Background: Histological examination of mucosal tissue in inflammatory bowel diseases (IBD) is a sensitive tool to measure disease activity, and histological remission is emerging as a potentially important treatment target. There are several existing histopathological indices, but they often encompass caveats such as not primarily having been designed to measure the degree of inflammation, encompassing subjective components with poor intra- and interindividual reproducibility, and requiring expert pathologists who are scarce, thus resulting in extended response times. Aim: To construct a new computerized, automated index to objectively measure histological disease activity in the ileal and colonic mucosa, applicable to both Crohn's disease (CD) and ulcerative colitis (UC). Materials and methods: Ileocolonic biopsies were collected from control subjects and patients with CD or UC. A group of CD patients was sampled before and after 12 weeks of anti-TNFα therapy. Another group of CD and UC patients functioned as a small validation cohort. Epithelial cells, neutrophils, macrophages, and T cells were immunohistochemically stained, followed by digitalization of the color signal and computerized delineation of the epithelial and lamina propria compartments. The various immune cell types within the epithelium and the lamina propria, respectively, were enumerated, and the numbers were compared between control subjects and patients with CD or UC. Results: The numbers of neutrophils and macrophages in the epithelium, and neutrophils in the lamina propria, showed the highest sensitivity and specificity for distinguishing control-subject tissues from CD and UC tissues. These three parameters were thus chosen to construct a new index, named QiC3 1.0, that could separate tissues from control subjects and patients with CD or UC with high precision. It performed equally well in a small validation cohort of patients. The QiC3 index correlated well with previously described histopathological indices, fecal calprotectin, and endoscopic scores in UC, but showed worse correlation with endoscopic scores in CD and symptomatic scores. When applying the new index to tissues from CD patients before and after therapy, it showed good responsiveness, demonstrating a distinct amelioration in the microscopic inflammatory status that corresponded well to improvements in histopathological scores. Conclusion: We describe a new quantitative, computerized, automated, non-subjective, and response-sensitive immunohistological index (QiC3) for measuring disease activity in ileal and colonic mucosal biopsies, suitable for both CD and UC. ### Competing Interest Statement Erik Hertervig has served as consultant for Abbvie, Merck, Sharp & Dohme, and Takeda. Jonas S Erjefalt is the founder and CEO of Medetect AB. Jan Marsal has served as consultant for AbbVie, BMS, Ferring, Galapagos, Lilly, Takeda, Tillotts. Jan Marsal has received investigator-initiated study grants from AbbVie, Ferring, Pfizer, and Takeda. The other authors have no financial conflicts of interest. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was performed in accordance with the declaration of Helsinki and was approved by the regional ethics committees in Lund and Linkoping, Sweden (Dnr. 2011/60 and 2011-201-31, respectively). Written informed consent was obtained from all subjects before they were included. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. Hedlund Foundation Julin Foundation Bengt Ihres Foundation, https://ror.org/04v0hex10 Swedish Society for Medical Research, https://ror.org/0433fd238 Royal Physiographic Society of Lund, https://ror.org/05rnj0j91 Skåne University Hospital, https://ror.org/02z31g829 Swedish Society of Medicine, https://ror.org/016ks4x90 investigator-initiated study grant from AbbVie Healthcare Region of Southern Sweden Swedish government (ALFSKANE-539811)

Crohn’s disease significantly impairs health-related quality of life (HRQoL), even during remission. The double-blinded, randomised controlled STOP IT trial1 investigated outcomes following infliximab (IFX) withdrawal in patients in sustained clinical-biochemical-endoscopic remission, showing 48% relapse rate within 48 weeks of withdrawal, but did not assess HRQoL. This study evaluated longitudinal HRQoL trajectories to determine whether a decline in HRQoL is detectable prior to clinical relapse following discontinuation of biologics. Post hoc analysis of STOP IT.1 Patients were followed for 48 weeks after randomisation with predefined study visits. HRQoL was assessed at each visit using Short Inflammatory Bowel Disease Questionnaire (SIBDQ) comprising 10 questions each scored from 1 (severe problem) to 7 (not a problem at all). Relapse was defined as CDAI ≥150 together with CDAI increase ≥70 above baseline over 2 consecutive weeks. For patients who experienced clinical relapse between scheduled visits, an early termination visit was conducted, and this SIBDQ measurement was defined as event time. Longitudinal changes in SIBDQ were analysed using linear mixed-effects models. A segmented regression restricted to patients who relapsed was used to estimate the inflection point at which HRQoL began to decline prior to relapse. One hundred patients with Crohn’s disease were included. Forty-six patients discontinued treatment (intervention group), and 22 (48%) had relapse within 48 weeks. In the control group where all 54 patients continued IFX therapy, none experienced a relapse. Baseline SIBDQ was comparable between patients who later experienced relapse and those who did not (median 61, IQR 56–65 vs. 61, 54–66; p = 0.98). At time of clinical relapse, SIBDQ was significantly lower among patients who relapsed (median 43, IQR 36-55 vs. 61, 54-65; p < 0.001). In mixed-effects analyses, SIBDQ remained stable in patients who did not relapse (β = -0.01 [-0.05 – 0.02]; p = 0.51), whereas patients who relapsed showed a significantly decline over time (β = -0.46 [-0.63 – -0.30]; p < 0.001). In segmented regression restricted to relapsing patients, an inflection point was identified 7 weeks prior to clinical relapse. SIBDQ remained stable until this time (β = 0.04, [-0.18 – 0.26]; p = 0.72) and thereafter sharply declined (β = -2.26 [-2.90 − -1.61]; p < 0.001). Significant HRQoL impairment presented 7 weeks prior to manifestation of clinical relapse in Crohn’s disease patients discontinuing IFX while in clinical-biologic-endoscopic remission, supporting SIBDQ as a practical, non-invasive tool for early detection of potential loss of disease control. References: 1Buhl S et al. NEJM Evidence 2022;1:EVIDoa2200061. Conflict of interest: Nissen, Mathilde Jepsen: No conflict of interest Gill, Prabhpreet: No conflict of interest Buhl, Sine: No conflict of interest Brynskov, Jørn: No conflict of interest Christensen, Katrine Risager: No conflict of interest Dorn-Rasmussen, Maria: No conflict of interest Thomsen, Ole Ostergaard: No conflict of interest Klausen, Tobias Wirenfeldt: No conflict of interest Dahlerup, Jens Frederik: No conflict of interest Sorensen, Heidi Gram: No conflict of interest Jahnsen, Jørgen: No conflict of interest Molazahi, Akbar: No conflict of interest Pedersen, Natalia: No conflict of interest Kjeldsen, Jens: No conflict of interest Almer, Sven: No conflict of interest Dahl, Eva: No conflict of interest Vind, Ida: No conflict of interest Cannon, Annett: No conflict of interest Marshall, Jan: No conflict of interest Sipponen, Tiana: No conflict of interest Agnholt, Jørgen Steen: No conflict of interest Kievit, Linda Hendrika Adriana: No conflict of interest Aure, Synnøve Louise: No conflict of interest Martinsen, Lars: No conflict of interest Meisner, Svetlana: No conflict of interest Møller Hansen, Jane: No conflict of interest Ainsworth, Mark Andrew: No conflict of interest Steenholdt, Casper: Lectures for Takeda, MSD and Janssen-Cilag research grant from Takeda.

Ulcerative colitis remains challenging to treat due to the need for localized control of inflammation, restoration of mucosal integrity, and avoidance of systemic toxicity. Here, we report a rectally administered, sprayable, thermo-responsive hyaluronic acid-based copolymer platform for the localized co-delivery of probiotic-derived extracellular vesicles (ProEVs) and 5-aminosalicylic acid. This system enables enhanced retention and sustained presentation of therapeutics at inflamed colonic sites. The combined formulation demonstrates improved therapeutic efficacy compared to individual treatments, promoting mucosal recovery and intestinal homeostasis. Mechanistically, the platform modulates inflammatory responses, supports epithelial barrier function, and contributes to microbiota rebalancing. Notably, extracellular vesicles provide a more effective and consistent therapeutic modality compared to live probiotics. Importantly, the formulation is designed for clinical translation, offering localized administration, minimal toxicity, and stability upon lyophilization, enabling off-the-shelf use. These findings highlight the potential of integrating extracellular vesicles with biomaterial-based delivery systems as a multifunctional therapeutic strategy for inflammatory bowel disease.

INTRODUCTION:Lynch syndrome (LS) carriers have a 20-46% lifetime risk of colorectal cancer (CRC) due to mismatch repair gene variants. Mesalamine (5-ASA, 5-aminosalicylic acid), used safely in patients with ulcerative colitis, may reduce CRC risk in LS by decreasing microsatellite instability, a key driver of LS-related cancer. This study evaluates 5-ASA's efficacy as a tolerable chemopreventive drug, aiming to improve long-term CRC prevention in LS. METHODS AND ANALYSIS:This multicentre, multinational, randomised, double-blind, two-arm, phase II clinical study will compare the effects of a 2-year daily intake of 5-ASA (2000 mg) to placebo in LS carriers. The primary objective is to assess whether mesalamine reduces colorectal neoplasia, both benign and malignant, compared with placebo in LS carriers, as detected by colonoscopy at the end of the treatment period (24 months±1 month) and on study completion. Secondary objectives include evaluating whether 5-ASA reduces neoplasia/tumour multiplicity and progression compared with placebo at specified time points, examining variations in the effects of 5-ASA versus placebo based on cancer history, sex and age (<45 years vs ≥45 years), and assessing the safety of 5-ASA in LS carriers. ETHICS AND DISSEMINATION:The trial is currently open for enrolment, having received ethical approval from the Regional Ethical Review Board in Stockholm and funding from the Swedish Research Council. The study protocol is the finalised V.10.0 (11 April 2024), transitioned to the European Clinical Trials Information System. LS remains underdiagnosed, which may limit recruitment. The results are of global interest and will be published in peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER:ClinicalTrials.gov: NCT04920149. EudraCT: 2019-003011-55. EU CT:2024-514765-19-01.

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INTRODUCTION:It is uncertain whether the risk of major congenital anomalies (mCAs) is increased in children of women with inflammatory bowel disease (IBD). METHODS:We aimed to determine the risk of mCAs in a Swedish nationwide cohort of 13,131 singleton live births from 1997 to 2020 to women with IBD and 61,909 matched children to women without IBD from the general population. We additionally examined mCAs according to periconceptional histological inflammation (vs remission: 1,124 and 646 births, respectively) or clinically active IBD (vs quiescent: 3,380 and 6,603 births, respectively). Adjusted risk ratios (aRRs) for overall and organ-specific mCAs were estimated using generalized linear models. These models adjusted for maternal sociodemographics, comorbidities, body mass index, and smoking. RESULTS:There were 38.0 (n = 499) mCAs per 1,000 births to women with IBD vs 33.9 (n = 2,101) in matched comparators and a risk difference of 1 extra mCA per 246 births to women with IBD (aRR 1.11; 95% confidence interval [CI] 1.01-1.23). Risks of heart defects and mCAs of the urinary system partly drove estimates. The risk of mCAs was similar in children of women with ulcerative colitis and Crohn's disease. Periconceptional histological inflammation (vs remission) or clinically active (vs quiescent) IBD did not further influence the risk of mCA in the child (aRR 0.87 [95% CI 0.55-1.40] and aRR 1.04 [95% CI 0.85-1.27], respectively). DISCUSSION:Children of women with IBD had a heightened susceptibility to mCAs, although absolute and relative risks were lower than previously reported. IBD activity was not linked to mCA risks, but those analyses included relatively few events.

Abstract Background Fatigue is characterized as an overwhelming sense of tiredness, weakness, or exhaustion, which can be physical, psychological, or a combination of both. Fatigue is a common symptom and a significant concern for patients with IBD. International studies indicate that between 44% and 86% of patients with active disease, and 22% to 41% of those in remission, experience fatigue. This symptom can limit individual activities and negatively impact health-related quality of life. Despite its profound effects on patients, fatigue is often overlooked by healthcare professionals, who find it challenging to measure and manage. The aim of this study is to assess the prevalence of fatigue in Swedish IBD patients, both in active disease and in remission. Methods The study was conducted using a disease-specific questionnaire, the IBD-Fatigue Scale, which has been translated and validated into Swedish. The IBD-Fatigue Scale and questions concerning demographic data was distributed electronically to IBD patients in Stockholm and Linköping. The IBD Fatigue Scale consists of three sections. Section I assess frequency and severity of fatigue. Section II is rating experience and impact of fatigue, and section III is asking for patients’ comments and issues related to fatigue. This study will show the results of section I. A total of 2208 patients were asked to participate in the study. Results A total of 760 (34%) patients accepted to participate in the study and of 674 of those answered the questionnaire. The IBD-Fatigue Scale´s first section shows that fatigue is a burdensome symptom in IBD patients (figure 1). The scoring ranges between 0-20, where 0 means no fatigue and 20 means severe fatigue. The mean value showed 12,1 in the Swedish population. When comparing between sex, diagnosis and active vs remission, the patients who perceived most fatigue were woman and those with active disease (table 1). Conclusion This study shows that IBD-patients in Sweden suffer from fatigue to similar extent as in international studies. Those with highest perceived fatigue are women and those with active disease and those with continuous symptoms.No studies have examined the prevalence of fatigue among Swedish patients with IBD or its impact on their lives, and there is a pressing need to explore the extent of fatigue among this population and to understand their experiences and the effects of fatigue on their daily lives.

BACKGROUND & AIMS:Microscopic colitis (MC) is a leading cause of chronic diarrhea, particularly in older adults. Although many patients respond to budesonide, refractory and dependent cases pose major therapeutic challenges. Although the off-label use of advanced inflammatory bowel disease therapies is expanding, robust real-world data remain scarce. METHODS:Through the ECCO CONFER network, we conducted a multinational, retrospective study in patients with MC treated with biologics or small molecules following budesonide failure or intolerance. We systematically analyzed clinical outcomes, treatment durability, and predictors of therapeutic success. RESULTS:Among 229 treatment cycles in 142 patients, anti-tumor necrosis factor (TNF) agents were most frequently initiated (55.9%), followed by vedolizumab (28.8%) and Janus kinase (JAK) inhibitors (9.2%). Short-term clinical response and remission rates were highest with JAK inhibitors (95.2% and 81.0%, respectively), significantly outperforming anti-TNFs, vedolizumab, and ustekinumab (P < .01). Long-term drug persistence mirrored these findings: JAK inhibitors demonstrated a markedly lower discontinuation rate (23.8%) compared with other agents (56.3%; odds ratio, 5.07; 95% confidence interval, 1.52-16.9; P = .008). Multivariate analysis confirmed drug class as the only independent predictor of therapy continuation. Despite advanced therapies, 4.2% of patients ultimately required surgical intervention. CONCLUSIONS:This real-world study demonstrates the promising short- and long-term effectiveness of advanced therapies-particularly JAK inhibitors-in budesonide-refractory and budesonide-dependent MC. These findings pave the way for dedicated prospective trials and highlight evolving therapeutic strategies in MC.

Background: Tofacitinib is a Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Prospective real-world data are scarce. Objectives: To collect data on clinical outcomes, including health-related quality of life (HRQoL) and fatigue during treatment with tofacitinib. Design: This is a prospective observational multicentre study in Sweden. In this analysis, outcomes at weeks 2, 8 and 16 are reported. Methods: Patients with active UC confirmed with endoscopy or faecal calprotectin (FC) were enrolled during 2020-2023 when starting tofacitinib therapy. Results: In total, 103 patients were included. After 2 weeks of treatment, 50% (39/78) had achieved symptomatic response and at week 16, 39% (35/89) had achieved corticosteroid-free clinical remission according to the partial Mayo score. At week 16, a reduction in FC by >= 50% was seen in 49% (35/71) and 24% (11/46) were in endoscopic remission. The frequency of arthralgia decreased from 29% (30/103) at baseline to 11% (10/89) at week 16. Regarding HRQoL at week 16; each of the four Short Health Scale dimensions (symptoms, social function, disease-related worry and general well-being) had improved by a median of 1 point (p < 0.01) and the European Quality of Life 5 Dimensions 5 Levels index improved from 0.80 to 0.87. Finally, the Inflammatory Bowel Disease Fatigue score measuring occurrence and severity showed an improvement with a decrease from 9 points at baseline to 6 at week 16 (p < 0.05). Conclusion: Induction therapy with tofacitinib therapy was associated with improvements in patient-reported outcome measures of symptoms, endoscopic activity, arthralgia, HRQoL and fatigue. These real-world data illustrate that tofacitinib is a fast-acting drug with broad therapeutic effects in UC.

Abstract Background Better prognostic measures for ulcerative colitis (UC) could significantly advance patient care. While the prognostic capacity of circulating proteins in UC has been explored, the role of mucosal proteins remains largely unknown. We examined mucosal protein markers in patients with incident ulcerative colitis and evaluated their prognostic value. Methods Biopsies from macroscopically inflamed colonic/rectal mucosa of adult patients in the Swedish inception cohort of IBD (SIC IBD) were obtained at diagnosis of UC. Patients were followed prospectively, and clinical data were recorded after 3 and 12 months. Disease course was categorised as indolent or aggressive at 12 months, based on a composite outcome of colectomy, hospital admission for active disease, treatment refractoriness towards ≥2 biological agents; the use of >2 courses of corticosteroids, or a cumulative dose of >2.5 g. Relative estimates of 162 protein markers were assessed in homogenised tissue supernatants, using proximity extension assay technology (Olink Proteomics, Uppsala, Inflammation and Oncology II panel). Mann-Whitney U test, with Benjamini-Hochberg correction was used to identify differentially regulated mucosal proteins in aggressive vs indolent disease course, with a 5% false discovery rate (FDR). Smoothly clipped absolute deviation regularised logistic regression models were used to identify prognostic signatures distinguishing aggressive from indolent disease course. Performance was estimated in a leave-one-out cross-validation and reported as the area under the receiver operating characteristic (ROC) curve (AUC). Results 117 patients provided a macroscopically inflamed colonic/rectal biopsy at diagnosis of UC. Basic demographics and clinical characteristics are presented in Table 1. Relative protein levels of WFdc2 and CCL20 were significantly lower in lysates from patients developing an aggressive course vs patients developing an indolent course, while estimates of MMP1, CCL11, WISP-1, OPG, RSPO3 and VEGFR2 were higher (Figure 1A). Regularized logistic regression identified signatures restricted to 28 proteins, distinguishing aggressive from indolent UC courses, yielding an AUC of 0.68 (95% confidence interval (CI): 0.56-0.80) for left-out samples (Figure 1B). Incorporating extent of inflammation at diagnosis in the model improved the AUC to 0.71 (95% CI: 0.60-0.83). Conclusion We identified prognostic mucosal protein signatures associated with future course of ulcerative colitis by analysing inflamed mucosal biopsies that were obtained at diagnosis. These protein markers may highlight pathways of relevance for ulcerative colitis outcomes.

BACKGROUND AND PURPOSE:Treatment of cancer with immune checkpoint inhibitors (ICIs) entails a risk of immune-related adverse events (irAEs). Data on the treatment of immune-related enterocolitis (irEC) in patients with inadequate symptom control after treatment with standard therapy including corticosteroids, infliximab, and vedolizumab are scarce. Based on limited data, recommendations include treatment with the pan-Janus kinase (JAK) inhibitor tofacitinib. Filgotinib is a more recently developed JAK inhibitor with preferential inhibition of JAK1, which might imply a more favorable safety profile. Filgotinib is approved for the treatment of ulcerative colitis and might thus be an option in refractory irEC. PATIENTS AND METHODS:We present two cases of metastatic melanoma treated with ICIs who developed corticosteroid and infliximab-refractory irEC. Given non-conventional pharmaceutical management, literature review was performed regarding mechanisms of action and safety profiles of JAK inhibitors. RESULTS:Both patients were treated with filgotinib, which resulted in rapid remission of symptoms in both cases. One of the patients was treated with off-label high-dose filgotinib, which has not been described previously. The rationale and safety regarding the use of JAK1 inhibitors in irAEs are discussed, including the seemingly diverging existing data on potential effects of JAK inhibition on ICI-induced anti-tumoral immune-responses. In addition, the rationale for the high-dose treatment is scrutinized. INTERPRETATION:This report suggests that filgotinib may be considered for treating irEC refractory to standard therapy.

Purpose There is a need for diagnostic and prognostic biosignatures to improve long-term outcomes in inflammatory bowel disease (IBD). Here, we describe the establishment of the Swedish Inception Cohort in IBD (SIC-IBD) and demonstrate its potential for the identification of such signatures.Participants Patients aged ≥18 years with gastrointestinal symptoms who were referred to the gastroenterology unit due to suspected IBD at eight Swedish hospitals between November 2011 and March 2021 were eligible for inclusion.Findings to date In total, 367 patients with IBD (Crohn’s disease, n=142; ulcerative colitis, n=201; IBD-unclassified, n=24) and 168 symptomatic controls were included. In addition, 59 healthy controls without gastrointestinal symptoms were recruited as a second control group. Biospecimens and clinical data were collected at inclusion and in patients with IBD also during follow-up to 10 years. Levels of faecal calprotectin and high-sensitivity C-reactive protein were higher in patients with IBD compared with symptomatic controls and healthy controls. Preliminary results highlight the potential of serum protein signatures and autoantibodies, as well as results from faecal markers, to differentiate between IBD and symptomatic controls in the cohort. During the first year of follow-up, 37% (53/142) of the patients with Crohn’s disease, 24% (48/201) with ulcerative colitis and 4% (1/24) with IBD-U experienced an aggressive disease course.Future plans We have established an inception cohort enabling ongoing initiatives to collect and generate clinical data and multi-omics datasets. The cohort will allow analyses for translation into candidate biosignatures to support clinical decision-making in IBD. Additionally, the data will provide insights into mechanisms of disease pathogenesis.

Real-world data on starting intravenous (IV) vedolizumab (VDZ) and transitioning to subcutaneous (SC) treatment in inflammatory bowel disease (IBD) are scarce. To assess treatment outcomes of patients with IBD starting IV VDZ and switching to SC VDZ in routine clinical care. Adult patients with IBD switching from IV to SC VDZ treatment between 1 March 2020 and 31 December 2021 were identified from the Swedish IBD quality register. The primary outcome was SC VDZ persistence. Secondary outcomes included clinical remission, changes in quality of life (QoL) according to EuroQual 5-Dimensions 5-Levels (EQ-5D-5L) and the Short-Health Scale (SHS) and inflammatory markers, including faecal Calprotectin (FCP). Altogether, 406 patients with IBD (Crohn's disease, n = 181; ulcerative colitis, n = 225) were identified. After a median follow-up of 30 months from starting IV VDZ treatment, the persistence rates were 98

Abstract Background Microscopic colitis (MC) is a chronic inflammatory condition of the colon, resulting in an impaired quality of life due to debilitating watery diarrhea. First-line therapy consists of budesonide, though a subset of patients is refractory or becomes budesonide- dependent. Evidence for the efficacy of biologicals or small molecules in MC is sparse and limited to small case series. Hence, we aimed to generate more real-life efficacy data. Methods This retrospective series was collected as part of the CONFER project by ECCO and supported by the European Microscopic Colitis Group (EMCG). Cases of MC patients treated with advanced therapies were included through a standardised collection form. Clinical response was defined as a 50% reduction in stool frequency (SF); clinical remission was defined according to the Hjortswang criteria as < 3 stools/day or < 1 watery stool/day. Results Ninety-nine patients were identified (Table 1), of whom all but one were previously treated with budesonide. Reasons for budesonide discontinuation included primary non-response (PNR, 16.3%), refractory disease (34.7%), budesonide dependency (38.8%), or adverse events (AE, 10.2%). In total, 165 treatment cycles with advanced therapy (47 IFX, 40 ADA, 47 VDZ, 10 UST, 14 JAK inhibitors, 7 other) were reported. First-line advanced therapies included mainly anti-TNF (76.8%) and VDZ (20.2%) (Figure 1A). Patients were exposed to anti-TNF therapy for a median of 1.4 [0.5-3.1] years, with a significant drop in SF after induction (p<0.001), resulting in 50.0% clinical remission (Figure 1B). However, 63.0% ultimately discontinued anti-TNF therapy, mainly due to PNR (37.9%), loss-of-response (LOR, 36.2%) or AE (20.7%). VDZ induced 46.8% clinical remission, reflected in a significant drop in SF (p<0.001). Though, a 59.6% discontinuation rate was observed after a median 0.6 [0.3-1.3] years, mainly due to PNR (63.0%) and LOR (22.2%). Similarly, for UST a 40.0% clinical remission rate was accompanied by 60.0% therapy withdrawal, primarily due to PNR (83.3%). In contrast, JAK inhibition resulted in 78.6% clinical remission, with a substantial drop in SF (p=0.002) and 21.4% discontinuation rate after a median exposure of 0.6 [0.3-1.6] years. Conclusion Almost all advanced therapies are used in budesonide refractory or dependent MC, with anti-TNF agents the most often used first-line options. However, anti-TNF discontinuation is frequent due to lack/loss of efficacy. VDZ and UST could be alternatives, but also have a substantial discontinuation rate. In this retrospective series, the small number (n=14) of JAK inhibitor treated patients had the highest remission rate, suggesting further research on the role of JAK inhibitors in MC.

Background & objectivesEndoscopy is the current gold standard for evaluation of disease activity in ulcerative colitis. The Mayo Endoscopic Subscore (MES) is commonly used for quantifying disease activity, but it has several weaknesses. Numerous new endoscopic indices have been developed but none of these have been widely implemented, likely due to limited feasibility. The primary objective of this study was thus to develop a simple, reliable, endoscopic index for ulcerative colitis. Secondary objectives were to evaluate and compare the MES, the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), and the Ulcerative Colitis Colonoscopic Index of Severity (UCCIS), as well as examining the agreement between full colonoscopy and sigmoidoscopy.MethodsConsecutive adult ulcerative colitis patients had their routine colonoscopies video recorded, each edited into five shorter segment-specific video sequences. In parallel, blood, fecal, and mucosal samples were collected, together with data on symptoms and quality-of-life. The video sequences were scored by three gastroenterologists and one resident gastroenterologist according to a form comprising six endoscopic disease activity descriptors and an overall endoscopic disease severity assessment.ResultsOne hundred unique video sequences from twenty patients were each evaluated three times by four assessors, generating a total of 7200 unique segment-specific data-points for the six descriptors and 1200 unique assessments of overall endoscopic disease severity. The intra- and interobserver agreement for the individual descriptors were overall moderate to very good. The MES, UCEIS, and UCCIS performed similarly with the latter being slightly superior in terms of reliability and correlation to biomarkers of disease activity. The descriptor vascular pattern was the best discriminator at the lower end of the disease activity spectrum, whereas the descriptor ulcers was the best at the medium to high end. These two descriptors were combined into a new index, the Simple Endoscopic Score for Ulcerative Colitis (SES-UC), which displayed similar levels of reliability and accuracy as the established indices. Finally, comparison of sigmoidoscopy and colonoscopy showed that up to 38% of patients had their most inflamed segment located proximally to the sigmoid colon.ConclusionsWe propose a new simplified endoscopic index for ulcerative colitis, the SES-UC, which is based on the two descriptors vascular pattern and ulcers. The performance of the SES-UC was similar to, and in some regards better than, that of the established indices (MES, UCEIS, and UCCIS). This together with its simplicity makes SES-UC a candidate index for use in clinical practice as well as in clinical studies.

Abstract Background Tofacitinib is a Janus kinase (JAK) inhibitor for the treatment of moderate to severe ulcerative colitis (UC). ODEN is an ongoing Swedish multicentre prospective observational study regarding effectiveness of tofacitinib in UC. In this interim analysis, we aimed to assess the clinical outcomes during the first 16 weeks. Methods Patients with active UC were enrolled 2020-2023 when starting tofacitinib as per clinical indication. Inclusion criteria were fecal (F) calprotectin >250 mg/kg or Mayo endoscopic score ≥2. Data were collected using an electronic case report form linked to the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG). Data concerning inflammatory markers, endoscopic activity, partial (p) Mayo, extra intestinal manifestations, health-related quality of life measures, corticosteroid use, and colectomy rates were collected regardless of tofacitinib discontinuation. Information collected at week 8 and 16 is presented here. Intention-to-treat (ITT) analysis was applied and tofacitinib discontinuation was considered as treatment failure (i.e., no tofacitinib-induced clinical or laboratory response or remission). McNemar’s test was used for proportion differences. Results The proportion of patients who previously had failed at least one biologic was 95% and at least two biologics, 62%. At inclusion, median p-Mayo was 5 and 39% of patients were on corticosteroids (Table 1a). Patients’ survival on drug is shown in Figure 1a. At week 8 and 16, 42% and 43%, respectively, achieved corticosteroid free clinical remission, Figure 1b. A 50% reduction in F-calprotectin was seen in 54% and 49% at week 8 and 16, respectively. The endpoint of Mayo endoscopic score 0 and/or F-calprotectin <100 mg/kg was achieved by 30% and 38% at week 8 and 16, respectively. Arthralgia frequency decreased significantly from baseline from 29% at inclusion to 13% and 11% at week 8 and 16 respectively. Three patients underwent colectomy the first 16 weeks (Table 1b). Conclusion After 16 weeks of treatment with tofacitinib, a substantial proportion of previously treatment refractory UC patients were in clinical and endoscopic corticosteroid-free remission, and a distinct improvement in F-calprotectin levels was observed. In addition, a significant reduction in arthralgia was noted.

Abstract Background Ulcerative colitis (UC) has a major impact on daily life. The Janus Kinas (JAK) inhibitor tofacitinib is effective in achieving remission in UC, but prospective real-world evidence concerning the effect on health-related quality of life (HRQoL) and fatigue are still scarce. Fatigue is a component of UC that is notoriously difficult to treat and not unambiguously related to inflammatory activity. ODEN is an ongoing Swedish multicentre prospective observational study of tofacitinib in UC. In this interim analysis, we assessed the effectiveness on HRQoL and fatigue during the first 16 weeks. Methods Patients with UC and active inflammation were enrolled 2020-2023 when starting tofacitinib as per clinical indication. To measure various aspects of impairment of daily life, the validated questionnaires Short Health Scale (SHS), EQ-5D-5L [Swedish value set], and IBD-fatigue scale (IBD-F) were used. These data and information concerning clinical, biochemical, and endoscopic outcomes were collected in an e-CRF linked to the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG). For HRQoL outcomes, per protocol analysis was applied. Paired t-test and Wilcoxon’s signed-rank test were used for mean and median differences, respectively. Results In total, 103 patients were included. Baseline data are shown in Table 1a. For patients still on tofacitinib treatment, all four dimensions of the SHS (symptoms, social function, disease related worry, and general well-being) improved significantly, Table 1b. A median decrease of one point from baseline was seen at week 8 in each of the parameters, which was maintained through week 16 with a tendency towards further improvement. EQ-5D-5L showed an impairment mainly in the aspects of pain/discomfort and ability to participate in common daily activities. Improvement in these dimensions was seen from baseline to week 16. The overall EQ-5D-5L index improved significantly from baseline (0.80) to week 8 (0.86) and week 16 (0.89), as did the EQ VAS 0-100 reflecting overall health (58, 71, and 74, respectively). A significant improvement in IBD-F part 1 and 2 was seen at week 8 and 16, Figure 1. Conclusion This study demonstrates that tofacitinib treatment covariates with positive changes in a variety of measures of patients’ quality of life, including improvements in self-assessed overall wellbeing. Finally, fatigue significantly improved during tofacitinib treatment. Thus, tofacitinib treatment shows association with meaningful improvements in multiple aspects of quality of life during the first 16 weeks of treatment.

Impairment of intestinal epithelium is a typical feature of inflammatory bowel disease (IBD) that causes leakage of bacteria and antigens from the intestinal lumen and thus results in persistent immune activation. Hence, healing and regeneration of the damaged gut mucosa is a promising therapeutic approach to achieve deep remission in IBD. Currently, available systemic therapies have moderate effects and are often associated with numerous side effects and malignancies. In this study, we aimed to develop a topical therapy by chemically conjugating a temperature-responsive polymer, i.e., poly(N-isopropylacrylamide), along with hyaluronic acid to obtain a sprayable therapeutic formulation that upon colon instillation adheres to the damaged gut mucosa due to its temperature-induced phase transition and mucoadhesive properties. An ex vivo adhesion experiment demonstrates that this therapeutic formulation forms a thin physical coating on the mucosal lining at a physiological temperature within 5 min. Physicochemical characterization of (P(NIPAM-co-NTBAM)-HA) established this formulation to be biocompatible, hemo-compatible, and non-immunogenic. Prednisolone was encapsulated within the polymer formulation to achieve maximum therapeutic efficacy in the case of IBD-like conditions as assessed in a custom-fabricated perfusion-based ex vivo model system. Histological analysis suggests that the prednisolone-encapsulated polymer formulation nearly restored the mucosal architecture after 2,4,6-trinitrobenzenesulfonic acid-induced damage. Furthermore, a significant (p ≤ 0.001) increase in mRNA levels of Muc-2 and ZO-1 in treated groups further confirmed the mucosal epithelial barrier restoration.