Ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD), poses significant clinical challenges because of its complex pathophysiology, long-term nature, and the limited efficacy of existing treatments. Small-molecule compounds, particularly those that are able to modulate inflammation-related signaling pathways and, in many cases, occur in nature, offer a promising alternative or supplement to conventional therapies. Studies on molecules for UC therapeutics reported in 1394 publications over the past 30 years were collected from the Web of Science (WOS) database. Only studies that verified therapeutic efficacy through animal experiments were included. Through an analysis of the molecular classes, structures, common targets, and pathways using network pharmacology, we identified 14 classes of compounds, 5 direct-target modules, and 3 crucial downstream pathways. Alkaloids, phenylpropanoids, flavonoids, and terpenes (and their derivatives) appeared most frequently and mainly targeted lipid metabolism, oxidative stress, immune regulation, signaling transduction, and cancer-related pathways. Notably, there has been an increasing trend of applying naturally sourced compounds in both preclinical and clinical trials, especially flavonoids, over the last five years. Although progress in UC research has been made, the majority of studies have focused on the overall therapeutic effects and biomarker alterations, with limited emphasis on the direct targets and underlying mechanisms. These findings highlight the need to explore novel small-molecule therapeutic strategies for UC, focusing on clearly defined targets and precise modes of action.

There is limited data on inflammatory bowel disease advanced therapy sequences. Therefore, we examined real-world advanced therapy sequences to compare persistence, healthcare use and costs in first-line advanced therapy.

Evaluable patient characteristics, treatments, sequences, and outcomes were extracted from the WIG2 claims benchmark database and observed from 2014 to 2021. Therapeutic effectiveness (persistence without discontinuation or inadequate response), healthcare resource utilization, and associated costs were analyzed. Advanced treatment group differences were adjusted by inverse probability weighting.

Two thousand nine hundred forty-eight patients with Crohn's disease or ulcerative colitis initiated at least one of the following advanced therapies during the study period: adalimumab (1,260), golimumab (111), infliximab (1,035), tofacitinib (17), ustekinumab (138) or vedolizumab (387). In patients with ulcerative colitis, vedolizumab as first-line advanced therapy demonstrated superior effectiveness in persistence without inadequate response over three years compared to infliximab (p < 0.05). Patients taking infliximab or ustekinumab had higher disease-related costs than those taking adalimumab, golimumab, tofacitinib or vedolizumab. In Crohn's disease patients, first-line treatment with adalimumab (p < 0.001), ustekinumab (p < 0.001) and vedolizumab (p < 0.017), showed superior persistence over 3 years compared to infliximab, and time to inadequate response was longer in patients taking adalimumab and vedolizumab (p < 0.001). Disease-specific treatment costs were lower in patients receiving adalimumab or vedolizumab as first-line advanced therapy. Compared to infliximab, patients treated with ustekinumab had significantly higher costs.

Anti-TNF agents were most frequently used in first-line advanced therapy; however, vedolizumab appeared to be a preferred choice in terms of persistence and cost measures over three years from the start of treatment.

The diagnostic performance and clinical utility of fecal calprotectin (FC), fecal immunochemical occult blood test (FIT), leucine-rich alpha-2 glycoprotein (LRG), C-reactive protein (CRP), and prostaglandin E-major urinary metabolite (PGE-MUM) as established biomarkers for ulcerative colitis (UC) were evaluated. Significant correlations were observed between the clinical activity index, Mayo endoscopic subscore (MES), and each biomarker. Among MES groups, fecal biomarkers demonstrated significant differences, except between MES 2 and MES 3. CRP and LRG showed significant differences, except between MES 1 and MES 2. PGE-MUM exhibited significant differences across all MES groups. Areas under the curve (AUCs) for receiver operating characteristic (ROC) analysis in predicting MES 0 or 1 were as follows: FC, 0.891; FIT, 0.853; LRG, 0.723; CRP, 0.747; PGE-MUM, 0.795. For predicting MES 0 alone, AUCs were as follows: FC, 0.885; FIT, 0.845; LRG, 0.708; CRP, 0.691; PGE-MUM, 0.732. In distinguishing between each MES group, fecal biomarkers exhibited the highest AUC and accuracy in differentiating MES 0 from MES 1, whereas LRG, CRP, and PGE-MUM were most effective in differentiating MES 2 from MES 3. In summary, in UC, fecal biomarkers effectively detect mucosal healing, whereas LRG, CRP, and PGE-MUM are valuable for assessing mucosal healing and active inflammation.

Primary sclerosing cholangitis (PSC) is a rare, progressive cholestatic disease of unknown etiology and characterized by inflammation and stricturing of intrahepatic and/or extrahepatic bile ducts. This process leads to bile duct scarring, progressive liver fibrosis, and end-stage liver disease. PSC is often associated with a specific form of inflammatory bowel disease and patients face a significant risk of developing cholangiocarcinoma and colorectal cancer. The clinical course of PSC can differ significantly between subtypes and affected individuals, representing a major obstacle to successful medical treatment trials. Numerous innovative therapeutic targets have been identified and, at least in part, explored, including nuclear and membrane receptors regulating bile acid metabolism and transport, modulation of gut microbiota, and signaling molecules involved in liver inflammation and fibrosis. Successful drug testing in preclinical PSC models as well as positive signals from some clinical studies justify hope. However, no medical treatment has so far been proven to improve transplant-free survival or overall survival in PSC patients. Disease-modifying drugs are urgently awaited. Despite ongoing efforts to improve study designs and implement treatment trials for novel drug targets, a central breakthrough has not yet been convincingly achieved. This situation might change in the near future. This article summarizes current research efforts aimed at developing medical treatments for PSC.

The association between vascular cell adhesion molecule-1 (VCAM-1) expression and intestinal mucosal inflammation and between VCAM-1 expression and the clinical course in patients with ulcerative colitis (UC) remains unclear. Therefore, we investigated not only the association between mucosal VCAM-1 expression and mucosal inflammation but also its association with subsequent relapse in UC patients with clinical remission.

Fifty-eight patients with UC in clinical remission and 16 patients in clinical active who visited Kyoto Prefectural University of Medicine for a 2-year follow-up period were included. VCAM-1 expression was compared between patients who subsequently relapsed and those who remained in remission, and it was examined in relation to endoscopic findings, histological activity, and cytokine expression. We also investigated the expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1).

VCAM-1 was associated with clinical disease activity and endoscopic severity and was significantly elevated in histologically active mucosa compared with inactive mucosa. VCAM-1 expression co-localized with MAdCAM-1 in the mucosal and submucosal microvessels of the colon and was significantly higher in the relapse group than in the remission group. Similar results were observed for MAdCAM-1 expression. VCAM-1 expression levels were also closely correlated with those of several other cytokines.

VCAM-1 expression in the colonic mucosa of patients with UC is associated with mucosal inflammation and subsequent relapse. These results suggest that VCAM-1 may serve as a marker for relapse and therapeutic effectiveness in UC, and that treatment targeting α4 integrin is efficient and rational.

Background/Objectives: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by relapsing inflammation and incomplete response to conventional therapies. Although biologics have advanced UC management, many patients with moderate-to-severe disease experience treatment failure, relapse, or adverse effects. This review evaluates the pharmacology, efficacy, and safety of oral Janus kinase (JAK) inhibitors-tofacitinib, upadacitinib, and filgotinib-to guide their clinical use in UC. Methods: A comprehensive literature review was conducted using the PubMed, Embase, Cochrane, and Web of Science databases to identify relevant studies on JAK inhibitors in UC. The review included Phase 3 randomized controlled trials (RCTs), real-world observational studies, and recent network meta-analyses. We assessed pharmacologic profiles, clinical efficacy, and safety data for tofacitinib, upadacitinib, and filgotinib. Additionally, we reviewed emerging pipeline agents and future directions in oral immunomodulatory therapy for UC. Results: All three agents demonstrated efficacy in the induction and maintenance of remission. Upadacitinib showed superior performance, including rapid symptom control, high clinical remission rates, and favorable long-term outcomes in both biologic-naïve and -experienced patients. Tofacitinib offered strong efficacy, particularly in early response, but was associated with higher risks of herpes zoster and thromboembolic events. Filgotinib provided moderate efficacy with a favorable safety profile, making it suitable for risk-averse populations. Meta-analyses consistently ranked upadacitinib highest in clinical efficacy and onset of action. Conclusions: JAK inhibitors offer effective and convenient oral treatment options for moderate-to-severe UC. Upadacitinib emerges as a high-efficacy agent; tofacitinib and filgotinib remain valuable based on patient-specific risk profiles. Future studies are needed to clarify optimal sequencing, long-term safety, and the role of emerging agents or combination therapies.

Vedolizumab (VDZ) is often used in older patients with ulcerative colitis (UC) in clinical practice; however, real-world evidence is still limited, including in those with late-onset UC.

This post hoc analysis of a multicenter, retrospective, observational chart review, enrolling 370 patients with UC receiving VDZ between December 2018 and February 2020, compared effectiveness and safety of VDZ among patients ≥ 70 (n = 40) versus < 70 years (n = 330), and among patients ≥ 70 years with and without late-onset UC (age at disease onset: ≥ 70 [n = 13] versus < 70 years [n = 26]).

There were no differences between patients ≥ 70 and < 70 years in clinical remission rates (week 6: 57.5% vs. 47.6%, p = 0.9174; week 14: 62.5% vs. 54.8%, p = 0.1317; week 54: 47.5% vs. 46.4%, p = 0.8149), primary nonresponse (10.0% vs. 15.5%, p = 0.6248), loss of response (12.5% vs. 9.4%, p = 0.5675), or overall safety. Among patients ≥ 70 years, the incidence of adverse drug reactions was numerically greater in those with concomitant corticosteroids than in those without. For older patients with and without late-onset UC, week 54 remission rates were 23.1% versus 57.7% (p = 0.0544); surgery was reported in 3/13 versus 2/26 patients and hospitalization in 5/13 versus 6/26 patients. One death was reported in patients with late-onset UC.

VDZ effectiveness and safety were similar in patients ≥ 70 and < 70 years; VDZ may be a suitable treatment option for patients ≥ 70 years with UC. Patients with late-onset UC tended to have more frequent surgery/hospitalization and lower effectiveness than those without, possibly necessitating greater caution when using VDZ.

Japanese Registry of Clinical Trials registration number: jRCT-1080225363.

Information on rates of safety outcomes in patients with ulcerative colitis [UC] is helpful to better understand the benefit-risk profile of more recent therapies approved for UC.

This narrative review provides an updated examination of the incidence and prevalence of safety outcomes in the UC patient population. Incidence and prevalence estimates were determined for outcomes including cardiac conduction disorders, infections, and malignancies from published literature [2013-2023].

While information for certain outcomes was more frequently recorded, such as herpes viral infection (incidence rate [IR] 0.0-4.47 per 100 person-years [PY]) and malignancies [all; IR 0.0-1.77 per 100 PY], rarer outcome estimates such as bradycardia [IR 0.2 per 100 PY] and macular edema [IR 0.2 per 100 PY] were limited. Our knowledge of certain, uncommon safety outcomes and concomitant medical conditions in the UC population remains limited given the lack of data available. Even though larger cohorts with longer follow-up are warranted, estimates provided in this review will contribute to an improved understanding of the safety profile of UC therapies.

This systematic review aims to elucidate the use of corticosteroids in randomized clinical trials (RCTs) evaluating biologics and small molecules for inflammatory bowel disease (IBD). We analyzed corticosteroid use during both the induction and maintenance phases, highlighting areas needing standardization and improvement in clinical research.

We selected placebo-controlled phase 3 RCTs involving adults with moderate to severe IBD. These studies included detailed reports on corticosteroid use during induction and maintenance phases, with clinical remission and/or corticosteroid-free clinical remission (CSF-CR) as primary endpoints.

Initially, 324 studies were identified and refined to 26 RCTs after screening. Analysis revealed variability in corticosteroid administration. Over time, corticosteroid use showed a decreasing trend (Spearman ρ = -0.42, P = .045). Studies allowing higher corticosteroid doses (up to 40 mg/day of prednisone or equivalent) reported a higher proportion of corticosteroid users (51.8%, range: 42.9%-61%) compared to those excluding patients on doses >20 mg/day (37.5%, range: 31.6%-51.8%; P = .007) or >30 mg/day (41.1%, range: 29.6%-53.7%; P = .023). Trials with mandatory tapering protocols showed a narrower gap between overall clinical remission and CSF-CR rates, with an average difference of 6% in the group without mandatory tapering and 1.2% in the group with forced tapering (T-test P = .038; Cohen's d ≈ 1.1).

This review highlights the variability in corticosteroid use across RCTs and its impact on evaluating new IBD therapies. Standardizing tapering protocols and defining CSF-CR are essential for accurate outcomes.

Real-world studies on vedolizumab in inflammatory bowel disease (IBD) are often limited by small sample size and short follow-up. In this study, we investigated the 2-year effectiveness and safety of vedolizumab in patients with IBD, and applied eXplainable Artificial Intelligence (XAI) to identify predictors of both.

The Long-term Italian Vedolizumab Effectiveness (LIVE) study is multicentric, ambispective, observational study enrolling 1111 IBD patients (563 Crohn's disease, CD, 542 ulcerative colitis, UC). Steroid-free clinical remission (SFCR) at 24 months was the primary endpoint. A XAI model (eXtreme Gradient Boosting, XGB) was applied to identify the main clinical predictors of SFCR and development of adverse events (AEs).

Rates of SFCR at 24 months were 31.6 % and 39.7 % in CD and UC patients, and 0.14 AEs per patient-year was recorded. On XGB analysis, previous exposure to anti-TNFα and older age were the most important drivers for the prediction of SFCR; lower baseline CRP levels and fewer comorbidities were the most important features associated with no development of AEs.

Vedolizumab is effective and safe in IBD patients. XAI yielded promising results in identifying the most important predictors of SFCR and development of AEs.

In real-world clinical settings, the clinical efficacy of vedolizumab (VDZ) in patients with ulcerative colitis (UC) remains unclear. In this study, we aimed to evaluate the efficacy of prednisolone (PSL)-VDZ combination therapy in patients with UC.

Changes in the clinical activity index (CAI), blood test results, and the factors affecting VDZ rate and continuity were investigated. Patients who received at least 20 mg PSL within 1 week of VDZ induction were included in the VDZ + rapid PSL induction (VDZ + rPSL) group, and the remaining were assigned to the non-VDZ + rPSL group. Failure and non-failure in both groups were compared.

We conducted a comparative analysis of 38 patients with UC treated with VDZ (VDZ + rPSL, n = 14; non-VDZ + rPSL, n = 24). The CAI in both groups improved significantly from week 2 to 24 compared with the pretreatment values (P < 0.01). Clinical remission and response at week 8 were significantly higher in the VDZ + rPSL group than in the non-VDZ + rPSL group (85.7% vs. 37.5%, P < 0.01 and 85.7% vs. 41.7%, P = 0.02, respectively). Kaplan-Meier analysis showed a significant difference in the failure-free rate between the two groups (log-rank test, P = 0.02). In the VDZ + rPSL group, only C-reactive protein (CRP) levels significantly improved in non-failure at week 2 (P=0.04).

VDZ + rPSL induction therapy is beneficial for UC treatment. CRP levels 2 weeks after VDZ induction may influence the continuation rate in the VDZ + rPSL group.

Tissue-directed therapies (TDTs) provide potential advantages, including improved tolerance, safety, and efficacy. This review provides a conceptual framework for understanding intestinal TDT and summarizes the current landscape of TDT in inflammatory bowel disease (IBD).

Vedolizumab, a mAb targeting the gut homing α4β7 integrin, served as revolutionary proof-of-principle for the power of advanced TDT in IBD. The development of other monoclonal antibodies targeting cell adhesion molecules followed including abrilumab (α4β7), etrolizumab (β7), and ontamalimab (MAdCAM-1). MORF-057, an oral small molecule inhibitor of α4β7, is now in development for ulcerative colitis. Efforts have also been made toward gut specific JAK inhibitors. Microbiome-based therapies, including engineered probiotics, bacteriophages, and postbiotics, are gaining interest. There are also a number of innovative drug delivery methods, including engineered yeast, hydrogels, and nanoparticles, and viral-based gene therapy.

Gut-targeted therapies range from novel variations on traditional drugs (i.e., mAbs and small molecules) to microbiome-based therapeutics and engineered delivery systems. They can be used alone or in combination with currently available therapies. Future directions should focus on the development of tried-and-true modalities (mAbs, small molecules) as well as the microbiome and more innovative delivery systems.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by persistent, recurrent, and relapsing inflammation of the mucosal layer. Its pathogenesis is complex and not yet fully understood, with current treatments mainly focused on alleviating symptoms through pharmacological methods. Direct drug administration for UC often leads to poor intestinal bioavailability, suboptimal targeting, and an increased risk of resistance. Therefore, there is an urgent need for effective drug delivery systems. Lipid nanoparticles (LNPs) are promising candidates for UC drug delivery due to their high biocompatibility, stability, and customizable properties. Oral administration, as a preferred treatment approach for UC, offers benefits such as convenience, cost-effectiveness, and better patient compliance. However, oral drug delivery systems must navigate the complex gastrointestinal tract to effectively target colonic lesions, posing significant challenges for LNP-based systems. Researchers are exploring ways to enhance oral delivery efficiency by adjusting LNP composition, surface functionalization, and coating. This article reviews recent advancements in oral LNP research aimed at improving drug delivery efficiency for UC treatment and discusses future prospects.

SAMP mice develop progressive Crohn's disease (CD)-like ileitis without spontaneous colitis that worsens over time without chemical, genetic, or immunological manipulation. Even growing in an identical vivarium and fed with the same diet, SAMP mice reveal a distinct fecal microbiome, metabolome, and lipidome profile compared to AKR mice, their non-inflamed parental control strain. Differences are already present in 5-week-old mice, with a tendency to increase in 15-week-old mice. SAMP and AKR mice metabolome and lipidome profiles were substantially different, belonging to two clusters in line with the progression of intestinal disease. Similarly, the 16S analysis confirmed differences between 15-week-old AKR and SAMP mice. The protective role of dietary polyphenols has been documented in inflammatory bowel diseases (IBD); thus, we supplemented the chow diet with an anthocyanin-rich extract (RED) to evaluate disease reduction in SAMP mice and changes in fecal microbiota/metabolome. Our data reveal that 10-week supplementation with anthocyanin-rich extract ameliorated disease severity in SAMP mice despite limited fecal microbiota/metabolome differences.

Vedolizumab is a gut-selective monoclonal anti-α4β7 integrin antibody treatment for Crohn's disease (CD). A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial (NCT03234907) assessed vedolizumab efficacy and safety in Chinese patients with moderate-to-severe CD and inadequate/loss of response/intolerance to previous conventional or anti-tumor necrosis factor-α therapy.

Eligible patients aged ≥18 to ≤80 years with moderate-to-severe CD (CD Activity Index [CDAI] total score 220-400) were randomized 2:1 to vedolizumab 300 mg intravenous infusion or placebo at Weeks 0, 2, 6 of induction, and every 4/8 weeks during Week 14-58 maintenance treatment. Primary and secondary endpoints at Week 10 were enhanced clinical response (≥100-point decrease from baseline CDAI score), and clinical remission (CDAI score ≤150), respectively. Additional Week 10 and/or Week 60 assessments included endoscopic and biomarker (C-reactive protein and fecal calprotectin) measurements.

The study was conducted at 30 centers (August 2017 through August 2020). Enrolled patients (n = 215) were randomized to vedolizumab (n = 144) or placebo (n = 71). By Week 10, 19.4 % vedolizumab-treated versus 24.3 % placebo-treated patients achieved an enhanced clinical response. The Cui-Hung-Wang-adjusted p-value for the primary endpoint was 0.347. After maintenance treatment at Week 60, rates of enhanced clinical response, clinical remission, endoscopic response, mucosal healing, and biomarker improvements appeared greater for vedolizumab-treated than placebo-treated patients.

There were no new safety findings for vedolizumab treatment of Chinese patients with CD. Although the primary endpoint was not met, vedolizumab-treated patients showed improvements in other disease activity measures at Weeks 10 and 60.

This post hoc analysis evaluated the corticosteroid-sparing effects of risankizumab (RZB) therapy in patients with moderate-to-severe ulcerative colitis in the phase 3 induction and maintenance studies, INSPIRE and COMMAND.

Patients were randomized (2:1) to 12 weeks of intravenous RZB or placebo (PBO) induction therapy; responders to intravenous RZB were randomized (1:1:1) to receive subcutaneous RZB 180 mg, 360 mg, or PBO (RZB withdrawal) maintenance therapy. Baseline corticosteroid doses were maintained during induction, with a mandatory taper beginning at maintenance week 0. Efficacy outcomes were evaluated by baseline corticosteroid use at induction week 12, while corticosteroid-free clinical and endoscopic outcomes were assessed at maintenance week 52 among the overall population and among patients on corticosteroids at baseline. Safety was also assessed.

At baseline, 35.7% (348/975) of patients were taking corticosteroids. At induction week 12, greater rates were observed for clinical, endoscopic, and patient-reported outcomes in RZB 1200 mg-treated patients compared with PBO, regardless of baseline corticosteroid use. RZB 180 mg and 360 mg treatment resulted in higher corticosteroid discontinuation rates (RZB 180 mg 64.9% [48/74]; RZB 360 mg 54.2% [32/59]; PBO [withdrawal] 36.8% [25/68], P ≤ .01) and corticosteroid-free clinical, endoscopic, and patient-reported outcomes at week 52, compared with PBO (withdrawal). The rates of treatment-emergent adverse events were similar regardless of baseline corticosteroid use during induction and maintenance.

The efficacy of RZB induction therapy was independent of corticosteroid use, with high rates of corticosteroid-free outcomes observed in the overall population and among patients with baseline corticosteroid use, reaffirming the potential of RZB to serve as a corticosteroid-sparing therapy for patients with ulcerative colitis.

NCT03398148 and NCT03398135.

Advanced combination therapy with biologics and small molecules has seen more widespread implementation for inflammatory bowel disease (IBD). However, there is a paucity of data available to guide the successful de-escalation of combination therapy following the achievement of disease remission. Therefore, we pursued this retrospective study to evaluate our center's approach to de-escalation of these patients.

IBD patients undergoing de-escalation of combination biologic therapy from May 2017 to March 2023 with a follow-up visit were included. The need for re-escalation, steroid therapy, and hospitalization at follow-up was compared between the de-escalation method, adherence, patient demographics, disease characteristics, and measures of disease activity.

Fifty IBD patients underwent de-escalation, with a median age of 35.7 years. All 50 patients had a follow-up visit within a median of 168 (111) days. Patients were divided into two groups with 12 (24%) patients requiring re-escalation of therapy and 38 (76%) able to maintain or further de-escalate. Of those that required re-escalation, 3 (25%) required the use of systemic steroids and none required hospitalization for IBD. Non-adherence to the de-escalation plan significantly correlated with the need for re-escalation (P < .001).

Patient adherence and the number of prior failed biologic therapies were identified as potential risk factors for re-escalation. The type of agent being de-escalated (biologic or Janus kinase inhibitors [JAKi] did not correlate with the need for re-escalation).

This systematic review and meta-analysis compared the efficacy, safety, and treatment persistence of vedolizumab and adalimumab in patients with inflammatory bowel disease (IBD).

Through a comprehensive search of three databases up to September 2024, we calculated pooled effect estimates for binary outcomes using risk ratios (RR) with 95% confidence intervals (CIs). Heterogeneity was evaluated using Cochran's I2 and Q statistics, with a random-effects model applied when I2 exceeded 50%, and a fixed-effects model used otherwise. For randomized trials, the Cochrane Risk of Bias Tool was applied; the Newcastle-Ottawa Scale assessed nonrandomized trials.

We analyzed 12 studies involving 4095 patients. The findings showed that vedolizumab had higher clinical remission and response rates compared to adalimumab (RR: 1.24, 95% CI 1.14-1.34, P < 0.01; RR: 1.11, 95% CI 1.01-1.22, P = 0.03). However, no significant differences were observed in endoscopic remission between the two treatments (RR: 0.74, 95% CI 0.47-1.18, P = 0.21). Safety outcomes, based on adverse and serious adverse event rates, have no significant differences (RR: 0.67, 95% CI 0.41-1.12, P = 0.13; RR: 0.78, 95% CI 0.36-1.68, P = 0.53). Treatment persistence also showed no significant difference between vedolizumab and adalimumab (RR: 0.78, 95% CI 0.55-1.12, P = 0.19).

Our study suggests that vedolizumab may be more effective than adalimumab in alleviating symptoms and achieving clinical response. Importantly, this effectiveness is achieved without an increase in adverse events. No significant difference was found in treatment persistence. However, high heterogeneity may weaken the evidence, requiring further randomized trials for confirmation.

Despite the availability of several biologics for ulcerative colitis (UC), there remains a critical need to identify first-line treatment biologics. The superiority of infliximab (IFX) over vedolizumab (VED) and ustekinumab (UST) was evaluated as initial UC treatments in patients with biologic-naïve UC.

This multicenter, randomized control trial was conducted across 20 Japanese medical institutions. An independent center randomly allocated patients with UC (Mayo score ≥ 6) who had not previously used biologics to three treatment groups (IFX, VED, UST). The primary endpoint was the clinical remission (CR) rate at week 12, with other endpoints including the treatment continuation rate at week 26 and adverse events (AEs).

From May 2021 to June 2023, 107 cases were registered, including 104 for safety and 97 for efficacy evaluation. CR rate at week 12 was 36.4% (95%CI:20.4-54.9), 32.4% (95%CI:17.4-50.5) and 43.3% (95%CI:25.5-62.6) in IFX, VED, and UST group, respectively. Continuation rates at week 26 were 50.0%(IFX), 58.3% (VED), and 82.4% (UST). AEs related to study medication were 14.7% (IFX), 16.7% (VED), and 5.9% (UST). Predictors for CR at week 12 were thiopurine use in IFX (p = 0.04), lower baseline Mayo score (p = 0.007), and lower Patient report outcome 2 (p = 0.003) at week 2 in VED.

Due to small sample size, it is challenging to make conclusions for main endpoints from this study while our study suggested that use of thiopurines in IFX group and lower activity at enrollment in VED group may enhance treatment efficacy. (jRCT1031200329; available at https://jrct.niph.go.jp/ ).

Approximately one in every four patients with ulcerative colitis will develop acute severe ulcerative colitis (ASUC). Historically, this was managed with intravenous steroids and surgery when steroids failed. The use of rescue therapy.

This review summarizes the latest research in the management of hospitalized patients with ASUC. Covering the historical data and success of rescue therapy with cyclosporine and then with infliximab changed outcomes and reduced the risk of colectomy during the hospitalization and at 1 year. More recently, more biologics and small molecules have been approved and more patients present to the hospital with ASUC already failing anti-tumor necrosis factor antagonists. More recent studies have shown some efficacy of rescue therapy with other classes of biologics (e.g. interleukins and anti-integrins). The more recently approved small molecules (i.e. tofacitinib and Upadacitinib) have shown a rapid onset in therapeutic efficacy in as little as 1 day with sustained response at 1 year in reducing the risk of colectomy following ASUC.

In the expert opinion, we discuss the challenges in the treatment of patients with ASUC. We summarize the data of current biologics and new small molecules and their emerging roles in the management of ASUC.

Ulcerative colitis (UC) is a chronic, relapsing and remitting, inflammatory bowel disease. Monoclonal antibodies targeting interleukin (IL)-23p19 have been developed to treat chronic inflammatory diseases mediated by aberrant IL23/Th17 responses, including psoriasis, psoriatic arthritis, and Crohn's disease. More recently, these agents have been evaluated for the treatment of moderately-to-severely active UC.

In this review, we summarize and discuss phase 2 and pivotal phase 3 clinical trials informing the efficacy and safety of mirikizumab (AMAC, LUCENT, and SHINE), risankizumab (INSPIRE, COMMAND), and guselkumab (QUASAR, VEGA). The literature search included original research publications, secondary publications, and preliminary data from conference abstracts presented at international gastroenterology meetings from the past 5 years.

The approval of IL23p19 antagonists expands the armamentarium of effective and safe therapies for patients living with moderately-to-severely active UC. These agents demonstrate potent efficacy for both inducing and maintaining symptomatic and objective disease endpoints, including endoscopic, histologic, and biomarker remission. These well-tolerated agents are effective in both advanced treatment-naïve and experienced patients. Accordingly, IL23p19 antagonists have the potential to be used in a diverse population of patients with UC, and as potential platform therapies for future combinations with other targeted immunomodulatory agents.

With the recent increase in available treatment options for inflammatory bowel disease (IBD), shared decision-making has gained considerable importance. To address potential disparities in patient and physician priorities, we conducted a survey to clarify these perspectives.

Patients with IBD and physicians treating IBD were asked to complete an online questionnaire focused on key factors influencing drug selection and preferred drug administration methods.

Responses were obtained from 400 patients (327 with ulcerative colitis and 73 with Crohn's disease) and 155 physicians. Among the factors in drug selection, physicians assigned significantly higher importance scores for experience with the drug than did patients. The expected time to onset of drug effects was significantly different between patients and physicians. Regarding preferences for drug administration method, patients and physicians assigned the highest acceptability scores for once-daily oral administration. For intravenous and subcutaneous routes, patients' scores were significantly lower than those of physicians' scores. Notably, 86.0% of patients and 62.0% of physicians preferred oral administration as the most preferred method. However, preferences varied based on treatment experience: 34.7% of patients with prior experience with subcutaneous injection preferred this method.

Patients and physicians generally shared similar priorities for drug selection; however, physicians emphasized their experience with the drug over patient preferences. Although the number of patients with prior treatment experience preferred intravenous or subcutaneous injections, oral formulations remained the preferred choice for both patients and physicians.

Ulcerative colitis (UC) is classified as a chronic inflammatory bowel disease (IBD) and can present in various degrees of severity. In addition to mild courses of the disease, such as uncomplicated proctitis, which can often be successfully treated with topical 5-ASA formulations, complicated courses can be observed, which can sometimes be life-threatening. Affected patients are often considerably burdened and often severely restricted in their quality of life, as they suffer from numerous, often bloody bowel movements, which are accompanied by abdominal cramps, urgency and sometimes even incontinence. In addition, many UC patients suffer from concomitant extraintestinal inflammatory manifestations including skin manifestations like psoriasis, erythema nodosum or joint involvement such as spondylarthritis. For many years, steroids and conventional immunosuppressants such as azathioprine were the only treatment options available. Twenty years ago, the approval of the first anti-TNF antibody, Infliximab, marked a significant turning point in IBD therapy. Despite the continuous progress in drug therapy, the rates of primary and/or secondary treatment failure are still considerable. With this in mind, a large number of additional substances have been developed and approved for the treatment of UC in the recent years. In addition to TNF antibodies and their biosimilars, the anti-integrin vedolizumab, various Janus kinase (JAK) inhibitors, an interleukin (IL)-12/-23p40 antibody, various IL-23p19 antibodies and sphingosine-1-phosphate receptor (S1PR) modulators have broadened the therapeutic landscape and found their way into the clinical treatment of UC patients. In this article we will discuss case-based decision paths for the selection of fitting anti-inflammatory treatments in UC patients and summarize the principles of the different therapeutic strategies for UC.

Inflammatory Bowel Disease (IBD) is a multifactorial gastrointestinal condition encompassing two major forms of intestinal inflammation: Crohn's disease (CD) and ulcerative colitis (UC). Both conditions are linked to auto-inflammatory reactions and genetic predispositions. Various drug therapies and biological treatments proposed to reduce IBD-associated inflammation. We induced IBD in a mouse model by stimulating bowel inflammation with an oral dextran sodium sulfate (DSS) beverage. Our novel cell therapy approach for IBD involves intramuscular (IM) and intraperitoneal (IP) delivery of non-matched, expanded, potent xenogeneic fetal human mesenchymal stromal cells (f-hPSCs) in 2 × 106 cell injections. This cell therapy has already been shown previously to induce pro-regenerative and anti-inflammatory effects in different systemic and local disorders, where the injected f-hPSCs were shown to respond to the stress of the host and secrete the adequate secretome in response to this stress. In the current study, the IP-injected f-hPSCs treatment of the DSS-induced IBD enhanced the regenerative processes of the damaged bowel and reduced the inflammatory process. This was associated with rapid regain of the mice's weight and a decrease in inflammation-associated parameters, such as colon edema, bowel shortening, and a threefold increase in bowel mass, as estimated by increased colon weight and reduced length. This ratio best emphasized the induced inflammatory response associated with the decrease in the inflamed colon length with an increase in its mass. Although IM f-hPSCs delivery was somehow effective by a few parameters, the IP delivery produced a superior response. The IP f-hPSCs treated mice lost only ~15% of their weight at the peak of the IBD effect, compared to ~25% in untreated mice. A reduction in the inflammatory response of the gut was also indicated by a decrease in neutrophil infiltration, as assayed by a myeloperoxidase (MPO) assay. Additionally, a significant improvement in the histological score of the gut and faster recovery to 90% of its original size was observed. These findings suggest that f-hPSC treatments could serve as an effective and safe anti-inflammatory and pro-regenerative treatment for IBD.

Ulcerative colitis is chronic inflammatory condition affecting the colon, necessitating remission inducing therapeutic interventions. With the emergence of newer more advanced options, their relative effectiveness remains unclear. This network meta-analysis (NMA) will compare the effectiveness of presently available biologics and small molecules in achieving and maintaining remission among patients of moderate-to-severe ulcerative colitis as part of induction and maintenance therapy.

A systematic search was conducted up to 21st February 2025, including only phase 2b/3 or 3 randomized controlled trials. The primary outcome was induction and maintenance of clinical remission (Full Mayo Score (FMS) ≤ 2, with no individual subscore > 1). Secondary outcomes assessed were clinical response, endoscopic improvement (Mayo Endoscopic Score (MES) ≤ 1 either with or without friability) and steroid free remission.

Across 22 studies (7,683 patients), upadacitinib had the highest likelihood of inducing clinical remission (99.08%), clinical response (97.44%) and endoscopic improvement (99.32%), followed by Infliximab and guselkumab following close by for specific outcomes. In maintenance of clinical remission and endoscopic improvement upadacitinib again ranked highest (95.60%) and (99.46%). Tofacitinib (92.43%) has the highest probability with upadacitinib (87.73%) following behind in achieving steroid free remission.

Upadacitinib displayed high efficacy across multiple outcomes in both induction and maintenance therapy with Infliximab, guselkumab, and filgotinib following closely behind. For achieving steroid free remission tofacitinib has the highest probability of doing so. Overall small molecules and selective IL-23 inhibitors seems promising alternative to older biologics though additional head-to-head trial are warranted along with more real-world data.

Background/Objectives: Evidence is needed on the real-world outcomes of upadacitinib in patients with ulcerative colitis. This systematic review and meta-analysis evaluated the real-world effectiveness of upadacitinib for active UC. Methods: The primary outcome was clinical remission evaluated at week 8. Secondary outcomes included response, steroid-free remission, biochemical remission, colectomy, and safety. A random-effects meta-analysis model was used to calculate the pooled effect sizes (percentages or incidence rates) of effectiveness and safety outcomes. Results: Twenty-four studies with 1388 patients were included. Ninety-four percent of patients had previously failed biologics or Janus kinase inhibitors (JAKi), including 53.2% with tofacitinib. Clinical remission at week 8 was achieved in 68.4% of patients (95% confidence interval 55.5-80.2). Clinical remission was achieved in 48.3%, 71.1%, and 64.6% of patients at weeks 2 to 6, 12 to 16, and 24 to 36, respectively. Response was achieved in 72.6%, 82.1%, and 78.7% of patients at weeks 2 to 6, week 8, and weeks 12 to 16, respectively. Steroid-free remission was achieved in 39% of patients at week 8. Upadacitinib results were unaffected by prior biologic or JAKi failure. Mean fecal calprotectin level decreased from 1485.0 µ/g at baseline to 454.8 µ/g post-treatment (p < 0.01). The mean CRP level decreased from 12.3 mg/L at baseline to 4.4 mg/L post-treatment (p = 0.02). The incidence rates of colectomy, serious adverse events, and herpes zoster were 13.3, 2.3, and 1.7 per 100 patient-years, respectively. Conclusions: This meta-analysis confirms the effectiveness and safety of upadacitinib in a highly treatment-refractory population of UC patients.

Vedolizumab (VDZ), a novel biologic targeting α4β7 integrin, is safe and effective for the treatment of patients with ulcerative colitis (UC). The objective of this study was to compare the potential of the Platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and systemic immune-inflammation index (SII) in predicting clinical remission and treatment failure in patients with moderate-to-severe UC on VDZ therapy and to explore the risk factors for treatment failure.

Seventy-four UC patients treated with VDZ at our institution between December 1, 2020, and October 1, 2023, who had medical records were included in this study. We retrospectively collected baseline NLR, PLR, and SII values and assessed the predictive ability of the three indices for clinical remission and treatment failure using the receiver operating characteristic (ROC) curves.

Patients in the severe group (n = 47) had significantly higher baseline PLR and SII values than those in the moderate group (n = 27) (p < 0.05). Patients with MES3 had significantly higher PLR and SII values than patients with MES2 (p < 0.05). At 14 weeks after VDZ treatment, 28 patients obtained steroid-free clinical remission, whereas 46 did not. The area under the ROC curve (AUC) for SII was 0.659 for predicting clinical remission and exhibited the best predictive ability. Of the 52 patients who achieved long-term remission, 35 patients responded consistently to VDZ, whereas 17 patients experienced disease relapse. The SII, with an AUC of 0.793, showed the best predictive ability (sensitivity: 94.1%; specificity: 57.1%; cut-off value: 602.0). Cox regression analysis revealed that SII ≥602.0, was a potential predictor of relapse after VDZ treatment in UC patients (p = 0.048, hazard ratio: 8.651; 95% confidence interval: 1.017-73.593).

The SII performed better than NLR and PLR in predicting clinical remission and relapse for UC patients on VDZ therapy. Moreover, patients with high SII may relapse after VDZ treatment and should be treated with caution.

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).

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.

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.

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.

Infliximab, a monoclonal antibody targeting tumor necrosis factor-alpha (TNF-α), is widely used in treating inflammatory bowel diseases (IBD), including ulcerative colitis (UC). While generally well-tolerated, infliximab is associated with rare but significant adverse effects, including autoimmune hemolytic anemia (AIHA). This report describes the case of a 54-year-old male diagnosed with UC, who developed hemolytic anemia secondary to infliximab therapy after 1 year of treatment. During the infusion preceding the onset of anemia, the patient experienced a severe infusion reaction characterized by urticaria, bronchospasm, chills, fever, and pulsating headache. Laboratory findings confirmed hemolytic anemia with a positive direct and negative indirect Coombs tests. The patient responded well to corticosteroid therapy (prednisone at 1 mg/kg/day for 30 days) and stopping anti-TNF-α, with hemoglobin levels improving from 7.2 g/dL at presentation to 14.6 g/dL after 1 month. AIHA should be considered an uncommon but serious complication of infliximab therapy, necessitating careful monitoring, especially in patients treated for gastrointestinal indications. This case underscores the importance of recognizing and managing infusion-related complications of biologic therapies.

In the randomized, double-blind, phase 3 GRAPHITE study (NCT03657160), anti-α4β7 integrin antibody vedolizumab showed greater efficacy than placebo for prevention of lower-gastrointestinal (GI) acute graft-versus-host disease (aGVHD) after unrelated allogenic hematopoietic stem cell transplantation (allo-HSCT). This post hoc analysis assessed the efficacy and safety of vedolizumab versus placebo for lower-GI aGVHD prevention in Japanese and non-Japanese patients, when added to standard GVHD prophylaxis (calcineurin inhibitor + methotrexate/mycophenolate mofetil + / - anti-thymocyte globulin [ATG]). The analysis included 35 (18 vedolizumab-treated, 17 placebo-treated) Japanese and 298 (150 vedolizumab-treated, 148 placebo-treated) non-Japanese patients. Lower-GI aGVHD-free survival by day + 180 after allo-HSCT (primary endpoint) was 94% in vedolizumab-treated versus 81% in placebo-treated Japanese patients (HR 0.36; 95% CI 0.03-4.01; P = 0.2) and 84% in vedolizumab-treated versus 70% in placebo-treated non-Japanese patients (HR 0.47; 95% CI 0.28-0.78; P = 0.002). The number of events for the 5 key secondary endpoints (lower-GI aGVHD-free and relapse-free survival, Grade C-D aGVHD-free survival, non-relapse mortality, overall survival, and Grade B-D aGVHD-free survival) by day + 180 was lower in vedolizumab- versus placebo-treated Japanese patients. No safety concerns were identified for vedolizumab use as lower-GI aGVHD prophylaxis in Japanese patients.

Targeting the interleukin (IL)-23 axis is an emerging treatment target for ulcerative colitis (UC), with several positive randomized controlled trials (RCTs). We aim to investigate the safety and efficacy of IL-23 inhibitors for the induction and maintenance treatment of moderate to severe UC.

A systematic review and meta-analysis synthesizing evidence from RCTs obtained from PubMed, Cochrane, Scopus, and Web of Science from inception to August 2024. We used the fixed-effects model to report dichotomous outcomes using the risk ratio (RR) with a 95% confidence interval (CI).

CRD42024589935.

Four records, reporting four induction trials and three maintenance trials, with 2,699 patients in the induction phase and 1,015 in the maintenance phase, were included. IL-23 inhibitors significantly increased the rate of clinical remission in the induction phase (RR: 2.19, 95%CI [1.72, 2.78]) and maintenance phase (RR: 1.55, 95%CI [1.26, 1.90]); endoscopic remission in induction phase (RR: 1.76, 95%CI [1.41, 2.18]) and maintenance phase (RR: 1.63, 95%CI [1.21, 1.85]); histo-endoscopic mucosal healing in induction phase (RR: 2.06, 95%CI [1.60, 2.64]) and maintenance phase (RR: 1.48, 95%CI [1.14, 1.90]). Also, IL-23 inhibitors significantly decreased the incidence of serious adverse events in the induction phase (RR: 0.37, 95%CI [0.26, 0.55]) and maintenance phase (RR: 0.53, 95%CI [0.33, 0.83]).

IL-23 inhibitors are effective as an induction and maintenance therapy for moderate to severe UC based on the significantly increased rates of clinical, endoscopic, and histological remission. Also, the safety profile of IL-23 inhibitors is favorable, with a significantly decreased incidence of serious adverse events compared to placebo.

Background/Objectives: In the current era of tailored therapy, biologics such as vedolizumab (VDZ) and ustekinumab (UST) are increasingly administered to inflammatory bowel disease (IBD) patients. The decision to discontinue biologics after side effects or a lack of response is usually simple, but the decision to stop treatment in patients in remission is more difficult: to date, no study has been conducted to investigate the effects of VDZ or UST withdrawal. Our study aims to investigate the rates and predictors of relapse of IBD after the discontinuation of VDZ and UST during a well-controlled disease phase and to evaluate the response to retreatment. Methods: In this observational, multicenter, retrospective study, we included IBD patients who discontinued VDZ or UST during a well-controlled disease phase after at least 1 year of treatment. We collected demographic and clinical data for each patient at the time of discontinuation and at follow-up visits. Results: We included 36 IBD patients from 5 different centers; 80.0%, 58.5%, and 48.3% of patients maintained clinical remission at 12, 24, and 48 months after discontinuation, respectively. Crohn's disease (CD) patients were more likely to maintain remission than ulcerative colitis (UC) patients at 48 months (70.0% vs. 40.0%). No predictors of relapse were identified, but UC patients had a higher risk of early relapse than CD patients (HR = 3.23); 81.3% of retreated IBD patients achieved clinical remission after induction and at 12 months. Conclusions: No predictors of disease relapse after treatment discontinuation were identified. Half of the patients had a relapse within 48 months after discontinuation, but most of them achieved clinical remission after retreatment.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with an idiopathic origin, characterized by persistent mucosal inflammation. Anoikis is a programmed cell death mechanism activated during carcinogenesis to eliminate undetected isolated cells from the extracellular matrix. Although existing evidence indicates that anoikis contributes to the modulation of immune response, the involvement of anoikis-related genes (ARGs) in UC pathogenesis and their interaction with infiltrating immune cells has not been thoroughly explored. The GSE75214, GSE92415, and GSE16879 datasets were acquired and integrated from the GEO database. Additionally, 58 ARGs were identified through the GSEA database. Key anoikis-DEGs in UC were identified using three machine learning algorithms, including least absolute shrinkage and selection operator (LASSO) Cox regression, random forest (RF), and support vector machine (SVM). Receiver operating characteristic (ROC) analysis was utilized to evaluate the diagnostic accuracy of each gene. Subsequently, Single sample GSEA (ssGSEA) was executed to explore the relationships within immune cell infiltration, UC subtypes, and key anoikis-DEGs. Besides, unsupervised cluster analysis was conducted to categorize the UC samples into distinct subgroups, followed by comparing subtype differences. Finally, the upstream regulatory network was constructed and visualized. A comprehensive analysis of the involvement of ARGs in UC was performed, revealing their expression profile, correlation with infiltrating immune cells, and enrichment analyses. We identified five key anoikis-DEGs (PDK4, CEACAM6, CFB, CX3CL1, and HLA-DMA) and demonstrated their high diagnostic accuracy for UC. Moreover, CEACAM6, CFB, CX3CL1, and HLA-DMA exhibited positive associations with infiltrating immune cells in UC, whereas PDK4 displayed a negative correlation with all immune cells. Unsupervised cluster analysis enabled the classification of UC patients into two clusters, both of which exhibited distinct gene expression profiles and immune signaling pathways. Further, based upon the upstream regulatory network, TP53, RARB, RXRB, and CTCF potentially exerted regulatory functions. Our analysis identified five key anoikis-DEGs as characteristic biomarkers of UC. These genes were strongly associated with the infiltration of both innate and adaptive immune cells, as well as immune pathways. This study highlights the role of anoikis genes in UC pathophysiology and offers valuable insights for further elucidating UC pathogenesis and individualized therapy.

Inflammatory bowel disease (IBD) trials often stratify patients by prior biologic exposure, including prior biologic failure or intolerance. This study aimed to assess clinical outcomes in IBD patients with prior biologic failure vs intolerance treated with ustekinumab or vedolizumab.

A post-hoc analysis of ulcerative colitis (UC) and Crohn's disease (CD) clinical trials for ustekinumab (UNITI and UNIFI) and vedolizumab (GEMINI-1 and GEMINI-2) was performed. Clinical response, clinical remission, and endoscopic improvement (for UC) were compared among biologic naïve, biologic failure, and biologic intolerant patients. Statistical analyses, including chi-square tests and logistic regression, were performed.

A total of 1178 UC and 1439 CD patients received either ustekinumab or vedolizumab. In UC, biologic intolerant patients exhibited higher clinical response (54.7% vs 38.8%, aOR 1.87 [95% CI, 0.93-3.73]), clinical remission (25.0% vs 11.0%, aOR 2.84 [95% CI, 1.47-5.49]), and endoscopic improvement (40.6% vs 24.8%, aOR 2.76 [95% CI, 1.28-5.94]) compared to biologic failure, with outcomes similar to biologic naïve patients. In biologic intolerant CD patients, clinical response was similar between prior biologic failure and intolerance (34.2% vs 32.8%), but after adjustment for potential confounders, biologic intolerance was associated with higher odds of clinical response (aOR: 1.67, 95% CI, 1.09-2.55), with no significant difference observed for clinical remission (aOR: 1.48, 95% CI, 0.88-2.49).

Improved treatment outcomes were generally observed in patients with biologic intolerance compared to failure, especially in UC, where outcomes were similar to biologic naïve patients. Future clinical trials should meticulously differentiate prior biologic failure vs intolerance to mitigate potential bias.

Infliximab and adalimumab are the only biologics thus far approved for paediatric patients with inflammatory bowel disease (IBD), so other biologics, such as vedolizumab, are prescribed off-label. Despite its frequent use, prospective data for vedolizumab treatment in children are available only for short-term induction outcomes. We aimed to evaluate the long-term efficacy and safety of maintenance therapy with vedolizumab in paediatric patients with IBD.

In this multicentre, prospective, cohort study (VEDOKIDS), children younger than 18 years with Crohn's disease, ulcerative colitis, or IBD unclassified (analysed with the ulcerative colitis group) who had initiated intravenous vedolizumab were enrolled from 17 centres in six countries (Israel, the USA, Italy, Ireland, Denmark, and Slovenia). Patients initiating vedolizumab to prevent postoperative recurrence were excluded. Vedolizumab dose or schedule were not standardised, and concomitant treatment with any other medication was permitted. Patients were prospectively followed up for 54 weeks, with repeated biosampling. The primary outcome was complete remission at week 54, defined as clinical remission (weighted Paediatric Crohn's Disease Activity Index [wPCDAI] of <12·5 points in Crohn's disease and Paediatric Ulcerative Colitis Activity Index [PUCAI] of <10 in ulcerative colitis) without the need for surgery, exclusive enteral nutrition for children with Crohn's disease, or steroids (steroid-free and exclusive enteral nutrition-free clinical remission) plus CRP concentration lower than 1·5 times the upper limit of normal (ULN) of 0·5 mg/dL. In cases of missing data on CRP, ESR was used instead (concentrations <1·5 times the ULN, which was 25 mm/h). Data were analysed by intention to treat. This study is registered with ClinicalTrials.gov, NCT02862132.

Between May 19, 2016, and April 1, 2022, we enrolled 142 patients. Five children who had received only one or two infusions of their three-infusion induction before switching drugs due to COVID-19 pandemic-related reasons were excluded, leaving 137 children (64 [47%] with Crohn's disease, 64 [47%] with ulcerative colitis, and nine [7%] with IBD unclassified; 63 [46%] male and 74 [54%] female; age range of 0·7-17·6 years) in the intention-to-treat population. The median wPCDAI score in children with Crohn's disease decreased from 35 (IQR 18 to 49) at baseline to 13 (0 to 25; median of differences -14 [95% CI -33 to 0]) at week 54, and the median PUCAI score in children with ulcerative colitis decreased from 25 (IQR 15 to 50) at baseline to 5 (0 to 25) at week 54 (median of difference -10 [-30 to 0]). Improvements in disease activity were significant by week 6, with no further significant changes between visits. At week 54, 16 (25%) of 64 children with Crohn's disease and 34 (47%) of 73 with ulcerative colitis or IBD unclassified were in complete remission. 38 vedolizumab-related adverse events were recorded in 29 (21%) of 137 children, the most common being headache (n=7), myalgia (n=4), and fever (n=4), and none were serious.

Vedolizumab maintenance seems safe and efficacious in children, with a higher efficacy in those with ulcerative colitis than in those with Crohn's disease.

The European Crohn's and Colitis Organisation, the European Society for Paediatric Gastroenterology Hepatology and Nutrition, and Takeda.