Dr. Mariana Kaplan highlights the role of systemic autoimmunity in the development of vasculopathy and atherosclerosis and discusses potential strategies to prevent these complications.


  • An introduction to systemic lupus erythematosus (SLE)
  • The role of cardiovascular disease and vasculopathy in SLE
  • The role of the innate immune system in SLE
  • An introduction to neutrophil extracellular traps (NETs), low density granulocytes (LDGs), and their role in SLE and vascular damage
  • The role of dyslipidemia in SLE
  • Treatment options for prevention of cardiovascular disease in SLE

Webinar Summary

Dr. Kaplan begins this webinar with an introduction to SLE, including the epidemiology, symptoms, current treatments, and role of interferon (IFN) dysregulation. Cumulative SLE mortality from the time of diagnosis increases with age and is associated with the prevalence of carotid plaque formation. The leading cause of death in SLE is cardiovascular (CV) disease, including myocardial infarction, accelerated atherosclerosis, and vasculopathy, but is only partially explained by traditional risk factors. Vasculopathy in SLE may lead to renal disease, central nervous system (CNS) involvement, and complications during pregnancy, and is of increasing concern in childhood SLE. Evidence of vascular damage prior to any vascular event in SLE patients is shown, such as endothelial dysfunction, arterial stiffness, perfusion abnormalities, as well as the presence of carotid and arterial plaques. Mechanisms involved in endothelial dysfunction and premature CV disease in SLE are then summarized, highlighting the challenge of identifying therapeutic targets.

“Overall this suggested that dysregulation of type I interferons in a chronic manner may play very prominent roles in promoting premature vascular disease.”

Dr. Kaplan explains that type I IFNs are elevated in SLE and their role in several pathways may contribute to premature vascular damage. Another innate immune system component of interest is dysregulation of neutrophil biology in SLE, including NETs, in which a number of autoantigens implicated in different autoimmune diseases can be found. Sex differences in neutrophils and NET activity are described, and may account for some of the observed differences in SLE prevalence between men and women. An additional feature of neutrophils in SLE is the presence of LDGs, a subset of cells with abnormal biomechanical properties that may exert vasculopathic effects via enhanced NET formation; LDGs are also found in other conditions in which vascular damage is observed. This is reinforced with clinical data demonstrating an association between LDG gene signature and vascular abnormalities, suggesting that the presence of high levels of LDGs is a risk factor for development of coronary atherosclerosis.

“There is a correlation between low density granulocyte gene signature and the severity of vascular damage.”

A number of mechanisms by which NETs may be deleterious to the vasculature are described; dysregulation of the type I IFN pathway and neutrophil responses may converge at the artery to amplify inflammation, initiate coagulation and plaque instability, and recruit additional inflammatory cells, ultimately leading to vascular damage.

In the next portion of the webinar, Dr. Kaplan discusses the role of dyslipidemia in SLE; a complex profile has been described in SLE patients, including increased very low density lipoproteins (VLDL), elevated triglycerides, variable LDL levels, and low levels of dysfunctional high density lipoprotein (HDL). HDL removes cholesterol from macrophages and this process, known as cholesterol efflux capacity, is decreased in SLE patients and associated with greater noncalcified plaque burden, possibly as a result of LDG NET-mediated oxidative damage. A summary of the effects of LDG NETs on HDL, inflammation, and cardiovascular disease is shown, in addition to similar observations on the role of LDGs in psoriasis patients.

“Is lupus a cardiovascular disease equivalent, and how do we follow the recommendations, for example, on lipid management, because the role of statins in lupus is unclear . . .?”

Guidance on SLE treatment remains unclear, and better defined guidelines are required to identify patients at greater risk for vascular damage. In the final portion of the webinar, Dr. Kaplan focuses on potential interventions to prevent cardiovascular disease in SLE, including following a Mediterranean diet, antimalarials, corticosteroids, methotrexate, and mycophenolate mofetil. Anifrolumab was recently approved by the FDA for treatment of SLE, and interferes with type I IFN signaling; Dr. Kaplan describes a recent Phase II study collaboration in which the effects of Anifrolumab on NET complexes and HDL function were examined. Additional possible approaches targeting NETs in autoimmunity are introduced, including the JAK/STAT pathway. JAK/STAT inhibitors such as Tofacitinib are commercially available and decreased a number of disease parameters associated with SLE such as kidney and skin disease in animal models, and also reduced NET formation and vascular dysfunction. The results of a recent Phase I randomized, placebo-controlled trial of Tofacitinib in mild to moderate SLE are shown, revealing that treatment was safe and reduced circulating LDGs and NETs in a subset of patients, and also increased HDL levels and cholesterol efflux capacity. Antimalarials may also interfere with NET pathways, with the added benefit that they are not immunosuppressive.

Dr. Kaplan concludes this webinar with a summary of cardiovascular risk in SLE, the potential mechanisms involved, and possible therapeutic strategies to target these mechanisms, ultimately highlighting the need for disease-specific guidelines for vascular disease prevention in SLE.

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  • How may these findings translate to other autoimmune diseases?
  • Are antiangiogenic genes and their protein products upregulated in SLE?
  • What is the time course of the neutrophil and cholesterol efflux changes relative to the diagnosis or onset of SLE?
  • What is the role of oxidative stress in SLE?
  • Has a proposed guideline for risk assessment been identified in SLE (similar to what has been identified in rheumatoid arthritis)?
  • Could chronic stress play a role in SLE?
  • Are there specific lipoproteins that are targeted in SLE?
  • Can blood markers be used to assess cardiovascular risk in SLE patients?
  • What is the next step to investigate the role of statins in SLE?
  • If SLE is a spectrum, are neutrophils targeted to specific tissues depending on the disease presentation?
  • Do medications targeting B cell antibody production improve cardiovascular function in SLE?
  • What accounts for differences in race and sex outcomes in SLE?
  • Neutralizing autoantibodies to type I IFNs have been found in some severe COVID-19 patients – have any such antibodies been found in SLE patients?

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Senior Investigator and Branch Chief
Systemic Autoimmunity Branch

Dr. Kaplan's research has focused on identifying mechanisms of immune dysregulation, organ damage, and premature vascular disease in systemic autoimmunity. More specifically, she investigates how innate immunity (in particular, type I interferons and myeloid cells) promote autoimmune responses and end-organ damage in systemic lupus erythematosus, rheumatoid arthritis, and other systemic autoimmune diseases. Recently, her research has focused on identifying abnormalities of neutrophil subsets and the role of neutrophil extracellular traps (NETs) in systemic autoimmune disorders, both of which may contribute to the development of autoimmune responses and end-organ damage. Dr. Kaplan also has an interest in identifying novel therapeutic targets that may prevent premature vascular damage in systemic autoimmunity, as well as the role of environmental triggers in the induction of autoimmunity. Moreover, she has led clinical trials to identify mechanisms that reduce blood vessel dysfunction and mitigate organ damage in autoimmune and chronic inflammatory disorders.

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