Treatment Of Ulcerative Colitis Patients Research Articles

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<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<0.001]), and white blood cell count (9,864 (3,514) and 8,067 (1,927), [P<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.

COST PER REMISSION FOR MIRIKIZUMAB VS USTEKINUMAB IN THE MAINTENANCE PHASE FOR MODERATELY-TO-SEVERELY ACTIVE ULCERATIVE COLITIS TREATMENT FROM THE UNITED STATES COMMERCIAL PAYER PERSPECTIVE

Abstract BACKGROUND In phase 3 studies, mirikizumab (MIRI), an IL-23p19 antibody, demonstrated efficacy vs placebo in adult patients with moderately-to-severely active ulcerative colitis (UC). It is being developed for the United States Food and Drug Administration approval for the treatment of UC. Ustekinumab (USTE), an IL-12/23p40 antibody, is currently the most utilized second line treatment in UC patients. Physicians may prescribe MIRI in a similar placement to USTE, and payers may compare them when making formulary decisions for IL-23 inhibitors. Given the need for continued maintenance therapy to manage UC, it is of interest to evaluate the relative cost-efficiency of MIRI vs USTE. We estimated and compared the cost of MIRI vs USTE for achieving remission in one additional patient during the maintenance phase in biologic/Janus kinase inhibitor (JAKi)-experienced patients with UC. METHODS This study used a network meta-analysis (NMA) of published randomized controlled trials of maintenance phase therapy to derive the number needed to treat (NNT) for achieving clinical remission among those who responded to induction therapy. In NMA, clinical remission was defined as a total Mayo score of ≤2 points, with no individual sub-score >1. An Excel-based analytic model was developed to estimate cost per additional patient achieving clinical remission at the end of maintenance trial period. The model included the cost of maintenance therapy from a US commercial payer perspective and the NNT of achieving clinical remission for MIRI and USTE in the biologic/JAKi-experienced population. Wholesale Acquisition Cost (WAC) of USTE was taken from Micromedex Redbook. A scenario with USTE biosimilar was also considered where NNT was considered the same as USTE, but the WAC was considered 50% lower than the current WAC of USTE. RESULTS The costs per biologic/JAKi-experienced patient achieving clinical remission during the maintenance phase were $501,472 and $1,027,799 for MIRI and USTE. The lower cost per remission for MIRI in maintenance was the result of both lower relative NNT and lower anticipated WAC of MIRI compared to USTE. The scenario also resulted in a comparable cost per remission for MIRI vs a USTE biosimilar. CONCLUSION MIRI is projected to have a lower cost per remission during maintenance therapy compared to USTE. Given the need for long-term treatment for this chronic condition, MIRI appears to be a cost-efficient treatment option based on its lower NNT and anticipated acquisition cost in the maintenance phase.

P106 Single-cell transcriptomic analysis reveals insights into the mechanism of action of Granulocyte-monocyte apheresis

Abstract Background Granulocyte-monocyte apheresis (GMA) is a non-pharmacological treatment approved for the management of ulcerative colitis (UC), particularly steroid-dependent cases. The exact mechanism of action and immunological changes associated with GMA remain undescribed. Gene expression analysis at the single-cell level (through scRNA-Seq) has emerged as a key tool of choice to characterize drug response at the molecular level. We used scRNA-Seq to characterize the transcriptomic effects and immune cell population alterations in GMA. Methods We generated scRNA-Seq from peripheral blood mononuclear cells (PBMC) of two ulcerative colitis (UC) patients undergoing GMA treatment. We compared the gene expression profile before and after 5 sessions of GMA treatment. The analytical pipeline included quality control and classical filtering steps, cell-type annotation, differential gene expression analysis and pathway enrichment profiling. Results We report three main results. First, we observed significant reductions of cell types directly affected by GMA treatment in UC patients. This includes classical CD14+ monocytes and Natural killers, which are central components of the innate system. Of note, we observed a remarkable increase in Double-negative T cells (dnT) after 5 sessions of GMA treatment, suggesting potential expansion of protective populations involved in decreased inflammation. Second, we observe a variety of genes and regulatory pathways altered by GMA treatment. In total, we detect 86 differentially expressed genes (DEGs), which overall are biased towards downregulation (63%). Of note, we detected dnT-s exhibiting upregulation of NEFL that is associated with the MAPK cascade and downregulation of genes related to immune response and signaling pathways. Finally, the effects of GMA treatment extend beyond the above mentioned populations, with particular alterations in CD4+ T cell populations such as CD4+ central memory and CD4+ Naive (7 and 13 DEGs, respectively). Conclusion For the first time, we generated single-cell transcriptomic profiles to characterize the effects of GMA treatment in peripheral blood of UC patients. Our preliminary analysis detects important alterations in the gene regulation and cell type composition in samples obtained after 5 sessions of GMA. Through expansion of this dataset to include more time points and profiles for more individuals, we will discuss the longitudinal changes and molecular mechanisms involved in response to GMA treatment.

Prediction of Clinical Remission with Adalimumab Therapy in Patients with Ulcerative Colitis by Fourier Transform-Infrared Spectroscopy Coupled with Machine Learning Algorithms.

We aimed to develop prediction models for clinical remission associated with adalimumab treatment in patients with ulcerative colitis (UC) using Fourier transform-infrared (FT-IR) spectroscopy coupled with machine learning (ML) algorithms. This prospective, observational, multicenter study enrolled 62 UC patients and 30 healthy controls. The patients were treated with adalimumab for 56 weeks, and clinical remission was evaluated using the Mayo score. Baseline fecal samples were collected and analyzed using FT-IR spectroscopy. Various data preprocessing methods were applied, and prediction models were established by 10-fold cross-validation using various ML methods. Orthogonal partial least squares-discriminant analysis (OPLS-DA) showed a clear separation of healthy controls and UC patients, applying area normalization and Pareto scaling. OPLS-DA models predicting short- and long-term remission (8 and 56 weeks) yielded area-under-the-curve values of 0.76 and 0.75, respectively. Logistic regression and a nonlinear support vector machine were selected as the best prediction models for short- and long-term remission, respectively (accuracy of 0.99). In external validation, prediction models for short-term (logistic regression) and long-term (decision tree) remission performed well, with accuracy values of 0.73 and 0.82, respectively. This was the first study to develop prediction models for clinical remission associated with adalimumab treatment in UC patients by fecal analysis using FT-IR spectroscopy coupled with ML algorithms. Logistic regression, nonlinear support vector machines, and decision tree were suggested as the optimal prediction models for remission, and these were noninvasive, simple, inexpensive, and fast analyses that could be applied to personalized treatments.

New Technologies in Digestive Endoscopy for Ulcerative Colitis Patients.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease primarily affecting the colon and rectum. Endoscopy plays a crucial role in the diagnosis and management of UC. Recent advancements in endoscopic technology, including chromoendoscopy, confocal laser endomicroscopy, endocytoscopy and the use of artificial intelligence, have revolutionized the assessment and treatment of UC patients. These innovative techniques enable early detection of dysplasia and cancer, more precise characterization of disease extent and severity and more targeted biopsies, leading to improved diagnosis and disease monitoring. Furthermore, these advancements have significant implications for therapeutic decision making, empowering clinicians to carefully consider a range of treatment options, including pharmacological therapies, endoscopic interventions and surgical approaches. In this review, we provide an overview of the latest endoscopic technologies and their applications for diagnosing and monitoring UC. We also discuss their impact on treatment decision making, highlighting the potential benefits and limitations of each technique.

Capsulized Fecal Microbiota Transplantation Induces Remission in Patients with Ulcerative Colitis by Gut Microbial Colonization and Metabolite Regulation.

Fecal microbiota transplantation (FMT) can induce clinical remission in ulcerative colitis (UC) patients. Enemas, nasoduodenal tubes, and colonoscopies are the most common routes for FMT administration. However, there is a lack of definitive evidence regarding the effectiveness of capsulized FMT treatment in UC patients. In this study, we administered capsulized FMT to 22 patients with active UC to assess the efficiency of capsulized FMT and determine the specific bacteria and metabolite factors associated with the response to clinical remission. Our results showed that the use of capsulized FMT was successful in the treatment of UC patients. Capsulized FMT induced clinical remission and clinical response in 57.1% (12 of 21) and 76.2% (16 of 21) of UC patients, respectively. Gut bacterial richness was increased after FMT in patients who achieved remission. Patients in remission after FMT exhibited enrichment of Alistipes sp. and Odoribacter splanchnicus, along with increased levels of indolelactic acid. Patients who did not achieve remission exhibited enrichment of Escherichia coli and Klebsiella and increased levels of biosynthesis of 12,13-DiHOME (12,13-dihydroxy-9Z-octadecenoic acid) and lipopolysaccharides. Furthermore, we identified a relationship between specific bacteria and metabolites and the induction of remission in patients. These findings may provide new insights into FMT in UC treatment and provide reference information about therapeutic microbial manipulation of FMT to enhance its effects. (This study has been registered at ClinicalTrails.gov under registration no. NCT03426683). IMPORTANCE Fecal microbiota transplantation has been successfully used in patients. Recently, capsulized FMT was reported to induce a response in patients with UC. However, limited patients were enrolled in such studies, and the functional factors of capsulized FMT have not been reported in the remission of patients with UC. In this study, we prospectively recruited patients with UC to receive capsulized FMT. First, we found that capsulized FMT could induce clinical remission in 57.1% of patients and clinical response in 76.2% after 12 weeks, which was more acceptable. Second, we found a relationship between the decrease of opportunistic pathogen and lipopolysaccharide synthesis in patients in remission after capsulized FMT. We also identified an association between specific bacteria and metabolites and remission induction in patients after capsulized FMT. These findings put forward a possibility for patients to receive FMT at home and provide reference information about therapeutic microbial manipulation of FMT to enhance its effects.

IL-22 alters gut microbiota composition and function to increase aryl hydrocarbon receptor activity in mice and humans

BackgroundIL-22 is induced by aryl hydrocarbon receptor (AhR) signaling and plays a critical role in gastrointestinal barrier function through effects on antimicrobial protein production, mucus secretion, and epithelial cell differentiation and proliferation, giving it the potential to modulate the microbiome through these direct and indirect effects. Furthermore, the microbiome can in turn influence IL-22 production through the synthesis of L-tryptophan (L-Trp)-derived AhR ligands, creating the prospect of a host-microbiome feedback loop. We evaluated the impact IL-22 may have on the gut microbiome and its ability to activate host AhR signaling by observing changes in gut microbiome composition, function, and AhR ligand production following exogenous IL-22 treatment in both mice and humans.ResultsMicrobiome alterations were observed across the gastrointestinal tract of IL-22-treated mice, accompanied by an increased microbial functional capacity for L-Trp metabolism. Bacterially derived indole derivatives were increased in stool from IL-22-treated mice and correlated with increased fecal AhR activity. In humans, reduced fecal concentrations of indole derivatives in ulcerative colitis (UC) patients compared to healthy volunteers were accompanied by a trend towards reduced fecal AhR activity. Following exogenous IL-22 treatment in UC patients, both fecal AhR activity and concentrations of indole derivatives increased over time compared to placebo-treated UC patients.ConclusionsOverall, our findings indicate IL-22 shapes gut microbiome composition and function, which leads to increased AhR signaling and suggests exogenous IL-22 modulation of the microbiome may have functional significance in a disease setting.Cw21cUiGabCHLYfc9EL5iqVideo

Mercaptopurine for the treatment of ulcerative colitis - a randomised placebo-controlled trial.

Scepticism about the efficacy of thiopurines for ulcerative colitis (UC) is rising.This study aimed to evaluate mercaptopurine treatment for UC. In this prospective, randomised, double-blind, placebo-controlled trial, patients with active UC, despite treatment with 5-aminosalicylates (5-ASA), were randomised for therapeutic drug monitoring (TDM)-guided mercaptopurine treatment or placebo for 52 weeks. Corticosteroids were given in the first eight weeks and 5-ASA was continued. Proactive metabolite-based mercaptopurine and placebo dose adjustments were applied from week six onwards by unblinded clinicians. The primary endpoint was corticosteroid-free clinical remission and endoscopic improvement (total Mayo score ≤2 points and no item >1) at week 52 in an intention-to-treat analysis. Between December 2016 and April 2021, 70 patients were screened and 59 were randomised at six centres. In the mercaptopurine group, 16/29 (55.2%) patients completed the 52-week study, compared to 13/30 (43.3%) on placebo. The primary endpoint was achieved by 14/29 (48.3%) patients on mercaptopurine and 3/30 (10%) receiving placebo (Δ=38.3%, 95% CI 17.1-59.4, p=0.002). Adverse events occurred more frequently with mercaptopurine (808.8 per 100 patient years) compared to placebo (501.4 per 100 patient years). Five serious adverse events occurred; four on mercaptopurine and one on placebo. TDM-based dose adjustments were executed in 22/29 (75.9%) patients, leading to lower mercaptopurine doses at week 52 compared to baseline. Optimised mercaptopurine treatment was superior to placebo in achieving clinical, endoscopic and histological outcomes at one year following corticosteroid induction treatment in UC patients. More adverse events occurred in the mercaptopurine group.

Etrasimod for the treatment of ulcerative colitis.

Sphingosine-1-phosphate (S1P) and its receptor (S1PR) are involved in the pathogenesis of multiple immune-mediated inflammatory disorders, including inflammatory bowel disease. The use of S1PR modulators represents a new therapeutic option for ulcerative colitis patients. Etrasimod is an oral selective S1PR1, S1PR4 and S1PR5 modulator that inhibits the trafficking of lymphocytes from the lymph nodes into the blood. Recently, etrasimod has demonstrated efficacy in the phase II OASIS study and its open-label extension for the treatment of ulcerative colitis patients. This article reviews the mechanism of action of etrasimod and summarizes the available clinical efficacy and safety data regarding etrasimod, which is a promising drug in the treatment of patients with moderate to severe ulcerative colitis.

Ulcerative Colitis and Acute Severe Ulcerative Colitis Patients Are Overlooked in Infliximab Population Pharmacokinetic Models: Results from a Comprehensive Review.

Ulcerative colitis (UC) is part of the inflammatory bowels diseases, and moderate to severe UC patients can be treated with anti-tumour necrosis α monoclonal antibodies, including infliximab (IFX). Even though treatment of UC patients by IFX has been in place for over a decade, many gaps in modelling of IFX PK in this population remain. This is even more true for acute severe UC (ASUC) patients for which early prediction of IFX pharmacokinetic (PK) could highly improve treatment outcome. Thus, this review aims to compile and analyse published population PK models of IFX in UC and ASUC patients, and to assess the current knowledge on disease activity impact on IFX PK. For this, a semi-systematic literature search was conducted, from which 26 publications including a population PK model analysis of UC patients receiving IFX therapy were selected. Amongst those, only four developed a model specifically for UC patients, and only three populations included severe UC patients. Investigations of disease activity impact on PK were reported in only 4 of the 14 models selected. In addition, the lack of reported model codes and assessment of predictive performance make the use of published models in a clinical setting challenging. Thus, more comprehensive investigation of PK in UC and ASUC is needed as well as more adequate reports on developed models and their evaluation in order to apply them in a clinical setting.

Critical Appraisal of Filgotinib in the Treatment of Ulcerative Colitis: Current Evidence and Place in Therapy.

Background and AimsPatients affected by moderate-to-severe Ulcerative Colitis (UC) demand a challenging management. Small molecules, administrated as oral agents, have the ambition of overcoming the limitations of the biologic agents (ie, parenteral administration, rapidity of action, primary and secondary non-responsiveness). Beyond tofacitinib, a pan-Janus kinase (JAK) inhibitor already approved for the treatment of moderate-to-severe UC, novel more selective molecules like filgotinib are being currently evaluated in randomized clinical trials. We aimed to review the current evidence on filgotinib, a JAK-1 preferential inhibitor, in the treatment of UC and its place in therapy in the current scenario.MethodsPubMed and EMBASE were searched to identify relevant studies: those investigating the efficacy and safety of filgotinib in the treatment of UC patients were included in this narrative review.ResultsThe current preliminary data have shown that filgotinib is safe and effective in inducing clinical end endoscopic response in both biologic-naïve and biologic-experienced patients with moderate-to-severe UC, also with high inflammatory burden at baseline. In the SELECTION trial, one case of pulmonary embolism occurred with filgotinib 200 mg induction, and three venous thrombosis cases were observed in the placebo maintenance/LTE; the incidence of herpes zoster was ≤1% in all UC treated patients. Filgotinib represents an appealing treatment option for its high selectiveness, route of administration and rapidity of action; cost-effectiveness studies and head-to-head trials are needed to better define its place in therapy.

Fecal microbiota transplantation for treatment of moderate to severe ulcerative colitis: a living systematic review protocol

Background: Primary studies and systematic reviews assessing the safety and effectiveness of fecal microbiota transplantation as a treatment for ulcerative colitis are being continuously published. The objective of this review is to synthesize and keep updated the evidence about the efficacy and safety of fecal microbiota transplantation for adult patients with moderate or severe ulcerative colitis through a living systematic review. Methods: We will carry out a living systematic review including only randomized controlled trials irrespective of publication type, year and language of publication. To prioritize the fecal microbiota transplantation administration route, comparators and outcomes more relevant for supporting the clinical decisions in the treatment of ulcerative colitis patients, we will perform a Delphi process conducted by an expert panel in the field of gastroenterology and colorectal surgery. Searches will be performed in Epistemonikos database and results will be incorporated into the L·OVE platform identified as “Fecal microbiota transplant in ulcerative colitis”. We will evaluate the risk of bias of the included randomized trials using the ROB-2 tool and assess the certainty of evidence using the GRADE approach. We will monitor the L ·OVE platform every two months searching for relevant trials that could imply changes in the available evidence. The living process will end after 12 months of surveillance. PROSPERO registration: CRD42021257579 (29/10/2021).

Inflammatory bowel diseases - therapy update 2022

Growing insights into the underlying immunopathogenesis of inflammatory bowel diseases (IBD) have led to the advent of targeted therapies, which selectively target pivotal mediators of the inflammatory process. This has enabled us to define and achieve novel therapeutic outcomes to prevent disease-associated complications and halt the progressive course of disease. In addition to already available treatment options, the selective Janus kinase type 1 inhibitor filgotinib and the selective sphingosine-1-phosphate receptor modulator Ozanimod have recently been approved for the treatment of ulcerative colitis patients. Furthermore, positive phase 2/3 induction and maintenance trial results have been reported for representatives of the class of IL-23p19 inhibitors, which are expected to further increase our therapeutic possibilities. All these agents can be applied as first-line or also subsequent treatment options and recent head-to-head trials have helped us to position these substances in our therapeutic algorithm. Nevertheless, there is still the currently unmet clinical need do establish predictive markers of response to identify the subgroup of IBD patients, that have a heightened probability of response to each therapy. In the following, we will give an overview of the recently approved or in late-stage clinical development tested substances and discuss their positioning in our therapeutic armamentarium.

P622 Comparison of long-term outcomes of infliximab and adalimumab in biologic-naïve patients with ulcerative colitis

Abstract Background The comparative efficacy and safety of infliximab (IFX) and adalimumab (ADA) have revealed variable results in biologic-naïve patients with ulcerative colitis (UC), and long-term comparison studies between IFX and ADA with or without immunomodulator therapy are still needed in patients with UC. Methods The aim of this study was to evaluate the long-term effectiveness and safety of IFX compared to ADA in biologic-naïve adult patients with UC. All data of patients between June 2007 and March 2021 were collected retrospectively. We compared UC-related hospitalisation, colectomy, steroid use, and serious infections leading to treatment cessation. Results Out of 86 UC patients, 41 started IFX first (mean age at onset: 34.4 years, 61.0% male) and 45 started ADA first (mean age at onset: 31.4 years, 60.0% male). Disease duration was 7.2 years for IFX and 8.1 years for ADA. There were no significant differences between the two groups with respect to age, gender, smoking, extraintestinal manifestations, immunomodulator usage, or disease extent at the onset of anti-TNF therapy (p > 0.05). Concomitant rates of medication including mesalazine, sulphapyridine, thiopurine, and steroids were the same in both groups (p > 0.05). In the IFX group, baseline haemoglobin (11.7 vs 13.2, p = 0.05) and albumin (3.8 vs 4.2, p = 0.02) levels were lower than those of the ADA group, while C-reactive protein was higher (14.0 vs 6.0, p = 0.04) than in the ADA group. Total MAYO score at baseline was similar in both groups (p = 0.10). During anti-TNF therapy, steroid use was significantly higher in the ADA group (44.4%) compared to IFX (14.6%, p = 0.003). The rates of UC-related hospitalisation (IFX 9.8% vs ADA 13.3%, p=0.74) and colectomy (IFX 4.9% vs ADA 2.2%, p = 0.60) were similar in IFX and ADA groups. Serious infection leading to treatment cessation was not different between the two groups (IFX 2.4% vs ADA 4.4%, p=0.54). These outcomes were similar in UC patients treated with IFX or ADA monotherapy or in combination with an immunomodulator within each group, and there was no significant difference between IFX and ADA in combination with an immunomodulator regarding those outcomes (p > 0.05). Conclusion In this study, steroid use in the ADA group was significantly higher than in the IFX group, although UC-related hospitalisation, colectomy, and serious infections were not different in biologic-naïve adult patients with UC. We also observed that outcomes were similar in patients treated with IFX and ADA monotherapy or in combination with an immunomodulator. In the present study, IFX revealed better long-term outcomes for first-time treatment of UC patients.

Histological remission of ulcerative colitis with combined anti-cytokine and cell therapy

To conduct comparative analysis of histological remission in patients with moderate and severe ulcerative colitis (UC), receiving biological therapy vedolizumab, mesenchymal stem cell (MSC) treatment and combined stem cells and vedolizumab therapy. We studied biopsies of 75 patients with total or left-sided moderate and severe ulcerative colitis, divided into groups depending on treatment. The first group of UC patients (n=29) received stem cell therapy 2 mln per kg; the second group of UC patients (n=27) received vedolizumab and the third group (n=19) MSC and vedolizumab. The efficacy of treatment was assessed by C reactive protein (CRP), Mayo score (MS), fecal calprotectin (FC) and Geboes score (GS). We determined medium correlation between basic FC and MS before treatment (r=0.6605, p0.05). After 12 weeks of treatment in the first group of UC patients (n=29) CRP was 7.82.1 mg/l, FC 409.344.85 g/g, medium GS 1.20.1 points. After 12 weeks of treatment in the second group of UC patients (n=27) CRP was 8.41.4 mg/l, FC 435.547.3 g/g, medium GS 1.350.15 points. After 12 weeks of treatment in the third group of UC patients (n=19) CRP was 6.41.1 mg/l, FC 290.617.5 g/g, medium GS 0.90.1 points. We proved strong direct relationship between FC and GS after 12 weeks of treatment in UC patients, receiving MSC (r=0.8392, p0.05). The statistically significant majority of patients, achieved histological remission, have less than 5-year duration of disease. Our study showed that clinical and endoscopic remission in UC patients does not always correlate with histological remission. Combined anti-cytokine and stem cells therapy contributes to achieve deep remission and decrease mucosa inflammation rather than single MSC or vedolizumab treatment. Deep remission could be achieved by earlier start of biological therapy. FC could be a predictor and marker of mucosa healing and histological remission.

P476 Effectiveness and safety of ustekinumab in ulcerative colitis: Real-world evidence from the ENEIDA registry

BackgroundThe development program (UNIFI) has shown promising results of ustekinumab in ulcerative colitis (UC) treatment that should be confirmed in clinical practice.AimsPrimary: to evaluate the durability of ustekinumab treatment in UC patients in clinical practice. Secondary: to assess the short-term response (at week 16) and the long-term effectiveness (at maximum follow-up) and to assess the safety of ustekinumab in clinical practice.MethodsPatients included in the prospectively maintained ENEIDA registry who received at least one intravenous dose of ustekinumab due to active UC [Partial Mayo Score (PMS) >2] were included. Clinical activity and effectiveness were defined based on PMS.Results95 patients were included (table 1). At week 16, 53% of patients had clinical response (including 35% of patients in remission) (figure 1). In the multivariate analysis, elevated serum C-reactive protein was the only variable significantly associated with clinical remission. Long-term remission is represented in figure 2. 36% of patients discontinued the treatment with ustekinumab during a median follow-up of 31 weeks. The probability of maintaining ustekinumab treatment was 87% at week 16, 63% at week 56, and 59% at week 72 (figure 3); primary failure was the main reason for ustekinumab discontinuation. No variable was associated with risk of discontinuation. Three patients reported adverse events; one of them had a fatal severe SARS-CoV-2 infection. ConclusionUstekinumab is effective both in the short and the long-term in real-life, even in a highly refractory cohort. Higher inflammatory burden at baseline correlated with lower probability of achieving remission. Safety was consistent with the known profile of ustekinumab.

Design and optimization of pellets formulation containing curcumin ascorbic acid co-amorphous mixture for ulcerative colitis management

Curcumin is known for its various therapeutic properties like anti-inflammatory, antioxidant, anticancer, however, its oral use is restricted due to its low solubility and dissolution rate in alkaline pH. In this study co-amorphous mixture of curcumin–ascorbic acid (CU:AA) of different molar ratios was prepared using the ball milling method. The solubility and characterization of the mixture were studied using FTIR, DSC, and XRD study. Mixture (1:0.50) molar ratio showed the highest solubility and was formulated in pellets dosage and optimized using 32 full factorial designs. The solubility results revealed that a significant increase (p < 0.005) in the solubility of curcumin by the ratio 1:0.50 (212 ± 12 µg/ml) compared to the pure drug (90.0 ± 10 µg/ml). XRD and DSC studies confirmed the formation of amorphous curcumin, whereas FTIR elucidated weak hydrogen interactions. In-vitro dissolution study results showed the (CU:AA) ratio (1:0.50) higher percent drug release (81.61 ± 5.12%) compared to the pure drug (19.44 ± 4.60%). The developed formulations are found to be stable. Therefore, the prepared pellets of co-amorphous mixture enhance the solubility, dissolution rate, and stability of curcumin in higher pH, which will become a promising approach for combination therapy in the treatment of ulcerative colitis patients.

Mucosal microbiota and gene expression are associated with long-term remission after discontinuation of adalimumab in ulcerative colitis

Given that sustained remission is the ultimate treatment goal in the management of patients with ulcerative colitis (UC), the decision to stop anti-tumor necrosis factor (anti-TNF) treatment in UC patients is difficult. The aim of this study was to evaluate mucosal microbiota and gene expression profiles associated with long-term remission after discontinuation of anti-TNF therapy. In nine UC patients who received anti-TNF therapy for 6 months, microbiota isolated from uninflamed mucosae and gene expression in inflamed and uninflamed mucosae were investigated at week 0 and at week 24. At treatment initiation, Fusobacterium sp. and Veillonella dispar were over-represented in the relapse group compared with the non-relapse group. After treatment, Dorea sp. and Lachnospira sp. were over-represented in the non-relapse group. In the relapse group only, a significant shift in gut bacterial community composition was found between week 0 and week 24. Gene expression of ALIX (PDCD6IP) and SLC9A3 was significantly higher in the non-relapse group than in the relapse group. Lastly, we used machine learning methods to identify relevant gene signatures associated with sustained remission. Statistical analyses of microbiota and expression profiles revealed differences between UC patients who did or did not keep remission after the discontinuation of TNF inhibitors.Trial registration: UMIN000020785: Evaluation of adalimumab therapy in mesalazine-resistant or -intolerant ulcerative colitis; an observational study (EARLY study).

Real-life experience with 4\xa0years of golimumab persistence in ulcerative colitis patients

Golimumab has demonstrated its long-term efficacy and safety in ulcerative colitis in clinical trials, but no data of long-term persistence has been published from real world. To estimate long-term persistence of golimumab, as well as factors associated with longer persistence, in patients with ulcerative colitis in real life. Observational multicentre study including adult patients with ulcerative colitis treated with golimumab and with at least twelve months of follow-up. We included 190 patients, 105 (55.26%) naive to anti-TNF, with mean disease duration of 9.32 ± 8.09 years. Probability of persistence was 63%, 46%, 39% and 27% at 1, 2, 3 and 4 years, respectively. Persistence was lower in patients with primary failure to previous anti-TNF. Eighty-two (43.16%) patients needed dose intensification during follow-up, with a mean time until intensification of 8.03 ± 8.64 months. Dose intensification and lower disease duration predicted higher persistence with golimumab (p = 0.037 and p = 0.008, respectively). During a follow-up of 17.25 ± 15.83 months, 32 (16.5%) patients needed hospitalisation and 11 (6%) underwent colectomy. No unexpected adverse events were reported. Golimumab has demonstrated good persistence and safety profile for long treatment in ulcerative colitis patients.

Rab27A promotes cellular apoptosis and ROS production by regulating the miRNA-124-3p/STAT3/RelA signalling pathway in ulcerative colitis.

Ulcerative colitis (UC) is a multifactorial inflammatory disease, and increasing evidence has demonstrated that the mechanism of UC pathogenesis is associated with excessive cellular apoptosis and reactive oxygen species (ROS) production. However, their function and molecular mechanisms related to UC remain unknown. In this study, Rab27A mRNA and protein were proven to be overexpressed in intestinal epithelial cells of UC patients and DSS‐induced colitis mice, compared with control (P < 0.05). And Rab27A silencing inhibits inflammatory process in DSS‐induced colitis mice (P < 0.05). Then, it was shown that knockdown of Rab27A suppressed apoptosis and ROS production through modulation of miR‐124‐3p, whereas overexpression of Rab27A promoted apoptosis and ROS production in LPS‑induced colonic cells. In addition, enhanced expression of miR‐124‐3p attenuated apoptosis and ROS production by targeting regulation of STAT3 in LPS‑induced colonic cells. Mechanistically, we found Rab27A reduced the expression and activity of miR‐124‐3p to activate STAT3/RelA signalling pathway and promote apoptosis and ROS production in LPS‑induced colonic cells, whereas overexpression of miR‐124‐3p abrogated these effects of Rab27A. More importantly, animal experiments illustrated that ectopic expression of Rab27A promoted the inflammatory process, whereas overexpression of miR‐124‐3p might interfere with the inflammatory effect in DSS‐induced colitis mice. In summary, Rab27A might modulate the miR‐124‐3p/STAT3/RelA axis to promote apoptosis and ROS production in inflammatory colonic cells, suggesting that Rab27A as a novel therapeutic target for the prevention and treatment of UC patients.