Dysregulation of lymphocyte function, accumulation of autoantibodies and defective clearance of circulating immune complexes and apoptotic cells are hallmarks of systemic lupus erythematosus (SLE). Moreover, it is now evident that an intricate interplay between the adaptive and innate immune systems contributes to the pathogenesis of SLE, ultimately resulting in chronic inflammation and organ damage. Platelets circulate in the blood and are chiefly recognized for their role in the prevention of bleeding and promotion of haemostasis; however, accumulating evidence points to a role for platelets in both adaptive and innate immunity. Through a broad repertoire of receptors, platelets respond promptly to immune complexes, complement and damage-associated molecular patterns, and represent a major reservoir of immunomodulatory molecules in the circulation. Furthermore, evidence suggests that platelets are activated in patients with SLE, and that they could contribute to the circulatory autoantigenic load through the release of microparticles and mitochondrial antigens. Herein, we highlight how platelets contribute to the immune response and review evidence implicating platelets in the pathogenesis of SLE.

The non-haemostatic role of platelets in systemic lupus erythematosus

Stroke is a major cause of morbidity, mortality and disability in systemic lupus erythematosus (SLE). Patients with SLE have a two-fold increase in the risk of stroke with younger patients (ie, less than 50 years of age) having an ever-higher risk (up to 10-fold). Although the prognosis of SLE has improved, mortality due to cerebrovascular events (CVE) remains unchanged. Cerebrovascular disease may be directly attributed to the disease per se, as a manifestation of neuropsychiatric SLE, or be the result of traditional cardiovascular risk factors accompanying the disease. Elucidation of the underlying mechanism(s) of CVE is essential as it may guide the type of therapy (ie, antithrombotic or anticoagulant therapy versus immunosuppressive). Strokes attributed to lupus usually occur early in the course of the disease and are often accompanied by evidence of activity in other organs; those related to antiphospholipid antibodies can occur at any time, in patients with either active or inactive SLE. In this review, we discuss the epidemiology, work-up, management and primary prevention of CVE in patients with lupus. In view of the effectiveness of thrombolysis, physicians need to educate lupus patients and their families for the early recognition of the signs of stroke and the need to seek prompt attention. To this end acronyms, such as FAST (Facial drooping, Arm weakness, Speech difficulties and Time to call emergency service) can be used as a mnemonic to help detect and enhance responsiveness to the needs of a person having a stroke.

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Cerebrovascular Events in Systemic Lupus Erythematosus: Diagnosis and Management.

The effects of statin use on inflammatory markers among patients with metabolic syndrome and related disorders: A systematic review and meta-analysis of randomized controlled trials.

Cellular cholesterol metabolism, lipid raft formation, and lipoprotein interactions contribute to the regulation of immune-mediated inflammation and response to pathogens. Lipid pathways have been implicated in the pathogenesis of bacterial and viral infections, whereas altered lipid metabolism may contribute to immune dysfunction in autoimmune diseases, such as systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis. Interestingly, dietary cholesterol may exert protective or detrimental effects on risk, progression, and treatment of different infectious and autoimmune diseases, although current findings suggest that these effects are variable across populations and different diseases. Research evaluating the effects of dietary cholesterol, often provided by eggs or as a component of Western-style diets, demonstrates that cholesterol-rich dietary patterns affect markers of immune inflammation and cellular cholesterol metabolism, while additionally modulating lipoprotein profiles and functional properties of HDL. Further, cholesterol-rich diets appear to differentially impact immunomodulatory lipid pathways across human populations of variable metabolic status, suggesting that these complex mechanisms may underlie the relationship between dietary cholesterol and immunity. Given the Dietary Guidelines for Americans 2015–2020 revision to no longer include limitations on dietary cholesterol, evaluation of dietary cholesterol recommendations beyond the context of cardiovascular disease risk is particularly timely. This review provides a comprehensive and comparative analysis of significant and controversial studies on the role of dietary cholesterol and lipid metabolism in the pathophysiology of infectious disease and autoimmune disorders, highlighting the need for further investigation in this developing area of research.

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Impact of Dietary Cholesterol on the Pathophysiology of Infectious and Autoimmune Disease.

Owing to safety concerns or insufficient efficacy, few drug candidates are approved for marketing. Drugs already on the market may be withdrawn due to adverse effects (AEs) discovered after market introduction. Comprehensively investigating the on-/off-target effects of drugs can help expose AEs during the drug development process. We have developed an integrative framework for systematic identification of on-/off-target pathways and elucidation of the underlying regulatory mechanisms, by combining promoter expression profiling after drug treatment with gene perturbation of the primary drug target. Expression profiles from statin-treated cells and HMG-CoA reductase knockdowns were analyzed using the framework, allowing for identification of not only reported adverse effects but also novel candidates of off-target effects from statin treatment, including key regulatory elements of on- and off-targets. Our findings may provide new insights for finding new usages or potential side effects of drug treatment.

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A framework for identification of on- and off-target transcriptional responses to drug treatment.

OBJECTIVES Systemic lupus erythematosus (SLE) is associated with a significant risk of cardiovascular mortality. The use of statins for lipid modulation and the prevention of cardiovascular disease in this population also may impart pleiotropic anti-inflammatory and immunomodulatory effects. Our aim was to identify studies that compared the use of statins and placebo or no statin therapy in patients with SLE. METHODS A meta-analysis was conducted on the follow-up measures of serum lipid levels, inflammatory markers, and disease activity, which was measured using the SLE Disease Activity Index (SLEDAI) score. The mean difference (MD) was calculated by the inverse variance method under a fixed or random-effects model, as appropriate. RESULTS A total of eight studies met our inclusion criteria, including five randomized controlled trials. The total number of patients was 814 (statins 446, placebo/no statins 368), and follow-up ranged from 1 month to 7 years. The total cholesterol (MD -23.48 mg/dL, 95% confidence interval [CI] -34.57 to -12.39, P < 0.0001), low-density lipoprotein (MD -20.7 mg/dL, 95% CI -30.51 to -10.89, P < 0.0001), and high-sensitivity C-reactive protein (MD -0.40 mg/dL, 95% CI -0.64 to -0.16, P = 0.001) levels were significantly reduced by statin therapy. There was no change with statin use in serum levels of high-density lipoprotein and conventional C-reactive protein, and there was no difference in the SLEDAI score. CONCLUSIONS The use of statins in SLE reduced the serum lipid and high-sensitivity C-reactive protein levels, which suggests a role for the primary prevention of cardiovascular disease. Statins did not affect the SLEDAI score, and therefore their use for modifying SLE disease activity levels is not presently supported.

Orlando Santana

Papers

Effects of Statin Therapy in Patients with Systemic Lupus Erythematosus.