Acute pancreatitis (AP) is a common and devastating inflammatory disorder of the pancreas. However, there are still no effective treatments available for the disease. Therefore, it is important to discover new therapeutic targets and strategies for better treatment and prognosis of AP patients. Toll-like receptor 3 (TLR3) ligand polyI:C is a double-stranded RNA mimic that can be used as an immune stimulant. Our current study indicates that polyI:C exerted excellent anti-inflammatory effects in a caerulein-induced AP mouse model and taurocholate-induced pancreatic acinar cell line injury model. We found that polyI:C triggers type I interferon (IFN) production and downstream IFN-α/β receptor (IFNAR)-dependent signaling, which play key roles in protecting the pancreas from inflammatory injury. Knockout of IFN-β and IFNAR in mice abolished the preventive effects of polyI:C on caerulein-induced AP symptoms, which include pancreatic edema, neutrophil infiltration, the accumulation of reactive oxygen species (ROS), and inflammatory gene expression. Treating pancreatic acinar 266-6 cells with an IFNAR inhibitor, which blocks the interaction between type I IFN and IFNAR, diminishes the downregulation of oxidative stress by polyI:C. Additionally, a subsequent transcriptome analysis on the role of polyI:C in treating pancreatitis suggested that chemotaxis of neutrophils and the production of ROS were inhibited by polyI:C in the pancreases damaged by caerulein injection. Thus, polyI:C may act as a type I IFN inducer to alleviate AP, and it has the potential to be a promising therapeutic agent used at the early stages of AP.
Background Patients (pts) with IBD are at increased risk of pancreatitis. Here, we report a post-marketing safety analysis to identify predictors of pancreatitis utilising data captured during treatment with VDZ in a large Global Safety Database (GSD). Methods Takeda’s GSD was queried for case reports (CRs) of adverse events (AEs) following VDZ treatment, from licensure (20 May, 2014) through 31 March, 2021. Unsolicited and solicited CRs of pancreatitis were coded using the Medical Dictionary for Regulatory Activities (version 24.0) high-level term “Acute and chronic pancreatitis”. A comparator was created using data from 600 CRs of random, non-pancreatitis AEs; cases meeting the regulatory definition of serious criteria were compared with serious CRs (SAEs) of pancreatitis. Unadjusted comparisons were performed using t-tests for continuous data and Chi-square tests, Fisher’s exact tests for categorical data. Logistic regression analysis was performed to adjust for covariates that allowed backward selection. Baseline characteristics included in the model were: age, gender, indication, medical history, concomitant medications and comorbid conditions. To account for differences in pt baseline characteristics between pancreatitis and random CRs, an adjusted analysis was performed using inverse probability treatment weighting to reduce biases on estimates of average group (gp) effects. A p value below 0.05 was considered statistically significant. Results Over the approximate 7 years since regulatory approval of VDZ, 196 pts reported pancreatitis. A higher proportion of pts reported SAEs in the pancreatitis gp (99.5%, n=195/196) vs the random gp (32.5%, n=195/600). An unadjusted comparison between pts with SAEs showed that females (p=0.015) and Crohn’s disease (p=0.001) were more common in the random gp vs the pancreatitis gp. In the pancreatitis gp, 17 pts (8.7%) with SAEs had a known history of pancreatitis vs none in the random gp. Fourteen pts (7.2%) with SAEs had concurrent cholelithiasis in the pancreatitis gp vs none in the random gp. Results of the logistic regression analysis are shown in the Table. A number of factors, including age, VDZ indication use, the use of concomitant medications, a history of pancreatitis and several comorbid conditions strongly associated with the development of pancreatitis. Conclusion This retrospective analysis identified several factors associated with 196 spontaneous CRs of pancreatitis captured in our large GSD of over 700,000 patient-years of exposure to VDZ. This offers useful insights into potential predictive factors that could be important to inform clinical management of patients with IBD regarding the risk of pancreatitis, but further research to confirm these observations is warranted.
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