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Vascular damage in systemic lupus erythematosus

Nature Reviews Nephrology volume 20, pages 251–265 (2024)Cite this article

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Abstract

Vascular disease is a major cause of morbidity and mortality in patients with systemic autoimmune diseases, particularly systemic lupus erythematosus (SLE). Although comorbid cardiovascular risk factors are frequently present in patients with SLE, they do not explain the high burden of premature vascular disease. Profound innate and adaptive immune dysregulation seems to be the primary driver of accelerated vascular damage in SLE. In particular, evidence suggests that dysregulation of type 1 interferon (IFN-I) and aberrant neutrophils have key roles in the pathogenesis of vascular damage. IFN-I promotes endothelial dysfunction directly via effects on endothelial cells and indirectly via priming of immune cells that contribute to vascular damage. SLE neutrophils are vasculopathic in part because of their increased ability to form immunostimulatory neutrophil extracellular traps. Despite improvements in clinical care, cardiovascular disease remains the leading cause of mortality among patients with SLE, and treatments that improve vascular outcomes are urgently needed. Improved understanding of the mechanisms of vascular injury in inflammatory conditions such as SLE could also have implications for common cardiovascular diseases, such as atherosclerosis and hypertension, and may ultimately lead to personalized therapeutic approaches to the prevention and treatment of this potentially fatal complication.

Key points

  • Systemic lupus erythematosus (SLE) is associated with an increased risk of developing cardiovascular disease (CVD), which is a leading cause of morbidity and mortality.

  • Traditional risk factors, such as older age, male sex, smoking, hypertension, total cholesterol levels and diabetes mellitus, do not fully account for the increased risk of CVD among patients with SLE.

  • Type 1 interferon and neutrophils may have important pathogenic roles in vascular damage in SLE.

  • SLE remains a leading cause of premature death in women, mainly as a result of CVD; therefore, treatments that improve vascular outcomes are urgently needed.

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Fig. 1: The role of IFN-I in innate immune system-mediated vascular damage in SLE.
Fig. 2: The role of neutrophils and NETs in innate immune system-mediated vascular damage in SLE.
Fig. 3: Adaptive immune-mediated vascular damage in SLE.

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Acknowledgements

The authors’ work was supported by the Intramural Research Program at NIAMS (ZIA AR041199).

Author information

Authors and Affiliations

  1. Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA

    William G. Ambler & Mariana J. Kaplan

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  1. William G. Ambler
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  2. Mariana J. Kaplan
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Contributions

Both authors researched the data for the article, discussed the content, wrote the text and edited or reviewed the manuscript before submission.

Corresponding author

Correspondence to Mariana J. Kaplan.

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Competing interests

NIAMS has collaborative research agreements with Astra Zeneca and Bristol Myers Squibb that relate to mechanisms of vascular damage in autoimmunity. M.J.K. is a member of the scientific advisory boards of Neutrolis and Cytrill.

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Nature Reviews Nephrology thanks Anne Davidson, who co-reviewed with YoungMin Cho, Keisa Mathis, Anisur Rahman and Alan Salama for their contribution to the peer review of this work.

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Supplementary information

Glossary

Emergency granulopoiesis

A rapid increase in neutrophil generation in the bone marrow with a subsequent increase in neutrophil output in the circulation that occurs in response to an increase in neutrophil growth factors such as granulocyte colony-stimulating factor owing to an immune response, often to an infection.

Foam cells

Macrophages with a specialized phenotype that are present within atherosclerotic plaques. These cells have a high lipid content in their cytoplasm, which results in a foamy appearance.

Resistant hypertension

Hypertension that persists despite treatment with three concurrent antihypertensive agents at the maximally tolerated doses.

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Ambler, W.G., Kaplan, M.J. Vascular damage in systemic lupus erythematosus. Nat Rev Nephrol 20, 251–265 (2024). https://doi.org/10.1038/s41581-023-00797-8

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