Therapy For Ulcerative Colitis Research Articles

A Biomimetic Sweeping Microrobot for Active Therapy of Ulcerative Colitis

AbstractOverproduction of pathogenic cell‐free DNA (cfDNA) and reactive oxygen species (ROS) plays crucial roles in the onset and perpetuation of ulcerative colitis (UC). Inspired by sweeping robots, a magnesium@polylactic acid‐glycolic acid copolymer@polyethylenimine (Mg@PLGA@PEI) microswimmer capable of cleaning off deleterious disease triggers along its path of progress is designed. Mg@PLGA@PEI is successfully synthesized by adopting a core‐shell structure with a small opening which allows for Mg‐water reaction. The distinctive motility performance resulting from sustained detachment of the produced hydrogen not only contributes to strengthened hydrogen diffusion concomitant with potentiated ROS neutralization, but also facilitates the contacting probability with microenvironmental cfDNA and thus enhances the DNA binding efficiency. By integrating these merits, the developed Mg@PLGA@PEI confers desirable curative efficacy in a classical DSS‐induced acute colitis mouse model. Enema administration of Mg@PLGA@PEI microswimmers substantially alleviates the manifestations related to UC, as evidenced by the body weight recovery, colon length retention, colon tissue protection, and attenuated intestinal inflammation, which is attributed to the active scavenging of cfDNA and ROS. This work provides a paradigm for a drug‐free strategy competent in spontaneously eliminating causative triggers with minimal side effects, which presents a promising alternative for the active therapy of UC or other cfDNA‐ and ROS‐related diseases in the clinic.

Promising protective treatment potential of endophytic bacterium Rhizobium aegyptiacum for ulcerative colitis in rats

Abstract Ulcerative colitis (UC) is an inflammatory condition of the intestine, resulting from an increase in oxidative stress and pro-inflammatory mediators. In this study, the extract of endophytic bacterium Rhizobium aegyptiacum was prepared for the first time using liquid chromatography-mass spectrometry (LC-MS). In addition, also for the first time, the protective potential of R. aegyptiacum was revealed using an in vivo rat model of UC. The animals were grouped into four categories: normal control (group I), R. aegyptiacum (group II), acetic acid (AA)-induced UC (group III), and R. aegyptiacum-treated AA-induced UC (group IV). In group IV, R. aegyptiacum was administered at 0.2 mg/kg daily for one week before and two weeks after the induction of UC. After sacrificing the rats on the last day of the experiment, colon tissues were collected and subjected to histological, immunohistochemical, and biochemical investigations. There was a remarkable improvement in the histological findings of the colon tissues in group IV, as revealed by hematoxylin and eosin (H&E) staining, Masson’s trichrome staining, and periodic acid-Schiff (PAS) staining. Normal mucosal surfaces covered with a straight, intact, and thin brush border were revealed. Goblet cells appeared magenta in color, and there was a significant decrease in the distribution of collagen fibers in the mucosa and submucosal connective tissues. All these findings were comparable to the respective characteristics of the control group. Regarding cyclooxygenase-2 (COX-2) immunostaining, a weak immune reaction was shown in most cells. Moreover, the colon tissues were examined using a scanning electron microscope, which confirmed the results of histological assessment. A regular polygonal unit pattern was seen with crypt orifices of different sizes and numerous goblet cells. Furthermore, the levels of catalase (CAT), myeloperoxidase (MPO), nitric oxide (NO), interleukin-6 (IL-6), and interlukin-1β (IL-1β) were determined in the colonic tissues of the different groups using colorimetric assay and enzyme-linked immunosorbent assay (ELISA). In comparison with group III, group IV exhibited a significant rise (P<0.05) in the CAT level but a substantial decline (P<0.05) in the NO, MPO, and inflammatory cytokine (IL-6 and IL-1 β) levels. Based on reverse transcription-quantitative polymerase chain reaction (RT-qPCR), the tumor necrosis factor-α (TNF-α) gene expression was upregulated in group III, which was significantly downregulated (P<0.05) by treatment with R. aegyptiacum in group IV. On the contrary, the heme oxygenase-1 (HO-1) gene was substantially upregulated in group IV. Our findings imply that the oral consumption of R. aegyptiacum ameliorates AA-induced UC in rats by restoring and reestablishing the mucosal integrity, in addition to its anti-oxidant and anti-inflammatory effects. Accordingly, R. aegyptiacum is potentially effective and beneficial in human UC therapy, which needs to be further investigated in future work.

P0570 Role of dynamic contrast-enhanced ultrasound (D-CEUS) in predicting clinical remission to advanced therapy in ulcerative colitis - a monocenter prospective pilot study

Abstract Background Ulcerative Colitis (UC) is a chronic inflammatory disease characterized by periods of relapse and remission. While colonoscopy is currently the gold standard for assessing disease activity, its invasiveness, low patient tolerance and associated risks make it unsuitable for frequent monitoring of intestinal inflammation. Despite these challenges, a "treat-to-target" approach is crucial in the era of biological therapies. Intestinal Ultrasound (IUS) offers a non-invasive, cost-effective and well-tolerated alternative to monitor treatment response. Indeed, the Milan Ultrasound Criteria (MUC), based on B-mode and color-doppler parameters, have been recently developed to assess disease activity in UC1,2. Dynamic Contrast-Enhanced Ultrasound (D-CEUS) allows visualization of tissue microvascularization, providing objective quantitative parameters derived from time-intensity curve analysis, potentially representing a promising tool to quantify bowel inflammation. The aim of our study was to assess the role of D-CEUS in predicting 6 months clinical remission to advanced therapies (biologic and small molecules). Methods We prospectively enrolled consecutive UC patients starting a new advanced treatment for clinical practice. Patients underwent IUS, D-CEUS and clinical assessment at baseline and at 8 (T1), 16 (T2) and 24 (T3) weeks after starting treatment. According to STRIDE-II consensus3, clinical remission at T3 was defined as partial Mayo score <3 and no subscore <1. Time-intensity curves were analyzed through VueBox® software (figure 1). Patients needing surgery or treatment change before T3 were classified as "non-responders". Logistic regression analysis was performed to evaluate the predictive role of D-CEUS in achieving clinical remission at T3. Statistical significance was defined as p<0.05. Results 40 patients were enrolled (mean age 39±13 years, 60% males), 44.4% (n=18) of which had previously failed at least one line of advanced therapy. At T3, 50% of patients achieved clinical remission (n=20). Univariate logistic regression analyses showed that reductions of Peak Enhancement (PE) and Wash-in Perfusion Index (WiPI) at T2 were predictive of clinical remission at T3 (OR=0.99, p=0.032 and OR=0.25, p=0.036 respectively). Moreover, the percentage changes between T2 and T0 (△% T2 – T0) of PE and WiPI were associated with 6 months clinical remission (OR=0.19 p=0.019 and OR=0.26 and p=0.04, respectively). Lastly, our results confirmed the value of MUC (at T1 and T2) in predicting clinical remission at T3 (OR=0.62, p=0.03 and OR=0.73, p=0.048, respectively). Conclusion D-CEUS provides early predictors of 6 months clinical remission in UC patients treated with advanced therapies.

Obesity Is Associated With Worsened Outcomes in Patients With Ulcerative Colitis on Advanced Therapies: A Propensity Matched Cohort Study From the U.S.

Obesity has been linked to a more severe phenotype in patients with ulcerative colitis (UC). To evaluate the impact of obesity on outcomes of advanced therapies in UC. We conducted a retrospective cohort study utilising the TriNetX database comparing the composite score of corticosteroid use, change in advanced therapy or colectomy within two years between two cohorts of patients with UC-those with obesity (BMI ≥ 30 kg/m2) and those without (BMI 18.5-24.9). The risk assessment was stratified to specific advanced therapies, including tumour necrosis factor α inhibitors (TNFi), vedolizumab, ustekinumab and Janus kinase inhibitors (JAKi). We performed 1:1 propensity score matching (PSM) for demographics, co-morbid conditions, laboratory values and IBD medications including corticosteroids. There were 3904, 2025, 1150 and 477 patients on TNFi, vedolizumab, ustekinumab and JAKi, respectively, in the UC obesity cohort. After PSM, the UC obesity cohort was at an increased risk of the composite outcome of corticosteroid use, change in therapy and colectomy compared to the UC control cohort in patients on TNFi (aHR 1.37, 95% CI 1.29-1.49), vedolizumab (aHR 1.29, 95% CI 1.16-1.43), ustekinumab (aHR 1.1.26, 95% CI 1.10-1.44) and JAKi (aHR 1.38, 95% CI 1.13-1.69). Sub-group analysis based on the specific TNFi also showed an increased risk of composite outcome for infliximab (aHR 1.36, 95% CI 1.22-1.52) and adalimumab (aHR 1.26, 95% CI 1.11-1.42) within 2 years. Obesity is associated with lower efficacy of several advanced therapies in patients with UC.

P0661 Effectiveness of upadacitinib for induction of remission in moderate-to-severe ulcerative colitis: real-world clinical outcomes appear independent of prior tofacitinib exposure

Abstract Background Upadacitinib (UPA), a selective JAK1 inhibitor, has shown efficacy in clinical trials for moderate-to-severe ulcerative colitis (UC), but real-world data remain limited, particularly on outcomes related to prior exposure to other JAK inhibitors, such as tofacitinib (TOFA). This study evaluates real-world outcomes of UPA induction therapy in UC, focusing on clinical remission and differences by prior TOFA exposure. Methods This retrospective, observational study was conducted at a tertiary care centre in Spain, including adult patients with moderate-to-severe UC who initiated UPA in routine clinical practice. Data were retrospectively collected from electronic records, capturing baseline characteristics, TOFA exposure, disease duration, and concomitant treatments. The primary outcome was clinical remission at end of induction, assessed via the Physician Global Assessment (PGA) based on symptoms and laboratory data. Secondary outcomes included changes in faecal biomarkers, adverse events, treatment discontinuation, and maintenance dosing. Results Twenty-six patients were included, with a mean age of 50.5 years, 61.5% female, and a median disease duration of 10 years. All patients had prior exposure to advanced therapies, with 53.8% treated with at least three different lines of therapy. TOFA-exposed patients had a higher rate of pancolitis (84.6% vs. 30.8%; p=0.013), though endoscopic severity was similar between groups. All patients began with 45 mg UPA once daily; 23% had concomitant treatments, including vedolizumab (n=1), apheresis (n=3), and prednisone tapering (n=2). Following induction, 65.4% achieved clinical remission and 88.5% at least a partial response based on PGA. Among TOFA-naïve patients, 76.9% achieved remission and 100% partial response, compared to 53.8% and 76.9%, respectively, in TOFA-exposed patients (p=0.9). Faecal calprotectin levels decreased, with reductions of 96.7% in TOFA-naïve patients (from median 4002 µg/g to 132 µg/g) and 97.9% in TOFA-exposed patients (from 3556 µg/g to 76 µg/g). Extended induction was needed in 38.4% of patients, with no difference based on prior TOFA exposure (46.2% vs. 30.8%, p=0.6). Discontinuation during induction occurred in 23%, due to lack of effectiveness in 50%, adverse events in 33%, and transition to vedolizumab monotherapy in 17%. Post-induction, 88.4% continued on 30 mg as maintenance, consistent across both groups. Conclusion UPA induction therapy shows promise in achieving clinical remission in moderate-to-severe UC, with comparable outcomes independent of prior TOFA exposure. Our data suggests UPA may be a valuable option in real-world, treatment-experienced UC populations. Further studies could help clarify its role in complex cases and refine treatment strategies

P0958 Curcumin-QingDai combination for active ulcerative colitis: A cost-effectiveness analysis

Abstract Background A combination of two herbal compounds, curcumin and QingDai (CurQD), was recently proposed as an effective treatment for patients with active ulcerative colitis (UC) based on randomized controlled and real-world evidence, but no cost-effectiveness analysis for this nutraceutical is currently available Methods A Markov model was generated to simulate the progression of patients with moderate-to-severe UC, by separate analysis for a cohort of advanced therapy-naïve and advanced therapy-experienced patients. Medications costs were derived from published average wholesale price (AWP) in the US. Efficacy data was modeled by synthesis of efficacy reports of randomized placebo-controlled trials and real-world cohort studies of all FDA-approved drugs for UC, and each compared with CurQD. The model used a time horizon of 54 weeks. The threshold of 50,000$/quality adjusted life-year (QALY) was chosen, and a one-way sensitivity analysis was performed for testing analysis robustness. Results The comparison of CurQD with the FDA approved advanced therapies for UC yielded an estimated incremental cost-effectiveness ratio (ICER) of over 200,000$/QALY for all comparisons. Differences ranged from -0.05 to a slight gain of 0.07 QALY in bio-experienced patients and from -0.1 to 0.04 QALY in bio-naïve patients. The one- way sensitivity analysis proved the robustness of the analysis. Conclusion The present analysis suggests that the markedly reduced cost and demonstrated efficacy of CurQD provides a significant cost-effectiveness benefit over advanced therapies for active UC, including over anti-TNF biosimilars.

P1089 Efficacy and safety of mirikizumab as induction and maintenance treatment in adults 60 years or older with moderately to severely active ulcerative colitis

Abstract Background Mirikizumab (MIRI), an anti-IL-23p19 antibody, has demonstrated efficacy and safety in adults with moderately to severely active ulcerative colitis (UC) in two Phase 3 trials (LUCENT-1/-2; NCT03518086, NCT03524092). [1] As novel therapies for UC are not well studied in adults ≥60 years (older adults), we aimed to evaluate the efficacy and safety of MIRI compared to placebo (PBO) during induction and maintenance treatment among this especially vulnerable subgroup of patients with UC. [2. 3] Methods In LUCENT-1, patients with UC were randomized to receive 3 intravenous (IV) doses of 300mg MIRI or PBO every four weeks (Q4W) at W0, W4, and W8. In LUCENT-2, responders to MIRI induction at W12 were re-randomized to subcutaneous (SC) 200mg MIRI or PBO Q4W for another 40 weeks (until W52 of continuous treatment). Endpoints evaluated in this post-hoc analysis included clinical response, clinical remission, symptomatic remission, endoscopic remission, corticosteroid (CS)-free remission (W52 only), histologic-endoscopic mucosal improvement (HEMI), histologic-endoscopic mucosal remission (HEMR), and bowel urgency (clinically meaningful improvement and remission). Efficacy in the subgroup of older adults was assessed at W12 and W52 using Fisher’s Exact tests. Safety data were summarized among patients aged 60 and older who received at least one dose of study treatment. Results At LUCENT-1 baseline, 13.3% of patients (n=154/1162) were ≥60 years, with a median age of 65 [Quartile (Q)1: 62.0, Q3: 69]. Apart from higher prevalence of comorbidities, longer disease duration, older age at diagnosis, and lower frequency of concomitant treatment with thiopurines, the baseline demographics and characteristics were similar to the overall patient population, including disease activity (per modified Mayo Score and Mayo Endoscopic Subscore), disease extent, and prior advanced therapy failure. At W12 and W52, a significantly greater proportion of older adults treated with MIRI vs. PBO achieved clinical response and symptomatic remission (Table 1). While the studies were not powered to detect differences between MIRI and PBO in this subgroup, there were numerically higher response rates for MIRI vs. PBO for all other outcomes. The safety profile for MIRI in older patients was consistent with the overall study population. There were no deaths and no discontinuations due to adverse events among MIRI-treated older adults (Table 2). Conclusion Mirikizumab induced and maintained clinical response and was well tolerated in patients 60 years of age and older with moderately to severely active UC. References 1)D’Haens G, Dubinsky M, Kobayashi T, et al. Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis [published correction appears in N Engl J Med. 2023 Aug 24;389(8):772. doi: 10.1056/NEJMx230004]. N Engl J Med. 2023;388(26):2444-2455. doi:10.1056/NEJMoa2207940 2)Ananthakrishnan AN, Nguyen GC, Bernstein CN. AGA Clinical Practice Update on Management of Inflammatory Bowel Disease in Elderly Patients: Expert Review. Gastroenterology. 2021;160(1):445-451. doi:10.1053/j.gastro.2020.08.060 3)Sturm A, Maaser C, Mendall M, et al. European Crohn’s and Colitis Organisation Topical Review on IBD in the Elderly. J Crohns Colitis. 2017;11(3):263-273. doi:10.1093/ecco-jcc/jjw188

P0536 Clinical profile and treatment outcomes in patients receiving advanced therapies for ulcerative colitis – the READ-UC real-world study

Abstract Background Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) that requires effective treatment with the main goal of inducing and maintaining remission. This study aimed to characterize UC patients receiving advanced therapies (AT), by describing their demographic and clinical characteristics and remission outcomes. Methods Cross-sectional and retrospective study in 5 IBD referral centres. Eligible subjects (≥18 years-old with UC diagnosis and receiving AT for ≥16 weeks) were consecutively enrolled at a standard of care appointment (study appointment). The primary endpoints were the proportion of patients achieving remission, defined as both symptomatic [Mayo subscores stool frequency of 0 or 1 and rectal bleeding of 0] and faecal biomarker remission [faecal calprotectin <150 µg/g]. Data on patients’ demographic and clinical characteristics, including extraintestinal manifestations (EIMs), comorbidities and treatment patterns, and on healthcare resource utilization were also collected. Results The study included 219 patients (50.9% female, median [P25;P75] age 46 [36;58] years) presenting a median disease duration of 9 [5;14] years. History or current evidence of EIMs and comorbidities were reported in 13.7% and 43.8% of patients, respectively. At diagnosis, 17.0% of patients had ulcerative proctitis, 38.1% had left-sided UC, and 44.8% had extensive UC. Over half (58.4%) were diagnosed with moderate or severe UC. Most patients (57.1%) were on their first AT, mostly on infliximab (47.5%) and vedolizumab (37.4%), while a minority received ustekinumab (5.9%), adalimumab (5.5%), tofacitinib (2.3%), and golimumab (1.4%). After treatment (26 [14; 47] months), symptomatic and faecal biomarker remission was achieved in 35.2% of patients, while 83.9% presented symptomatic remission and 46.1% of patients attained faecal biomarker remission (). There were no significant differences between patients who achieved symptomatic and faecal biomarker remission and those who did not (Table 1). Patients were prescribed concomitant specific therapies [5-ASA derivatives (78.0%), immunosuppressants (34.7%), and steroids (6.4%)]. Steroid-free remission was achieved in 34.9% of patients (Figure 1), who were off this medication for a median of 26 [15;45] months. Since AT initiation, 20.6% of patients relapsed, 11.9% were hospitalized, and 27.4% visited an emergency department. Conclusion The READ-UC study provides a detailed real-world characterization of UC patients on AT. The high proportion of patients not achieving symptomatic and faecal biomarker remission or steroid-free remission, highlights the urgent need for implementing strategies that improve UC management and outcomes of these patients.

P0667 Therapeutic Optimization of Biologic Therapy in Ulcerative Colitis: A Retrospective Analysis of Endoscopic and Biomarker Outcomes

Abstract Background Biologic therapies have transformed the management of ulcerative colitis (UC), offering effective options for achieving remission. However, some patients require therapy optimization, guided by clinical and endoscopic assessments, to enhance outcomes. Despite their routine use, real-world comparisons of optimization strategies for different biologics remain limited. This study evaluates the impact of endoscopy-guided optimization on remission rates and safety profiles in a UC cohort. Methods This retrospective study included consecutive patients at the Humanitas outpatient clinic from 2021 to 2023 who underwent endoscopy-guided therapy optimization. All patients had minimal clinical activity (pMayo score <2) and underwent colonoscopy to assess biologic therapy response. Statistical analyses included the Student’s t-test or Mann-Whitney U test for continuous variables, and chi-square or Fisher’s exact test for categorical variables. Propensity score matching (PSM) was used to balance baseline characteristics, including bio-experienced status. Results A cohort of 176 UC patients was included. Among them, therapy optimization with anti-TNFs was used in 41.2% for infliximab, 19.9% for adalimumab, and 4.6% for golimumab, while 14.4% received ustekinumab and 17.1% vedolizumab. Multivariate logistic regression analysis identified key predictors for outcomes: patients who were biologic-experienced at baseline had significantly reduced odds of achieving endoscopic remission at 12 months following optimization (odds ratio [OR] = 0.223, 95% CI: 0.070–0.711, p = 0.011). Other variables, including age at diagnosis, disease extent, and specific biologic therapy (anti-TNF vs. ustekinumab vs. vedolizumab), were not statistically significant predictors of remission. In the PSM-adjusted dataset, endoscopic remission rates were 61.5% for anti-TNFs, 33.3% for ustekinumab, and 60.0% for vedolizumab (p = 0.666, chi-square test). Biochemical remission was also highest in the anti-TNF group (61.8%), significantly greater than in ustekinumab (26.7%) and vedolizumab (53.3%) (p = 0.042, chi-square test). Adverse events were least frequent in the ustekinumab and vedolizumab groups, with only 3.5% reported for anti-TNFs (p = 0.293, Fisher’s exact test). Adverse events remained low across all groups, with a tendency toward fewer events in the ustekinumab and vedolizumab groups compared to anti-TNFs, though these differences were not statistically significant (p = 0.324, Fisher’s exact test). Conclusion The optimization of Anti-TNFs showed superior endoscopic healing and biomarker remission rates compared to ustekinumab and vedolizumab, with all groups exhibiting low adverse event rates.

P0121 Molecular features of extracellular matrix activity persist in patients who achieve mucosal healing with ustekinumab induction

Abstract Background Phase 3 trials demonstrate rates of secondary loss of response of up to 40% for many advanced therapies in ulcerative colitis (UC). At a molecular level, this may be explained by persistence of inflammatory mediators in the mucosa despite successful treatment induction, and transcripts involved in leukocyte infiltration persist in patients responding to infliximab and vedolizumab compared to non-IBD controls [1]. We considered if any disease-relevant transcripts persisted in ustekinumab induction responders and if these differed depending on symptom resolution. Methods We interrogated data from the UNIFI trial, where baseline mucosal biopsies from patients treated with ustekinumab for moderate-to-severe UC underwent RNA profiling (Gene Expression Omnibus, GSE206285). Patients who achieved combined histo-endoscopic (mucosal) healing either with (disease clearance, “DC”) or without (mucosal healing, “MH only”) clinical remission at week 8 were included in subsequent analyses, along with non-IBD controls from this cohort (n=18). We compared gene expression and the enrichment of functional pathways using limma and GSEA (gene set enrichment analysis), respectively, between the two groups of responders and controls in R (v 4.2.3, Vienna). The Reactome database of pathway annotations was used. Gene signature enrichment was calculated by gene set variation analysis. Results Of the 54 patients who responded to ustekinumab, 15 experienced MH only and 39 had DC. Principal component analysis showed that these responders were distinct from controls but overlapped with each other (figure 1). For MH only compared to controls, there were 8375 differentially expressed genes (DEGs), of which 4936 were upregulated. There were 8778 DEGs between DC and controls, with 5331 upregulated. GSEA revealed that the DEGs in each comparison mainly represented pathways relating to the extracellular matrix (ECM), such as ECM degradation and collagen formation. There were no DEGs between MH only and DC but GSEA suggested that interleukin signalling and ECM organisation were upregulated in MH only. Interestingly, there was large heterogeneity in enrichment of the DEGs amongst all the responders. Similarly, there was wide variation in the enrichment of genes relating to the ECM. Conclusion Despite resolution of histo-endoscopic disease activity at week 8 in ustekinumab-treated UC patients, there was persistence of molecular inflammation, particularly ECM-related genes. However, the extent of this varied between patients; future work will examine if this explains why some eventually lose response whilst others maintain long-term remission. Ongoing inflammatory mechanisms may explain symptom persistence despite mucosal healing.

P1084 Safety of tofacitinib and upadacitinib compared to other advanced therapies in ulcerative colitis: a large real-world comparison

Abstract Background Whether adverse events of special interest[1] related to JAK inhibitors (JAKi) are a concern compared to other drugs used in ulcerative colitis (UC) needs investigation. We aimed to assess and compare the frequency of adverse events of special interest by JAKi within the class, and with other advanced therapies, on a large real-world population of UC patients. Methods This was a non-interventional, retrospective study conducted with data obtained from TriNetX from patients with diagnosis of adult UC, exposed to advanced therapies (range 1-1095 days). The final cohort included 866 patients over 444,424 UC patients available in the database who matched the query criteria. Adverse events (any), herpes zoster, cardiovascular events, thromboembolic events, cancer (any), non-melanoma skin cancer were investigated. We compared each JAKi with TNF, IL-23 antagonists, and vedolizumab, and within the class by survival analyses and log-rank test. Propensity score matching and adjustment for confounders, such as age, sex, first or second line advanced therapy, smoking habit and other known baseline risk factors, was done. Statistical significance was set as a p value < 0.05. Results Only tofacitinib and upadacitinib were included, as data on filgotinib were not available. Tofacitinib was associated with statistically significant lower rates of thromboembolic events than anti-TNFs (HR 0.61, 95% CI 0.38-098, p=0.04), and lower rates of cancer than vedolizumab (HR 0.63, 95% CI 0.41-0.96, p=0.03), but higher rates of herpes zoster than anti-IL23 (p=0.001). Upadacitinib showed lower rates of thromboembolic events (p=0.001), but higher rates of herpes zoster reactivation than IL-23 (p=0.001). Similar safety profile was found between tofacitinib and upadacitinib when they were directly compared. Conclusion Anti-JAK show a similar safety profile than all the other drug classes used in UC. Herpes zoster infection/reactivation remains the only adverse event of note for both JAKi.

P0149 Deep functional analysis of a defined sulphide-reducing diet (4-SURE diet) as a novel therapy for ulcerative colitis (UC) demonstrates all specific luminal micro environmental objectives were achieved

Abstract Background As a dietary approach to reducing inflammation in ulcerative colitis (UC), the 4-SURE diet was designed to correct pathogenic alterations of excessive protein fermentation and hydrogen sulphide (H2S) production in the distal colon. Specific dietary objectives were achieved (Day et al,J Nutr 2022;152:1690) but it is uncertain whether mechanistic objectives could be achieved with 8 weeks of diet. Therefore, we aimed to perform a deep functional analysis (microbial and metabolomic) of the faeces. Methods Faecal samples of 28 adults with mild-moderately active UC were collected at week 0 and 8 of diet intervention, subsampled and stored at−80 °C. Shotgun metagenomic sequencing was used to identify genes involved in H2S metabolism. Metagenomic reads were trimmed, reads mapping to the human genome removed. Gene identification was performed using Diamond v2.1.9 for alignment against a database of genes involved in global sulphur cycling. Gas-chromatography mass-spectrometry was used to characterise volatile organic compounds (VOCs) with specific analysis of products of protein fermentation. Microbiota capacity to produce H2S was assessed by anaerobic incubation of homogenates followed by spectrophotometric determination of total H2S production. Results Majority of microbiome members belonged to the Bacteroidota and Bacillota phyla, with no significant difference in bacterial diversity determined between time points (p=0.16). However, using a Random Forest Classifier, known H2S producers, Odoribacter and Peptostreptococcaceae, were identified as the most important taxa in discriminating between pre and post-diet samples, with abundances markedly lower after diet intervention. A shift in microbiota metagenomic profiles putatively involved in H2S metabolism was identified post-diet, with differences (p<0.05, Wilcoxon signed-rank with Benjamini-Hochberg correction) in 12 of 23 analysed genes involved in H2S cycling determined, including iscS, cysK (Fig), metC, luxS, asrC and sseA. 173 faecal VOCs were identified across all samples. Indole (a specific marker of protein fermentation) decreased from 0.42 [-0.25,0.61] at week 0 to -0.28 [-0.77,0.48] at week 8 (p=0.007, FDR correction; Fig). Faecal H2S reduced from median 2.61 (interquartile range 2–4.96)µmol to 1.41 (0.81-2.27)µmol of H2S/g stool (wet weight)(p=0.002)(Fig). Conclusion Deep functional analysis of the faeces demonstrated the micro-environmental objectives of the 4-SURE diet successfully reduced protein fermentation, changed microbial community sulphur-metabolic gene profile and reduced H2S production ex vivo. Applying functional analysis to a diet study is novel, highlighting exemplar framework for including biomarkers of pathogenic relevance in analysis of therapeutic diets.

P1246 Fatigue trajectory and the impact of disease course through the first year after diagnosis in patients with Inflammatory Bowel Disease (the IBSEN III study)

Abstract Background Fatigue is common in both Crohn's disease (CD) and ulcerative colitis (UC), but the pathogenesis is still unclear. The primary aim of this study was to assess the odds for substantial fatigue (SF) and chronic fatigue (CF) one year after diagnosis based on the presence of SF at baseline. The secondary aim was to identify clinical factors that may be associated with SF one year after diagnosis. Methods Patients ≥18 years with a definite diagnosis of CD or UC at 1-year follow-up were recruited from the Inflammatory Bowel Disease South-Eastern Norway (IBSEN III) study, a population-based, observational inception cohort. Patients who completed the Fatigue Questionnaire (FQ) at the time of diagnosis and at the 1-year follow-up were included. CF was defined as a dichotomized FQ score ≥4 (SF) with duration ≥ 6 months. Univariate binary logistic regression analysis was used to estimate the odds for SF/CF one year after diagnosis depending on the presence of SF at baseline. Associations between SF at the 1-year follow-up and possible predictive clinical factors were included in a multivariate logistic regression model. All analysis were performed stratified by type of diagnosis. Results In total, 596/1370 (43.5%) patients were included (CD: 196 (32.9%), UC: 400 (67.1%)). The presence of SF at the time of diagnosis compared to no initial fatigue, significantly increased the odds for SF (CD: OR=8.23, 95% CI [4.13; 16.39], UC: OR=6.67, 95% CI [4.24; 10.49]) and CF (CD: OR=6.38, 95% CI [2.71; 15.03], UC: OR=4.59, 95% CI [2.68; 7.83]) at the 1-year follow-up. Among patients with CD, development of non-passable stricture and/or surgically treated stricture within first year of disease (OR=4.37, 95%CI [1.58;12.11]), subjective flares since diagnosis (OR=2.22, 95%CI [1.11; 4.43]), female gender (OR=2.96, 95%CI [1.47; 5.95]) and presence of comorbidities (OR=4.36, 95%CI [2.06; 9.22]) were all independently associated with SF at the 1-year follow-up. For patients with UC, current biological treatment (OR=5.14, 95%CI [1.56; 16.96]), Mayo endoscopic score (0-3) at the 1-year follow-up (OR=1.54, 95%CI [1.01; 2.35]), subjective flares since diagnosis (OR=2.66, 95%CI [1.24; 5.72]) and female gender (OR=2.20, 95%CI [1.06; 4.57]) were independently associated with SF at the 1-year follow-up. Conclusion Fatigue may be expected to persevere during the first year of disease if present at the time of diagnosis. For patients with CD as well as UC, clinical factors reflecting severe disease, as severe stricturing disease in CD, biological therapy and higher Mayo endoscopic score in UC, were significantly associated with SF one year after diagnosis. Furthermore, comorbidities (only CD), female gender and subjective flares since diagnosis increased the odds for SF.

DOP051 Upadacitinib for induction of remission in pediatric Ulcerative Colitis: An international multicenter study

Abstract Background Data on upadacitinib therapy in children with ulcerative colitis (UC) or unclassified inflammatory bowel disease (IBD-U) are scarce. We aimed to evaluate the effectiveness and safety of upadacitinib as an induction therapy in pediatric UC or IBD-U. Methods In this multicenter retrospective study, children treated with upadacitinib for induction of remission of active UC or IBD-U from 30 centers worldwide were enrolled. Demographic, clinical and laboratory data as well as adverse events (AEs) were recorded at week 8 post induction. Results One hundred children were included (90 UC and 10 IBD-U, median age 15.6 [interquartile range 13.3–17.1] years). Ninety-eight were previously treated with biologic therapies, and 76 were treated with ≥2 biologics. At the end of the 8-week induction period, clinical response, clinical remission, and corticosteroid-free clinical remission (CFR) were observed in 84%, 62%, and 56% of the children, respectively. The median pediatric ulcerative colitis activity index (PUCAI) decreased from 45 [33-60] to 0 [0-20] at week 8 (p < 0.001; Figure 1). Normal C-reactive protein and fecal calprotectin (FC) <150 mcg/g were achieved in 75% and 50%, respectively. The median FC level declined from 1645 [628-2263] mcg/g at baseline to 140 [33-669] mcg/g at week 8 (p < 0.001) (Figure 1).Combined CFR and FC remission was observed in 18/46 (39%) children with available data at 8 weeks. AEs were recorded in 37 children, including one serious AE of an appendiceal neuroendocrine tumor. The most frequent AEs were hyperlipidemia (n=13), acne (n=12), and infections (n=10, five of whom with herpes viruses). Conclusion In this largest and first multicenter study on a cohort of children with UC treated with upadacitinib, upadacitinib was an effective induction therapy for refractory pediatric UC and IBD-U. Efficacy should be weighed against the potential risks of AEs.

P1211 Factors Associated with the Optimization of Biological Therapy in Crohn's Disease and Ulcerative Colitis: Insights from the National GEDIIB Patient Registry in Brazil

Abstract Background Biological therapy has revolutionized the treatment of inflammatory bowel disease (IBD); however, a subset of patients still requires therapy optimization to achieve therapeutic goals. This study aimed to identify patients who underwent biological therapy optimization (TO) and compare their characteristics with those who did not require such adjustments. Methods A retrospective study was conducted using data from the national patient registry of GEDIIB (Brazilian Crohn's and Colitis Organization). A total of 1,660 patients with Crohn's disease (CD) and 530 patients with ulcerative colitis (UC) undergoing biological therapy were included. The need for TO was determined based on clinical or endoscopic criteria specific to each participating center. Statistical analyses included association tests and Poisson regression. Results The need for TO was more frequent among patients with CD(33.3%) compared to those with UC (26.2%) (p=0.003). In CD, optimization was associated with younger age (p=0.016), stenosing (p=0.03) or penetrating behavior (p=0.015), perianal disease (p<0.001), presence of fistula (p=0.019), and prior surgery (p=0.044). Table 1 displays the adjusted frequency ratio (FR) for TO in CD patients. After adjusting for confounding factors, the most significant predictors for optimization in CD were younger age, perianal disease, and prior surgery. In UC, optimization was associated with younger age (p=0.013), pancolitis extent (p<0.001), previous surgery (p=0.037), hospitalization (p=0.025), and chronic liver disease (p=0.024). Table 2 presents the adjusted FR for therapy optimization in UC patients. After adjustment, the factors most strongly associated with optimization in UC were prior surgery and chronic liver disease. Conclusion Approximately 30% of patients required optimization of biological therapy. This need was associated with younger age, a more severe disease profile, and the presence of complications, such as perianal disease in CD, as well as a history of surgery and hospitalization in UC. References Papamichael K, Cheifetz AS, Melmed GY, Irving PM, Vande Casteele N, Kozuch PL, Raffals LE, Baidoo L, Bressler B, Devlin SM, Jones J, Kaplan GG, Sparrow MP, Velayos FS, Ullman T, Siegel CA. Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol. 2019 Aug;17(9):1655-1668.e3. doi: 10.1016/j.cgh.2019.03.037. Fróes RSB, Andrade AR, Faria MAG, de Souza HSP, Parra RS, Zaltman C, Dos Santos CHM, Bafutto M, Quaresma AB, Santana GO, Luporini RL, de Lima Junior SF, Miszputen SJ, de Souza MM, Herrerias GSP, Junior RLK, do Nascimento CR, Féres O, de Barros JR, Sassaki LY, Saad-Hossne R. Clinical factors associated with severity in patients with inflammatory bowel disease in Brazil based on 2-year national registry data from GEDIIB. Sci Rep. 2024 Feb 21;14(1):4314. doi: 10.1038/s41598-024-54332-1.

P0685 Endoscopic severity at presentation and C-reactive protein predict immediate and twelve-month outcomes of second-line medical therapy in Acute Severe Ulcerative Colitis

Abstract Background Medical rescue therapy (MRT) is effective in intravenous corticosteroid refractory acute severe ulcerative colitis (ASUC). Our primary objective was to identify parameters which identify initial and sustained response to MRT. Methods Two cohorts were studied retrospectively. Analysis of 66 adult ASUC admissions receiving MRT between 2015-19 at Gold Coast University Hospital and Logan Hospital was first performed. Clinical, endoscopic and laboratory data were collected. Response was defined as avoiding colectomy during the same admission. Univariable and multivariable logistic regression were employed to identify predictors of response. The predictors were validated in 99 patients admitted to Gold Coast University Hospital and Sunshine Coast University Hospital between 2020-23. Results In the development cohort, 55/66 patients (83.3%) responded to MRT. On multivariable analysis, UCEIS score at admission [Coef - 0.105 (-0.19 to – 0.007), p=0.03] and CRP on day 3 of post commencement of MRT (CRP on day R+3) [Coef -0.004 (-0.0008 to -0.0004), p=0.03] identified response to MRT. All patients (n=20) with a UCEIS score < 6 [Sensitivity 41.7%, Specificity 100%, PPV 100%, NPV 26.3%] and 97.1 % (33/34) patients with a CRP on day R+3 < 22mg/L responded to MRT [Sensitivity 71.7%, Specificity 90%, PPV 97.1%, NPV 40.9%]. In the validation cohort, 93/99 (94%) patients responded to MRT; 92.6% (25/27) with a UCEIS score < 6 [Sensitivity 26.9%, Specificity 66.7%, PPV 92.6%, NPV 5.6%] and 100% (72/72) patients with CRP on day R+3 < 22mg/L responded to MRT [Sensitivity 85.7%, Specificity 100%, PPV 100%, NPV 33.3%]. In patients with both UCEIS <6 and CRP on day R+3 < 22mg/L, 15/15 (100%) and 18/18 (100%), in the development and validation cohorts respectively, responded to MRT. At 12 months after hospitalisation, in the development cohort, 45 (68.1%) patients had avoided colectomy. Of the patients with a UCEIS score <6, 19 (95%) patients and 28/34 (82.4%) patients with CRP on day R+3 < 22mg/L avoided colectomy. In the validation cohort, at 12 months, 84 (84.9%) patients had avoided colectomy. Of the patients with a UCEIS score < 6, 24/27 (88.9%) and 66/72 (91.7%) patients with CRP on day R+3 < 22mg/L had avoided a colectomy at 12 months. In patients with both UCEIS <6 and CRP on day R+3 < 22mg/L, 14/15 (93.3%) and 17/18 (94.4%), in the development and validation cohorts respectively, had avoided colectomy at 12 months. Conclusion UCEIS score < 6 at admission and CRP on day R+3 < 22mg/L predict response to second-line MRT and colectomy is extremely unlikely either on the index admission or within 12 months.

P0878 Early lymphocytosis is a novel predictor of response to rescue infliximab in acute severe ulcerative colitis: results from PREDICT-UC

Abstract Background The ability to predict failure of infliximab (IFX) in acute severe ulcerative colitis (ASUC) is crucial to identify patients who may benefit from dose-escalation, sequential rescue or early colectomy. Methods PREDICT-UC (NCT02770040) was a randomised controlled trial that compared IFX dosing strategies in ASUC.1 Clinical factors and biomarkers were collected daily between day 0 to 3 post-IFX and assessed on their ability to predict IFX failure (Lichtiger score ≥10 on day 14) and 3-month colectomy. Stepwise logistic regression was used to develop a Risk of IFX Failure (RIF) index, which was calibrated against the observed risk of IFX failure. The RIF index represents the predicted probability of IFX failure and takes on values between 0 and 1. Internal validation was performed using bootstrap validation. Results Of 138 patients, 46 received a first IFX dose of 10mg/kg and 92 received 5mg/kg; 39 (28%) experienced IFX failure and 17 (12%) required colectomy by 3 months. There was no difference in lymphocyte count (LC, ×109/L) on day 0 (prior to IFX) in patients who failed or responded to IFX (median [IQR] 1.1 [0.9–1.6] vs 1.3 [0.9–1.8], P=0.47). LC rose by day 3 in both groups, though to a lesser degree in patients who failed IFX (median [IQR] 1.9 [1.4–2.8]) compared to responders (3.3 [2.1–4.9]; P=0.004), and lower in patients requiring colectomy (median [IQR] 1.4 [1.1–1.9] vs 3.0 [2.0–4.8]; P<0.001). A lower day 3 LC was predictive of IFX failure (AUC 0.71, 95% CI 0.60–0.81) and colectomy (AUC 0.83, 95% CI 0.74–0.92). A higher CRP was predictive of both IFX failure and colectomy at all time-points from days 0 to 3 (day 3 CRP AUC 0.68, P=0.003 and 0.70, P=0.019 respectively). A lower day 3 albumin predicted IFX failure (AUC 0.63, P=0.039) while a lower day 2 albumin predicted colectomy (AUC 0.66, P=0.042). The final RIF index comprised day 3 stool frequency, rectal bleeding score, CRP and LC. The RIF index had a naïve AUC of 0.80 and an optimism-adjusted AUC of 0.73 (95% CI 0.65–0.80) for predicting IFX failure, and a naïve AUC of 0.90 and an optimism-adjusted AUC of 0.88 (95% CI 0.81–0.94) for predicting colectomy. A RIF index threshold of ≥0.15 had an 85% sensitivity and 90% negative predictive value (NPV) for IFX failure and a 94% sensitivity and 98% NPV for colectomy, while a threshold of ≥0.50 had a 92% specificity and 69% positive predictive value (PPV) for IFX failure, and an 88% specificity and 42% PPV for colectomy. Conclusion Lymphocytosis by day 3 is a novel predictor of response to IFX rescue in ASUC. The RIF index is a simple on-treatment risk index that predicts IFX failure and colectomy, and may be used to inform IFX dose-optimisation or switch to alternate therapies. References 1Choy MC, Li Wai Suen CFD, Con D, et al. Intensified versus standard dose infliximab induction therapy for steroid-refractory acute severe ulcerative colitis (PREDICT-UC): an open-label, multicentre, randomised controlled trial. Lancet Gastroenterol Hepatol 2024; 9(11): 981-96.

P0378 Normalization or reduction of at least 50% in faecal calprotectin levels after 3 months of treatment predicts clinical and endoscopic remission at 1 year in patients with ulcerative colitis: results of the prospective MIROIR study

Abstract Background The STRIDE-2 consensus considers the improvement of faecal calprotectin (Fcal) (biochemical response) as an intermediate goal in ulcerative colitis (UC). However, no consensual definition of biochemical response is currently available. MIROIR study evaluated the performance of Fcal levels three months after initiating treatment to predict clinical and endoscopic remission at 12 months in UC. Methods In this prospective longitudinal prediction study, any adult UC patient with partial Mayo score (>2) and endoscopic Mayo score (MES) ≥2, requiring starting therapy for UC was included. Patients with acute severe colitis or prior colectomy were excluded. Clinical and biological data, including Fcal levels, were collected, at baseline, month 3 (M3), M6, M9, and M12. Endoscopic and histological (Nancy index) evaluations were performed at inclusion, 3 months, and 12 months. Physicians were blinded from Fcal levels. The primary endpoint was Fcal level at 3 months, while the primary dependent variable was therapeutic success defined as clinical remission (total Mayo score ≤ 2 with endoscopic Mayo score (MES) = 0 or 1) at M12, without dose escalation or treatment discontinuation due to failure. Results Among 62 included patients, the mean age at inclusion was 43.9 ± 14.4 years, with 55.5% being male. UC extent was proctitis (E1) in 13.7%, left-sided colitis (E2) in 39.2%, and pancolitis (E3) in 47.1%. At baseline, endoscopic activity was Mayo 2 and Mayo 3 in 46.3% and 53.7%, respectively. and median ffcal level was 665 µg/g [296-1800]. Initiated therapies were 5-ASA (13.0%), corticosteroids (13.0%), immunosuppressants (5.5%), anti-TNF agents (26.4%), vedolizumab (22.6%), ustekinumab (35.8%), and tofacitinib (3.7%). At M3, 10 patients (18.5%) achieved endoscopic remission (MES 0), 23 (42.6%) showed endoscopic improvement (MES 0 or 1), while 10 (18.5%) and 13 (24.1%) still had endoscopic activity, MES 2 or 3, respectively. The median Fcal level at M3 correlated with MES at M3: 27 [14-142], 115 [20-460], 665 [135-1830], 755 [472-1340] (p = 0.0006) for MES 0, 1, 2 and 3, respectively, and with endoscopic activity (MES ≥2) at M3 (90 [18-192] vs. 679 [428-1830], p = 0.0001) with a substantial effect size (1.32 [0.72-1.91]). Fcal level <150 µg/g at M3 was the best threshold to predict therapeutic success at M12. A decrease of at least 50% in Fcal level at M3 was the best threshold for predicting therapeutic success at M12, with high negative predictive value: 92.3%[74.9% - 99.1%]. Conclusion Our study demonstrates that normalization or reduction of at least 50% in Fcal level after 3 months of treatment predicts therapeutic success at 1 year in ulcerative colitis. This could therefore be proposed as a definition of biochemical response.

P1145 Comparison of Clinical Relapse between Tofacitinib and Filgotinib as Maintenance Therapy in Ulcerative Colitis Patients in Clinical Remission: A Retrospective Propensity Score-Matched Cohort Study

Abstract Background Strategies to reduce relapse after induction therapy using JAK inhibitor are controversial in patients with ulcerative colitis (UC). In this study, we aimed to compare relapse rate between tofacitinib (TOF) treatment and filgotinib (FIL) treatment for UC patients in clinical remission. Methods We used the data of UC patients who received TOF 10mg/day or FIL 200mg/day as maintenance therapy between May 2018 and October 2024. We included UC patients in clinical remission at baseline. Clinical remission was defined as follows: partial Mayo score ≤2, each subscore ≤1 and a rectal bleeding subscore of 0. The primary outcome was the time to relapse, defined as the requirement of dose escalation or switching therapy for UC with the worsening of clinical symptoms. The secondary outcome was safety during the observation period. Kaplan-Meier analysis and log-rank test were used in order to assess difference in therapy duration between two groups. A propensity score-matched (PSM) analysis was performed to adjust for potential confounders. Results We enrolled patients with UC who received either TOF 10mg/day (n = 101) or FIL 200mg/day (n = 43) as maintenance therapy. The median age was 39 [IQR 28–50] and 44 [34–55] years, and the median disease duration was 4 [1–11] and 7 [5–16] years, respectively. The number of previous exposures to anti-TNF agent was 52 (51.5%) and 18 (41.9%), respectively. In the TOF group, cumulative relapse rates at 8, 16, 24, and 48 weeks were 0%, 8.8%, 12.7%, and 25.5%, respectively. On the other hand, in the FIL group, cumulative relapse rates at 8, 16, 24, and 48 weeks were 0%, 2.3%, 4.7%, and 7.0%, respectively. After PSM, forty-three patients in both the TOF and FIL groups were isolated. The cumulative clinical relapse rate was significantly higher in the TOF group than in the FIL group (p = 0.039). Adverse events that required treatment discontinuation were reported in 8 patients in the TOF group, but no adverse events leading to discontinuation were observed in the FIL group. Conclusion Our findings suggested that FIL could prevent relapse in UC patients who are in clinical remission more effectively than TOF.

P0961 Establishing a new cellular therapy for patients with Ulcerative Colitis

Abstract Background Inflammatory Bowel Diseases (IBD), which include Crohn’s Disease and Ulcerative Colitis (UC), show an accelerated incidence rate, affecting up to 1% in Western countries, and an increased burden in healthcare costs, reaching up to 5.6 billion euros per year. Although there are several treatment options, the remission rates are around 30-60%, with primary non-response and loss of response to be the main reasons for changing treatment plans. Thus, there is a need for new therapeutic strategies targeting these groups of non-responding patients. Towards this, we are developing a novel cellular therapy for UC, using autologous transplantation of intestinal epithelial organoids. Methods Here, colonic epithelial cells will be isolated, expanded under GMP conditions, and transplanted into ulcerated colonic regions of patients with UC, to promote and accelerate mucosal healing. This initial strategy targets patients with localized ulceration unresponsive to first- and second-lines of treatments. Results We have established a robust protocol for expanding intestinal epithelial organoids. These organoids contain all major cell type populations that orchestrate the intestinal epithelium. We have successfully transplanted both murine and human colonic organoids into NOG mice. After successful engraftment onto the damaged intestinal mucosa, they promote and accelerate mucosal healing. Currently, we are establishing scale-up culturing methodologies, in order to expand our cell cultures to a number of cells that would be enough to promote mucosal healing during transplantation in humans. Finally, we are refining the cell culture conditions to be GMP-approved, and thus, registering our final product as acceptable to be used during human clinical trials. Conclusion Our approach could offer a new therapeutic option for patients with UC that do not respond to current drug regimens and are in need for an effective treatment.