Ulcerative colitis (UC) is a chronic inflammatory disease characterized by loss of immune tolerance to luminal antigens and progressive intestinal tissue injury. Thus, the re-establishment of immune tolerance is crucial for suppressing aberrant immune responses and UC progression.

This study aimed to investigate the mechanisms underlying the action of CDD-2103 and its bioactive compounds in mediating immune regulation in mouse models of colitis.

Two experimental colitis models, chronic 2,4,6-trinitrobenzene sulfonic acid (TNBS)- and T-cell transfer-induced Rag1-/- mice, were used to determine the effects of CDD-2103 on colitis progression. Single-cell transcriptome analysis was used to profile the immune landscape and its interactions after CDD-2103 treatment. Liquid chromatography-mass spectrometry (LC-MS) was used to analyze the major components interacting with lymphoid cells. A primary cell co-culture system was used to confirm the effects of bioactive component.

CDD-2103 dose-dependently suppresses the progression of colitis induced by chemicals or T cell transplantation in Rag1-/- mice. The effect of CDD-2103 is primarily attributable to an increase in the de novo generation of regulatory T cells (Tregs) in the lamina propria (LP). Single-cell transcriptomic analysis revealed that CDD-2103 treatment increased the number of tolerogenic dendritic cells (DCs). Mechanistically, CDD-2103 promoted tolerogenic DCs accumulation and function by upregulating several genes in the electron transport chain related to oxidative phosphorylation, leading to increased differentiation of Tregs. Further LC-MS analysis identified several compounds in CDD-2103, particularly those distributed within the mesenteric lymph nodes of mice. Subsequent studies revealed that palmatine and berberine promoted tolerogenic bone marrow-derived dendritic cells (BMDC)-mediated Treg differentiation.

Overall, our study demonstrated that the clinically beneficial effect of CDD-2103 in the treatment of UC is based on the induction of immune tolerance. In addition, this study supports berberine and palmatine as potential chemical entities in CDD-2103 that modulate immune tolerance.

The Mayo Endoscopic Subscore (MES) is widely utilized for assessing mucosal activity in ulcerative colitis (UC). Artificial intelligence has emerged as a promising tool for enhancing diagnostic precision and addressing interobserver variability. This study evaluated the diagnostic accuracy of ChatGPT-4, a multimodal large language model, in identifying and grading endoscopic images of UC patients using the MES.

Real-world endoscopic images of UC patients were reviewed by an expert consensus board. Each image was graded based on the MES. Only images that were uniformly graded were subsequently provided to three inflammatory bowel disease (IBD) specialists and ChatGPT-4. Severity gradings of the IBD specialists and ChatGPT-4 were compared with assessments made by the expert consensus board.

Thirty of 50 images were graded with complete agreement among the experts. Compared with the consensus board, ChatGPT-4 gradings had a mean accuracy rate of 78.9% whereas the mean accuracy rate for the IBD specialists was 81.1%. Between the two groups, there was no statistically significant difference in mean accuracy rates ( P = 0.71) and a high degree of reliability was found.

ChatGPT-4 has the potential to assess mucosal inflammation severity from endoscopic images of UC patients, without prior configuration or fine-tuning. Performance rates were comparable to those of IBD specialists.

The expanding portfolio of targeted therapies for ulcerative colitis (UC) suggests that a more precise approach to defining disease activity will aid clinical decision-making. This prospective study used genome-wide microarrays to characterize gene expression in biopsies from the most inflamed colon segments from patients with UC and analyzed associations between molecular changes and short-term outcomes while on standard-of-care treatment. We analyzed 141 biopsies-128 biopsies from 112 UC patients and 13 biopsies from eight inflammatory bowel disease unclassified (IBDU) patients. Endoscopic disease was associated with expression of innate immunity transcripts, e.g. complement factor B (CFB); inflammasome genes (ZBP1 and PIM2); calprotectin (S100A8 and S100A9); and inflammation-, injury-, and innate immunity-associated pathway analysis terms. A cross-validated molecular machine learning classifier trained on the endoscopic Mayo subscore predicted the endoscopic Mayo subscore with area-under-the-curve of 0.85. A molecular calprotectin transcript score showed strong associations with fecal calprotectin and the endoscopic Mayo subscore. Logistic regression models showed that molecular features (e.g. molecular classifier and molecular calprotectin scores) improved the prediction of disease progression over conventional, clinical features alone (e.g. total Mayo score, fecal calprotectin, physician global assessment). The molecular features of UC showed strong correlations with disease activity and permitted development of machine-learning predictive disease classifiers that can be applied to expanded testing in diverse cohorts.

Mucosal healing is the mainstream goal of modern treat-to-target strategy as it is associated with a significantly more favorable disease course in IBD patients with either ulcerative colitis or Crohn's disease. Recent advances in endoscopic imaging technologies have overcome the traditional concept of mucosal healing assessed with conventional white light imaging, allowing for multiple levels of endoscopic healing up to the boundaries of molecular and functional evaluation. In this review, we focused on conventional and emerging strategies to assess endoscopic healing in ulcerative colitis and ileocolonic Crohn's disease, examining their pros and cons in real life practice.

Endoscopic healing is generally defined as Mayo endoscopic subscore (MES) ≤1 in ulcerative colitis (UC). However, patients with an MES of 1 are at higher relapse risk than those with an MES of 0. This study evaluated the therapeutic efficacy of proactive dose escalation of oral 5-aminosalicylic acid (5-ASA) in UC patients with an MES of 1.

An open-label, randomized controlled trial was conducted in 5 hospitals between 2018 and 2022. Ulcerative colitis patients in clinical remission under oral 5-ASA therapy and diagnosed as having an MES of 1 were enrolled. Patients receiving maintenance therapy other than 5-ASA and immunomodulator were excluded. Patients were randomly assigned in a 1:1 ratio to receive either a dose-escalated (intervention) or constant dose (control) of 5-ASA. Concomitant immunomodulator was used as the stratification factor in the randomization. The primary end point was relapse within 1 year. The subgroup analysis was stratified for the use of immunomodulators.

The full analysis set included 79 patients (39 intervention and 40 control). Immunomodulators were used in 20 (25.3%) patients. Relapse was less in the intervention group (15.4%) than the control group (37.5%; P = .026). In the subgroup with concomitant immunomodulators, relapse was also less in the intervention group (10.0%) than the control group (70.0%; P = .020). In patients without immunomodulators, the difference was not significant between 2 groups (intervention, 17.2%; control, 26.7%; P = .53).

Dose escalation of 5-ASA reduced relapse within 1 year in UC patients in clinical remission with an MES of 1.

The performance of endoscopic evaluation of ulcerative colitis (UC) using conventional scoring, including Mayo endoscopic subscore (MES) and ulcerative colitis endoscopic index of severity (UCEIS), is not satisfactory. Recently, the usefulness of novel image-enhanced endoscopy (IEE) such as texture and color enhancement imaging (TXI) and red dichromatic imaging (RDI) has been reported in the endoscopic evaluation of UC. We evaluated the performance of IEEs in UC, particularly focusing on the correlation with MES and UCEIS, and prediction of relapse.

This is a prospective, observational study. UC patients in clinical remission who underwent colonoscopy with evaluation of IEEs and follow-up for > 3 months were analyzed. TXI and RDI were evaluated using the previously reported scoring system (TXI 0-2 and RDI 1-4). The IEE scores were compared with the conventional scoring, fecal calprotectin levels, and histological findings using Geboes score, and patient's clinical relapse rate stratified by each IEE score was examined.

Both TXI and RDI scores were well-correlated with MES and UCEIS (both p < 0.001), fecal calprotectin levels (p = 0.015 and p = 0.006), and histology evaluated with Geboes score. In the Geboes subscore, the subscore 2B (neutrophil infiltration in lamina propria) was the most correlated with each endoscopic scoring. RDI 3-4 was significantly correlated with subsequent relapse (hazard ratio 3.56, 95% confidence interval 1.13-11.24), but TXI scoring did not predict relapse significantly.

The assessment using RDI could be a convenient and useful endoscopic evaluation method for predicting the prognosis of UC.

Ulcerative colitis (UC) can be treated with infliximab (IFX). Therapeutic drug monitoring (TDM) can yield superior outcomes, but its cost-effectiveness is unknown.

We used a decision analytic Markov model to conduct a cost-effectiveness analysis comparing proactive TDM, reactive TDM, no TDM, and combinations of proactive and reactive TDM in 25-year-old patients with UC started on IFX. Under proactive TDM, IFX concentration and anti-drug antibodies were measured every 6 months and during a flare; under reactive TDM, these were only measured during a flare. Patients with flares experienced decreased quality of life (QoL) and risked further complications. We evaluated lifetime costs (2021 U.S. dollars), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios, all discounted at 3% annually, from a healthcare sector perspective. We performed probabilistic sensitivity analysis (PSA) and deterministic sensitivity analyses. We used a willingness-to-pay threshold of $100,000 per QALY gained.

All TDM strategies increased QALYs and healthcare costs. Compared to no TDM, reactive TDM increased costs from $496,700 to $497,500 ($3,200 per QALY gained). 1 year of proactive TDM followed by reactive TDM increased costs to $508,600 ($63,800 per QALY gained relative to reactive TDM). In 46% of PSA samples, 1 year of proactive TDM followed by reactive TDM was most likely to be the optimal strategy. This strategy was less likely to be cost-effective when remission QoL was lower and when post-surgical QoL was higher.

1 year of proactive TDM followed by reactive TDM is cost-effective in patients with UC on IFX.

Mucosal healing (MH) is a key therapeutic target in Crohn's disease (CD) and is associated with improved outcomes. While adult studies indicate a positive correlation between serum anti-tumor necrosis factor (TNF) levels and MH, data in pediatric patients is limited. We aimed to define the association of serum anti-TNF levels with MH in pediatric patients with CD during maintenance therapy.

Retrospective data (2014-2023) was collected from pediatric CD patients treated with infliximab or adalimumab who performed an ileocolonoscopy at least 26 weeks after initiating therapy. Serum anti-TNF levels around endoscopic time were compared with endoscopic findings. MH was defined as complete absence of inflammatory or ulcerative lesions across all segments of the gastrointestinal tract. Univariable and multivariable logistic regression analysis was conducted to identify factors associated with MH.

Data were obtained from 107 patients (41 infliximab and 66 adalimumab), with a median age at diagnosis of 12.6 (9.9-14.0) years. Median time until ileocolonoscopy following anti-TNF initiation was 89.0 (56.3-152.3) weeks. MH was identified in 31 (29.0%) patients. Anti-TNF serum levels were comparable in the MH and non-MH groups (9.5 [4.9-13.9] vs. 9.3 [6.4-15.7] µg/mL; p = 0.73), without differences in patients treated with infliximab or adalimumab. In multivariable analysis, diagnosis weight Z-score (odds ratio [OR] = 2.860, 95% confidence interval [CI] = 1.005-8.138; p = 0.049), along with C-reactive protein (OR = 0.037, 95% CI = 0.002-0.687; p = 0.027) and fecal calprotectin (OR = 0.995, 95% CI = 0.990-1.000; p = 0.037) at time of ileocolonoscopy were significantly associated with MH.

In our cohort, anti-TNF levels during maintenance were not associated with MH in pediatric CD.

Ulcerative colitis is a chronic inflammatory condition of the colon driven by aberrant immune activation. Although advanced medical therapies form the cornerstone of ulcerative colitis management, unmet needs include failure to induce and sustain remission in a substantial proportion of patients and in managing acute severe ulcerative colitis. We review new treatment strategies that might improve patient outcomes in the management of moderate-to-severe ulcerative colitis.

A literature search was conducted using the PubMed database, including studies published from inception to October 2024, selected for their relevance. Recognizing current limitations, this article reviews strategies to improve treatment outcomes in ulcerative colitis using advanced therapies. These approaches include early treatment initiation, dose optimization, positioning newer agents as first-line therapies, combination therapy, targeting novel therapeutic endpoints, and the management of acute severe ulcerative colitis.

The strategies discussed may contribute to establishing new standards of care aimed at achieving long-term remission and enhancing patient outcomes. Personalized therapy, which tailors treatment based on individual disease characteristics and risk factors, is anticipated to become a critical aspect of delivering more effective care in the future.

In inflammatory bowel disease therapy, thiopurines have been essential.　However, several reports have investigated factors affecting thiopurine metabolism to date.　This study investigated factors affecting intracellular concentrations of 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP) in a real-world setting.

Between May 2013 and October 2021 in one institution, 44 patients (median age 44 years;male 35, female 9;ulcerative colitis 32, Crohn's disease 12) receiving thiopurines were reviewed.　Intracellular 6-TGN/6-MMP concentrations were measured by high-performance liquid chromatography, and the initial measurement in each patient was used for the study.

The 6-TGN level was significantly higher in females, with mild disease activity, absence of NUDT15 polymorphism, and allopurinol administration.　A higher trend was observed with high thiopurine dosage (>50 mg).　6-MMP levels were significantly lower with concomitant use of time-dependent 5-aminosalicylic acid (5-ASA) and allopurinol, and higher with high thiopurine dosage.　On multivariate analysis of variance, logarithmically transformed 6-TGN levels were significantly higher in females, with high thiopurine dosage, and allopurinol administration.　Similarly, logarithmically transformed 6-MMP levels were significantly higher with time-dependent 5-ASA administration and high thiopurine dosage.

Patients who received allopurinol, a high dose of thiopurine, or were female showed higher 6-TGN levels.

The Mayo endoscopic subscore [MES] is the most popular endoscopic disease activity measure of ulcerative colitis [UC]. Artificial intelligence [AI]-assisted colonoscopy is expected to reduce diagnostic variability among endoscopists. However, no study has been conducted to ascertain whether AI-based MES assignments can help predict clinical relapse, nor has AI been verified to improve the diagnostic performance of non-specialists.

This open-label, prospective cohort study enrolled 110 patients with UC in clinical remission. The AI algorithm was developed using 74 713 images from 898 patients who underwent colonoscopy at three centres. Patients were followed up after colonoscopy for 12 months, and clinical relapse was defined as a partial Mayo score > 2. A multi-video, multi-reader analysis involving 124 videos was conducted to determine whether the AI system reduced the diagnostic variability among six non-specialists.

The clinical relapse rate for patients with AI-based MES = 1 (24.5% [12/49]) was significantly higher [log-rank test, p = 0.01] than that for patients with AI-based MES = 0 (3.2% [1/31]). Relapse occurred during the 12-month follow-up period in 16.2% [13/80] of patients with AI-based MES = 0 or 1 and 50.0% [10/20] of those with AI-based MES = 2 or 3 [log-rank test, p = 0.03]. Using AI resulted in better inter- and intra-observer reproducibility than endoscopists alone.

Colonoscopy using the AI-based MES system can stratify the risk of clinical relapse in patients with UC and improve the diagnostic performance of non-specialists.

The emerging role of artificial intelligence (AI) in automated endoscopic diagnosis represents a significant advancement in managing inflammatory bowel disease (IBD). AI technologies are increasingly being applied to endoscopic imaging to enhance the diagnosis, prediction of severity, and progression of IBD and dysplasia-associated colitis surveillance. These AI-assisted endoscopy aim to improve diagnostic accuracy, reduce variability of endoscopy imaging interpretations, and assist clinicians in decision-making processes. By leveraging AI, healthcare providers have the potential to offer more personalized and effective treatments, ultimately improving patient outcomes in IBD care.

The inflammatory bowel diseases (IBD) occur in genetically susceptible individuals that mount inappropriate immune responses to their microbiota leading to chronic intestinal inflammation. The natural history of IBD progression begins with early subclinical stages of disease that occur before clinical diagnosis. Improved understanding of those early subclinical stages could lead to new or improved strategies for IBD diagnosis, prognostication, or prevention. Here, we review our current understanding of the early subclinical stages of IBD in humans including studies from first-degree relatives of patients with IBD and members of the general population who go on to develop IBD. We also discuss representative mouse models of IBD that can be used to investigate disease dynamics and host-microbiota relationships during these early stages. In particular, we underscore how mouse models of IBD that develop disease later in life with variable penetrance may present valuable opportunities to discern early subclinical mechanisms of disease before histological inflammation and other severe symptoms become apparent.

Recent advances in the field of endoscopy have found fertile ground for application in inflammatory bowel diseases (IBD). Mucosal healing is a primary goal of IBD therapy, and current evidence shows that histologic remission (HR) is an additional desirable outcome. However, with the use of standard endoscopy, a considerable number of patients with histologically active disease go unrecognized. This narrative article examines the role, current or potential, of each endoscopic technique, from standard white-light endoscopy to molecular imaging, in the assessment of mucosal healing and HR in IBD.

A significant proportion of inflammatory bowel disease (IBD) patients fail to respond to advanced therapies. Combining advanced therapies may improve treatment outcome. This study aimed to assess the effectiveness, adverse events, and costs associated with combining advanced therapies in IBD patients.

Combination advanced therapy was defined as the concurrent use of two biological agents or one biological agent with a small molecule therapy. Clinical data, including disease characteristics, treatment regimens, and adverse events, were collected from electronic patient records. Clinical response rates, biochemical markers, and treatment costs were evaluated.

The study included 109 IBD patients receiving combination advanced therapies from 9 academic centers in Ireland. Corticosteroid-free clinical response rates at 12 weeks and 52 weeks were 39 % and 38 %, respectively. Adverse events occurred in 26 % of therapeutic trials, with disease-related events being the most common. Notably, there were 3 cases of non-melanomatous skin cancer and 10 infectious complications. The annual cost of maintenance therapy for combination advanced therapies ranged from €17,560 to €30,724 per patient.

Combination advanced therapies demonstrated effectiveness and acceptable safety profiles in a cohort of treatment-refractory IBD patients. Further large, prospective trials are required to definitively evaluate the role of combination advanced therapies in IBD.

Obtaining and maintaining corticosteroid-free remission are important goals of treatment for ulcerative colitis (UC). Characteristics associated with achieving corticosteroid-free remission were assessed in filgotinib-treated patients in SELECTION, a 58-week, phase 2b/3 trial in moderately to severely active UC.

This post hoc analysis used data from filgotinib-treated patients receiving corticosteroids at maintenance baseline in SELECTION. Univariate logistic regression was performed to assess induction baseline characteristics associated with 6 months of corticosteroid-free remission at week 58, defined as clinical remission without using corticosteroids for at least 6 months.

At maintenance baseline, 92 and 81 patients were receiving corticosteroids in the filgotinib 200 mg and filgotinib 100 mg groups, respectively. Age, body mass index, history of pancolitis, disease duration, fecal calprotectin levels, C-reactive protein levels, Mayo Clinic Score, concomitant corticosteroids, immunomodulators, and aminosalicylates had no statistically significant effect on the likelihood of achieving corticosteroid-free remission. Baseline characteristics associated with increased odds of corticosteroid-free remission were Mayo Clinic Endoscopic Subscore of 2 (vs. 3) in the filgotinib 200 mg and filgotinib 100 mg groups, and female (vs. male) sex, current (vs. former or never) smoking, and being biologic‑naive (vs. experienced) in the filgotinib 200 mg group.

Steroid tapering can be achieved in patients with UC receiving filgotinib 200 mg independently of baseline characteristics such as clinical activity and duration of illness. However, the likelihood of achieving corticosteroid-free remission was higher among patients who were biologic-naive, current smokers, had low endoscopic inflammatory burden and who were female.

The advantages of endoscopic vs histologic assessments of inflammation in inflammatory bowel disease remain unclear. We compared endoscopic and histologic inflammation in a prospective cohort. Furthermore, in patients with discordant findings, we compared the ability of endoscopy vs histology to predict disease course.

Ulcerative colitis (UC) or Crohn's disease (CD) patients underwent routine colonoscopies with intestinal biopsies, which included ratings of inflammation severity. Tetrachoric correlation analysis between the endoscopic and histologic inflammation ratings was performed. In postsurgical CD patients, major adverse outcomes (MAOs) were recorded.

The analysis included 749 patients (60.2% CD patients), with 2807 biopsied segments. We found high concordance between endoscopist and pathologist inflammation ratings (0.84, 95% confidence interval, 0.81-0.87, p < 0.0001). Only 12.5% of biopsied segments exhibited microscopic inflammation without endoscopic inflammation. Neo-terminal ileum (neo-TI) biopsies exhibited the highest discordance; UC colonic biopsies had the highest concordance. Postsurgical CD patients who completed the 48-month follow-up (n = 138) were included in the survival analysis. The probability of MAO-free survival was significantly higher in patients with a Rutgeerts score of i0 at baseline than in those with higher scores. Microscopic inflammation in the neo-TI did not predict a higher risk of MAOs (p = 1.00).

In a real-world setting, endoscopic inflammation predicted histologic inflammation with high accuracy. In patients with a Rutgeerts score of i0, microscopic inflammation in neo-TI biopsies did not predict more aggressive disease behavior over the next 4 years. These results have implications for the design of clinical trials, suggesting the use of endoscopic healing as an endpoint.

Standardized evaluation of endoscopic disease activity using valid, responsive and reliable instruments is crucial for optimizing the efficiency of clinical trials with therapeutic agents for Crohn's disease (CD). Achieving endoscopic remission and/or mucosal healing is associated with improved long-term outcomes, making it an important treatment goal.

Several endoscopic indices have been used over the past two decades, though they lack complete validation. The Crohn's Disease Endoscopic Index of Severity (CDEIS) and Simple Endoscopic Score for Crohn's Disease (SES-CD) demonstrate fair reliability and responsiveness to treatment. The CDEIS is rather complex and time-consuming, and both endoscopic indices are prone to variability. The Lewis Score and Capsule Endoscopy CD Activity Index (CECDAI) provide useful alternative instruments using video capsule endoscopy, but they need further validation. The Rutgeerts score predicts post-surgical recurrence but lacks evaluation for follow-up.

While recent guidelines emphasize co-primary clinical and endoscopic endpoints to improve trial effectiveness, these are typically based on expert consensus rather than empirical data. We advocate to use SES-CD as the preferred endoscopic index given its simplicity, strong correlation with CDEIS, and treatment responsiveness. Future research should focus on establishing clinically relevant cutoff values for endoscopic response and endoscopic remission in CD trials, including post-operative settings.

Background: Janus kinase-inhibitors (JAK-i) have recently been approved for treating patients with Ulcerative Colitis (UC); therefore, further information is needed, particularly regarding efficacy and safety. Objectives: To provide a comprehensive review regarding the efficacy and safety of currently available JAK-i in UC. Methods: The PubMed and Scopus databases were considered, searching for 'JAK', 'JAK-inhibitor', 'Janus Kinases', 'Tofacitinib', 'Filgotinib', 'Upadacitinib', individually or in combination with 'IBD', 'Ulcerative Colitis', 'safety', 'efficacy', 'study' and 'trial'. The search was focused on full-text papers published in English, with no publication date restrictions. Results: The efficacy and safety of JAK-i approved for treating patients with UC have been summarized. These included Tofacitinib, Filgotinib and Upadacitinib. Findings from both clinical trials and real-life studies in UC were reported, with particular regard to their efficacy in inducing clinical response and remission, steroid-free remission and endoscopic and histological healing. Overall, JAK-i proved to be effective and safe in selected subgroups of patients with UC. The rapid onset of action and the oral route of administration represent the most relevant characteristics of these drugs. Safety concerns using Tofacitinib in subgroups of patients (infections, hypercholesterolemia, venous thromboembolism and cardiovascular events) were initially raised. More recently, all JAK-i for UC showed an overall satisfactory safety profile. However, indication should be carefully given. Conclusions: The use of JAK-i UC is promising, although no predictive markers of response are currently available. Optimizing their use, as monotherapy or combined with other immunomodulators, may increase their efficacy in appropriately selected subgroups of patients with UC.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by growing incidence and prevalence around the world in the last few decades. The range of available existing treatment and strategies for its management is being implemented. Given the introduction of newly developed molecules and the lack of specific guidelines, drug positioning may represent a tough clinical challenge. UC management is mostly medical, and it has been shifting toward a more personalized approach with the aim to create a tailored strategy depending on the patient's profile. A treat-to target strategy seems to be the best approach to reach disease control as it allows to carry out therapeutic choices based on objective and specific parameters: histological, ultrasonographic, and molecular targets may add to the already used clinical, endoscopic, and biochemical targets. In addition, dual-targeted therapy has emerged as an attractive therapeutic strategy for patients not achieving remission. This review aims to provide an overview of the available strategies to raise the bar in UC.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic and often debilitating condition requiring complex and individualized management. Over the past few decades, advancements in understanding IBD pathophysiology have led to a transformative shift in therapeutic approaches. This article provides a comprehensive overview of the evolution of IBD treatments, from early symptom-focused therapies to modern biologics, small molecule agents, and emerging treatment strategies. We discuss therapeutic goals centered on achieving clinical remission, endoscopic/mucosal healing, and enhancing patient quality of life. Additionally, we explore the rationale for the early and personalized use of biologic therapies in moderate-to-severe cases, review the current FDA-approved agents as of 2024, and highlight the advantages and limitations of these treatments. Special attention is given to the evolving role of novel oral therapies, including Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators, and future new directions. This paper aims to guide clinicians in navigating the expanding therapeutic landscape of IBD, emphasizing patient-centered decision-making and addressing ongoing challenges in achieving optimal disease control.

: The genetic expression in the active inflammatory regions is increased in ulcerative colitis (UC) with endoscopic activity. The aim of this study was to investigate the molecular activity of inflammation and tissue remodeling markers in endoscopically inflamed and uninflamed regions of UC.

: Patients with UC (n=47) and controls (n=20) were prospectively enrolled at the Seoul National University Bundang Hospital. Inflamed tissue was obtained at the most active lesion, and uninflamed tissue was collected from approximately 15 cm above the upper end of the active lesion via colonoscopic biopsies. The messenger RNA expression levels of transforming growth factor β (TGF-β), interleukin (IL)-1β, IL-6, IL-17A, E-cadherin, olfactomedin-4 (OLFM4), leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), vimentin, fibroblast-specific protein-1 (FSP1), and α-smooth muscle actin (SMA) were evaluated. Mucosal healing (MH) was defined according to a Mayo endoscopic score of 0, 1 or non-MH (Mayo endoscopic score of 2 or 3).

: The messenger RNA expressions of TGF-β, IL-1β, OLFM4, FSP1, vimentin, and α-SMA were significantly higher, and that of E-cadherin was significantly lower in inflamed and uninflamed regions of patients with UC than those in controls. In the inflamed regions, patients in the non-MH group had significantly increased genetic expression of TGF-β, FSP1, vimentin, and α-SMA compared to patients in the MH group. Similarly, the non-MH group had significantly higher genetic expression of TGF-β, IL-1β, IL-6, vimentin, and α-SMA than the MH group in the uninflamed regions.

: Endoscopic activity in UC suggests inflammation and tissue remodeling of uninflamed regions similar to inflamed regions (ClinicalTrials.gov, NCT05653011).

Background and aim Tacrolimus (tac) is used for induction therapy in refractory and severe ulcerative colitis (UC) cases. The aim of this study was to identify the factors contributing to the induction of remission and to assess the endoscopic or histologic improvement rates following induction of remission by tac. Methods This study examined data from 67 UC patients treated with tac for induction of remission out of 515 patients attending Dokkyo Medical University Hospital. The primary endpoint of the study was the analysis of factors contributing to successful induction of remission treatment with tac. The secondary endpoints were the corticosteroid-free remission rate at 52 weeks after tac induction and the endoscopic and histologic improvement rates following induction of remission. Results Analysis of factors contributing to successful induction of remission by tac showed the Lichtiger index at the beginning of remission induction therapy was 9.5 ± 2.5 for the successful remission group and 11.5 ± 2.4 for the unsuccessful remission group (p = 0.002). The proportions of patients who had used immunomodulators were 13/45 (28.9%) for the successful remission group and 14/22 (63.6%) for the unsuccessful remission group (p = 0.006). The proportions of patients who had used anti-tumor necrosis factor (TNF)α biologics were 4/45 (8.9%) for the successful remission group and 8/22 (36.4%) for the unsuccessful remission group (p = 0.006). Conclusion Patients with UC who are potential candidates for intensification of remission maintenance therapy are good candidates for induction of remission with tac. Moreover, improvement in endoscopic inflammation might be a predictive marker of response to remission induction therapy with tac.

Inflammatory bowel disease (IBD) follows a heterogenous disease course and predicting a patient's prognosis is challenging. There is a wide burden of illness in IBD and existing tools measure disease activity at a snapshot in time. Comprehensive assessment of IBD severity should incorporate disease activity, prognosis, and the impacts of disease on a patient. This review investigates the concept of disease severity in adults with IBD to highlight key components contributing to this.

To perform this narrative review, a Medline search was conducted for full-text articles available at 1st March 2024 using search terms which encompassed disease activity assessment, disease severity, prognosis, natural history of Crohn's disease (CD) and ulcerative colitis (UC), and the burden of IBD.

Current methods of disease assessment in IBD have evolved from a focus on the burden of symptoms to one that includes inflammatory targets, genetic, serological, and proteomic profiles, and assessments of quality-of-life (QoL), disability, and psychosocial health. Longitudinal studies of IBD suggest that the burden of illness is driven by disease phenotype, clinical markers of complicated disease course (previous intestinal resection, corticosteroid use, perianal disease in CD, recent hospitalisations in UC), gut inflammation, and the impact of IBD on the patient.

Disease severity in IBD can be difficult to conceptualise due to the multitude of factors that contribute to IBD outcomes. Measurement of IBD severity may better encapsulate the full burden of illness rather than gut inflammation alone at a single timepoint and may be associated with longitudinal outcomes.

Ulcerative colitis (UC) is associated with epithelial metabolic derangements which exacerbate gut inflammation. Patient-derived organoids recapitulate complexities of the parent tissue in health and disease; however, whether colon organoids (colonoids) model metabolic impairments in the pediatric UC epithelium is unclear. This study determined the functional metabolic differences in the colon epithelia using epithelial colonoids from pediatric patients.

We developed biopsy-derived colonoids from pediatric patients with endoscopically active UC, inactive UC, and those without endoscopic or histologic evidence of colon inflammation (non-IBD controls). We extensively interrogated metabolic dysregulation through extracellular flux analyses and tested potential therapies that recapitulate or ameliorate such metabolic dysfunction.

Epithelial colonoids from active UC patients exhibit elevated oxygen consumption and proton leak supported by enhanced glycolytic capacity and dysregulated lipid metabolism. The hypermetabolic features in active UC colonoids were associated with increased cellular stress and chemokine secretion, specifically during differentiation. Transcriptomic and pathway analyses indicated a role for PPAR-α in lipid-induced hypermetabolism in active UC colonoids, which was validated by PPAR-α activation in non-IBD colonoids. Accordingly, limiting neutral lipid accumulation in active UC colonoids through pharmacological inhibition of PPAR-α induced a metabolic shift towards glucose consumption, suppressed hypermetabolism and chemokine secretion, and improved cellular stress markers. Control and inactive UC colonoids had similar metabolic and transcriptomic profiles.

Our pediatric colonoids revealed significant lipid-related metabolic dysregulation in the pediatric UC epithelium that may be alleviated by PPAR-α inhibition. This study supports the advancement of colonoids as a preclinical human model for testing epithelial-directed therapies against such metabolic dysfunction.

Background and Context: Colon mucosa healing in pediatric UC requires reinstating normal epithelial function but a lack of human preclinical models of the diseased epithelium hinders the development of epithelial-directed interventions.

Using colon biopsy-derived epithelial organoids, samples from pediatric patients with active UC show hyperactive metabolic function largely driven by enhanced lipid metabolism. Pharmacologic inhibition of lipid metabolism alleviates metabolic dysfunction, cellular stress, and chemokine production.

Though our epithelial colon organoids from active UC patients show targetable metabolic and molecular features from non-IBD controls, they were cultured under sterile conditions, which may not fully capture any potential real-time contributions of the complex inflammatory milieu typically present in the disease.

Current therapies for pediatric UC mainly target the immune system despite the need for epithelial healing to sustain remission. We identified a pharmacologic target that regulates epithelial metabolism and can be developed for epithelial-directed therapy in UC.Basic Research Relevance: Pediatric UC patient tissue adult stem cell-derived colon epithelial organoids retain disease-associated metabolic pathology and can serve as preclinical human models of disease. Excess reliance on lipids as an energy source leads to oxidative and inflammatory dysfunction in pediatric UC colon organoids. Preprint: This manuscript is currently on bioRxiv. doi: https://doi.org/10.1101/2024.08.22.609271 Lay Summary: Using patient tissue-derived colon epithelial organoids, the investigators identified epithelial metabolic dysfunction and inflammation in pediatric ulcerative colitis that can be alleviated by PPAR-a inhibition.

Aim: We have previously shown that CRP < 2.9 mg/L is a better predictor of endoscopic remission (ER) than CRP < 5 mg/L in ulcerative colitis (UC). Here, we prospectively evaluate CRP and FCP cut-offs and compare them in predicting ER and histological remission (HR) in UC. Method: One hundred thirty-five steroid-free UC patients were evaluated prospectively. ER was defined as Mayo endoscopic sub-score 0-1. In colonoscopy, the colon was evaluated as seven segments: rectum, sigmoid, descending, proximal-transverse, distal-transverse, ascending colon, and cecum. Two biopsies of each segment were evaluated for histological inflammation and graded using the Nancy and Geboes scores. All segment biopsies with Nancy < 1 and Geboes < 2 were defined as HR. Results: The optimum cut-off values for FCP and CRP were 120 μg/g and 2.75 mg/L for ER, respectively. AUC values of FCP and CRP were similar for ER and Mayo-0 disease in ROC analysis. CRP and FCP also had similar performances with these cut-offs regarding ER. While CRP was a predictor to assess the extensiveness of active UC, FCP was not. ROC analysis showed no difference between CRP and FCP regarding HR. Cut-off values for HR were 2.1 mg/L and 55 μg/g for CRP and FCP, respectively. CRP and FCP, in combination with the mentioned cut-off values, detected ER and HR in nearly 2/3 and ½ of the patients, respectively, with high specificity. Conclusions: Reappraised CRP (ER: 2.75 mg/L, HR: 2.1 mg/L) has as much diagnostic contribution as relevant FCP in predicting ER and HR and contributes more to revealing the proximal extension in active colitis compared to FCP. Relevant CRP and FCP combinations may improve the prediction rates.

Introduction: Acute severe ulcerative colitis (ASUC) represents a life-threatening medical emergency. One-third of ASUC patients are steroid non-responders. Our study aimed to create a new ASUC algorithm to predict corticosteroid response in the early course of the disease. Materials and Methods: A cross-sectional study included 103 patients with ASUC (65 male, 38 female). We calculated the serum CRP to 25-hydroxy 25 OH vitamin D ratio at admission. Logistic regression determined patients' response to glucocorticoids, depending on the CRP/25 OH vitamin D ratio value. Results and Discussion: Significant differences were observed in the CRP/25 OH vitamin D ratio at admission between glucocorticoid responders and non-responders (p = 0.001). A negative correlation was found between glucocorticoid response and CRP/25 OH vitamin D levels (Spearman's rho = -0.338, p < 0.01). Logistic regression revealed a significant association (p = 0.003) with a model chi-square value of 11.131 (p = 0.001). ROC curve analysis showed an AUC of 0.696 (p = 0.001), indicating moderate discriminatory ability. To achieve 91% sensitivity, the CRP/25 OH vitamin D ratio must be less than 3.985 to predict a complete glucocorticoid response. Conclusions: The serum CRP to 25 OH vitamin D ratio on the first day of hospital admission can potentially determine the response to glucocorticoids in patients with ASUC and significantly affect the mortality of these patients.

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.

The STRIDE consensus intends to complement the clinical endpoint with an endoscopic endpoint of mucosal healing and others as treatment targets in ulcerative colitis. If these targets are not reached, STRIDE requires dose or timing adjustments or switching the medication. This narrative review provides a critique of this concept.

We analyze and discuss the limitations of current endpoints as targets, their currently limited achievability, and the lacking evidence from controlled trials relating to 'treat to target.' The relevant publications in PubMed were identified in a literature review with the key word 'ulcerative colitis.'

In ulcerative colitis, the standard clinical target is measured traditionally by the MAYO-score, but in variable combinations of patient and physician reported outcomes as well as also different definitions of the endoscopic part. Only a score of 0 is more stringent than clinical remission but is only achieved by a minority of patients in first and even less in second line therapy. The concept is not based on clear evidence that patients indeed benefit from appropriate escalation of treatment. Until the STRIDE approach is proven to be superior to standard treatment focusing on clinical well-being, the field should remain reluctant.

Ustekinumab, a new anti-interleukin-12/23 antibody, is an effective treatment for ulcerative colitis; however, data regarding predictive factors of its efficacy are limited. Predicting treatment efficacy in advance would be useful for selecting a therapeutic agent. This study aimed to identify biomarkers that can predict the long-term outcome of ustekinumab treatment.

We retrospectively reviewed the records of patients with active ulcerative colitis treated with ustekinumab at Osaka Medical and Pharmaceutical University Hospital from June 2020 to January 2023. We divided patients into non-remission and remission groups, and examined whether baseline biomarkers, including C-reactive protein-to-lymphocyte ratio, and early treatment response could predict clinical remission at week 48 of ustekinumab treatment.

Of the 33 patients included in the study, 21 (63.6%) were in clinical remission at week 48 of ustekinumab treatment. Baseline C-reactive protein-to-lymphocyte ratio values were significantly higher in the non-remission than in the remission group. The baseline C-reactive protein-to-lymphocyte ratio value was identified as an independent prognostic factor for clinical remission at week 48 (odds ratio: 10, 95% confidence interval: 1.6-62.4, p = 0.014), with the cutoff value of 3.353 showing excellent prognostic performance (sensitivity: 71.4%, specificity: 83.3%). Furthermore, the clinical response at week 4 (odds ratio: 10, confidence interval: 1.78-56.1, p = 0.009) and that at week 8 (odds ratio: 12, confidence interval: 2.16-66.5, p = 0.005) were significantly associated with clinical remission at week 48.

The baseline C-reactive protein-to-lymphocyte ratio value and early treatment response are useful biomarkers to predict the long-term efficacy of ustekinumab treatment.

Though colonoscopy plays a crucial role in assessing active ulcerative colitis [aUC], its scope is limited to the mucosal surface. Endoscopic ultrasound [EUS] coupled with contrast-enhancement [dCEUS] can precisely quantify bowel wall thickness and microvascular circulation, potentially enabling the quantitative evaluation of inflammation. We conducted a prospective, longitudinal study to assess therapy response using dCEUS in aUC patients undergoing treatment with adalimumab [ADA] or infliximab [IFX].

Thirty ADA- and 15 IFX-treated aUC patients were examined at baseline and at 2, 6, and 14 weeks of therapy and 48 weeks of follow-up. Bowel wall thickness [BWT] was measured by EUS in the rectum. Vascularity was quantified by dCEUS using rise time [RT] and time to peak [TTP]. Therapy response was defined after 14 weeks using the Mayo Score.

Patients with aUC displayed a mean BWT of 3.9 ± 0.9 mm. In case of response to ADA/IFX a significant reduction in BWT was observed after 2 weeks [p = 0.04], whereas non-responders displayed no significant changes. The TTP was notably accelerated at baseline and significantly normalized by week 2 in responders [p = 0.001], while non-responders exhibited no significant alterations [p = 0.9]. At week 2, the endoscopic Mayo score did not exhibit any changes, thus failing to predict treatment responses.

dCEUS enables the early detection of therapy response in patients with aUC, which serves as a predictive marker for long-term clinical success. Therefore, dCEUS serves as a diagnostic tool for assessing the probability of future therapy success.

The development of noninvasive markers to assess mucosal healing in ulcerative colitis (UC) is essential in the treat-to-target era. The aim of this study was to evaluate the performance of intestinal ultrasound (IUS), fecal calprotectin (FC), and their combination to assess mucosal healing in UC patients.

All consecutive patients between January 2021 and September 2022 with UC who underwent a complete colonoscopy and IUS and/or an FC test within 4 weeks were included in a prospective cohort. Bowel wall thickness (BWT) and the color Doppler signal (CDS) were assessed for each segment. Endoscopic mucosal healing was defined by a Mayo score of 0 to 1.

A total of 61 patients were included, of whom 79% showed endoscopic healing (26 Mayo 0 and 11 Mayo 1). Among the patients, 16 (27.6%) of 58 had a BWT <3 mm, and 41 (70.7%) of 58 had no CDS. The sensitivity, specificity, positive predictive value, and negative predictive value of a BWT <3 mm to predict endoscopic mucosal healing were 37%, 77%, 72%, and 44%, respectively. The association of FC <150 µg/g, a BWT <3 mm, and a CDS = 0 increased the specificity and positive predictive value (sensitivity 33%, specificity 94%, positive predictive value 89%, negative predictive value 48%). The combination of a normal IUS, no rectal bleeding, and an FC <172 µg/g identified all patients with mucosal healing.

The combination of IUS and FC is effective in identifying mucosal healing in UC. Noninvasive evaluation of mucosal healing is possible for most UC patients.

The severe course of inflammatory bowel diseases (IBDs) refractory to advanced therapies in children results in the search for new therapeutic methods. The aim of this study was to evaluate the efficacy and safety of dual therapy with biologics in a cohort of children with IBD.

Retrospective analysis of data from 29 children with a diagnosis of IBD, 19 with ulcerative colitis (66%), 10 with Crohn's disease (CD) (34%) qualified for dual biological therapy (DBT). The median age of patients was five (interquartile range [IQR], 1-15) years at diagnosis of IBD and 14 (IQR, 3-17) years at eligibility for dual therapy. Thirteen (45%) patients were treated with vedolizumab/adalimumab (VDZ + ADA), 13 (45%) with ustekinumab/adalimumab (UST + ADA), three (10%) with infliximab/vedolizumab (IFX + VDZ).

Clinical remission was achieved in 13 (45%; seven UC and six CD) and 12 (41%; seven UC and five CD) Pediatric Weighted Crohn's Disease Activity Index (wPCDAI)/Pediatric Ulcerative Colitis Activity Index (PUCAI) patients after 4 and 12 months at the initiation of dual therapy. Clinical response based on wPCDAI/PUCAI was reported in 16 (55%; nine UC and seven CD) and 12 (41% seven UC and five CD) children after 4 and 12 months of follow-up, respectively. The median fecal calprotectin decreased significantly from 1240 µg/g (53-10,100) to 160 µg/g (5-2500; p = 0.004) between baseline and Month 4 and from 749 at baseline (57-10,100) to 17 (5-3110; p = 0.12) over 12 months. Moreover, 34% (six UC and four CD) of patients achieved endoscopic remission.

DBT seems to be an effective alternative therapeutic option for patients with moderate and severe IBD.

Endoscopic healing (EH) is a therapeutic target in ulcerative colitis (UC). However, even patients who have achieved EH relapse frequently.

To investigate the association between recent steroid use and relapse risk in UC patients with EH.

This multi-centre cohort study included 1212 UC patients with confirmed EH (Mayo endoscopic subscore ≤1). We excluded patients with current systemic steroid use or history of advanced therapy. We divided patients into a recent steroid group (last systemic steroid use within 1 year; n = 59) and a non-recent or steroid-naïve group (n = 1153). We followed the patients for 2 years to evaluate relapse, defined as induction of systemic steroids or advanced therapy. We used logistic regression to estimate the odds ratio (OR) of relapse.

Relapse occurred in 28.8% of the recent steroid group and 5.6% of the non-recent/steroid-naïve group (multi-variable-adjusted OR 5.53 [95% CI 2.85-10.7]). The risk of relapse decreased with time since the last steroid use: 28.8% for less than 1 year after steroid therapy, 22.9% for 1 year, 16.0% for 2 years and 7.9% beyond 3 years, approaching 4.0% in steroid-naïve patients. (ptrend <0.001).

Even for patients with UC who achieved EH, the risk of relapse remains high following recent steroid therapy. Physicians need to consider the duration since last steroid use to stratify the relapse risk in UC patients with EH.

Managing inflammatory bowel disease (IBD) is becoming increasingly complex and personalized, considering the advent of new advanced therapies with distinct mechanisms of action. Achieving mucosal healing (MH) is a pivotal therapeutic goal in IBD management and can prevent IBD progression and reduce flares, hospitalization, surgery, intestinal damage, and colorectal cancer. Employing proactive disease and therapy assessment is essential to achieve better control of intestinal inflammation, even if subclinical, to alter the natural course of IBD. Periodic monitoring of fecal calprotectin (FC) levels and interval endoscopic evaluations are cornerstones for evaluating response/remission to advanced therapies targeting IBD, assessing MH, and detecting subclinical recurrence. Here, we comment on the article by Ishida et al Moreover, this editorial aimed to review the role of FC and endoscopic scores in predicting MH in patients with IBD. Furthermore, we intend to present some evidence on the role of these markers in future targets, such as histological and transmural healing. Additional prospective multicenter studies with a stricter MH criterion, standardized endoscopic and histopathological analyses, and virtual chromoscopy, potentially including artificial intelligence and other biomarkers, are desired.

Biological therapies have become the standard treatment for ulcerative colitis (UC). However, clinical remission rates post-induction therapy remain modest at 40-50%, with many initial responders losing response over time. Current treatment strategies frequently rely on a 'trial and error' approach, leading to prolonged periods of ineffective and costly therapies for patients, accompanied by associated treatment complications.

This review discusses current evidence on risk stratification tools for predicting therapeutic efficacy and minimizing adverse events in UC management. Recent studies have identified predictive factors for biologic therapy response. In the context of personalized medicine, the goal is to identify patients at high risk of progression and complications, as well as those likely to respond to specific therapies. Essential risk stratification tools include clinical decision-making aids, biomarkers, genomics, multi-omics factors, endoscopic, imaging, and histological assessments.

Employing risk stratification tools to predict therapeutic response and prevent treatment-related complications is essential for precision medicine in the biological management of UC. These tools are necessary to select the most suitable treatment for each individual patient, thereby enhancing efficacy and safety.