Histologic mucosal healing (HMH) has emerged as a crucial target in managing inflammatory bowel disease, complementing the established goal of endoscopic mucosal healing. This review evaluates the significance of HMH in both Crohn's disease (CD) and ulcerative colitis (UC). In UC, strong evidence shows that HMH correlates with improved long-term outcomes, including reduced hospitalization rates, and decreased need for corticosteroids and colectomy. Histologic healing is increasingly being incorporated as an endpoint in RCTs. Small-molecule therapies, such as S1P modulators and Jak inhibitors, have demonstrated particular efficacy in achieving HMH in UC. Real-world evidence (RWE) further supports HMH's utility as a predictive marker for favorable clinical outcomes in UC. In CD, however, HMH's role is less clear, given challenges in assessing and standardizing histologic healing. RCTs, such as SERENITY and VIVID, show that advanced therapies can achieve HMH in CD, though inconsistent histologic scoring and remission criteria complicate conclusions. Some studies suggest that histologic remission at induction may predict sustained remission, but real-world data offer mixed results regarding its prognostic value. This review provides an overview of current literature, emphasizing the need for standardized histologic assessment and extended studies, particularly for CD, while affirming HMH's growing importance in achieving deeper remission in UC.

Ulcerative colitis (UC) is a chronic relapsing disease with significant associated risks such as colectomy, hospitalization, or colorectal cancer. A treat-to-target approach that mitigates disease activity and progression from an early stage is needed. The latest STRIDE II guidelines advocate for clinical and endoscopic remission as the main therapeutic targets in the management of UC; however, histological remission is increasingly being recognized as an important outcome. The concept of disease clearance, a composite outcome comprising clinical, endoscopic, and histological remission, has been proposed as a potential target for patients with UC and has been precisely defined by the International Organization for the Study of Inflammatory Bowel Disease, with the aim of standardizing its use in clinical practice and research. Despite challenges, including variable standardized definitions and uncertainties regarding the timing of reaching different definitions of remission, disease clearance corresponds to comprehensive disease control, and its use as an outcome could help clinicians to better evaluate the actual status of the disease. Furthermore, achieving disease clearance may be related to an improved disease course, positive long-term outcomes, and an improvement in health-related quality of life. Real-world evidence supports the feasibility of achieving disease clearance with various treatment modalities, including vedolizumab, the only gut-selective antilymphocyte trafficking drug. The aim of this narrative review is to explore the concept of disease clearance in patients with disease clearance, mainly focusing on trials evaluating vedolizumab but also other biologics.

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory conditions requiring continuous monitoring. Today, endoscopy is the gold standard for assessing disease activity, with histological evaluation providing additional insights. Studies suggest that persistent histological inflammation, despite endoscopic remission, may be associated with a higher risk of relapse in UC, suggesting its role in treatment decisions. In CD, histological assessment is limited by its patchy nature, transmural inflammation and lack of validated scoring systems. Few retrospective studies with conflicting results have examined the prognostic value of histological remission in CD, and its role in predicting long-term outcomes remains unclear. This narrative review aims to summarize and discuss the available evidence regarding the additional value of histological assessment in IBD management. In UC, the ongoing VERDICT study is expected to provide evidence on the impact of incorporating histological remission as a treatment target compared to a strategy based on clinical and endoscopic activity. Recently published interim results indicate that targeting histological remission does not lead to better clinical/biochemical disease activity. Thus, while patients achieving histological healing are associated with better outcomes, the question arises whether achieving histological remission is an intrinsic (biological) characteristic of the patient and indicator of an easier to treat patient group or a result of more effective therapy.

In recent years, we have seen a considerable increase in the number of patients with inflammatory bowel diseases of unknown etiology, including both Crohn's disease and ulcerative colitis. Inflammatory bowel diseases can cause intestinal lesions throughout the gastrointestinal tract, necessitating gastrointestinal endoscopy for examining all relevant aspects, especially lesion characteristics, for differential diagnosis and histological diagnosis, to select the appropriate treatment options, determine treatment effectiveness, etc. Specific guidelines are necessary to ensure that endoscopy can be performed in a safe and more tailored and efficient manner, especially since gastrointestinal endoscopy, including enteroscopy, is a common procedure worldwide, including in Japan. Within this context, the Japan Gastroenterological Endoscopy Society has formulated the "Guidelines for the Endoscopic Diagnosis and Treatment of Inflammatory Bowel Diseases" to provide detailed guidelines regarding esophagogastroduodenoscopy, enteroscopy, and colonoscopy procedures for definitive diagnosis, as well as determination of treatment effectiveness in clinical cases of inflammatory bowel diseases.

Inflammatory bowel diseases (IBDs), comprising Crohn's disease (CD) and ulcerative colitis (UC), are chronic immune-mediated inflammatory diseases of the gastrointestinal (GI) tract with still-elusive etiopathogeneses and an increasing prevalence worldwide. Despite the growing availability of more advanced therapies in the last two decades, there are still a number of unmet needs. For example, the achievement of mucosal healing has been widely demonstrated as a prognostic marker for better outcomes and a reduced risk of dysplasia and cancer; however, the accuracy of endoscopy is crucial for both this aim and the precise and reproducible evaluation of endoscopic activity and the detection of dysplasia. Artificial intelligence (AI) has drastically altered the field of GI studies and is being extensively applied to medical imaging. The utilization of deep learning and pattern recognition can help the operator optimize image classification and lesion segmentation, detect early mucosal abnormalities, and eventually reveal and uncover novel biomarkers with biologic and prognostic value. The role of AI in endoscopy-and potentially also in histology and imaging in the context of IBD-is still at its initial stages but shows promising characteristics that could lead to a better understanding of the complexity and heterogeneity of IBDs, with potential improvements in patient care and outcomes. The initial experience with AI in IBDs has shown its potential value in the differentiation of UC and CD when there is no ileal involvement, reducing the significant amount of time it takes to review videos of capsule endoscopy and improving the inter- and intra-observer variability in endoscopy reports and scoring. In addition, these initial experiences revealed the ability to predict the histologic score index and the presence of dysplasia. Thus, the purpose of this review was to summarize recent advances regarding the application of AI in IBD endoscopy as there is, indeed, increasing evidence suggesting that the integration of AI-based clinical tools will play a crucial role in paving the road to precision medicine in IBDs.

Inflammatory bowel diseases with the 2 main forms - ulcerative colitis and Crohn's disease - are chronic relapsing diseases of the gastrointestinal tract in which dysregulation of the intestinal immune system against commensal components of the microbiome leads to perpetuated intestinal inflammation based on a genetic predisposition. While in the past symptom control was the focus of therapy, more recent data show that achieving endoscopic remission is superior to sole clinical symptom control for the further course and prognosis of the diseases. In this review article, we will present the significance of endoscopy for inflammatory bowel diseases, describe established scoring systems for endoscopic graduation of inflammatory activity and, last but not least, also present and review new endoscopic developments.

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.

Growing evidence suggests histologic healing (HH) improves clinical outcomes in ulcerative colitis (UC) patients beyond endoscopic healing (EH). We hypothesize that HH is associated with better clinical outcomes in Asian UC patients, for whom data is lacking.

We performed a retrospective study of UC patients in clinical remission (CR) with a follow-up colonoscopy and minimum 1-year follow-up post-colonoscopy. Primary outcome was clinical relapse (CRL), defined as either a Simple Clinical Colitis Activity Index score of > 2, medication escalation, hospitalization or colectomy. Predictors of CRL and HH were assessed.

One hundred patients were included with a median follow-up of 22 months. At index colonoscopy, 80 patients were in EH. On follow-up, 41 patients experienced CRL. Of 80 patients in EH, 34 (42.5%) had persistent histologic activity (Nancy Index ≥ 2) and 29 (36.3%) relapsed during the follow-up period. Amongst patients in CR and EH, those with HH had lower CRL rate (26.1% vs. 50.0%, P= 0.028) and longer CRL-free survival (mean 46.1 months vs. 31.5 months, P= 0.015) than those with persistent histologic activity. On bivariable analysis of 100 patients in CR, HH, and Mayo endoscopic score (MES) of 0 were significantly associated with lower risk of CRL. On multivariable analysis, only MES 0 remained predictive of lower CRL risk.

Above and beyond CR and EH, achieving HH improves clinical outcomes in Asian UC patients. However, HH may not confer incremental benefit if MES 0 has been achieved. Further prospective studies evaluating the benefit of histologically guided therapeutic decisions are needed.

Targeted immunomodulators (eg, advanced therapies) effectively achieve symptomatic remission in patients with inflammatory bowel disease (IBD). However, ~25%-50% of patients with IBD achieving symptomatic remission with an advanced therapy may have continued endoscopically/radiologically active bowel inflammation, and it is uncertain whether changing alternative advanced therapies in asymptomatic patients with IBD will reduce bowel inflammation and achieve durable deep remission.

The QUality Outcomes Treating IBD to Target (QUOTIENT) study is an open-label, multicentre, pragmatic, randomised, controlled trial that aims to compare the efficacy and safety of switching to an alternative advanced therapy targeting endoscopic/radiological remission (treat-to-target) versus continuing the initial, or index, advanced therapy, in asymptomatic patients with IBD with moderate-to-severe endoscopic/radiological bowel inflammation. Enrolment is planned for ~250 participants in Canada/USA, randomised 1:1 to switching to alternative advanced therapy or continuing index advanced therapy, and then followed 104 weeks within routine clinical practice. Patient-reported outcomes measure efficacy and quality of life/treatment burden/safety. Primary endpoint is the time from randomisation to treatment failure.

The study is conducted in compliance with the protocol, ICH Good Clinical Practice, applicable regulatory requirements and appropriate review boards/independent ethics committees (approval numbers: Pro00077486; Pro00061437; STUDY00002062; 22-004171; i22-01269; IRB22-0890; IRB_00154397; 2000032384; SHIRB#2022.095-2; STUDY00007146; MMC#2024-18; REB#125290; 17784; Pro00142214; 20240660-01H), with documented written informed consent. Findings will be disseminated through peer-reviewed journals, scientific presentations, and publicly available Patient-Centered Outcomes Research Institute (PCORI) websites, including lay summaries. The Crohn's & Colitis Foundation Education, Support, and Advocacy Department, and our patient advocacy stakeholder, will develop educational and marketing resources to communicate findings to a broad audience (>250 000 patients/caregivers/healthcare professionals).

NCT05230173.

Integrating artificial intelligence (AI) into histologic disease assessment is transforming the management of inflammatory bowel disease (IBD). AI-aided histology enables precise, objective evaluations of disease activity by analysing whole-slide images, facilitating accurate predictions of histologic remission (HR) in ulcerative colitis and Crohn's disease. Additionally, AI shows promise in predicting adverse outcomes and therapeutic responses, making it a promising tool for clinical practice and clinical trials. By leveraging advanced algorithms, AI enhances diagnostic accuracy, reduces assessment variability and streamlines histological workflows in clinical settings. In clinical trials, AI aids in assessing histological endpoints, enabling real-time analysis, standardising evaluations and supporting adaptive trial designs. Recent advancements are further refining AI-aided digital pathology in IBD. New developments in multimodal AI models integrating clinical, endoscopic, histologic and molecular data pave the way for a comprehensive approach to precision medicine in IBD. Automated assessment of intestinal barrier healing - a deeper level of healing beyond endoscopic and HR - shows promise for improved outcome prediction and patient management. Preliminary evidence also suggests that AI applied to colitis-associated neoplasia can aid in the detection, characterisation and molecular profiling of lesions, holding potential for enhanced dysplasia management and organ-sparing approaches. Although challenges remain in standardisation, validation through randomised controlled trials and ethical considerations. AI is poised to revolutionise IBD management by advancing towards a more personalised and efficient care model, while the path to full clinical implementation may be lengthy. However, the transformative impact of AI on IBD care is already shining through.

Inflammatory bowel disease is marked by significant clinical heterogeneity, posing challenges for accurate diagnosis and personalized treatment strategies. Conventional approaches, such as endoscopy and histology, often fail to adequately and accurately predict medium- and long-term outcomes, leading to suboptimal patient management. Artificial intelligence is emerging as a transformative force enabling standardized, accurate, and timely disease assessment and outcome prediction, including therapeutic response. Artificial intelligence-driven intestinal barrier healing assessment provides novel insights into deep healing, facilitating the discovery of novel therapeutic targets. In addition, the automated integration of multi-omics data can enhance patient profiling and personalized management strategies. The future of inflammatory bowel disease care lies in the artificial intelligence-enabled "endo-histo-omics" integrative real-time approach, harmoniously fusing endoscopic, histologic, and molecular data. Despite challenges in its adoption, this paradigm shift has the potential to refine risk stratification, improve therapeutic precision, and enable personalized interventions, ultimately advancing the implementation of precision medicine in routine clinical practice.

Vedolizumab (VDZ) is a humanized, gut-selective biologic used in the treatment of ulcerative colitis (UC). However, data on predictive factors for treatment response are limited. This study aims to develop a nomogram to predict VDZ treatment responsiveness in UC. We retrospectively collected clinical data from patients with moderate-to-severe active UC who received VDZ induction therapy at Chongqing General Hospital from December 2020 to March 2024. Full-slide images of colon biopsies from UC patients prior to VDZ treatment were analyzed to quantify mean mucosal eosinophil density (MMED). Based on clinical response 14-week post-treatment, patients were categorized into responsive and non-responsive groups. In total, 84 UC patients were analyzed, with 58 responding to VDZ treatment and 26 not responding. Significant differences were observed in pathological indices, with MMED showing a statistically significant difference between the groups (p < 0.001). Serum biomarkers, including C-reactive protein (CRP), also showed a significant difference (P = 0.015), as did the CRP/albumin (CRP/ALB) ratio (P = 0.018). Additionally, UCEIS scores differed significantly between the groups (P = 0.025). Independent risk factors identified through multivariate logistic regression analysis were used to establish a predictive model, presented as a nomogram. The area under the curve (AUC) for the combined MMED and CRP predictive model was 0.867 (95% CI: 0.781-0.953, p < 0.001), indicating high accuracy in predicting VDZ efficacy. These data are easily accessible even in primary healthcare settings, allowing our predictive model to support improved treatment decisions for patients.

Tamuzimod (VTX002) is a selective sphingosine 1-phosphate receptor 1 modulator in development for ulcerative colitis. We aimed to assess the safety and efficacy of tamuzimod in patients with moderately-to-severely active ulcerative colitis.

This double-blind, randomised, placebo-controlled, phase 2 induction trial was conducted at 122 centres across 15 countries in Asia, Europe, and North America. Patients aged 18-80 years with a modified Mayo score (MMS) of 4-9 and an inadequate response or a loss of response, or intolerance to one or more approved ulcerative colitis therapies were randomly assigned (1:1:1) to once-daily oral tamuzimod (60 mg or 30 mg) or placebo for 13 weeks. Randomisation was stratified by previous advanced therapy, baseline corticosteroid, and baseline MMS. The primary endpoint was clinical remission (defined as an MMS stool frequency subscore of ≤1, rectal bleeding subscore of 0, and endoscopic subscore ≤1, excluding friability) at week 13. Adverse events and laboratory abnormalities were assessed for safety. Efficacy and safety analyses included all randomly assigned patients who received at least one study dose, with the efficacy analysis restricted to patients with a baseline MMS of 5-9 based on regulatory feedback. The study was registered with ClinicalTrials.gov, NCT05156125, and EudraCT, 2021-003050-23.

Between Nov 4, 2021, and Aug 30, 2023, 367 patients were screened, and 213 (mean age 40·6 years [SD 14·2]; 116 [54%] males and 97 [46%] females) were randomly assigned to tamuzimod 60 mg (n=70), tamuzimod 30 mg (n=73), or placebo (n=70). Two in the tamuzimod 30 mg group and two in the tamuzimod 60 mg group with baseline modified Mayo score of 4 were excluded from the efficacy analysis. At week 13, clinical remission was reached by 19 (28%) of 68 patients receiving tamuzimod 60 mg, 17 (24%) of 71 patients receiving tamuzimod 30 mg, and eight (11%) of 70 patients receiving placebo (risk difference 16·5% [95% CI 3·2 to 29·4], p=0·018, for tamuzimod 60 mg vs placebo and 12·5% [-0·2 to 24·9], p=0·041, for tamuzimod 30 mg vs placebo). Treatment-emergent adverse events occurred in 33 (47%) of 70 patients receiving tamuzimod 60 mg, 34 (47%) of 73 patients receiving tamuzimod 30 mg, and 24 (34%) of 70 patients receiving placebo. Most adverse events were mild or moderate. The most frequently reported treatment-emergent adverse events (in ≥5% of in any treatment group) were upper respiratory tract infection (six [9%] of 70 patients in the tamuzimod 60 mg group, one [1%] of 73 in the tamuzimod 30 mg group, and one [1%] of 70 in the placebo group), anaemia (three [3%], four [5%], and six [9%]), and headache (four [6%], five [7%], and two [3%]). No adverse events of atrioventricular block, bradycardia, macular oedema, severe or opportunistic infections, malignancies, or deaths occurred.

Induction therapy with tamuzimod was effective and well tolerated in patients with ulcerative colitis. These results and the favourable risk-benefit profile of tamuzimod collectively support the continued clinical development of tamuzimod for the treatment of moderately-to-severely active ulcerative colitis.

Ventyx Biosciences.

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.

Disulfidptosis and ferroptosis are different programmed cell death modes, which are closely related to the development of a variety of diseases, but the relationship between them and ulcerative colitis (UC) is still unclear. Therefore, our study aimed to explore the molecular subtypes and biomarkers associated with disulfidptosis-related ferroptosis (DRF) in UC.

We used Pearson analysis to identify DRF genes. Then, we classified 140 UC samples into different subtypes based on the DRF genes and explored the biological and clinical characteristics between them. Next, the hub genes were identified by differential analysis and WGCNA algorithms, and three machine learning algorithms were used to screen biomarkers for UC from hub genes. In addition, we analyzed the relationship between biomarkers of immune cells and transcription factors and predicted natural compounds that might be used to treat UC. Finally, we further verified the reliability of the markers by RT-qPCR experiments.

118 DRF genes were identified using Pearson analysis. Based on the expression level of the DRF genes, we classified UC patients into C1 and C2 subtypes, with significant differences in the abundance of immune infiltration and disease activity between the two subtypes. The machine learning algorithms identified three biomarkers, including XBP1, FH, and MAP3K5. Further analyses revealed that the three biomarkers were closely associated with a variety of immune cells and transcription factors. In addition, six natural compounds corresponding to the biomarkers were predicted, which may contribute to the effective treatment of UC. Finally, the expression trends of XBP1, FH, and MAP3K5 in animal experiments were consistent with the results of bioinformatics analysis.

In this study, we systematically elucidated the role of DRF genes in the development of UC, and identified three potential biomarkers, providing a new idea for the diagnosis and treatment of UC.

Clinical, endoscopic, histological, and composite instruments are currently used to measure disease activity in patients with ulcerative colitis (UC). We compared the responsiveness of the Mayo Clinic score (MCS), modified MCS (mMS; excluding physician global assessment), partial MCS (pMS; MCS without endoscopic subscore), Robart's Histopathology Index (RHI), and UC-100 score to change after ustekinumab treatment in patients with moderately to severely active UC.

Post hoc analysis of the phase 3 UNIFI induction trial (ClinicalTrials.gov: NCT02407236) was conducted. Participants with moderately to severely active UC were randomized to receive ustekinumab or placebo. Treatment assignment was the criterion to assess responsiveness, which was quantified using the probability of a treated participant having a larger change in score than a placebo participant, termed the win probability (WinP), and estimated using nonparametric methods.

The UC-100 score demonstrated large responsiveness (WinP 0.72 [95% confidence interval: 0.66-0.78]), and the MCS (0.68 [0.62-0.73]), mMS (0.69 [0.63-0.75]), and pMS (0.65 [0.59-0.71]) demonstrated similar effect sizes. Of the component items of the Mayo score, the endoscopic subscore (WinP 0.76 [0.69-0.82]) and the stool frequency subscore (WinP 0.74 [0.69-0.79]) were the most responsive. The Inflammatory Bowel Disease Questionnaire (IBDQ) quality-of-life questionnaire was also responsive (WinP 0.78 [0.72-0.82]).

UC disease activity indices are similarly responsive. Depending on the treatment setting, time point of evaluation, and feasibility of measurement, different scores may be used to demonstrate response. These results support the use of mMS as a composite primary endpoint, incorporating both patient-reported and endoscopic outcome measures. The UC-100 score may be more appropriate in settings that also routinely incorporate histological evaluation.

There is no funding for this study.

TongXieYaoFang (TXYF), a classical formula used in Traditional Chinese Medicine, is renowned for its efficacy in treating chronic abdominal pain and diarrhoea. Modern research suggests that fundamental relief from these symptoms depends on complete intestinal mucosal healing, which normalises gut secretory functions. Consensus between traditional and modern medical theories indicates that TXYF is particularly suitable for treating the remission phase of ulcerative colitis (UC). Unfortunately, its potential in the remission phase has not received sufficient attention, and its use has been largely limited to a supportive role during the acute phase.

This study aimed to elucidate the efficacy of TXYF in promoting intestinal mucosal healing and enhancing gut secretory function during the non-acute damage phase, as well as to identify the underlying mechanisms contributing to its effects.

A mouse model of dextran sulphate sodium salt (DSS)-induced colitis was optimised to specifically evaluate the effects of TXYF on mucosal healing during the repair phase. The effects of TXYF on murine colon function were assessed by measuring faecal pellet count and water content, and further evaluated through immunohistochemical analyses. The underlying mechanisms of action of TXYF were elucidated using mouse intestinal organoid cultures, intestinal stem cell (ISCs) transplantation, immunofluorescence, and western blotting. Active components of TXYF were identified via LC-MS/MS analysis and integrated with network pharmacology for bioinformatics assessment.

TXYF significantly promoted mucosal healing, as reflected by reduced disease activity scores, increased colon length, enhanced epithelial proliferation, and decreased histological damage. Furthermore, TXYF enhanced the recovery of critical intestinal functions, including barrier integrity, absorption, secretion, and motility. Notably, the improvement in the secretory function was particularly pronounced. Mechanistically, these therapeutic effects were mediated by the upregulation of the Atonal homolog 1/SAM pointed domain containing ETS transcription factor/Mucin 2 pathway, which facilitates the differentiation and maturation of ISCs into goblet cells, thereby contributing to both mucosal repair and enhanced secretory function.

Our study demonstrated that TXYF significantly promotes intestinal mucosal healing and enhances secretory function. These findings offer a solid basis for exploring the potential applications of TXYF in UC management during the remission phase.

Growing interest exists in deep remission, beyond clinical and endoscopic remission, to enhance long-term prognosis in patients with ulcerative colitis (UC). Our study aimed to evaluate the risk of relapse according to tissue expression levels of calprotectin and neutrophil elastase (NE) in patients with quiescent UC.

Rectal biopsies were performed on 218 patients with UC in clinical and endoscopic remission. Histological activity was prospectively scored using the Robarts Histological Index. Tissue calprotectin and NE levels were evaluated using immunohistochemistry. Optimal tissue calprotectin and NE cutoffs for relapse were determined using log-rank analysis. Cox proportional hazard analyses evaluated relapse risk factors.

Tissue calprotectin and NE levels were significantly higher in patients with histological activity than in those in histological remission (P < .001). The optimal cutoffs of tissue calprotectin and NE for relapse were 10.61 and 22.08 per mm2, respectively. The 3-year clinical relapse risk was significantly lower in the low-tissue NE group than in the high-tissue NE group (P = .009); however, it did not differ between the low- and high-tissue calprotectin group (P = .094). In multivariate analyses, a low level of tissue NE expression was independently associated with a lower risk of 3-year clinical relapse (adjusted hazard ratio = 0.453, 95% confidence interval = 0.225-0.911, P = .026), unlike histological index and tissue calprotectin.

In patients with UC who have achieved clinical and endoscopic remission, tissue expression of NE is a better predictor of long-term relapse than histological activity.

Cross-sectional imaging techniques, including intestinal ultrasonography (IUS), computed tomography enterography (CTE), magnetic resonance enterography (MRE), are increasingly used for the evaluation of inflammatory bowel diseases (IBD). We aimed to systematically review literature evidence on the assessment of disease activity, and/or severity through cross-sectional imaging in IBD patients, and to offer guidance on their most effective utilization.

We performed a systematic review of PubMed, EMBASE, and Scopus to identify citations pertaining to the assessment of disease activity and/or severity at cross-sectional imaging techniques compared to a reference standard (ie, other radiological techniques, endoscopy, histopathology, and surgery) in IBD patients published until December 2023.

Overall, 179 papers published between 1990 and 2023 were included, with a total of 10 988 IBD patients (9304 Crohn's disease [84.7%], 1206 ulcerative colitis [11.0%], 38 IBD-U [0.3%], 440 unspecified [4.0%]). Of the 179 studies, 39 investigated IUS, 22/179 CTE, and 101/179 MRE. In the remaining papers, 2 techniques were addressed together. In 81.6% of the papers, endoscopy (with or without histopathology) was used as a reference standard. All studies included evaluated disease activity, while just over half (100/179, 55.8%) also evaluated disease severity of the addressed cross-sectional methodology. Pooled sensitivity, specificity, and overall accuracy of IUS, MRE, and CTE compared to the reference standard were 60%-99%, 60%-100%, and 70%-99%, respectively.

All cross-sectional imaging techniques demonstrated moderate-to-good accuracy in assessing disease activity and severity of IBD. This finding highlights the potential, especially for MRE and IUS to be widely utilized in managing IBD in both clinical practice and clinical trials.

Histologic remission, a potentially important treatment target in ulcerative colitis (UC), is associated with favorable long-term outcomes. Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active UC. This post-hoc analysis of the ELEVATE UC program evaluated the efficacy of etrasimod according to histologic and composite (histologic/endoscopic/symptomatic) endpoints and examined their prognostic value.

Patients with moderately to severely active UC were randomized 2:1 to once-daily oral etrasimod 2 mg or placebo. Histologic and composite endpoints, including disease clearance (endoscopic/histologic/symptomatic remission), were assessed at Weeks 12 (ELEVATE UC 52; ELEVATE UC 12) and 52 (ELEVATE UC 52). Logistic regressions examined associations between baseline and Week 12 histologic/composite endpoints and Week 52 outcomes.

At Weeks 12 and 52, significant improvements with etrasimod vs placebo were observed in histologic/composite outcomes, including endoscopic improvement-histologic remission and disease clearance. The proportion of patients treated with etrasimod achieving clinical remission at Week 52 was higher among those with disease clearance at Week 12 vs those without disease clearance (73.9% [17/23] vs 28.3% [71/251]). Histologic improvement and endoscopic improvement at Week 12 were moderately and strongly associated with clinical remission at Week 52 (odds ratio [OR], 2.37; 95% confidence interval [CI], 1.27-4.41; and OR, 6.36; 95% CI, 3.47-11.64, respectively). Histologic remission and endoscopic improvement at Week 12 were strongly associated with endoscopic improvement-histologic remission at Week 52 (OR, 3.21; 95% CI, 1.70-6.06 and OR, 5.47; 95% CI, 2.89-10.36, respectively).

Etrasimod was superior to placebo for achievement of stringent histologic and composite endpoints.

gov, Number: NCT03945188; ClinicalTrials.gov, Number: NCT03996369.

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.

Achieving histological remission is a desirable emerging treatment target in ulcerative colitis (UC), yet its assessment is challenging due to high inter- and intraobserver variability, reliance on experts, and lack of standardization. Artificial intelligence (AI) holds promise in addressing these issues. This systematic review, meta-analysis, and meta-regression evaluated the AI's performance in assessing histological remission and compared it with that of pathologists.

We searched Medline/PubMed and Scopus databases from inception to September 2024. We included studies on AI models assessing histological activity in UC, with or without comparison to pathologists. Pooled performance metrics were calculated: sensitivity, specificity, positive and negative predictive value (PPV and NPV), observed agreement, and F1 score. A pairwise meta-analysis compared AI and pathologists, while sub-meta-analysis and meta-regression evaluated heterogeneity and factors influencing AI performance.

Twelve studies met the inclusion criteria. AI models exhibited strong performance with a pooled sensitivity of 0.84 (95% CI, 0.80-0.88), specificity 0.87 (0.84-0.91), PPV 0.90 (0.87-0.92), NPV 0.80 (0.71-0.88), observed agreement 0.85 (0.82-0.89), and F1 score 0.85 (0.82-0.89). AI models demonstrated no significant differences with pathologists for specificity, observed agreement, and F1 score, while they were outperformed by pathologists for sensitivity and NPV. AI models for the adult population were linked to reduced heterogeneity and enhanced AI performance at meta-regression.

AI shows significant potential for assessing histological remission in UC and performs comparably to pathologists. Future research should focus on standardized, large-scale studies to minimize heterogeneity and support widespread AI implementation in clinical practice.

Inflammatory bowel diseases (IBD) including Crohn's disease (CD) and ulcerative colitis (UC) are chronic, relapsing conditions characterized by dysregulated immune responses and persistent intestinal inflammation. This review aims to examine new potential therapeutic targets in IBD starting from the STRIDE-II statements. Key targets now include clinical remission, endoscopic remission, and biomarker normalization (such as C-reactive protein and fecal calprotectin). Moreover, histologic remission, transmural remission, and in the future molecular targets are emerging as important indicators of sustained disease control. The treatment goals for inflammatory bowel disease are varied: to relieve symptoms, prevent permanent intestinal damage, promote inflammation remission, and minimize complications. Consequently, the therapeutic targets have evolved to become broader and more ambitious. Integrating these advanced therapeutic targets has the potential to redefine IBD management by promoting deeper disease control and improved patient outcomes. Further research is essential to validate these strategies and optimize their clinical implementation.

Biomarkers have been proposed as surrogate treatment targets for the management of inflammatory bowel disease (IBD); however, their relationship with IBD-related complications remains unclear. This study investigated the utility of neutrophil biomarkers fecal calprotectin (fCal) and fecal myeloperoxidase (fMPO) in predicting a complicated IBD course.

Participants with IBD were followed for 24 months to assess for a complicated IBD course (incident corticosteroid use, medication escalation for clinical disease relapse, IBD-related hospitalizations/surgeries). Clinically active IBD was defined as Harvey-Bradshaw index >4 for Crohn's disease (CD) and simple clinical colitis activity index >5 for ulcerative colitis (UC). Area under the receiver-operating-characteristics curves (AUROC) and multivariable logistic regression assessed the performance of baseline symptom indices, fCal, and fMPO in predicting a complicated disease IBD course at 24 months.

One hundred and seventy-one participants were included (CD, n = 99; female, n = 90; median disease duration 13 years [interquartile range, 5-22]). Baseline fCal (250 μg/g; AUROC = 0.77; 95% confidence interval [CI], 0.69-0.84) and fMPO (12 μg/g; AUROC = 0.77; 95% CI, 0.70-0.84) predicted a complicated IBD course. Fecal calprotectin (adjusted OR = 7.85; 95% CI, 3.38-18.26) and fMPO (adjusted OR = 4.43; 95% CI, 2.03-9.64) were associated with this end point after adjustment for other baseline variables including clinical disease activity. C-reactive protein (CRP) was inferior to fecal biomarkers and clinical symptoms (pdifference < .05) at predicting a complicated IBD course. A combination of baseline CRP, fCal/fMPO, and clinical symptoms provided the greatest precision at identifying a complicated IBD course.

Fecal biomarkers are independent predictors of IBD-related outcomes and are useful adjuncts to routine clinical care.

The Nancy Histological Index (NHI) is used to score histologic disease activity in patients with ulcerative colitis (UC). Our goal was to assess the utility of NHI at diagnosis in predicting clinical outcomes in pediatric patients with UC, in comparison to clinical and endoscopic scores. We retrospectively reviewed data at diagnosis of 106 children with UC (59 [55.7%] females; median age 14.4 [11.2-15.9] years, median Pediatric Ulcerative Colitis Activity Index [PUCAI] 35 [25-55]). During a follow-up of 116 (55-171) weeks, 33 patients (31.1%) required azathioprine therapy, and 32 (30.2%) were escalated to anti-tumor necrosis factor alpha (anti-TNFa). The PUCAI and Mayo endoscopic scores at diagnosis were significantly associated with escalation to anti-TNFa (p = 0.036 and p = 0.02, respectively), but not with initiation of azathioprine or subsequent acute severe colitis (ASC) events. However, the NHI was not associated with subsequent immunomodulators or anti-TNFa therapy (p = 0.42 and p = 0.78, respectively), nor with future ASC events (p = 0.70). In conclusion, the NHI failed to predict clinical outcomes in newly diagnosed pediatric patients with UC.

The worldwide prevalence of inflammatory bowel disease (IBD) is increasing, with its potential evolution as a global disease and a consequent increase in its burden on healthcare systems. These estimates do not factor in the 'real' price of IBD, which, beyond curbing career aspirations, instilling social stigma, and impairing the quality of life in patients, could also significantly affect the environment.

To highlight potential areas for intervention and develop management strategies aimed at minimising environmental impacts in the field of IBD over time.

Various aspects of IBD care (organisation of IBD centres, diagnostics and therapeutics) are examined from an environmental sustainability perspective.

Each stage, from the patient's means of transport to the hospital to the physician's diagnostic and therapeutic decisions, contribute to CO2 and waste production. Strategies to contain the environmental impact are feasible. Some are easy to implement, such as ensuring the appropriateness of the diagnostic and therapeutic pathway for patients; others need to be implemented in synergy with healthcare providers' policies and pharmaceutical companies.

With an inevitable increase in the number of patient visits, endoscopies, laboratory testing, and long-term therapeutic strategies for IBD, the clinical community should be aware of environmental concerns and investigate possible strategies to reduce the environmental impact of IBD care.

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.

There are several available endoscopic scoring systems that are designed to assess disease activity in inflammatory bowel disease. The most widely known is the Mayo endoscopic subscore for ulcerative colitis. These schemas are not routinely used in clinical practice, largely due to their complexity or lack of granularity, although they are standard for outcomes measurement in large clinical trials. While some schemas have been validated using independent cohorts, there is high inherent interobserver variation. Furthermore, derivation of these scoring systems has been subject to selection bias and limited challenge bias.

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.

Cytomegalovirus (CMV) infection exacerbates intestinal inflammation in ulcerative colitis (UC) patients, yet the effect of CMV infection on UC relapse has not been fully elucidated. This study aimed to investigate the impact of CMV infection on UC relapse and identify associated risk factors.

This multicenter retrospective cohort study included UC patients who visited research centers from January 2016 to December 2020. Univariate and multivariate Cox regression analyses were conducted to explore risk factors for UC relapse. Propensity score matching was used to balance the differences in the clinical characteristics between the groups.

A total of 298 UC patients participated in this study, including 19 with CMV colitis, 37 with CMV viremia, and 242 CMV-negative patients. The 2-year cumulative recurrence rate was higher in patients with CMV colitis than that in CMV-negative patients (84.21% vs 51.65%, p = 0.01). Univariate and multivariate Cox regression analyses confirmed that fecal calprotectin ≥ 250 µg/g, Montreal classification E3, CMV colitis, duration > 48 months, and serum albumin < 30 g/L were independent risk factors for UC relapse at 2 years, whereas the use of biologics for induction of remission was identified as an independent protective factor.

Our study suggests that the risk of relapse increases among UC patients with CMV colitis over two years. Risk factors for UC relapse at 2 years include fecal calprotectin ≥ 250 μg/g, Montreal classification E3, CMV colitis, UC duration > 48 months, and albumin < 30 g/L, whereas the use of biologics during induction is a protective factor.

: 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).

Treatment options for the medical management of inflammatory bowel disease (IBD) have expanded substantially over the past decade. Multiple classes of advanced therapies, including both monoclonal antibodies and novel oral small molecules, are now available for the treatment of moderately-to-severely active Crohn's disease and ulcerative colitis, highlighted by the approvals of the first IL23p19 antagonists, selective Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators. These advances have been accompanied by the identification of novel targets and the rapid growth in both the number and size of IBD clinical trials. Over a dozen landmark randomized controlled trials (RCTs) have been completed in the past 5 years, including the first head-to-head biologic trials, the first combination biologic studies, and multiple phase III registrational trials of novel compounds with new co-primary and composite end points that will change the treatment landscape for years to come. Importantly, the methodology of RCTs in IBD has evolved substantially, with new trial designs, evaluation of unique patient populations, and different types of efficacy and safety end points being key innovations. In this Review, we provide a comprehensive evaluation of how modern RCTs of IBD medical therapies have evolved and the implications for their appraisal that will help guide the application of these data to clinical practice.

Treatment of ulcerative colitis (UC) aims to reduce symptoms and complications by decreasing intestinal inflammation. A proportion of patients do not respond to, do not tolerate, or are inappropriate candidates for current therapies. Interleukin (IL)-23 is a therapeutic target and mirikizumabis the first p19-targeted IL-23 antibody approved for the treatment of moderately to severely active UC.

This review summarizes the pro-inflammatory effects of IL-23 and outlines the pharmacokinetics of mirikizumab. It provides a synopsis of the available phase II and phase III evidence for the efficacy and safety of mirikizumab in UC.

The mirikizumab clinical development program demonstrated its superiority over placebo and its favorable safety profile in the treatment of UC. Its positioning in therapeutic algorithms remains to be fully understood but mirikizumab has proven efficacy in both advanced therapy (AT)-naïve and AT-experienced patients. The inclusion in the license of extended induction for non-responders as well as rescue intravenous dosing allows for flexibility in patient with limited primary response and secondary loss of response.

The gap between endoscopy and histology is getting closer with the introduction of sophisticated endoscopic technologies. Furthermore, unprecedented advances in artificial intelligence (AI) have enabled objective assessment of endoscopy and digital pathology, providing accurate, consistent, and reproducible evaluations of endoscopic appearance and histologic activity. These advancements result in improved disease management by predicting treatment response and long-term outcomes. AI will also support endoscopy in raising the standard of clinical trial study design by facilitating patient recruitment and improving the validity of endoscopic readings and endoscopy quality, thus overcoming the subjective variability in scoring. Accordingly, AI will be an ideal adjunct tool for enhancing, complementing, and improving our understanding of ulcerative colitis course. This review explores promising AI applications enabled by endoscopy and histology techniques. We further discuss future directions, envisioning a bright future where AI technology extends the frontiers beyond human limits and boundaries.

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.