The role of cell death in the pathogenesis of autoimmune disease: HMGB1 and microparticles as intercellular mediators of inflammation

Cell death is critical to normal homeostasis, although this process, when increased aberrantly, can lead to the production of pro-inflammatory mediators promoting autoimmunity. Two novel intercellular mediators of inflammation generated during cell death are high mobility group box 1 (HMGB1) protein and microparticles (MPs). HMGB1 is a nuclear protein that functions in transcription when inside the nucleus but takes on pro-inflammatory properties when released during cell death. Microparticles are small, membrane-bound structures that extrude from cells when they die and contain cell surface proteins and nuclear material from their parent cells. MPs circulate widely throughout the vasculature and mediate long-distance communication between cells. Both MPs and HMGB1 have been implicated in the pathogenesis of a broad spectrum of inflammatory diseases, including the prototypic autoimmune conditions systemic lupus erythematosus and rheumatoid arthritis. Given their range of activity and association with active disease, both structures may prove to be targets for effective therapy in these and other disorders

Risk Factors of Drug Interaction between Warfarin and Nonsteroidal Anti-Inflammatory Drugs in Practical Setting

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to interact with the oral anticoagulant warfarin and can cause a serious bleeding complication. In this study, we evaluated the risk factors for international normalized ratio (INR) increase, which is a surrogate marker of bleeding, after addition of an NSAID in a total of 98 patients who used warfarin. Patient age, sex, body mass index, maintenance warfarin dose, baseline INR, coadministered medications, underlying diseases, and liver and kidney functions were evaluated for possible risk factors with INR increase ≥15.0% as the primary end-point. Of the 98 patients, 39 (39.8%) showed an INR elevation of ≥15.0% after adding a NSAID to warfarin therapy. Multivariate analysis showed that high maintenance dose (>40 mg/week) of warfarin (P=0.001), the presence of coadministered medications (P=0.024), the use of meloxicam (P=0.025) and low baseline INR value (P=0.03) were the risk factors for INR increase in respect to NSAID-warfarin interaction. In conclusion, special caution is required when an NSAID is administered to warfarin users if patients are taking warfarin >40 mg/week and other medications interacting with warfarin

HDL Interfere with the Binding of T Cell Microparticles to Human Monocytes to Inhibit Pro-Inflammatory Cytokine Production

BACKGROUND: Direct cellular contact with stimulated T cells is a potent mechanism that induces cytokine production in human monocytes in the absence of an infectious agent. This mechanism is likely to be relevant to T cell-mediated inflammatory diseases such as rheumatoid arthritis and multiple sclerosis. Microparticles (MP) generated by stimulated T cells (MPT) display similar monocyte activating ability to whole T cells, isolated T cell membranes, or solubilized T cell membranes. We previously demonstrated that high-density lipoproteins (HDL) inhibited T cell contact- and MPT-induced production of IL-1beta but not of its natural inhibitor, the secreted form of IL-1 receptor antagonist (sIL-1Ra). METHODOLOGY/PRINCIPAL FINDINGS: Labeled MPT were used to assess their interaction with monocytes and T lymphocytes by flow cytometry. Similarly, interactions of labeled HDL with monocytes and MPT were assessed by flow cytometry. In parallel, the MPT-induction of IL-1beta and sIL-1Ra production in human monocytes and the effect of HDL were assessed in cell cultures. The results show that MPT, but not MP generated by activated endothelial cells, bond monocytes to trigger cytokine production. MPT did not bind T cells. The inhibition of IL-1beta production by HDL correlated with the inhibition of MPT binding to monocytes. HDL interacted with MPT rather than with monocytes suggesting that they bound the activating factor(s) of T cell surface. Furthermore, prototypical pro-inflammatory cytokines and chemokines such as TNF, IL-6, IL-8, CCL3 and CCL4 displayed a pattern of production induced by MPT and inhibition by HDL similar to IL-1beta, whereas the production of CCL2, like that of sIL-1Ra, was not inhibited by HDL. CONCLUSIONS/SIGNIFICANCE: HDL inhibit both MPT binding to monocytes and the MPT-induced production of some but not all cytokines, shedding new light on the mechanism by which HDL display their anti-inflammatory functions

Relationship between time-integrated disease activity estimated by DAS28-CRP and radiographic progression of anatomical damage in patients with early rheumatoid arthritis

<p>Abstract</p> <p>Background</p> <p>The main aim of the study was to investigate the relationship between persistent disease activity and radiographic progression of joint damage in early rheumatoid arthritis (ERA).</p> <p>Methods</p> <p>Forty-eight patients with active ERA was assessed every 3 months for disease activity for 3 years. Radiographic damage was measured by the Sharp/van der Heijde method (SHS). The cumulative inflammatory burden was estimated by the time-integrated values (area under the curve-AUC) of Disease Activity Score 28 joint based on C-reactive protein (DAS28-CRP) in rapid progressors versus non-progressors. Bland and Altman's 95% limits of agreement method were used to estimate the smallest detectable difference (SDD) of radiographic progression. The relationship between clinical and laboratory predictors of radiographic progression and their interactions with time was analysed by logistic regression model.</p> <p>Results</p> <p>After 3-years of follow-up, radiographic progression was observed in 54.2% (95%CI: 39.8% to 67.5%) of patients and SDD was 9.5 for total SHS. The percentage of patients with erosive disease increased from 33.3% at baseline to 76% at 36 months. The total SHS of the progressors worsened from a median (interquartile range) of 18.5 (15-20) at baseline to 38.5 (34-42) after 3 years (p < 0.0001) whereas non-progressors worsened from a median of 14.5 (13-20) at baseline to 22.5 (20-30) after 3 years (p < 0.001). In the regression model, time-integrated values of DAS28-CRP and anti-CCP positivity have the highest positive predictive value for progression (both at level of p < 0.0001). Radiographic progression was also predicted by a positive IgM-RF (p0.0009), and a high baseline joint damage (p = 0.0044).</p> <p>Conclusions</p> <p>These data indicate that the level of disease activity, as measured by time-integrated DAS28-CRP, anti-CCP and IgM-RF positivity and a high baseline joint damage, affects subsequent progression of radiographic damage in ERA.</p

Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles

Release of membrane vesicles, a process conserved in both prokaryotes and eukaryotes, represents an evolutionary link, and suggests essential functions of a dynamic extracellular vesicular compartment (including exosomes, microparticles or microvesicles and apoptotic bodies). Compelling evidence supports the significance of this compartment in a broad range of physiological and pathological processes. However, classification of membrane vesicles, protocols of their isolation and detection, molecular details of vesicular release, clearance and biological functions are still under intense investigation. Here, we give a comprehensive overview of extracellular vesicles. After discussing the technical pitfalls and potential artifacts of the rapidly emerging field, we compare results from meta-analyses of published proteomic studies on membrane vesicles. We also summarize clinical implications of membrane vesicles. Lessons from this compartment challenge current paradigms concerning the mechanisms of intercellular communication and immune regulation. Furthermore, its clinical implementation may open new perspectives in translational medicine both in diagnostics and therapy

Incremental cost-effectiveness of cyclooxygenase 2-selective versus nonselective nonsteroidal anti-inflammatory drugs in a cohort of coumarin users: A pharmacoeconomic analysis linked to a case-control study

Background: A previous case-control study involving concomitant users of coumarin and nonsteroidal anti-inflammatory drugs (NSAIDs) found that cyclooxygenase 2 (COX-2)-selective NSAIDs were associated with fewer bleeding complications than nonselective NSAIDs.\ud \ud Objective: The goal of this study was to determine the incremental cost-effectiveness of COX-2-selective versus nonselective NSAIDs in relation to the occurrence of bleeding complications in a cohort of concomitant coumarin users.\ud \ud Methods: The pharmacoeconomic evaluation was linked to a case-control analysis (patients with and without bleeding complications) based on data from the earlier study in users of concomitant coumarin and NSAIDs. Medical costs associated with NSAID use and bleeding complications were estimated according to Dutch guidelines for pharmacoeconomic analyses, based on Dutch drug prices and national averages for health care costs. Rofecoxib, meloxicam, and nabumetone were considered COX-2 selective. Total costs were calculated and compared for 2 hypothetical scenarios in which patients used either COX-2-selective or nonselective NSAIDs. Sensitivity analyses were performed in which both the odds ratios (ORs) and the costs of NSAIDs and bleeding episodes were varied.\ud \ud Results: A total of 1491 bleeding complications occurred in 4400 coumarin users: among the 221 (15%) NSAID users with a bleeding episode, 96% used a nonselective NSAID and 4% used a COX-2-selective NSAID. The adjusted OR of a bleeding episode for nonselective compared with COX-2-selective NSAIDs was 3.07 (95% CI, 1.18–8.03). The estimated mean cost of a bleeding episode was 478 per patient. Factoring in the excess cost of a COX-2-selective NSAID compared with a nonselective NSAID, as well as the cost savings in averted bleeding episodes, it was determined that there would be net medical cost savings of 53,800 and 162 averted bleeding episodes if the entire patient group received COX-2-selective NSAIDs rather than nonselective NSAIDs. The sensitivity analysis showed these results to be robust.\ud \ud Conclusion: In this study population of concomitant coumarin and NSAID users, the reduction in bleeding complications with the use of more expensive COX-2-selective inhibitors was associated with net medical cost savings compared with nonselective NSAIDs