Active Ulcerative Colitis Research Articles

Deucravacitinib in Patients With Inflammatory Bowel Disease: 12-Week Efficacy and Safety Results From Three Randomized Phase 2 Studies in Crohn's Disease and Ulcerative Colitis.

Tyrosine kinase 2 is a downstream intracellular mediator of interleukin-23 signaling, which has a key role in the pathogenesis of inflammatory bowel disease. Deucravacitinib is a novel, oral, selective, allosteric tyrosine kinase 2 inhibitor currently approved for the treatment of adults with moderate to severe plaque psoriasis. Here we describe three randomized, double-blind, placebo-controlled phase 2 studies of deucravacitinib in patients with moderately to severely active Crohn's disease (LATTICE-CD [NCT03599622]) or ulcerative colitis (LATTICE-UC [NCT03934216] and IM011-127 [NCT04613518]). Patients were randomized to receive placebo or twice-daily deucravacitinib 3mg or 6mg (LATTICE-CD), 6mg (LATTICE-UC), or 12mg (IM011-127) for 12 weeks. Coprimary endpoints for LATTICE-CD were clinical remission and endoscopic response at Week 12. The primary endpoint was clinical remission (per modified Mayo score) at Week 12 for LATTICE-UC and clinical response (per modified Mayo score) at Week 12 for IM011-127. A total of 239 (LATTICE-CD), 131 (LATTICE-UC), and 38 (IM011-127) patients were randomized. The primary endpoints were not met for all three studies, which resulted in early study termination for LATTICE-CD and IM011-127. High efficacy rates were observed in placebo groups throughout the studies. In all studies, the safety profile of deucravacitinib was consistent with the known safety profile observed in patients with psoriasis, and no new safety signals were observed. Deucravacitinib at multiple doses did not demonstrate significant clinical benefit vs placebo in moderately to severely active Crohn's disease or ulcerative colitis. Deucravacitinib was safe and well-tolerated.

Cytomegalovirus infection in patients with active ulcerative colitis: a prospective observational study.

The role of cytomegalovirus (CMV) infection in the course of inflammatory bowel disease is still controversial. We aimed to prospectively evaluate the course of ulcerative colitis in patients with exacerbation, in whom CMV status was examined using immunohistochemistry of bowel biopsies. In a single centre, we followed-up consecutive patients admitted for moderate or severe ulcerative colitis flare between 2016 and 2019. Colectomies, repeated hospitalisations, major treatment modifications, and quality of life (QoL) were recorded. The relationship between categorical variables was examined with the χ2 statistical test or Fisher's exact test. Of 84 patients, 16 (19%) were CMV-positive. A Mayo endoscopic score of 3 was more frequent in CMV-positive than CMV-negative patients (81.2 vs. 51.5%; P = 0.048) as was corticosteroid treatment (81.2 vs. 54.4%; P = 0.015). Median follow-up was 2.1 years (range: 0.3-3.6 years). Colectomy was performed in 20 (23.8%) patients, with similar rates in CMV-positive (25%) and CMV-negative patients (23.5%; P = 1.0). Similarly, no differences were found in the frequency of hospitalisation and QoL. The percentage of patients who started biological treatment was higher in the CMV-negative than in the CMV-positive group (58.8 vs. 18.8%; P = 0.005). CMV infection was present in 19% of consecutive patients hospitalised for ulcerative colitis flare. Corticosteroid treatment and severe endoscopic lesions were observed more often in patients with CMV-positive. In the following 2.1 years, the colectomy rate did not differ between patients with CMV-positive and CMV-negative. Routine screening for CMV in ulcerative colitis exacerbation is not advisable.

Reduced Sulfur Diet Reshapes the Microbiome and Metabolome in Mild–Moderate Ulcerative Colitis

This pilot study investigated the effects of a reduced sulfur (RS) diet on the gut microbiome composition and fecal metabolome in individuals with remitted or active ulcerative colitis (UC). Thirteen participants maintained their habitual diet (control), while nine followed an RS diet for eight weeks (Wk8). Stool and plasma samples were collected at the baseline and Wk8. The sulfur intake decreased in the RS group (−28 g/1000 kcal) versus the control group (−1.7 g/1000 kcal; p < 0.001). The RS group exhibited a significant decrease in lipopolysaccharide-binding protein (−5280 ng/mL), while these levels increased in the control group (620 ng/mL; p < 0.05). The microbiome analysis showed an increased alpha diversity at Wk8 (p < 0.01), suggesting a microbial shift with a RS intake. The metabolic alterations indicated enhanced nitrogen disposal (increased uric acid, methyluric acid, N-acetyl-L-glutamate) and a higher energy demand (elevated ubiquinol and glucose-pyruvate). The RS diet increased beneficial microbes Collinsella stercoris, Asaccharobacter celatus, and Alistipes finegoldii, while decreasing pathobionts Eggerthella lenta and Romboutsia ilealis. Methyluric acid correlated positively with C. stercoris (β = 0.70) and negatively with E. lenta (β = −0.77) suggesting these microbes utilized this metabolite and influenced the microbiome composition. In conclusion, a RS diet promoted microbial diversity, metabolic adaptations, and reduced inflammation, highlighting its potential as a novel strategy for UC management.

Association between Dietary Inflammatory Index and Ulcerative Colitis: a case–control study

IntroductionDiet plays a crucial role in the activity and onset of ulcerative colitis (UC). The aim of this study was to comprehensively explore the association between the dietary inflammatory index (DII) and UC.MethodsParticipants completed the Food Frequency Questionnaire to obtain data on their dietary intake. Individual DII scores were calculated to assess inflammatory potential of each participant’s diet. A logistic regression model was used to analyze the correlation between the DII and UC activity, including the active and remission phases.ResultsIn this study, 100 controls and 106 patients with UC were enrolled, including 50 patients in remission and 56 patients with active UC. Dietary nutrient intake was generally slightly lower in patients with UC than in the controls, including energy, protein, dietary fiber, vitamin D, vitamin E, vitamin B1, vitamin B2, vitamin C, folic acid, fat, monosaturated fatty acids, and n-3 fatty acids (P < 0.05). Compared with the low pro-inflammatory potential diet, patients with higher DII had a higher correlation with UC before and after adjustment for relevant confounders. In consecutive DII, the correlation with UC increased with each 1 increase in DII. No significant correlation was observed between DII and UC activity.ConclusionsDiets with a high inflammatory index are correlated with UC. Therefore, consuming a diet with a low inflammatory index may be beneficial for patients with UC.

Cost per remission for mirikizumab versus ustekinumab for moderately to severely active ulcerative colitis treatment from the United States commercial payer perspective

Cost per remission for mirikizumab versus ustekinumab for moderately to severely active ulcerative colitis treatment from the United States commercial payer perspective

Value of serum soluble syndecan- 1 as a biomarker of disease activity in ulcerative colitis patients

BackgroundInflammatory bowel disease (IBD) is a chronic and incurable disease that includes Crohn’s disease (CD) and ulcerative colitis (UC); UC is characterized by repeated episodes of relapse and remission despite treatment; Soluble syndecan-1(Sdc1) is a marker of activity for UC. This study aimed to identify the role of Sdc1 in assessment of disease activity in UC.MethodsSeventy-five consecutive patients with UC were included in this cross-sectional case–control study. Patients were stratified into two groups: group I (patients with UC) and then subdivided into group IA (patients with active disease), group IB (patients with inactive disease); and Group II (healthy controls). Detailed history, clinical examination, routine laboratory investigations, and full colonoscopy with biopsy were performed. Colonoscopic and histopathological findings were analyzed to determine the presence of organic diseases.ResultsSerum Sdc1 levels were significantly higher in active UC (7.60 ± 1.85 ng/mL) compared to inactive UC (4.48 ± 1.55 ng/mL) and controls (2.69 ± 1.09 ng/mL) (p < 0.001). Sdc1 levels correlated positively with bowel movement frequency, fecal calprotectin, ESR, and C-reactive protein (CRP), while negatively correlating with albumin (p < 0.05). Analysis showed that Sdc1 levels > 5.61 ng/mL distinguished active from inactive UC with 84% sensitivity and 76% specificity (AUC = 0.898, p < 0.001).ConclusionsSdc1 is a valuable biomarker for assessing disease activity in UC patients that shows strong correlations with clinical indicators and endoscopic findings.

Efficacy and safety of advanced therapies for moderately to severely active ulcerative colitis in induction and maintenance: systematic literature review and Bayesian network meta-analysis.

Aim: Several therapies have recently been licensed for the treatment of patients with moderately to severely active ulcerative colitis (UC). To provide comparative evidence of newly available treatments, Bayesian network meta-analyses were conducted to compare their relative efficacy and safety profiles in both the induction and maintenance phases. Materials & methods: A systematic literature review was conducted to identify the available literature on randomized controlled trials for advanced treatments (AT) of moderately to severely active UC. Bayesian network meta-analyses were used to synthesize evidence on prespecified efficacy and safety outcomes. Primary efficacy end points clinical response and clinical remission were measured at the end of induction and clinical response and clinical remission among induction phase responders were assessed at the end of the maintenance period. Efficacy outcomes were analyzed separately for AT-naive and -experienced populations. Safety outcomes included serious infections over the induction period, and serious infections among others over the maintenance period. Treat-through trial outcomes were adjusted to align with responder rerandomized trial outcomes. Results: The systematic review identified 58 relevant trials of which 28 met criteria for inclusion in the main analysis networks. At the end of the induction period, all treatments were efficacious against placebo for both AT-naive and AT-experienced populations. Upadacitinib 45mg demonstrated a higher likelihood of clinical response and remission compared with other treatments. Adalimumab had less favorable performance over the induction period. Among induction phase responders, most treatments demonstrated similar efficacy at the end of the maintenance period. Tofacitinib 10mg was more likely to achieve clinical response and remission than several other treatments in the AT-naive population. In the AT-experienced population, upadacitinib 30mg demonstrated a higher likelihood of clinical response and remission compared with other treatments. The safety outcomes among treatments were similar. Conclusion: This study provides an updated comparison of treatments for moderately to severely active UC. Most treatments demonstrated comparable efficacy at the end of maintenance. The findings from this study can inform decision making in treatment choice for patients with moderately to severely active UC.

AI-Assisted Glucocorticoid Treatment Response Prediction of Active Ulcerative Active Patients.

Glucocorticoids are recommended for the induction and remission phase of ulcerative colitis (UC). Early identification of glucocorticoid therapy response contributes to more precise treatment management. We aim to use deep learning model to predict glucocorticoid response prognosis in active UC. From January 2006 to December 2023, 485 intestinal histological whole slide images (WSIs) of 212 UC patients from two medical centers in China was collected. We developed and validated a deep learning model (UCG-SwinT) based on WSI and clinical data to predict the treatment response of glucocorticoid induction therapy. Response was defined as steroid effectiveness and steroid dependence. We used area under the curves (AUCs) to evaluate the performance of the model and compared it to clinical factors. Grad-CAM was used to visualize the histological features the model focused when predicting treatment response. The AUCs of predicting response in training, validation, and external testing set were 0.750, 0.727, and 0.723, respectively. The UCG-SwinT model performs better while combining histopathological images with clinical data than simply inputting histopathological images, with AUCs of 0.826, 0.731, and 0.725 in predicting treatment response in the training, validation, and external testing cohorts and outperformed all clinical factors. Grad-CAM showed that increased inflammatory cells and intestinal mucosal microvascular dilation are related to glucocorticoid response in UC patients. UCG-SwinT has the potential to predict glucocorticoid response in active UC patients and has guiding significance for individualized clinical treatment.

Comparing Outcomes With Subcutaneous Infliximab (CT-P13 SC) by Baseline Immunosuppressant Use: A Post Hoc Analysis of the LIBERTY-CD and LIBERTY-UC Studies.

Superior efficacy of subcutaneous infliximab (CT-P13 SC) over placebo for maintenance therapy in patients with Crohn's disease (CD) and ulcerative colitis (UC) was demonstrated in the randomized LIBERTY-CD and LIBERTY-UC studies. The current post hoc analysis compared outcomes with CT-P13 SC by baseline immunosuppressant use. Patients with moderately to severely active CD or UC randomized to the CT-P13 SC maintenance arm of the 54-week LIBERTY trials at week 10 and who were treated in the open-label extension (weeks 56-102) were included. Pharmacokinetic, efficacy, biomarker, safety, and immunogenicity endpoints were evaluated by baseline immunosuppressant use (monotherapy vs combination therapy). A total of 192 patients with CD (monotherapy, n = 126; combination therapy, n = 66) and 237 patients with UC (monotherapy, n = 180; combination therapy, n = 57) were included. In both studies, efficacy outcomes were generally comparable between monotherapy and combination therapy at week 54 or week 102. Serum concentrations were generally higher, and antidrug antibody-positive conversion rates were lower, with combination therapy relative to monotherapy. In combined analyses of CD and UC, comparable safety profiles were observed between monotherapy and combination therapy. Despite some differences in pharmacokinetics and immunogenicity between CT-P13 SC received alone or in combination with immunosuppressants in patients with CD or UC, efficacy outcomes at week 54 or week 102 were generally comparable. The overall safety profile and incidence of systemic injection reactions were also comparable between monotherapy and combination therapy.

Anti-integrin αvβ6 autoantibody in patients with ulcerative colitis after proctocolectomy: a cross-sectional study in Japan.

Pouchitis is a common complication in patients with ulcerative colitis (UC) following colectomy with ileal pouch-anal anastomosis (IPAA). Recent studies have identified a novel autoantibody against integrin αvβ6 in patients with UC, correlated with disease activity. This study aimed to assess the association between serum anti-integrin αvβ6 antibody levels and pouch inflammation in patients with postoperative UC. Serum anti-integrin αvβ6 antibodies were measured using enzyme-linked immunosorbent assay in patients after IPAA, patients with UC, and controls. We examined sera from 71 subjects, including 28 patients who underwent IPAA, 23 controls, and 20 patients with mild and moderate-to-severe UC. Post-IPAA, patients with UC had higher median anti-integrin αvβ6 levels than that of controls (P<0.001) but lower than that of patients with active UC (P=0.001). Patients with pouchitis had higher antibody levels than those without (P=0.047). The receiver operating characteristics curve for anti-integrin αvβ6 showed an area under the curve of 0.724. The pouchitis activity index endoscopic sub-score was correlated with antibody levels (r= 0.48, P=0.011). Serum anti-integrin αvβ6 antibody levels remain elevated in patients with UC even after total colectomy, and were significantly higher in patients with pouchitis than in those without. This antibody could be a novel and useful biomarker for the diagnosis of pouchitis and assessment of disease activity.

A case of ulcerative colitis in a patient undergoing surgery due to exacerbation resulting in toxic megacolon after SARS-CoV-2 vaccination.

We herein report a case involving a patient with quiescent ulcerative colitis (UC) in long-term clinical remission whose condition rapidly worsened after receiving a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, leading to colectomy due to toxic megacolon. The patient received the fifth dose of the Spikevax (mRNA-1273) vaccine and experienced a severe flare-up of UC 6days later. Pathologic findings of the surgical specimens were consistent with severe active UC concomitant with cytomegalovirus infection. Because mRNA vaccines stimulate both humoral and cellular immunogenicity, it is important to note that they can be a triggering factor for the relapse of UC.

Utility of rotational thrombo-elastometry as an objective measure of hypercoagulability in ulcerative colitis.

Inflammatory bowel disease (IBD) has an increased risk of venous thromboembolism (VTE), with factors such as hospitalization and surgery enhancing this risk. This studywas aimed at evaluating rotational thrombo-elastometry (ROTEM) for assessing blood coagulation status in ulcerative colitis (UC) and determining its relationship with disease severity and response to treatment. This was a prospective age and sex-matched study with 60 patients each in UC and irritable bowel syndrome groups, the latter being controls. Clinical details and blood investigations, including ROTEM (clotting time [CT], clot formation time [CFT], alpha angle [AA], maximum clot firmness [MCF], maximum lysis [ML]) and D-dimer, were collected, analyzed and compared between the two groups. A hypercoagulable state was defined by Kaufmann et al. as having two or more of the following: short CT and/or CFT time, increased AA and increased MA. There were 60 patients with UC (age, 38.6 ± 11.64 years; 44 males). The UC group significantly had more patients with hypercoagulable ROTEM than the control group (66.7% vs. 36.7%, p = 0.001). In UC patients with hypercoagulable ROTEM, nine patients were in remission and 31 patients had active disease. Compared to controls, CT, CFT, AA, MCF and D-dimer levels were significantly abnormal in the UC group. Among UC patients with increasing severity, only CFT, AA and D-dimer differed significantly across the groups. There were no significant differences in ROTEM values and D-dimer in patients with severe UC at admission compared to one-week post-discharge. Only hemoglobin (OR, 0.61; 95% CI, 0.38-0.98; p = 0.04) was found to be a significant independent predictor of a hypercoagulable state of active UC, on multivariate analysis. More patients with UC had hypercoagulable ROTEM compared to controls, which increased with disease severity. Low hemoglobin was predictive of a hypercoagulable state in active UC.

Efficacy and safety of etrasimod in Japanese patients with ulcerative colitis: results from a phase 2 dose-ranging study.

Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). However, its efficacy, safety, and the appropriate dosage have not been extensively investigated in the Japanese population. This phase 2, multicenter, randomized, double-blind, placebo-controlled dose-ranging, 12-week trial was carried out among Japanese patients with moderately to severely active UC. Patients were randomized 1:1:1 to receive etrasimod 1 mg once daily (QD), etrasimod 2 mg QD, or placebo. The primary efficacy endpoint was the proportion of patients achieving clinical remission at week 12. Secondary efficacy endpoints and treatmentemergent adverse events (TEAEs) were also investigated. Efficacy endpoints were presented as proportions of patients achieving each outcome. Overall, 17, 19, and 18 patients received etrasimod 1 mg QD, etrasimod 2 mg QD, and placebo, respectively. One patient receiving etrasimod 1 mg (6.7%), 5 patients receiving etrasimod 2 mg (26.3%), and no patients receiving placebo (0%) achieved clinical remission. More patients receiving etrasimod versus placebo achieved secondary endpoints, except endoscopic normalization, at week 12. TEAEs were experienced by 9 patients receiving etrasimod 1 mg (52.9%), 13 patients receiving etrasimod 2 mg (68.4%), and 10 patients receiving placebo (55.6%). None of the TEAEs were serious and none experienced by patients receiving etrasimod led to treatment discontinuation. Overall, etrasimod 2 mg QD for up to 12 weeks appeared efficacious and safe in these Japanese patients with moderately to severely active UC. All TEAEs were mild to moderate in severity. (ClinicalTrials.gov: NCT05061446).

Predictive Factors of Cytomegalovirus Colonic Reactivation in Patients with Active Ulcerative Colitis.

Cytomegalovirus (CMV)-associated colitis reflects the adverse impact of CMV reactivation on ulcerative colitis (UC). Its diagnosis requires the detection of viral markers in intestinal biopsies sampled during endoscopy, which may constitute invasive and expensive analyses. Moreover, less than 30% of acute flare-ups in steroid refractory UC are associated with CMV colitis. This retrospective study aimed to identify non-invasive factors that are predictive of CMV reactivation, and was conducted from 2014 to 2019 in a cohort of UC patients consulting at the University Hospital of Saint-Etienne, France. Patient characteristics, disease activity, immunosuppressive treatment and tissue CMV DNA load were collected at the time of UC relapse. Factors potentially associated with CMV reactivation were analyzed through a multivariate analysis. A total of 173 UC patients providing 323 pairs of intestinal biopsies were analyzed. In the CMV seropositive subgroup, a Mayo endoscopic score ≥2 (OR 2.553, 95% CI 1.353-4.818, p = 0.004) was identified as a predictive factor of CMV colitis in the multivariate analysis; in contrast, biological parameters exhibited no predictive value. In addition, the use of anti-TNFα monoclonal antibodies was associated with a reduced risk of CMV reactivation (OR 0.384, 95% CI 0.158-0.935, p = 0.035). Intestinal biopsies appear to be unavoidable for assessing disease activity and CMV reactivation in UC patients.

Increased Colonic Levels of CD8+ Cytotoxic T lymphocyte-Associated Mediators in Patients With Microscopic Colitis.

For unidentified reasons, possibly due to increased immune surveillance, patients with collagenous colitis (CC) and lymphocytic colitis (LC), both forms of microscopic colitis (MC), have lower risk of colorectal cancer than controls and ulcerative colitis (UC) patients. Levels of secreted and cell-bound mediators in MC patients with active disease and in histological remission (HR) compared to UC patients and controls were investigated. Median fluorescence intensity of 54 analytes in colonic biopsies from patients with active CC (n = 21), LC (n = 11), and UC (n = 19); CC-HR (n = 6), LC-HR (n = 9), UC in remission (n = 19), non-diarrhea controls (n = 48), and diarrhea controls (n = 25) was measured using Luminex. Granzyme B and CCL5 levels were higher in active CC than in UC, whereas CCL4 and CD163 levels were similar in CC and UC, and both groups had higher levels of matrix metalloproteinase (MMP)-1, MMP-3, and tumor necrosis factor receptor II than both control groups. APRIL, BAFF, BCMA, CCL20, CXCL8, chitinase 3-like 1, pentraxin-3, Fas, and IL-33 were higher in UC than MC. Increases in 4-1BB and perforin in MC compared to controls were lower than in UC. Levels of gp130 and IL-6Rα were decreased in MC but increased in UC compared to controls. Microscopic colitis patients exhibit increased levels of several analytes, including some associated with CD8+ T lymphocytes, suggesting a different pathogenesis of MC compared to UC. Higher levels of MMP-1 and MMP-3 in CC than LC indicate separate disease entities.

Effect of Tofacitinib on Hemostasis in Patients with Ulcerative Colitis: A Comparative Ex Vivo Study.

Background: Tofacitinib is effective for refractory ulcerative colitis (UC), a chronic inflammatory disease of the colonic mucosa. However, its use has been associated with an increased risk of thromboembolic events, prompting regulatory restrictions. Understanding the pathophysiological mechanisms contributing to these potential risks is critical for patient safety. We aim to evaluate and compare ex vivo the effects of tofacitinib and anti-TNF on coagulation parameters and platelet function. Methods: Whole blood and platelet-rich plasma from 10 active UC (aUC) and 10 quiescent UC (qUC) patients and 10 healthy controls (HC) were spiked ex vivo with tofacitinib, anti-TNF (as comparator), or a sterile solution. Coagulation kinetics were measured by rotational thromboelastometry (ROTEM), platelet aggregation by aggregometry, and platelet activation by flow cytometry. The study was conducted at Hospital Universitario de La Princesa. Results: Flow cytometry showed increased expression of activation markers CD62P and CD63 and higher PAC-1 binding in platelets from both aUC and qUC patients incubated with either tofacitinib or anti-TNF versus no drug. No differences were found between the drugs. CD63 expression also increased in HC after drug exposure, with no differences between anti-TNF or tofacitinib. Platelet aggregation and coagulation parameters did not differ between tofacitinib, anti-TNF, and no drug in aUC, qUC, and HC. Conclusions: Tofacitinib does not alter platelet function or coagulation in UC patients under ex vivo conditions compared to anti-TNF. The increased thromboembolic risk observed in some populations treated with tofacitinib cannot be attributed to these factors in UC patients.

Tauroursodeoxycholic Acid (TUDCA) Reduces ER Stress and Lessens Disease Activity in Ulcerative Colitis.

In inflammatory bowel disease, protein misfolding in the endoplasmic reticulum (ER) potentiates epithelial barrier dysfunction and impairs mucosal healing. Tauroursodeoxycholic acid (TUDCA), a naturally occurring bile acid, acts as a chemical chaperone to reduce protein aggregation and colitis severity in preclinical models. We conducted an open label trial evaluating oral TUDCA as therapy in patients with active ulcerative colitis (UC). Patients with moderate-to-severely active UC (Mayo score ≥6, endoscopic subscore ≥1) received oral TUDCA at 1.75 or 2 g/day for 6 weeks. Exclusion criteria included known hepatic disorders or change in UC therapy within 60 days. Clinical disease activity questionnaires, endoscopy with biopsy, blood, and stool were collected at enrollment and after 6 weeks. The primary outcome measure was change in ER stress markers while safety, tolerability and change in UC disease activity were secondary outcomes. Thirteen participants completed the study with eleven evaluable for clinical response. TUDCA was well-tolerated with transient dyspepsia being the most common side effect. Mucosal biopsies revealed significant reductions in ER stress and inflammation as well as an increase in markers of epithelial restitution. Clinical, endoscopic, and histologic disease activity were significantly improved at week 6 (mean total Mayo Score: 9 to 4.5, p<0.001). Six weeks of oral TUDCA treatment was well-tolerated in patients with active ulcerative colitis and promoted mucosal healing, lessened ER stress, and reduced clinical disease activity. A randomized controlled trial of adjunctive TUDCA therapy in patients with UC is warranted. ClinicalTrials.gov ( NCT04114292 ). chemical chaperones, unfolded protein response, inflammatory bowel disease, protein misfolding.

Assessment and Impact of Age on the Safety and Efficacy of Etrasimod in Patients With Ulcerative Colitis: A Post Hoc Analysis of Data From the ELEVATE UC Clinical Program

Abstract Background Patient age can impact the safety and efficacy of ulcerative colitis (UC) treatments. Etrasimod is an oral, once daily (QD), selective sphingosine 1-phosphate1,4,5 receptor modulator for the treatment of moderately to severely active UC. Here, we evaluate the impact of age on etrasimod safety and efficacy in patients with UC in the phase 3 ELEVATE UC clinical program. Methods Data were pooled from ELEVATE UC 52 and ELEVATE UC 12 in patients receiving etrasimod 2 mg QD or placebo. Proportions and incidence rates (IRs) per 100 patient-years of treatment-emergent adverse events (AEs) were stratified by age (&amp;lt;40, 40-59, and ≥60 years). With the same age stratifications, efficacy was evaluated in patients with baseline Modified Mayo scores of 5-9 and 4-9 for the primary efficacy endpoint (clinical remission) and secondary efficacy endpoints. Results Overall, 787 patients were enrolled (&amp;lt;40 years, n = 420 [53.4%]; 40-59 years, n = 276 [35.1%]; and ≥60 years, n = 91 [11.6%]). Arthralgia, fatigue, and hypertension IRs were higher in older patients, irrespective of treatment. Serious AEs and AEs leading to treatment discontinuation were low and consistent across age groups. Significantly more patients receiving etrasimod 2 mg QD vs placebo achieved efficacy endpoints, regardless of age. Conclusions The safety profile of etrasimod 2 mg QD in the ELEVATE UC population was consistent across age groups, with no change in the incidence of AEs. Patients receiving etrasimod vs placebo showed significant clinical benefit, regardless of age. ClinicalTrials.gov NCT03945188; NCT03996369.

Importance of rectal over colon status in ulcerative colitis remission: the role of microinflammation and mucosal barrier dysfunction in relapse.

Ulcerative colitis (UC) is a refractory inflammatory disease that affects the rectum and colon, with pivotal involvement of the rectal environment in relapse initiation. This study was conducted in two phases to examine the differences in gene expression between the rectum and colon and to identify relapse factors. In ***Study 1, RNA sequencing was performed on biopsies from the colon and rectum of patients with active UC, those with remission UC, and controls. In Study 2, the mucosal impedance (MI) values reflecting mucosal barrier function and the mRNA expression of tight junction proteins and inflammatory cytokines were examined in 32 patients with remission UC and 22 controls. Relapse was monitored prospectively. In Study 1, comprehensive genetic analysis using RNA sequencing revealed distinct gene profiles in the rectum and sigmoid colon of patients with remission UC. The rectum of these patients exhibited an enriched immune response and apical junction phenotype with persistent upregulation of CLDN2 gene expression. In Study 2, even in patients with remission UC, the MI values in the rectum, but not in the sigmoid colon, were significantly decreased, whereas they were negatively correlated with CLDN2, IL-1β, and IL-6 expressions. The status of the rectum in patients with remission UC differs from that of the colon, with microinflammation and impaired mucosal barrier function, which are associated with the upregulation of CLDN2, playing a role in relapse.

Patient-donor similarity and donor-derived species contribute to the outcome of fecal microbiota transplantation for ulcerative colitis.

Clinical applications of fecal microbiota transplantation (FMT) for treating ulcerative colitis (UC) have shown promising results. However, whether the beneficial effects of FMT are due to the transfer and colonization of donor-derived species in patients remains unclear. Here, we investigated the factors affecting the efficacy of the administration of triple antibiotics (A-FMT) and the criteria for appropriate donor and patient-donor matching. Ninety-seven patients with active UC who were enrolled between March 2014 and October 2019 underwent FMT. The clinical features were assessed based on a reduction in Lichtiger's clinical activity index 4 weeks after A-FMT, with long-term responders (LTR) defined as those with no increase or intensification within 12 months after A-FMT. Microbiome analysis was performed on 147 fecal samples (pre-A-FMT, post-A-FMT, and donor) from 49 patient-donor combinations that were assigned using the one-patient-to-one-donor strategy. Of the 97 patients, 61 achieved a clinical response, and of those, 35 were classified as having clinical remission. The efficacy of A-FMT was affected by UC severity and previous administration of steroids (P = .027), immunosuppressants (P = .049), and biologics (P = .029). Effective donors were rich in taxa such as Bacteroidota, which are lost in UC, and the abundances of "patient-origin" and "new-amplicon sequence variant" taxa were significantly lower in Responders compared to Nonresponders (Remission; P = .03, LTR; P = .05). "Donor-derived" amplicon sequence variant sequences, Oscillospiraceae UCG-002 and Alistipes, were significantly enriched in Responders (P < .05). Our results showed that the taxonomic composition of patients and the similarity of Bacteroides and butyric-acid-producing bacteria in the patient-donor microbiota significantly influenced A-FMT efficacy (P < .05). This study provides important insights for developing patient-tailored FMT-based therapies for UC.