Explore the vast range of titles available.

BackgroundOptimization of treatment with biologics is currently an unmet need for patients with ulcerative colitis (UC). Real-world studies provide neutral estimates of drug efficacy and safety within unselected patient populations and allow for the recognition of specific characteristics that affect response to therapy.AimsWe aimed to depict the efficacy of vedolizumab in patients with UC in a real-world setting and identify prognosticators of improved outcomes.MethodsPatients with active UC who commenced treatment with vedolizumab were prospectively followed up. Patient-reported outcomes (PROs) and clinical/endoscopic-reported outcomes were recorded at baseline and at weeks 14 and 54. Predefined endpoints of early and persistent efficacy were analyzed against clinical characteristics to identify prognostic factors for response.ResultsWe included 96 patients (anti-TNF-exposed = 38.5%). At week 14, 73 patients (76%) had clinical response and 54 (56.3%) clinical remission. At week 54, the primary endpoint of vedolizumab persistence was met by 72 patients (75%), whereas steroid-free clinical remission by 59.4%. Among patients who had endoscopy, rates for mucosal healing (Mayo endoscopic score of 0) were 29.8% at week 14 and 44.6% at week 54, respectively. Vedolizumab treatment led to significant improvements in quality of life. Corticosteroid-refractory or anti-TNF-refractory disease, articular manifestations, and high baseline UC-PRO2 were associated with decreased efficacy of vedolizumab in the primary and secondary outcomes.ConclusionsVedolizumab is characterized by high efficacy and long-term treatment persistence in UC. More aggressive disease, as indicated by refractoriness to steroids or anti-TNFs and elevated baseline PROs, may predict suboptimal response and help pre-treatment prognostic stratification of patients.

Background and aims: Tofacitinib is a Janus kinase inhibitor (JAKi) recently approved for the treatment of moderate to severe ulcerative colitis (UC) based on robust efficacy and safety data derived from OCTAVE clinical trials. Evidence on the outcomes of tofacitinib therapy in real-world UC patients is needed, as a number of these patients would be deemed ineligible for clinical trials. We have therefore summarised data derived from observational, real-world evidence (RWE) studies on the effectiveness and safety of tofacitinib in moderate to severe UC patients. Methods: We searched the PubMed, EMBASE, Scopus, Web of Science and Cochrane databases for observational studies on the use of tofacitinib in UC patients, published between 30 May 2018 and 24 January 2021. Pooled induction (8–14 weeks) and maintenance (16–26 weeks) clinical response and remission rates were calculated, as well as the proportion of reported adverse events using random effects models. Results: Nine studies were included, comprising 830 patients, of which 81% were previously treated with anti-tumour necrosis factor (TNF) and 57% with vedolizumab. Induction of clinical response and remission were achieved in 51% (95% confidence interval, 41–60%) and 37% (26–45%) of patients, after a median follow-up of 8 weeks. At the end of a median follow-up of 24 weeks, maintenance of clinical response and remission were met in 40% (31–50%) and 29% (23–36%) of patients, respectively. Thirty-two percent of the patients had at least one adverse event, the most commonly reported being mild infection (13%) and worsening of UC, requiring colectomy (13%). A third of the patients (35%) discontinued tofacitinib, most frequently due to primary non-response (51%). Conclusion: Tofacitinib is a safe and effective therapy in real-world UC patients, as previously reported by clinical trials.

Inflammatory bowel disease (IBD)-associated colorectal cancer (CRC) remains a significant clinical challenge due to its link with chronic inflammation and the inherent limitations of current prevention and surveillance strategies. The cGAS-STING pathway has emerged as a key player in the immune regulation of inflammation-driven carcinogenesis, demonstrating both protective and pathogenic roles. This review examines the contrasting roles of the cGAS-STING signaling pathway in intestinal inflammation and colitis-associated cancer (CAC), emphasizing its promise as a target for cancer prevention strategies. Evidence suggests that modulating this pathway could preserve epithelial integrity, limit chronic inflammation, and bolster anti-tumor immunity. Despite advancements in therapies like mesalazine and surveillance colonoscopy programs, gaps in efficacy remain, particularly for Crohn’s disease and high-risk populations. Future research should focus on integrating cGAS-STING-targeted approaches with existing modalities to provide personalized and less invasive strategies for CAC prevention. By harnessing this pathway’s therapeutic potential, a paradigm shift in managing IBD-associated CRC may be achieved, addressing the challenges of long-term disease surveillance and prevention.

IntroductionThere are no unified criteria to risk stratify patients under 50 with lower gastrointestinal bleed (LGIB) for endoscopic investigations. We evaluated this cohort to identify predictors for significant bowel disease (SBD), defined as malignancy, high risk adenoma (≥3 adenomas or any adenoma ≥1 cm) or new diagnosis of Inflammatory bowel disease (IBD).MethodsAll patients under 50 in NHS Lothian with no colorectal cancer or IBD history referred for endoscopy for LGIB in 2019 were identified through the endoscopy reporting system. Electronic patient records were reviewed to extract variables including LGIB history, diarrhoea, abdominal pain, weight loss, and diagnoses. Univariate analysis, with Chi-square or t-test/Wilcoxon test as appropriate, was used to identify significant associations with SBD. Normality was tested with Shapiro-Wilk test. Complete case analysis was used where data were missing.Results532 patients were included in the analysis, 223 and 309 patients underwent flexible sigmoidoscopy and colonoscopy respectively. Mean age was 38.0 years (IQR 32.0 to 45.6) and 57.4% were females. SBD were present in 17.3% of all cases (1.3% malignancy; 1.3% advanced adenoma; 14.7% IBD). Normal assessment was reported in 42.7% of endoscopies and haemorrhoids were the only finding in 29.5% of cases.A significant proportion of GP referrals contained missing data for duration (37.4%) and frequency (35.9%) of LGIB. In those with data for frequency (n=341), referrals that reported ‘frequent’ LGIB were more likely to have SBD than those with infrequent LGIB (28.0% vs 11.2%; p=0.002), but the duration was not associated with SBD (p=0.19). All other recorded symptoms in clinical history were insignificant, including diarrhoea (p=0.28), which was present in 58.5% of cases.83% of patients had full blood count measured before endoscopy. Faecal calprotectin (FC) was missing in over half of patients. Iron studies were performed in 12.4% of cases. Patients with SBD were more likely to be anaemic (24.7% vs 10.7%; p=0.004) or have raised FC (89.4% vs 44.3%; p<0.001) than those without SBD. Age and gender were not associated with SBD. LGIB frequency remained the only significant predictor of SBD (OR 2.34; IQR: 1.36-4.13) after multivariate stepwise regression using age, gender, and haemoglobin as covariates.ConclusionsDetermining appropriate investigations for LGIB in under 50 can be hampered by limited referral details. A dedicated GP referral proforma may improve risk stratification. In a limited dataset, our study identifies LGIB frequency, anaemia and raised FC as factors that could be used to prioritise endoscopy referrals.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and presents a continuously growing incidence and high mortality rates worldwide. Besides advances in diagnosis and promising results of pre-clinical studies, established curative therapeutic options for HCC are not currently available. Recent progress in understanding the tumor microenvironment (TME) interactions has turned the scientific interest to immunotherapy, revolutionizing the treatment of patients with advanced HCC. However, the limited number of HCC patients who benefit from current immunotherapeutic options creates the need to explore novel targets associated with improved patient response rates and potentially establish them as a part of novel combinatorial treatment options. Glucocorticoid-induced TNFR-related protein (GITR) belongs to the TNFR superfamily (TNFRSF) and promotes CD8+ and CD4+ effector T-cell function with simultaneous inhibition of Tregs function, when activated by its ligand, GITRL. GITR is currently considered a potential immunotherapy target in various kinds of neoplasms, especially with the concomitant use of programmed cell-death protein-1 (PD-1) blockade. Regarding liver disease, a high GITR expression in liver progenitor cells has been observed, associated with impaired hepatocyte differentiation, and decreased progenitor cell-mediated liver regeneration. Considering real-world data proving its anti-tumor effect and recently published evidence in pre-clinical models proving its involvement in pre-cancerous liver disease, the idea of its inclusion in HCC therapeutic options theoretically arises. In this review, we aim to summarize the current evidence supporting targeting GITR/GITRL signaling as a potential treatment strategy for advanced HCC.

Background and Aim. Crohn’s disease (CD) is a chronic inflammatory condition of the gastrointestinal tract with the potential to progress to a severe debilitating state. Treatment with biological agents is highly efficient, improving both short-term outcomes and long-term prognosis. Nonetheless, up to 60% of patients receiving biological therapy will exhibit nonresponse at some point. The optimal management of such patients is not clearly defined. Besides traditional anti-TNF agents (infliximab, adalimumab, and certolizumab), alternative biological therapies (natalizumab, vedolizumab, and ustekinumab) are currently available for the treatment of CD. Our aim was to analyze all available evidence regarding efficacy of a second biological in “biological-treatment-experienced” patients. Methods. A systematic review of the literature was conducted using specific criteria for selecting relevant randomized clinical trials evaluating response to administration of secondary biological therapy in “anti-TNF-experienced” CD patients. Data from these studies was used to perform (a) traditional meta-analysis to ascertain the effect of secondary treatment versus placebo and (b) network meta-analysis to compare indirectly the efficacy of available biological agents. Results. Out of initially 977 studies, only eight were included for analysis, providing a total of 1281 treated and 733 placebo-receiving CD patients. Treatment with a second biological was found to be superior to placebo for both induction of remission (OR 2.2, 95% CI 1.7 to 3) and response (OR 1.9, 95% CI 1.5 to 2.5), with global rates of 24% and 42%, respectively (placebo rate: 11% and 27%, p<0.0001 for both). Indirect comparisons performed with network meta-analysis suggest no specific agent is clearly superior to others, with relatively better results observed for adalimumab in inducing disease remission. Conclusion. In anti-TNF-experienced CD patients, secondary biological administration may be efficient, while no specific agent seems to outperform the others. Further research is needed to identify optimal management strategies for this challenging subset of patients.

Background Preventing disease progression and viral suppression are the main goals of antiviral therapy in chronic hepatitis B (CHB). Liver stiffness measurement (LSM) by transient elastography is a reliable non-invasive method to assess liver fibrosis in patients with CHB. Our aim was to explore factors that may affect changes in LSMs during long term tenofovir (TDF) monotherapy in a well characterized cohort of patients with compensated CHB. Methods We analyzed serial LSMs in 103 adult patients with CHB who were on TDF monotherapy and had at least three LSMs over a period of 90 months. Results Twenty-five (24%) patients had advanced fibrosis at baseline. A significant decline in mean LSM between baseline and last visit (8.7 ± 6.2 kPa vs. 6.7 ± 3.3, p  = 10 − 3 ) was observed. Twenty-four (23%) patients had progression of liver fibrosis with mean increase in liver stiffness of 2.8 kPa (range: 0.2–10.2 kPa). Multivariate analysis showed that BMI ≥ 25 (OR, 0.014; 95% CI, 0.001–0.157; p  = 0.001) and advanced fibrosis (OR, 5.169; 95% CI, 1.240–21.540; p  = 0.024) were independently associated with a fibrosis regression of > 30% of liver stiffness compared to baseline value. Conclusions In CHB patients TDF monotherapy resulted in liver fibrosis regression, especially in patients with advanced fibrosis. Despite the successful antiviral effect of TDF, 1 out of 4 patients had liver fibrosis progression. Obesity and advanced fibrosis at baseline were independently associated with significant liver fibrosis regression.

With increasing international travel and migration, tropical and infectious diseases once largely confined to specialist institutes now present more widely. Amoebiasis is a potentially dangerous example since it may closely mimic the presentation of inflammatory bowel disease. Misdiagnosis and treatment with immunosuppressants can result in fulminant amoebiasis and death. This review considers the epidemiology, pathogenesis, clinical features, diagnosis and treatment of intestinal and extraintestinal amoebiasis. It is written primarily for gastroenterologists, surgeons and acute physicians.

Tumor necrosis factor (TNF)-like cytokine 1A (TL1A) is a member of the TNF superfamily of proteins (TNFSF15), which signals through association with death domain receptor 3 (DR3). Decoy receptor 3 (DcR3) competes with DR3 for TL1A binding and inhibits functional signaling. These proteins are significantly upregulated in inflamed intestinal tissues, and their pathogenetic importance for inflammatory bowel disease (IBD) is suggested by accumulating evidence. TL1A/DR3 induce costimulatory signals to activated lymphocytes, including the gut-specific populations of CD4+CD161+ and CD4+CCR9+ cells, affecting all major effector pathways and inducing the mucosal upregulation of Th1, Th2, and Th17 factors. They may also participate in mucosal homeostasis and defense against pathogens through their effects on the development and function of the recently described innate lymphoid cells. T-regulatory lymphocytes highly express DR3, and they respond to TL1A stimulation also. Mechanistic studies by transgenic expression of TL1A, deletion of TL1A or DR3, and therapeutic blockade by anti-TL1A antibodies all support the critical involvement of the corresponding pathways in the pathogenesis of chronic mucosal inflammation. Wide genome association studies have identified IBD-specific polymorphisms in TNFSF15 gene, which have functional implications and serve as poor prognostic factors. Recently, TL1A blockade in mice was presented as a unique pharmacological treatment for the reversal of established intestinal fibrosis. Finally, TL1A/DR3 signaling seems to critically participate in extraintestinal inflammatory conditions that are frequently associated with IBD as part of the gut-joint-skin-eye axis. These converging lines of evidence make TL1A/DR3 a suitable model for personalized approaches to IBD therapy.

Mucosal expression of immunological mediators is modified in inflammatory bowel disease (IBD). Quantification of target gene messenger RNA (mRNA) transcripts depends on the normalization to a housekeeping or reference gene. Stability of housekeeping gene expression is critical for the accurate measurement of transcripts of the target gene. No studies have addressed the optimization of reference gene performance for mRNA studies in healthy intestinal mucosa and during mucosal inflammation.MethodsRNA was extracted from endoscopically obtained intestinal biopsies from healthy control subjects and patients with active IBD or non-IBD inflammatory diseases. Comparative analysis of 10 candidate housekeeping genes for quantitative real-time PCR was carried out according to predefined criteria, including use of the Web-based RefFinder platform.ResultsWe demonstrate that intestinal inflammation may significantly affect the stability of mucosal expression of housekeeping genes. Commonly used controls, such as glyceraldehyde-3-phosphate dehydrogenase, β-actin, or β2-microglobulin displayed high variability within the control group and/or between the healthy and inflamed mucosae. In contrast, we have identified novel genes with optimal stability, which may be used as appropriate housekeeping controls. The ribosomal proteins encoding genes (RPLPO and RPS9) were the most stable because their expression was not affected by interindividual differences, the presence of inflammation, or intestinal location. Normalization ofthe mRNA expression of mucosal tumor necrosis factor-α was highly dependent on the specific reference gene and varied significantly when normalized to genes with high or low stability.ConclusionsValidation for optimal performance of the housekeeping gene is required for target mRNA quantification in healthy intestine and IBD-associated lesions. Suboptimal reference gene expression may explain conflicting results from published studies on IBD gene expression.