Remission In Ulcerative Colitis Research Articles

Arginase 2 attenuates ulcerative colitis by antioxidant effects of spermidine.

Spermidine suppress oxidative stress and is involved in various disease pathogenesis including ulcerative colitis (UC). Arginase 2 (ARG2) plays a central role in the synthesis of spermidine. This study aimed to clarify the effect of endogenously produced spermidine on colitis. The physiological role of ARG2 and spermidine was investigated using Arg2-deficient mice with reduced spermidine. Immunohistochemical staining of the rectum was used to analyze ARG2 expression and spermidine levels in healthy controls and UC patients. In mice with dextran sulfate sodium-induced colitis, ARG2 and spermidine levels were increased in the rectal epithelium. Spermidine protects colonic epithelial cells from oxidative stress and Arg2 knockdown cells reduced antioxidant activity. Organoids cultured from the small intestine and colon of Arg2-deficient mice both were more susceptible to oxidative stress. Colitis was exacerbated in Arg2-deficient mice compared to wild-type mice. Supplementation with spermidine result in comparable severity of colitis in both wild-type and Arg2-deficient mice. In the active phase of UC, rectal ARG2 expression and spermidine accumulation were increased compared to remission. ARG2 and spermidine levels were similar in healthy controls and UC remission patients. ARG2 produces spermidine endogenously in the intestinal epithelium and has a palliative effect on ulcerative colitis. ARG2 and spermidine are potential novel therapeutic targets for UC.

Effects of Thiopurine Withdrawal on Vedolizumab-Treated Patients With Ulcerative Colitis: a Randomized Controlled Trial

Background and aimsThe impact of thiopurine de-escalation whilst on vedolizumab versus continuing thiopurine therapy in ulcerative colitis (UC) is unclear. We aimed to determine the effect of thiopurine withdrawal for patients with UC in remission on vedolizumab. MethodsThis multi-centre randomized controlled trial recruited UC patients on vedolizumab 300mg IV every 8 weeks and a thiopurine. Patients in steroid-free clinical remission for ≥6 months and endoscopic remission/improvement (Mayo endoscopic subscore[MES]≤1) were randomized 2:1 to withdraw or continue thiopurine. Primary outcome was comparing week 48 vedolizumab trough concentrations. Secondary outcomes were clinical relapse (partial Mayo score≥3 and fecal calprotectin>150μg/g or increase in MES≥1 from baseline), fecal calprotectin remission (<150μg/g), C-reactive protein remission (<5mg/L), centrally-read endoscopic remission (MES=0), histologic remission (Nancy index=0), histo-endoscopic remission and adverse events. ResultsIn total, 62 patients were randomized to continue (n=20) or withdraw (n=42) thiopurine. At week 48, vedolizumab trough concentrations were not significantly different between continue and withdrawal groups (14.7μg/mL [IQR:12.3-18.5μg/mL] versus 15.9μg/mL [IQR:10.1-22.7μg/mL] respectively, P=0.36). The continue group had significantly higher fecal calprotectin remission (95.0% [19/20] versus 71.4% [30/42], P=0.03), histologic remission (80.0% [16/20] versus 48.6% [18/37], P=0.02) and histo-endoscopic remission (75.0% [15/20] versus 32.4% [12/37], P=0.002) than the withdrawal group. Histological activity (HR:15.5 [95%CI:1.6-146.5],P=0.02) and prior anti-TNF exposure (HR:6.5 [95%CI:1.3-33.8],P=0.03) predicted clinical relapse after thiopurine withdrawal. ConclusionThiopurine withdrawal did not affect vedolizumab trough concentrations. However, it may increase fecal calprotectin, histologic and histo-endoscopic activity. Histological activity and prior anti-TNF exposure may predict disease relapse upon thiopurine withdrawal for patients using vedolizumab for UC; Australian and New Zealand Trial Registry, number ACTRN12618000812291.

Avoidant/restrictive food intake disorder symptoms are not as frequent as other eating disorder symptoms when ulcerative colitis is in remission.

Recent studies have shown that up to 53% of patients with inflammatory bowel disease (IBD) screen positive for avoidant/restrictive food intake disorder (ARFID). There is however concern that ARFID screening rates are over-inflated in patients with active disease. We aimed to evaluate the frequency and characteristics of ARFID symptoms using the Nine Item ARFID Screen (NIAS), and to use another eating disorder measure, the Eating Disorder Examination-Questionnaire 8 (EDE-Q8), to rule-out/characterize other eating disorder cognitive and behavioral symptoms. Participants included adults with UC who are enrolled in an in an ongoing cohort study with quiescent UC (SCCAI ≤2 or fecal calprotectin <150 µg/g with corticosteroid-free clinical remission for ≥ 3 months) at baseline. We used self-reported data on demographics, gastrointestinal medications, medical comorbidities, NIAS scores, and other eating disorder symptom scores (8-item Eating Disorder Examination-Questionnaire; EDE-Q-8). We included 101 participants who completed the NIAS at their baseline cohort assessment (age 49.9±16.5 years; 55% female). Eleven participants (11%) screened positively for ARFID on at least one NIAS subscale (n=8 male). Up to thirty participants (30%) screened positive for other eating disorder symptoms (EDE-Q-8 Global ≥2.3). Overall score distributions on the EDE-Q-8 showed that participants scored highest on the Weight Concern and Shape Concern subscales. Among adults with UC in remission, we found a low rate of ARFID symptoms by the NIAS but a high rate of positive screens for other eating disorder symptoms.

Probiotics for inflammatory bowel disease: Is there sufficient evidence?

Inflammatory bowel disease (IBD) refers to chronic inflammatory disorders of the gut. Ulcerative colitis (UC) and Crohn's disease (CD) are two subtypes of IBD. Evidence suggests that the intestinal microbiota plays a role in the pathogenesis of IBD, so probiotics have garnered a lot of interest as a potential treatment or prevention for IBD. However, clinical evidence of the efficacy of probiotics is still debatable. We performed a literature review. An advanced search considered clinical studies on probiotic for IBD from inception to 2023 in PubMed, Embase, Cochrane Library, and Web of Science. In the treatment of UC with probiotics, only Escherichia coli Nissle 1917 for maintenance treatment of UC in remission, and Bifidobacterium and VSL#3 for induction of remission in patients with mild to moderately active UC have shown strong evidence. Currently, there are no definitive conclusions regarding the effectiveness of probiotics in CD. The mechanism of probiotic treatment for IBD may be related to reducing oxidative stress, repairing the intestinal barrier, regulating intestinal flora balance, and modulating intestinal immune response. Differences in the benefits of probiotics between CD and UC may be attributable to the different lesion extent and immune-mediated pathophysiology. More robust randomized clinical trials are required to validate the efficacy and safety of diverse probiotic strains in IBD.

Serum Amyloid A as a non-invasive predictive biomarker of mucosal healing in ulcerative colitis patients

Ulcerative colitis is a chronic immune-mediated inflammatory condition of large intestine that is frequently associated with inflammation of the rectum but often extends proximally to involve other areas of the colon. The ultimate target of therapy is complete healing in the form of clinical remission, complete endoscopic and histological healing, and transmural healing for which endoscopy is mandatory. Colonoscopy may not always be applicable due to possible complications in active ulcerative colitis. Therefore, non-invasive biomarkers are needed to avoid the disadvantageous complications of invasive diagnostic procedures. The aim of this study was to evaluate the role of serum Amyloid-A (SAA) as a non-invasive predictive biomarker of mucosal healing in comparison to different laboratory biomarkers, and endoscopic activity scores. The study included 100 ulcerative colitis patients classified into two groups: 50 patients in clinical, and biochemical remission and 50 patients in activity. Complete blood picture, C-reactive protein, erythrocyte sedimentation rate, fecal calprotectin, and SAA were measured and recorded, colonoscopies with histopathological examination were done for all patients. SAA levels were significantly higher in patients with active ulcerative colitis than in clinical remission patients (p &lt;0.001). In clinical, remission patients without full mucosal healing, SAA was positively correlated with endoscopic disease activity represented with Mayo score, Mayo endoscopic sub-score and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) (p&lt; 0.001). However, there was no significant correlation between SAA and endoscopic scores among the activity patients’ group. The cut off value of SAA for determining disease activity was &gt; 5.199 µg/ml with 100 % sensitivity, specificity of 92 %, and accuracy of 99.6%. In conclusion, SAA can be used for prediction of mucosal healing in ulcerative colitis remission patients despite not being superior to fecal calprotectin. However, it was unable to differentiate between the different disease activities or extents.

Clinical statistical analysis plan for the ACCURE trial: the effect of appendectomy on the clinical course of ulcerative colitis, a randomised international multicentre trial

BackgroundThe primary treatment of ulcerative colitis (UC) is medical therapy using a standard step-up approach. An appendectomy might modulate the clinical course of UC, decreasing the incidence of relapses and reducing need for medication. The objective of the ACCURE trial is to assess the efficacy of laparoscopic appendectomy in addition to standard medical treatment in maintaining remission in UC patients. This article presents the statistical analysis plan to evaluate the outcomes of the ACCURE trial.Design and methodsThe ACCURE trial was designed as a multicentre, randomised controlled trial. UC patients with a new diagnosis or a disease relapse within the past 12 months, treated with 5-ASA, corticosteroids, or immunomodulators until complete clinical and endoscopic remission (defined as total Mayo score < 3 with endoscopic subscore of 0 or 1), were counselled for inclusion. Also, patients previously treated with biologicals who had a washout period of at least 3 months were considered for inclusion. Patients were randomised (1:1) to laparoscopic appendectomy plus maintenance treatment or a control group (maintenance therapy only). The primary outcome is the 1-year UC relapse rate (defined as a total Mayo-score ≥ 5 with endoscopic subscore of 2 or 3, or clinically as an exacerbation of symptoms and rectal bleeding or FCP > 150 or intensified medical therapy other than 5-ASA therapy). Secondary outcomes include number of relapses per patient, time to first relapse, disease activity, number of colectomies, medication usage, and health-related quality of life.DiscussionThe ACCURE trial will provide comprehensive evidence whether adding an appendectomy to maintenance treatment is superior to maintenance treatment only in maintaining remission in UC patients.Trial registrationDutch Trial Register (NTR) NTR2883. Registered May 3, 2011. ISRCTN, ISRCTN60945764. Registered August 12, 2019.

Effect of Tofacitinib on One-Year Colectomy Risk in Anti-TNF Refractory Ulcerative Colitis: A Prospective Multicenter Italian Study.

Tofacitinib is an oral Janus kinase inhibitor recently approved to induce and maintain remission in ulcerative colitis (UC). Considering the number of anti-TNF non-responders, this study aims to assess the effectiveness and safety of tofacitinib in a cohort of multi-failure patients with moderate-to-severe UC at 52weeks. From January 2021 to March 2023, we performed a prospective multicenter study observing adult patients with moderate-to-severe UC starting tofacitinib after an anti-TNF failure for a 52-week-long period. Effectiveness and safety were assessed in terms of colectomy rate, clinical remission and response, endoscopic remission, steroid-free clinical remission, and rate of adverse events. We included 58 patients with UC with an age of 42 ± 14.4years, 59% males, 96.6% left-sided or pancolitis, who were failure to a single (65.5%) or more than one anti-TNF (34.5%). Only 6 (10.3%) patients underwent colectomy. Colectomy was clinically associated with the necessity and the number of extra cycles of tofacitinib 10mg bid at W8 (p = 0.023) and W24 (p = 0.004), and with a higher partial Mayo score at W8 (p = 0.025). At W52, clinical remission, clinical response, and steroid-free clinical remission were 53.4%, 43.1%, and 48.3%, respectively. Of 22 performed colonoscopies at W52, 11 (50%) showed endoscopic remission. Adverse events occurred in 14 (24.1%) patients, but only 2 (3.4%) led to tofacitinib discontinuation. In a real-life setting of patients with anti-TNF refractory UC, tofacitinib has proved to be effective in preventing colectomy and inducing clinical and endoscopic remission at 52weeks with a good safety profile.

Human-derived bacterial strains mitigate colitis via modulating gut microbiota and repairing intestinal barrier function in mice

BackgroundUnbalanced gut microbiota is considered as a pivotal etiological factor in colitis. Nevertheless, the precise influence of the endogenous gut microbiota composition on the therapeutic efficacy of probiotics in colitis remains largely unexplored.ResultsIn this study, we isolated bacteria from fecal samples of a healthy donor and a patient with ulcerative colitis in remission. Subsequently, we identified three bacterial strains that exhibited a notable ability to ameliorate dextran sulfate sodium (DSS)-induced colitis, as evidenced by increased colon length, reduced disease activity index, and improved histological score. Further analysis revealed that each of Pediococcus acidilactici CGMCC NO.17,943, Enterococcus faecium CGMCC NO.17,944 and Escherichia coli CGMCC NO.17,945 significantly attenuated inflammatory responses and restored gut barrier dysfunction in mice. Mechanistically, bacterial 16S rRNA gene sequencing indicated that these three strains partially restored the overall structure of the gut microbiota disrupted by DSS. Specially, they promoted the growth of Faecalibaculum and Lactobacillus murinus, which were positively correlated with gut barrier function, while suppressing Odoribacter, Rikenella, Oscillibacter and Parasutterella, which were related to inflammation. Additionally, these strains modulated the composition of short chain fatty acids (SCFAs) in the cecal content, leading to an increase in acetate and a decrease in butyrate. Furthermore, the expression of metabolites related receptors, such as receptor G Protein-coupled receptor (GPR) 43, were also affected. Notably, the depletion of endogenous gut microbiota using broad-spectrum antibiotics completely abrogated these protective effects.ConclusionsOur findings suggest that selected human-derived bacterial strains alleviate experimental colitis and intestinal barrier dysfunction through mediating resident gut microbiota and their metabolites in mice. This study provides valuable insights into the potential therapeutic application of probiotics in the treatment of colitis.

Formulation, Characterization and In Vitro Evaluation of Mesalamine and Bifidobacterium bifidum Loaded Hydrogel Beads in Capsule System for Colon Targeted Delivery.

Mesalamine is a first-line drug for the treatment of inflammatory bowel diseases. However, its premature release associated with marketed formulations leads to adverse effects like gastric trouble, vomiting, and diarrhoea. To minimize these side effects, colon-targeted drug delivery is essential. Besides conventional pharmacotherapy, bifidogenic probiotics with anti-inflammatory activity has been reported to elicit a significant impact on the remission of ulcerative colitis. Bifidogenic probiotics being acid-labile necessitate developing a gastro-resistant formulation for enhancing the delivery of viable cells to the colon. The present study was aimed at developing a fixed-dose unit dosage form of mucoadhesive hydrogel beads loaded with mesalamine and Bifidobacterium bifidum further encapsulated in Eudragit® capsules for the targeted drug delivery at colonic pH. The hydrogel beads were prepared by ionotropic gelation, with the effect of single and dual-crosslinking approaches on various formulation characteristics studied. Standard size 00 Eudragit® gastro-resistant capsules were prepared and the dried beads were filled inside the capsule shells. The formulation was then evaluated for various parameters, including physicochemical characterization, in vitro biocompatibility and anti-inflammatory activity. No interaction was observed between the drug and the polymers, as confirmed through FTIR, XRD, and DSC analysis. The mean particle size of the beads was ~ 457-485µm. The optimized formulation showed a drug entrapment efficiency of 95.4 ± 2.58%. The Eudragit® capsule shells disintegrated in approximately 13min at pH 7.4. The mucoadhesive hydrogel beads sustained the drug release above 18h, with 50% of the drug released by the end of 12h. The optimized formulation demonstrated significant (p < 0.05) gastro-resistance, biocompatibility, sustained drug release, cell viability, and anti-inflammatory activity.

Real-world effectiveness of ustekinumab and vedolizumab in TNF-exposed pediatric patients with ulcerative colitis.

Vedolizumab (VDZ) and ustekinumab (UST) are second-line treatments in pediatric patients with ulcerative colitis (UC) refractory to antitumor necrosis factor (anti-TNF) therapy. Pediatric studies comparing the effectiveness of these medications are lacking. Using a registry from ImproveCareNow (ICN), a global research network in pediatric inflammatory bowel disease, we compared the effectiveness of UST and VDZ in anti-TNF refractory UC. We performed a propensity-score weighted regression analysis to compare corticosteroid-free clinical remission (CFCR) at 6 months from starting second-line therapy. Sensitivity analyses tested the robustness of our findings to different ways of handling missing outcome data. Secondary analyses evaluated alternative proxies of response and infection risk. Our cohort included 262 patients on VDZ and 74 patients on UST. At baseline, the two groups differed on their mean pediatric UC activity index (PUCAI) (p = 0.03) but were otherwise similar. At Month 6, 28.3% of patients on VDZ and 25.8% of those on UST achieved CFCR (p = 0.76). Our primary model showed no difference in CFCR (odds ratio: 0.81; 95% confidence interval [CI]: 0.41-1.59) (p = 0.54). The time to biologic discontinuation was similar in both groups (hazard ratio: 1.26; 95% CI: 0.76-2.08) (p = 0.36), with the reference group being VDZ, and we found no differences in clinical response, growth parameters, hospitalizations, surgeries, infections, or malignancy risk. Sensitivity analyses supported these findings of similar effectiveness. UST and VDZ are similarly effective for inducing clinical remission in anti-TNF refractory UC in pediatric patients. Providers should consider safety, tolerability, cost, and comorbidities when deciding between these therapies.

C-reactive protein-to-albumin ratio and neutrophil-to-albumin ratio for predicting response and prognosis to infliximab in ulcerative colitis.

The C-reactive protein-to-albumin ratio (CAR) and neutrophil-to-albumin ratio (NAR) serve as established markers for inflammatory diseases. However, limited studies have investigated their potential in predicting response and prognosis following infliximab (IFX) treatment. The objective of this paper was to evaluate feasibility of CAR and NAR as biomarkers to assess response to IFX induction therapy. Additionally, we attempted to determine the capacity to predict clinical remission in ulcerative colitis (UC) after 54 weeks of IFX treatment. We enrolled a total of 157 UC patients diagnosed via endoscopic mucosal biopsy at our hospital between October 2018 and June 2023. Additionally, 199 patients presenting with gastrointestinal symptoms, who underwent physical examinations, constituted the control group. Comprehensive clinical data, laboratory indicators, and endoscopic findings were systematically collected. CAR and NAR values were computed before treatment, post-induction, and subsequently at 8-week intervals. Comparisons between two groups were analyzed using the Wilcoxon rank-sum test or the independent samples t-test, and comparisons between multiple groups were analyzed using the one-way ANOVA (analysis of variance) or the Kruskal-Wallis rank sum test. We found CAR and NAR emerged as sensitive biomarkers for assessing disease activity. Notably, our findings indicated their dual predictive capability: foreseeing response post-IFX induction therapy and prognosticating the likelihood of UC patients achieving clinical remission following 54 weeks on IFX therapy.

Update for surgeons on novel induction treatments for acute severe inflammatory bowel disease associated colitis.

The landscape of biologic agents for the treatment of inflammatory bowel disease (IBD) associated colitis is rapidly evolving, requiring surgeons to be up-to-date as part of multi-disciplinary, evidence-based care. An update on novel therapies used to induce remission in IBD-associated colitis is presented. A systematic search through Ovid MEDLINE and CENTRAL using a combination of MeSH terms and Boolean operators was conducted. One thousand and twenty articles from which 38 articles were selected for inclusion in this review. Novel agents were trialled as 4th or 5th line treatment following conventional treatment failure. Rates of serious adverse effects were low. Janus kinase (JAK) inhibitors (upadacitinib and tofacitinib) were efficacious in inducing remission in ulcerative colitis, and IL-23p19 inhibitors (mirikizumab, guselkumab, and risankizumab) in Crohn's colitis. Evidence was limited for other drug classes. JAK-inhibitors and IL-23p19 inhibitors were found to be the most effective agents for inducting remission following failure of standard of care treatment. A significant proportion of patients did not respond, highlighting the inherent challenge in optimizing treatment for moderate to severe IBD-associated colitis. More robust study designs and comparator trials are required.

Ustekinumab in the Treatment of Inflammatory Bowel Diseases: Evolving Paradigms.

Inflammatory bowel diseases, comprising Crohn's disease (CD) and ulcerative colitis (UC), are chronic, relapsing, and remitting immune-mediated inflammatory diseases affecting the gastrointestinal tract. Ustekinumab (UST) is a monoclonal antibody that blocks the p40 subunit of the anti-interleukin (IL) 12/23. Pivotal trials (CERTIFI and UNITI-IM for CD, UNIFI for UC) established the efficacy of UST for the induction and maintenance of remission in both CD and UC, with the most favorable results in naïve patients to biologics. In recent years, a wealth of 'real-world' data has emerged supporting positive clinical, endoscopic, and histological outcomes in patients treated with UST, as well as reassuring safety data. More recently, the results of the first head-to-head trials of UST and tumor necrosis factor (TNF) antagonists were reported. Moreover, a number of studies exploring the role of UST in specific clinical settings, such as perianal CD, postoperative complications and recurrence, extraintestinal manifestations, chronic antibiotic-refractory pouchitis, and pregnancy, were reported. This review explores the results reported to date on UST, including those from pivotal trials, real-world data, and emerging studies regarding therapeutic drug monitoring and immunogenicity. The safety profile of UST was also reviewed.

THE ROLE OF MICROBIOTA IN INFLAMMATORY BOWEL DISEASES: A LITERATURE REVIEW

The gut microbiome is an ecosystem of the digestive system that synthesizes enzymes and vitamins needed for the proper functioning of the digestive process. In addition, it plays a key function in homeostasis between the digestive and immune systems. Abnormalities in the composition of the gut microbiome have been linked to the occurrence of inflammatory bowel diseases. Numerous reports in the literature suggest that microbes, or substances produced by them, can be a treatment in themselves, or an adjunctive treatment in inflammatory bowel diseases. Methods: In our work we used scientific sources such as publications, guidelines and textbooks. Purposes: In this paper we have compiled information on the mechanism of action of the human gut microbiota. Its influence on the immune system, as well as the mechanism of action of processes occurring in the intestinal wall. In addition, we have compiled information on the relationship between the gut microbiota and inflammatory bowel disease alongside potential treatment and effects of probiotics, prebiotics, antibiotics and fecal microbiota transplantation. Our work focuses mainly on crohn's disease and ulcerative colitis. We have discussed their current treatments and the possibilities and effectiveness of probiotic therapy for both diseases. Conclusion: Intestinal flora disorders are observed both in ulcerative colitis and Crohn's disease. It is believed that it may also be one of the etiopathogenetic factors of these diseases. It has been noted that the use of probiotics in combination with standard treatment promotes remission in ulcerative colitis but has no effect in patients with Crohn's disease.

New trends associated with disease activity in patients with ulcerative colitis

Background/Aim: The severity and extent of ulcerative colitis (UC) guide us in determining the treatment method for each case. It has been suggested in the literature that high neutrophil-lymphocyte and platelet-lymphocyte ratios can serve as markers of active ulcerative colitis. This study retrospectively analyzes the relationship between neutrophil-lymphocyte ratio and platelet-lymphocyte ratio with clinical activity indices and endoscopic activity indices in predicting disease severity in patients with ulcerative colitis. There are few studies in the literature regarding the relationship between platelet-lymphocyte ratio (PLR) and disease activation in ulcerative colitis. This study contributes to the follow-up and outcomes of these patients, as there is a lack of sufficient retrospective studies on the platelet/lymphocyte ratio in patients diagnosed with UC in our country and worldwide. Methods: This study is a population-based, single-center, case-controlled study. It was conducted by retrospectively analyzing the hospital information system for data recorded during the routine diagnosis and treatment of ulcerative colitis patients followed and treated at Celal Bayar University Medical Faculty Gastroenterology Division between January 2014 and December 2021. A total of 135 patients with ulcerative colitis were included in the study. The patients were divided into 2 groups, active disease and disease in remission, based on clinical activity indices and endoscopic activity indices. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hemoglobin (Hb), white blood cell (WBC), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) levels were checked during routine follow-up of patients with ulcerative colitis. These values were recorded at the first presentation to the hospital and 3 months after treatment. Results: Laboratory values at presentation were compared with those at the third month of treatment in a group of 113 patients with UC in remission: NLR (5.529 (3.485) and 4.374 (2.335), [P&lt;0.001]), erythrocyte sedimentation rate (26.81 (20.42) and 21.78 (19.32), [P=0.015]), C-reactive protein (4.087 (6.729) and 1.696 (3.525), [P&lt;0.001]), and white blood cell count (9,864 (3,514) and 8,067 (1,927), [P&lt;0.001]) were found to be lower than the baseline values. As expected, decreases in inflammatory markers were observed in patients in remission. In a group of 22 patients with active disease, values at presentation were compared with those at the third month of treatment: neutrophil count (8,508 (2,908) and 9,646 (3,265), [P=0.037]) and platelet count (289,591 (95,123) and 323,364 (127,647), [P=0.010]) were found to be high. Similarly, ESR (19.63 (15.43) and 27.89 (21.11), [P=0.036]) was found to be high. These values were higher in active disease compared to the time of admission. Conclusion: In our study, neutrophil-lymphocyte ratios and platelet-lymphocyte ratios were significantly higher in patients with active ulcerative colitis. The level of inflammatory markers in ulcerative colitis patients at the time of diagnosis and in the early stages of the disease is helpful in predicting the course of the disease, and this was shown to be related to clinical, endoscopic, and laboratory indices. These inflammatory markers can predict disease activity alone or in combination. However, a threshold value could not be calculated due to the insufficient number of patients, and thus, more comprehensive prospective studies are needed.

A273 A PILOT PROSPECITVE, MULTI-CENTRE, RANDOMIZED CONTROLLED TRIAL COMPARING FECAL MICROBIOTA TRANSPLANTATION (FMT) TO PLACEBO AT INDUCING REMISSION IN MILD TO MODERATE CROHN'S DISEASE

Abstract Background FMT has shown promise at inducing remission in ulcerative colitis. The effect of FMT on inducing remission in Crohn’s disease however remains unknown. Aims To evaluate the efficacy of FMT at inducing remission in mild-to-moderate Crohn’s disease Methods This double-blind, randomized, trial conducted at 3 Canadian academic centers (Edmonton, Hamilton and Calgary) randomized. Adult patients with mild-to-moderate Crohn’s disease with modified Harvey Bradshaw Index (mHBI) score of ampersand:003E5 and at least one objective measure of inflammation (CRP ≥ 8mg/L or fecal calprotectin (FCP) ≥ 250 ug/g) on stable dosing of concomitant therapy were assigned to FMT or placebo. First assigned treatment was by colonoscopy followed by 20 [DK1] capsules weekly for 7 weeks. Endoscopic severity (SES-CD) was assessed at baseline during colonoscopic delivery of assigned treatment and at week 8 by a blinded central reader using video recording. The primary endpoint was the proportion of patients in both clinical (mHBI ampersand:003C 5) and endoscopic remission (SES-CD ≤ 5) at week 8. Responders (reduction of HBI ≥ 3 or HBI ≤ 5 and reduction of CRP or FCP by ≥ 10%) in FMT group were eligible to continue with open-label FMT capsule every 2 weeks. Non-responders in the placebo group were permitted to restart the trial at week 0 with open-label FMT. Secondary outcomes included patient reported outcomes and safety outcomes. Results Between July 2017 to Jun 2021, 28 were randomized (16 to FMT and 12 to placebo). The study team voluntarily suspended the trial twice due to Health Canada safety warnings regarding potential transmission of multi-drug resistant organisms and SARS-CoV-2 through FMT. At week 8, 0% (0/16) of patients in the FMT group versus 8.3% (1/12) in the placebo group reached the primary endpoint of combined clinical and endoscopic remission. Of the 50% (8/16) in the FMT group who achieved a clinical response and continued on open-label FMT every 2 weeks, 12.5% (1/8) achieved the primary endpoint. Of the 7 non-responders in the placebo group who restarted the trial at week 0 and received open-label FMT, 28.6% (2/7) achieved primary endpoint at week 8 on open-label FMT. No death or hospitalization were observed. The study was terminated early at the recommendation of the Data Safety Monitoring Board. Conclusions FMT was not effective at inducing remission in Crohn’s disease using the FMT regimen in this study. However, this study was limited by a small sample size and recruitment barrier during the COVID pandemic. Future studies may consider other strategies to potentially enhance treatment response, including antibiotic pre-treatment, optimized donor-recipient pairing, and concomitant anti-inflammatory diet. Funding Agencies CIHR

A182 EXPLORING THE LINK BETWEEN SPECIFIC MICROBIAL STRAINS AND ANXIETY AND DEPRESSION IN PATIENTS WITH ULCERATIVE COLITIS

Abstract Background Anxiety and/or depression (A/D) have been identified as significant co-morbidities of ulcerative colitis (UC), and even considered as extraintestinal manifestations, with emerging evidence to support the role for gut microbial dysbiosis in the natural history for both UC and A/D. However, there is a paucity of knowledge regarding the specific attributes of the gut bacteriome in individuals with UC with concomitant A/D. Aims To explore the connection between the gut bacteriome and A/D in a cohort of patients with UC. Methods This cross-sectional study included 29 participants diagnosed with UC either in remission or with mild to severe disease. To test for depression and anxiety, participants completed the Patient Health Questionnaire-8 (PHQ-8) and General Anxiety Disorder-7 (GAD-7) respectively. Participants provided a stool sample for microbiome analysis and the fecal bacteriome was assessed using metagenomic shotgun sequencing. Results Among the 29 patients, 55% were female (n=16) and 45% were male (n=13), 34.5 % (n=10) had a Partial Mayo Score over 5 indicating moderate-severe disease activity (median 3, IQR 1-6). Mean age was 38.3 years (± 12.2 years). Sixty-nine percent were on 5-ASA, 42.9% on steroids, 31.0% on Anti-TNF, and 20.7% on immunomodulators. Mean FCP was 976.4 μg/g (± 1589.2). Forty-four percent (n=12) screened positive for anxiety with a median GAD-7 score of 5.0 (IQR: 1-8), while 26% screened positive for depression with a median PHQ-8 of 3 (IQR: 3-10). Principal Coordinate Analysis (PCoA) reveals distinct clustering between UC patients with or without A/D (Figure 1). Regarding the microbial analyses, the log fold change of Firmicutes bacterium CAG:424, Holdemanella biformis, Blautia hansenii, Bifidobacterium pullorum, Anaerostipes caccae, and Ruminococcus gnavus exhibited positive associations with both A/D, whereas Roseburia sp. CAG:303, Prevotella copri, and Bacteroides stercoris demonstrated negative associations. Uniquely, Faecalicoccus pleomorphus and Lachnospira pectinoschiza showed negative associations only with the PHQ-8. Conclusions Our research affirms the presence of anxiety and depression in a cohort of UC patients. The severity of A/D measured by the GAD-7 and PHQ-8 were linked to the levels of specific fecal microbes. We introduce several novel species that warrant further examination in UC patients with and without A/D. As this was an exploratory study, the findings need replication in a larger sample size. PCoA results reveal distinct bacterial clustering patterns between individuals with minimal anxiety/depression (absence) versus those with mild/moderate/severe anxiety and depression as measured by GAD-7 and PHQ-8. Funding Agencies None

Tofacitinib use in ulcerative colitis: An expert consensus for day-to-day clinical practice.

Rising number of inflammatory bowel disease (IBD) cases in developing countries necessitate clear guidance for clinicians for the appropriate use of advancedtherapies. An expert consensus document was generated to guide the usage of tofacitinib, a Janus kinase inhibitor, in ulcerative colitis. Tofacitinib is a usefulagent for the induction and maintenance of remission in ulcerative colitis. It can be used in the setting of biological failure or even steroid-dependent andthiopurine refractory disease. Typically, the induction dose is 10 mg BD orally. Usually, clinical response is evident within eight weeks of therapy. In those with clinical response, the dose can be reduced from 10 mg BD to 5 mg BD. Tofacitinib should be avoided or used cautiously in the elderly, patients with cardiovascular co-morbidity, uncontrolled cardiac risk factors, previous thrombotic episodes and those at high risk for venous thrombosis or previous malignancy. Baseline evaluation should include testing for and management of hepatitis B infection and latent tuberculosis. Where feasible, it is prudent to ensure complete adult vaccination, including Herpes zoster, before starting tofacitinib. The use of tofacitinib may be associated with an increased risk of infections such as herpes zoster and tuberculosis reactivation. Maternal exposure to tofacitinib should be avoided during pre-conception, pregnancy, and lactation. There is emerging evidence of tofacitinib in acute severe colitis, although the exact positioning (first-line with steroids or second-line) is uncertain.

Intestinal barrier biomarkers in clinical evaluation of patients with inflammatory bowel disease.

Inflammatory bowel disease (IBD) is associated with chronic intestinal barrier dysfunction, though its non-invasive assessment remains challenging. This study aimed to determine how four putative circulating markers vary across differing states of intestinal inflammation and with therapy in patients with IBD. Plasma samples from one prospective cross-sectional and four longitudinal studies, including healthy controls, were analysed for markers of lipopolysaccharide translocation, lipopolysaccharide-binding protein (LBP) and soluble-CD14 (sCD14), and markers of epithelial injury, syndecan-1 and intestinal-type fatty acid-binding protein (IFABP). Inflammatory activity was determined using objective measures. Compared with healthy subjects, concentrations of LBP and sCD14 were higher in patients with active (P < 0.001) and severe ulcerative colitis (UC) (P < 0.0001) and active Crohn's disease (CD) (P < 0.001). In UC in remission, LBP was less than in active disease (P = 0.011) LBP levels decreased longitudinally before and after induction of medical therapy in patients with IBD (P = 0.030) and as severe UC was brought into remission at weeks 2 and 12 (P ≤ 0.022). Response to treatment was associated with higher baseline levels of LBP (P = 0.019) and soluble-CD14 (P = 0.014). Concentrations of syndecan-1 and IFABP were or tended to be lower in UC and CD in active disease and did not change with successful therapy. While markers of epithelial injury were subnormal with active disease and did not change with therapy, markers of lipopolysaccharide translocation directly reflected intestinal inflammation, reduced with successful therapy and predicted treatment response.

DIFFERENTIAL MORTALITY OUTCOMES AMONG DIFFERENT CLASSES OF DRUGS IN ELDERLY PATIENTS WITH ULCERATIVE COLITIS USING A MULTI-CENTER RESEARCH NETWORK

Abstract BACKGROUND Several medical therapies exist for ulcerative colitis (UC) including 5-aminosalicylates (5-ASAs), immunomodulators (IMM), biologics and Janus Kinase (JAK) inhibitors that aim to induce and sustain both clinical and endoscopic remission of UC. Selection of treatment is dictated by disease severity and patient characteristics and preference. Long-term differences in mortality risk among these therapies is unknown. The aim of this study is to compare 10-year mortality among older adult UC patients exposed to different treatment regimens. METHODS Using TriNetX, a multicenter research database, elderly patients with UC who are 65 years or older were identified using ICD-10 code for ulcerative colitis(K51) on the Research Network, accessed on September 26th, 2023. Cohorts were subdivided according to exclusive different lines of therapy as shown in table 1: 5-ASAs, IMM, Biologics, and JAK inhibitors. Advanced therapy included the latter three classes of drugs whereas simple therapy included 5-ASA agents. Comparison of 10-year mortality profiles was done for advanced therapy and each different therapeutic class in reference to simple therapy (5-ASAs). Analyses were performed on a built-in statistical software on TriNetX. RESULTS When comparing advanced therapy to simple amino-salicylate-based therapies, elderly patients demonstrated higher 10-year mortality with advanced therapy (13.5% vs 12.4%, OR=1.10, 95 % CI [1.13,1.29], p=0.017) as shown in table 2. When breaking down the classes of advanced therapies, immunomodulators had the highest risk of mortality as compared to simple therapy ( 19.1% vs 12.4%, 1.67 95%CI [1.52, 1.84], p&amp;lt;0.0001). However, biologic therapies had a lower mortality risk when compared to simple therapy (9.3% vs 12.4%, OR=0.73, 95% CI [0.64, 0.83], p&amp;lt;0.0001). Further data are needed to assess the mortality risk of JAK inhibitors as they were recently approved for ulcerative colitis and 10-year mortality risk could not be examined. CONCLUSION Among the different drug classes, immunomodulators were significantly associated with higher 10-year mortality risk compared to simple therapy whereas biologic therapies had the lowest mortality risk. Table 1 Lines of Therapy Table 2 Characteristics and Mortality Outcome of Patients on Different Lines of Therapy