Severe Ulcerative Colitis Research Articles

P928 "Metabolism and Response to Stress" (MARS) gene signatures reveal heterogeneity in patients with Ulcerative Colitis and identify characteristics of patients with increased response to therapy

Abstract Background Ulcerative colitis (UC) therapies lead to variable remission in participants in clinical trials likely due to interindividual variability, differences in active biological pathways, feedback, and/or resistance mechanisms. We sought to characterise these differences using mucosal biopsy transcriptomics datasets from two recent UC clinical trials. Methods Two clinical trial datasets including patients with moderate to severe UC with mucosal biopsy RNA-Sequencing analysis were used: a phase 2/3 study of andecaliximab (anti-matrix metalloproteinase-9, NCT02520284) and a phase 3 study of ustekinumab (anti-interleukin-12/23, UNIFI, NCT02407236). Samples were scored for enrichment of ~5200 MSigDB signatures using Geneset Variation Analysis and were evaluated for correlation to the sample Robarts Histopathology Index (RHI) (Figure). Results From the andecaliximab baseline and follow-up samples, 11 Reactome pathways were specifically selected that were moderately correlated with RHI (r=~0.4) and had low correlation to each other (r<0.7). The 11 genesets, called Metabolism and Response to Stress (MARS) signatures, can generally be sorted into 2 categories: 5 metabolism-related and 6 related to stress response. Clustering of baseline andecaliximab samples scored with MARS signatures revealed 3 major sample groups (baseline and follow-up samples). Group 1 had low metabolism/high stress scores, group 2 had high metabolism/low stress scores, and group 3 had a mixture of samples that had high metabolism/low stress and low metabolism/high stress. Group 2 was associated with a lower proportion of current smokers (p=.04), and group 3 had a higher proportion of immunomodulator failure (p=.03), but not associated with disease duration or prior biologic use. Group 2 had lower Geboes score for epithelial neutrophils (p=.02), lamina propria neutrophils (p=.002), and inflammatory infiltrate (p=.03), while eosinophils increased (p=.01). To evaluate prediction of response to therapy, we evaluated the UNIFI dataset baseline samples using the MARS signatures and identified 4 groups. Group 2 had low metabolism/high stress response, group 3 had high metabolism/low stress response, and groups 1 and 4 had a mixture. The mucosal healing response rate was 3- to 4-fold lower for group 2 than other groups (5.3% [group 2] and 19%, 23%, and 21% for other groups, p=.0009). Conclusion We describe the MARS signatures which characterise the heterogeneity of participants with UC clinical trials and identify participants most likely to respond to ustekinumab at baseline. These signatures may be generally useful to predict patient response, match therapeutics to patient profiles, or identify pathways to target in difficult-to-treat patients.

P077 The Immunometabolic Bimodal Mechanism of NLRX1 Agonist NX-13 in a Pig Model of Ulcerative Colitis

Abstract Background In mouse models, NX-13 is an orally active, gut-restricted NLRX1 agonist that has been shown to reduce severity of disease in multiple UC models through a novel immunometabolic, bimodal mechanism. Most preclinical UC studies rely upon rodent models, the human gastrointestinal physiology, microbiome, and immune system bear a greater similarity to that of pigs. Therefore, we sought to expand and validate our preclinical NX-13 results in mice using the dextran sulfate sodium (DSS) pig model of colitis. Here, we describe the disease severity, cellular, and biomarker results, and confirm the immunometabolic MOA observed in other species. Methods Pigs were randomized by weight (n=6 per group) and were administered tablets of excipient alone (placebo), NX-13 10 mg, NX-13 50 mg, or NX-13 100mg once daily. Pigs were challenged with 1% DSS in drinking water for 6 days and monitored daily for weight gain (loss). Composite disease activity score (0-12) was taken based on the sum of three subscores (0-4) for rectal bleeding, stool consistency and overall health/activity. Necropsy was conducted on day 7. Feces were collected for fecal calprotectin (FCP) quantification. Colonic tissue was macroscopically scored and collected for analysis by flow cytometry, histopathology and gene expression. Results Oral NX-13 treatment protected against weight loss and reduced colitis development with differences as early as day 2, becoming significant between days 4 and 6 as disease worsens in placebo treated pigs (Fig1A). NX-13 yielded a dose-dependent improvement in macroscopic lesion severity and microscopic immune cell infiltration (Fig1B). Specifically, Th1 cells (Fig1C) and TNF producing myeloid cells in the colonic lamina propria were reduced by NX-13, as well as FCP levels in stool (Fig1D) and mRNA expression in the colon (Fig1E). Oral NX-13 treatment reduced inflammatory markers including TNF, monocyte and neutrophil chemo attractants, IL-6, and IL-23 (Fig3F). Additionally, NX-13 treatment affected markers specific to the bimodal immunometabolic MOA of NLRX1 activation, namely upregulation of NLRX1 and mitochondrial metabolism gene COX3 (Fig1G), and reduction of NFkB and NLRP3 (Fig1H). Conclusion NX-13 demonstrated fast and clinically meaningful improvement in disease activity, and significantly impacted on key inflammatory markers in a DSS colitis model in pigs. These results align with previous murine results and observations in the phase 1b clinical program. Therefore, they can be used to generate additional mechanistic hypotheses for translational studies in the ongoing NEXUS phase 2 trial in moderate to severe UC.

P150 Ulcerative Colitis Patients’ Luminal Zinc Induces Clostridioides difficile Virulence and Exacerbates Inflammatory Responses

Abstract Background The refractory acute severe UC patients are often complicated by C. difficile infection (CDI), resulting in higher surgery and mortality rates. However, few studies have observed C. difficile’s pathogenicity in real UC patients’ gastrointestinal microenvironments, and the actual role of C. difficile in UC development remains unknown. We found zinc concentrations among UC patients’ feces were significantly higher than those among Crohn’s disease patients and healthy subjects. Additionally, we previously reported that excessive zinc would promote the growth and virulence of C. difficile. Therefore, we hypothesized that the increased UC patients’ luminal zinc may up-regulate C. difficile virulence and promote intestinal inflammatory responses, leading to an exacerbated UC progression. Methods UC patients’ stool samples (n=40) were collected and analyzed by qPCR and ICP-MS to determine the presence of C. difficile and the fecal zinc concentrations. C. difficile was cultured in BHIs with or without zinc (ZnSO4) in an anaerobic chamber. Expression of virulence genes was analyzed using RT-qPCR, transcriptome sequencing, and western blot. Human colonic organoids and Caco-2 cells were co-cultured with C. difficile or zinc-treated C. difficile, and cytotoxicity, permeability, and inflammatory cytokine release were assessed. TLR5 knock-out Caco-2 cells were constructed using sgRNA-guided Cas9 nuclease and co-cultured with C. difficile or zinc-treated C. difficile to verify whether zinc-induced C. difficile’s pathogenicity was mainly through flagellar formation. Results C. difficile was detected in ~35% of UC patients’ fecal samples. Luminal zinc concentrations (~915μM, p<0.01) were significantly higher among UC patients than CD patients or healthy subjects. The UC patients’ luminal concentration of zinc promoted C. difficile growth, suppressed its exotoxins release, and induced higher expression of its flagella-related genes, resulting in higher cytotoxicity and inflammatory responses in human colonic organoids and Caco-2 cells. However, zinc-treated C. difficile did not induce higher inflammation and pathogenicity in TLR5 knock-out Caco-2 cells. Conclusion The association between C. difficile and UC aggravation may partially stem from UC patients’ excess luminal zinc promoting C. difficile flagellin expression, inducing inflammatory responses, and worsening UC progression.

P297 Differences in disease characteristics and treatment exposures between pediatric- and adult-onset Ulcerative Colitis

Abstract Background previous studies highlighted differences between pediatric-onset ulcerative colitis (pUC) and adult-onset UC (aUC), showing a more severe phenotype in pUC. However, most studies lacked prolonged follow-up, and some were conducted prior to the biologic era. We utilized a large cohort database to compare disease characteristics and treatment exposures between pUC and aUC. Methods Single-center IBD registry from the Sheba Medical Center was used and included aUC (age ≥ 18 years) and pUC (age ≥ 6 and < 18 years) patients diagnosed between 2000 and 2022. Data were retrieved from the medical record to a computerized and periodically updating registry in a unified manner. Retrieved data included demographics, clinical disease characteristics and phenotype, and prescribed treatments during routine clinical follow-up. We used descriptive statistics, T-test, and chi-square test for between-group analyses. Results This study included 1332 UC patients, of them 682 were females (51.2%, Table 1). The cohort comprised 1058 aUC and 274 pUC patients. The median (IQR) age at diagnosis for pUC was 14.9 (12.5-16.8) years and 31.7 (23.6-48.9) years for aUC. Disease duration and the interval from diagnosis to last follow-up were similar between pUC and aUC, with a median (IQR) disease duration of 8.9 years (4.6-14.2) in pUC and 8.5 (4.5-14.1) in aUC, and a median interval from diagnosis to last follow-up of 7.3 years (3.5-12.3) in pUC and 7.3 years (3.4-13.0) in aUC. Significantly more pUC presented with pancolitis: 59.1% vs. 39.4% in aUC (p<0.00001), (Table 1). During long-term follow-up, treatment exposures also varied significantly between pUC and aUC (Figure 1); 61.3% of pUC were treated with systemic steroids vs. only 42.4% in the aUC group. Thiopurines were used in 40.5% of pUC vs. only 16.7% of aUC, and biological therapy was used in 46.0% of pUC vs. 34.1% of aUC. Time to initiation of biologic treatment was shorter in pUC with a median (IQR) of 33.0 months (15.0-71.3) vs. 36.6 months (15.8-96.1) in aUC (p=0.04). Finally, the number of biologics lines used was also higher in pUC vs. aUC ((mean of 2.1±1.4 vs. 1.8±1.0, p=0.01). Limiting the comparison to only UC patients who presented with pancolitis included 163 pUC and 417 aUC. Within this more severe UC phenotype, exposure to steroids and thiopurines was still significantly higher in pUC vs. pUC, but exposure to a biologic was similar with 54.6% of pUC vs. 50.1% of aUC. Conclusion pUC presents with more pancolitis, considered a more severe form of UC. This more aggressive presentation at diagnosis likely leads to a higher rate of exposure to systemic steroids, thiopurines, and biologics during a median of ~7 years of follow-up.

P1014 Faecal loss of vedolizumab is associated with UC severity, lower serum vedolizumab levels and rates of clinical response – Results from the FAVOUR study

Abstract Background Infliximab is detectable in the faeces of patients with active UC and faecal loss is associated with more severe disease and with primary non-response. Detection of vedolizumab (VED) in faeces and its importance in patients with UC has not been investigated. We conducted a prospective, observational study of patients with UC commencing VED to investigate faecal VED loss as well as its impact on serum VED levels (SVL) and association with treatment outcomes. Methods The FAVOUR study recruited UC patients with moderate to severe UC commencing vedolizumab between April 2019 and May 2022. Patients were treated with 300mg VED IV at weeks 0, 2, 6 and 14. Trough SVL were measured at weeks 2, 6 and 14. Faecal samples at days 1, 4, 7 and at weeks 2, 6 and 14 were homogenised and centrifuged to produce supernatants which were analysed for faecal VED levels (FVL) using a commercially available ELISA (LISA TRACKER, Theradiag, France). Clinical (SCCAI) and biochemical disease activity (CRP and faecal calprotectin) were measured at each infusion. Endoscopy was performed at baseline and week 14 to measure endoscopic (UCEIS/Mayo) and histologic activity (NHI). Correlations were calculated using the Spearman correlation coefficient (r). Categorical variables were compared using Mann-Whitney U. Results 36 patients (median age 34 (range 18-73); 13 Female) were recruited, of whom 33 completed induction therapy (3 withdrew early and were considered non-responders). 26/36 (72%) achieved a clinical response (SCCAI≤5 and reduction of ≥2) and 18/36 (50%) achieved endoscopic remission (UCEIS≤2). Faecal VED was detectable in 80/203 (39%) samples. Statistically significant correlations were observed between FVL and markers of clinical, biochemical, baseline endoscopic and histologic disease activity at day 1, and weeks 2 and 6 (table 1). Week 14 clinical non-responders had higher FVL than responders at that time point (median 1.0 vs 0.0ug/mL, p=0.004) but not at other timepoints. A statistically significant negative correlation was observed between week 2 FVL and SVL measured at weeks 6 and 14 (table 1). SVL did not differ significantly between week 14 responders and non-responders at any time point. Conclusion Active colonic inflammation results in faecal loss of vedolizumab. This appears to correlate with lower SVL and rates of response to treatment. However, SVL were not observed to directly influence rates of response. It is possible that FVL may be a marker of disease activity or that faecal loss results in lower rates of drug exposure at a tissue level and negatively impacts rates of response by this mechanism.

Choosing the optimal concentration of dextran sulfate sodium for reproducing chemically induced colitis in rabbits

Background. Due to the fact that inflammatory bowel diseases (IBD) are widespread among the population, the development of new drugs for the treatment of IBD is a public health priority. Preclinical drug testing is inextricably linked with the modeling of IBD in laboratory animals. This study purpose was to develop a model of chemically induced colitis in rabbits. Methods. The study was performed on male rabbits of the “Soviet Chinchilla” breed. Colitis was simulated by oral administration of dextran sulfate sodium (DSS) in a concentration of 0.1% to 2% solution for five consecutive days. Euthanasia of laboratory animals was carried out on the seventh day, after the end of taking the DSS solution. A histological examination of the intestine was performed. Results. It was found that using 0.1% DSS solution allows to obtain a model of mild erosive colitis. The use of 0.5% DSS solution gave the intermediate severity of erosive ulcerative colitis. DSS concentration of more than 1% led to the development of severe ulcerative colitis in rabbits and the death rate of 71.4% among them. Conclusion. The obtained results indicate that the use of 0.5% DSS solution makes it possible to create a model of erosive ulcerative colitis in rabbits suitable for studying human IBD.

Lung Involvement in Patients with Ulcerative Colitis: Relationship between Exhaled Nitric Oxide and Lung Function.

Ulcerative colitis (UC) is characterized by immune system dysregulation with frequent extraintestinal manifestations, including airway involvement. A reduction in CO diffusing capacity and functional alterations in small airways have been described. An extended analysis of fractional exhaled nitric oxide (FeNO) may distinguish the sites of production, and the presence of small airway inflammation may be a useful, non-invasive marker for patient follow-up. The aim of our study was to compare the PFTs as well as FeNO and CANO values of UC patients with different clinical disease activities and healthy subjects to reveal lung function abnormalities and the presence of subclinical airway inflammation. We enrolled 42 adult outpatients at different clinical activity stages of UC (39 ± 13 years) and a healthy control group of 41 subjects (29 ± 3 years). C-reactive protein (CRP) and FeNO values at different flows (50,100, and 200 mL/s) were collected. All patients performed pulmonary function tests (PFTs) with static volumes and diffusing capacity (DLCO). FeNO and CANO values were significantly increased in UC patients when compared with controls (p = 0.0008 and p < 0.0001, respectively) and were proportional to disease activity (FeNO class 3: 28.1 ppb vs. classes 1-2: 7.7 ppb; CANO values class 3: 8.6 ppb vs. classes 1-2: 2.7 ppb (p < 0.0001)). TLC and DLCO were significantly reduced in severe (Mayo 3) UC patients (p = 0.010 and p = 0.003, respectively). The results of this study show significant lung functional abnormalities in UC patients and suggest the presence of airway inflammation directly correlated with disease activity, suggesting the need for an integrated approach in routine assessment.

Efficacy and safety of tacrolimus in older adults with ulcerative colitis: a retrospective study

Background/aimsThe prevalence of ulcerative colitis (UC) has been increasing, also in older adults. Here, we retrospectively compared the efficacy and safety of tacrolimus (TAC) in older and younger patients with UC.MethodsWe included younger (age < 65 years; n = 116) and older patients (age ≥ 65 years; n = 21) with UC who received TAC from April 2009 through December 2022(mean follow-up, 1230 ± 175 days) and achieved remission. Evaluations included age at onset, laboratory values, estimated glomerular filtration rate (eGFR), use of 5-aminosalicylic acid (5-ASA), biological experience, colonoscopy scores, remission at 1 month after treatment initiation, and adverse events. Treatment duration and renal function were assessed in patients with follow-up data (younger patients, n = 110; older patients, n = 19).ResultsOlder patients had a higher age at onset and treatment initiation but less 5-ASA use and biological experience. Before treatment, hemoglobin, albumin, and eGFR were significantly lower in the older group and CRP was significantly higher. The remission rate was 80.1% in the younger group and 66.6% in the older group (P = 0.1862). Adverse events were similar in both groups. The older group had a shorter treatment duration and significantly less change in renal function at all time points.DiscussionRates of TAC-induced remission and adverse events were similar in older and younger adults with UC.ConclusionTAC can be used safely in elderly patients with moderate to severe UC with careful monitoring.

Long-term outcomes after appendicectomy as experimental treatment for patients with therapy-refractory ulcerative colitis.

This study assessed 25 patients with severe ulcerative colitis undergoing appendicectomy. During a median postoperative follow-up of 7.5 years, the median duration of clinical response, as observed in 15 patients, was 80 months; the median duration of endoscopic improvement, as observed in 12 of patients, was 46 months.

Comparison of microbial communities and the profile of sulfate-reducing bacteria in patients with ulcerative colitis and their association with bowel diseases: a pilot study.

Considerable evidence has accumulated regarding the molecular relationship between gut microbiota (GM) composition and the onset (clinical presentation and prognosis of ulcerative colitis (UC)). In addition, it is well documented that short-chain fatty acid (SCFA)-producing bacteria may play a fundamental role in maintaining an anti-inflammatory intestinal homeostasis, but sulfate- and sulfite reducing bacteria may be responsible for the production of toxic metabolites, such as hydrogen sulfide and acetate. Hence, the present study aimed to assess the GM composition - focusing on sulfate-reducing bacteria (SRB) - in patients with severe, severe-active and moderate UC. Each one of the six enrolled patients provided two stool samples in the following way: one sample was cultivated in a modified SRB-medium before 16S rRNA sequencing and the other was not cultivated. Comparative phylogenetic analysis was conducted on each sample. Percentage of detected gut microbial genera showed considerable variation based on the patients' disease severity and cultivation in the SRB medium. In detail, samples without cultivation from patients with moderate UC showed a high abundance of the genera Bacteroides, Bifidobacterium and Ruminococcus, but after SRB cultivation, the dominant genera were Bacteroides, Klebsiella and Bilophila. On the other hand, before SRB cultivation, the main represented genera in patients with severe UC were Escherichia-Shigella, Proteus, Methanothermobacter and Methanobacterium. However, after incubation in the SRB medium Bacteroides, Proteus, Alistipes and Lachnoclostridium were predominant. Information regarding GM compositional changes in UC patients may aid the development of novel therapeutic strategies (e.g., probiotic preparations containing specific bacterial strains) to counteract the mechanisms of virulence of harmful bacteria and the subsequent inflammatory response that is closely related to the pathogenesis of inflammatory bowel diseases.

Predictive Value of MHR and NLR for Ulcerative Colitis Disease Activity.

Numerous non-invasive serologic tests are available to diagnose and monitor ulcerative colitis (UC), but their accuracy levels are limited. Thus, there is a pressing need for a serologic biomarker with higher precision for clinical practice. This study aims to evaluate the predictive capacity of monocyte/HDL ratio (MHR) and neutrophil/lymphocyte ratio (NLR) for UC disease activity. We conducted a retrospective analysis of 81 UC patients and 77 age- and sex-matched healthy controls. UC patients were categorized into active and inactive groups based on the Mayo score. The Mayo endoscopic subscore classified them into mild-to-moderate and severe UC groups. The optimal cut-off values for diagnosing UC were 0.34 for MHR (85.7% sensitivity, 76.0% specificity, 88.9% positive predictive value, 70.4% negative predictive value) and 2.49 for NLR (66.1% sensitivity, 88.0% specificity, 92.5% positive predictive value, 53.7% negative predictive value). The optimal MHR and NLR cut-off values to differentiate between mild-to-moderate UC and severe UC were 0.38 (92.9% sensitivity, 56.6% specificity, 53.1% positive predictive value, 93.7% negative predictive value) and 3.46 (71.4% sensitivity, 88.7% specificity, 76.9% positive predictive value, 85.5% negative predictive value), respectively. NLR and MHR are simple yet effective biological predictors of disease activity in UC patients.

Cytomegalovirus Colitis in a Patient with Severe Treatment Refractory Ulcerative Colitis.

Cytomegalovirus (CMV) can be reactivated in ulcerative colitis (UC), but its role in progression of inflammation is unclear. Risk factors include severe colitis and treatment with immunosuppressive medications, particularly corticosteroids and immunomodulators. We report a case of cytomegalovirus colitis in a pediatric patient with pancolitis who had been refractory to aminosalicylate, infliximab, and ustekinumab and was in clinical remission and with transmural response on upadacitinib. This is a case of a 13-year-old male with UC refractory to multiple therapies who were in clinical remission on upadacitinib 30mg daily. He developed an acute increase in symptoms and did not respond to therapy escalation with increased upadacitinib 45mg daily for 2 weeks and prednisone for 1 week. He was diagnosed with cytomegalovirus colitis on flexible sigmoidoscopy biopsy. He was treated with intravenous ganciclovir with tapering of immunosuppressive regimen. Despite initial response, he underwent subtotal colectomy and subsequent restorative proctocolectomy with ileal pouch anal-anastomosis. Despite our patient having multiple risk factors for developing CMV colitis, upadacitinib may have played a role when considering its known impact on the herpes family of viruses. CMV colitis should be evaluated for in any patient who presents with worsening symptoms without evidence of other infection or response to increase in therapy.

Cerebral Hemorrhage Caused by Venous Thrombosis Due to Newly Diagnosed Severe Ulcerative Colitis

Cerebral Hemorrhage Caused by Venous Thrombosis Due to Newly Diagnosed Severe Ulcerative Colitis

Impact of cytomegalovirus on outcomes in acute severe ulcerative colitis: a retrospective observational study.

Concomitant cytomegalovirus (CMV) is highly prevalent in acute severe ulcerative colitis (ASUC) but data for outcomes of CMV positivity in ASUC and the benefit of antiviral therapy remain unclear. We aim to determine the impact of CMV positivity, and antiviral therapy, on outcomes such as colectomy-free survival, length of hospital stay and readmission rate, among hospitalized patients with ASUC. This is a retrospective, multicentre study of patients admitted with ASUC. CMV positivity was diagnosed from blood CMV DNA and inpatient colonic biopsies. Background demographics and disease characteristics, clinical characteristics and outcomes during admission and long-term outcomes were obtained from electronic medical records and compared according to the presence of CMV and the use of antiviral therapy. CMV was detected in 40 (24%) of 167 ASUC admissions. Previous steroid exposure was the only clinical predictor of CMV positivity on multivariate analysis. Outcomes of greater requirement for rescue therapy (60% versus 33%), longer hospital stay (14.3 versus 9.9 days) and higher readmission rates at 3 and 12 months were associated with CMV positivity. No difference was found in the rate of colectomy or colectomy-free survival. Antiviral therapy was not associated with a lower risk of colectomy but did extend the time to colectomy (126 versus 36 days). CMV positivity was associated with worse outcomes of need for rescue therapy, hospital stay and readmissions. Antiviral therapy was not found to reduce the risk of colectomy but did extend the time to colectomy. Further prospective studies will be required to more clearly determine its benefit in patients with concomitant CMV and ASUC.

Is Tofacitinib an Option for Salvage Therapy in Active Acute Severe Ulcerative Colitis?

Is Tofacitinib an Option for Salvage Therapy in Active Acute Severe Ulcerative Colitis?

Long-term outcomes of cyclosporin induction and ustekinumab maintenance combination therapy in patients with steroid-refractory acute severe ulcerative colitis.

Effective management of patients with acute severe ulcerative colitis (ASUC) is a major challenge and there remains a paucity of available maintenance treatment options after efficacious cyclosporin induction therapy. We investigated the long-term effectiveness and safety of cyclosporin and ustekinumab combination therapy in patients with steroid refractory ASUC. Monocentric, prospective study. We included patients with steroid refractory ASUC with multiple failed prior advanced therapies, who were treated with cyclosporin and ustekinumab combination therapy. Among the 11 included patients, 10 had prior failure to infliximab and 8 failed at least three previous biological therapies. The mean baseline Mayo and Lichtiger scores were 10.9 (9-12) and 13.3 (11-14), respectively. Ustekinumab was initiated 3.2 weeks (1-8) after initiation of cyclosporin treatment and combination therapy was continued for a mean of 11.5 (4-20) weeks. Clinical response was achieved in six patients at week 16 and clinical steroid-free clinical remission in five patients at week 48. Endoscopic remission was achieved in five patients at week 16 and together with histological remission in five patients at week 52. Intestinal ultrasound demonstrated mean bowel wall thickening in the sigmoid colon of 5.5 mm at baseline and 3.5 mm at week 52, respectively. Two patients had to undergo colectomy (mean 4.5 months, range 3-6) and three stopped ustekinumab therapy due to ineffectiveness. Overall, combination therapy was well tolerated. Combination of cyclosporin and ustekinumab therapy allowed nearly half of ASUC patients to reach clinical and endoscopic remission after 52 weeks, warranting further studies. Not applicable.

Management of Severe Colitis and Toxic Megacolon.

Severe colitis is a well-defined condition encompassing several etiologies but is most often caused by severe ulcerative colitis or Clostridioides difficile infection. Severe colitis can evolve into toxic colitis, or toxic megacolon when associated with bowel dilation and systemic manifestations, resulting in a life-threatening scenario where multidisciplinary management is often required. Medical management continues to play an important role in the initial treatment of toxic megacolon. However, timely surgical intervention can be lifesaving.

Clinical value of the Toronto inflammatory bowel disease global endoscopic reporting score in ulcerative colitis.

Endoscopic evaluation in diagnosing and managing ulcerative colitis (UC) is becoming increasingly important. Several endoscopic scoring systems have been established, including the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score and Mayo Endoscopic Subscore (MES). Furthermore, the Toronto Inflammatory Bowel Disease Global Endoscopic Reporting (TIGER) score for UC has recently been proposed; however, its clinical value remains unclear. To investigate the clinical value of the TIGER score in UC by comparing it with the UCEIS score and MES. This retrospective study included 166 patients with UC who underwent total colonoscopy between January 2017 and March 2023 at the Affiliated Hospital of Qingdao University (Qingdao, China). We retrospectively analysed endoscopic scores, laboratory and clinical data, treatment, and readmissions within 1 year. Spearman's rank correlation coefficient, receiver operating characteristic curve, and univariate and multivariable logistic regression analyses were performed using IBM SPSS Statistics for Windows, version 26.0 (IBM Corp., Armonk, NY, United States) and GraphPad Prism version 9.0.0 for Windows (GraphPad Software, Boston, Massachusetts, United States). The TIGER score significantly correlated with the UCEIS score and MES (r = 0.721, 0.626, both P < 0.001), showed good differentiating values for clinical severity among mild, moderate, and severe UC [8 (4-112.75) vs 210 (109-219) vs 328 (219-426), all P < 0.001], and exhibited predictive value in diagnosing patients with severe UC [area under the curve (AUC) = 0.897, P < 0.001]. Additionally, the TIGER (r = 0.639, 0,551, 0.488, 0.376, all P < 0.001) and UCEIS scores (r = 0.622, 0,540, 0.494, and 0.375, all P < 0.001) showed stronger correlations with laboratory and clinical parameters, including C-reactive protein, erythrocyte sedimentation rate, length of hospitalisation, and hospitalisation costs, than MES (r = 0.509, 0,351, 0.339, and 0.270, all P < 0.001). The TIGER score showed the best predictability for patients' recent advanced treatment, including systemic corticosteroids, biologics, or immunomodulators (AUC = 0.848, P < 0.001) and 1-year readmission (AUC = 0.700, P < 0.001) compared with the UCEIS score (AUC = 0.762, P < 0.001; 0.627, P < 0.05) and MES (AUC = 0.684, P < 0.001; 0.578, P = 0.132). Furthermore, a TIGER score of ≥ 317 was identified as an independent risk factor for advanced UC treatment (P = 0.011). The TIGER score may be superior to the UCIES score and MES in improving the accuracy of clinical disease severity assessment, guiding therapeutic decision-making, and predicting short-term prognosis.

Sphingosine 1-phosphate (S1P) receptor modulators as an induction and maintenance therapy for ulcerative colitis: a systematic review and meta-analysis of randomized controlled trials.

One sphingosine-1-phosphate (S1P) receptor modulator is approved (ozanimod) and another (etrasimod) is under investigation for the induction and maintenance of remission of ulcerative colitis (UC). We aim to evaluate the efficacy and safety of S1P modulators in patients with active UC. We conducted a systematic review and meta-analysis synthesizing randomized controlled trials (RCTs), which were retrieved by systematically searching: PubMed, Web of Science, SCOPUS, and Cochrane through May 13th, 2023. We used the fixed-effect model to pool dichotomous data using risk ratio (RR) with a 95% confidence interval (CI). Five RCTs with a total of 1990 patients were included. S1P receptor modulators were significantly associated with increased clinical response during both the induction (RR 1.71 with 95% CI [1.50, 1.94], P = 0.00001) and maintenance phases (RR 1.89 with 95% CI [1.33, 2.69], P = 0.0004); clinical remission rates during both induction (RR 2.76 with 95% CI [1.88, 4.05], P = 0.00001) and maintenance phases (RR 3.34 with 95% CI [1.41, 7.94], P = 0.006); endoscopic improvement during both induction (RR 2.15 with 95% CI [1.71, 2.70], P = 0.00001) and maintenance phases (RR 2.41 with 95% CI [1.15, 5.05], P = 0.02); and histologic remission during both induction (RR 2.60 with 95% CI [1.89, 3.57] [1.17, 2.10], P = 0.00001) and maintenance phases (RR 2.52 with 95% CI [1.89, 3.37], P = 0.00001). Finally, there was no difference regarding safety outcomes as compared to placebo in both the induction and maintenance phases. S1P receptor modulators are effective in inducing and maintaining remission in patients with moderate to severe UC.

Efficacy and Safety of Vedolizumab in Patients with Inflammatory Bowel Disease in Association with Vedolizumab Drug Levels.

Vedolizumab (VDZ) is a well-established and important therapeutic option in the treatment of patients with inflammatory bowel disease (IBD). However, the significance of therapeutic drug monitoring (TDM) with VDZ remains a contradictory field in daily clinical practice. Our study aims to clarify the predictive impact of VDZ drug levels in long-term clinical outcomes in a real-world cohort. Patients with moderate to severe ulcerative colitis (UC) and Crohn's disease (CD) from a tertiary IBD referral center at the University Hospital Augsburg, Germany, were enrolled in this single-center retrospective data analysis. Clinical and endoscopic data were collected at month 6, month 12, and at the last time of follow-up, and outcomes were correlated with VDZ levels at week 6. This study included 95 patients, 68.4% (n = 65) with UC, 24.2% (n = 23) with CD, and 7.4% (n = 7) with indeterminate colitis (CI). Patients with a mean VDZ treatment time of 17.83 months ± 14.56 showed clinical response in 29.5% (n = 28) and clinical remission in 45.3% (n = 43) at the end of the study. Endoscopic response occurred in 20.0% (n = 19) and endoscopic remission in 29.5% (n = 28) at the end of the study. The sustained beneficial effect of VDZ was also reflected in a significant change in biomarker levels. VDZ trough level at week 6 was determined in 48.4% (n = 46) with a mean of 41.79 µg/mL ± 24.58. A significant association between VDZ level at week 6 and both short and long-term outcomes could not be demonstrated. However, numerically higher VDZ levels were seen in patients with endoscopic and clinical improvement at month 6 and at the time of last follow-up. This study demonstrated efficacy and safety for VDZ in a real-world cohort. Although, for some parameters, a clear trend for higher VDZ levels at week 6 was seen, the efficacy of VDZ was not significantly correlated to VDZ level at week 6, which questions the predictive value of VDZ levels in the real world.