lymphoma at High Magnification.

Clostridioides difficile infection (CDI) is known for significant morbidity and mortality. Fecal microbiota transplantation (FMT) is an effective therapy for recurrent and resistant CDI. However, its impact on the mortality rate of patients with severe and fulminant CDI has not been rigorously studied yet. We aimed to evaluate the effectiveness of FMT on the mortality rate of patients with severe or fulminant CDI in a community hospital system. Our study included 106 inpatients with severe or fulminant CDI. Both standard-of-care (SOC) and FMT were provided to 14 (13.2%) patients (the FMT group). SOC antibiotics alone were provided to 92 (86.8%) patients, out of whom 28 patients were included via propensity score matching in a 2:1 ratio (the SOC group). The primary outcome was defined as the composite end-point of mortality during admission, within 30 and 90 days after discharge, and discharge with comfort measures only. Each component was a secondary end-point. The primary outcome rate in the FMT group was 7.1% (1/14) compared to 25.0% (7/28) in the SOC group. Univariate analysis demonstrated that FMT decreases mortality (odds ratio [OR] 0.08, 95% confidence interval [CI] 0.01–0.58, P  = 0.01). However, multivariate regression did not show statistical significance (OR 0.15, 95% CI 0.01–2.53, P  = 0.19), possibly due to the small sample size. FMT may decrease the mortality of patients with severe and fulminant CDI. Large studies are needed to validate these findings.