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Research ArticleAccepted Article

Neutrophil extracellular traps identify patients at risk of increased disease activity and cardiovascular comorbidity in systemic lupus erythematosus

Stanley Moore, Hsin-Hsuan Juo, Christoffer T. Nielsen, Helena Tyden, Anders A. Bengtsson and Christian Lood
The Journal of Rheumatology December 2019, jrheum.190875; DOI: https://doi.org/10.3899/jrheum.190875
Stanley Moore
Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA. Department of Autoimmunity and Biomarkers, Statens Serum Institut, Copenhagen, Denmark. Division of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. This work was supported by the Lupus Research Alliance (grant number 519414) and the Institute of Translational Health Sciences (ITHS). Address correspondence to Christian Lood, PhD, University of Washington, Division of Rheumatology, 750 Republican Street, Room E-545, Seattle, WA, 98109, USA. Email: Loodc@uw.edu>
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Hsin-Hsuan Juo
Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA. Department of Autoimmunity and Biomarkers, Statens Serum Institut, Copenhagen, Denmark. Division of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. This work was supported by the Lupus Research Alliance (grant number 519414) and the Institute of Translational Health Sciences (ITHS). Address correspondence to Christian Lood, PhD, University of Washington, Division of Rheumatology, 750 Republican Street, Room E-545, Seattle, WA, 98109, USA. Email: Loodc@uw.edu>
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Christoffer T. Nielsen
Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA. Department of Autoimmunity and Biomarkers, Statens Serum Institut, Copenhagen, Denmark. Division of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. This work was supported by the Lupus Research Alliance (grant number 519414) and the Institute of Translational Health Sciences (ITHS). Address correspondence to Christian Lood, PhD, University of Washington, Division of Rheumatology, 750 Republican Street, Room E-545, Seattle, WA, 98109, USA. Email: Loodc@uw.edu>
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Helena Tyden
Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA. Department of Autoimmunity and Biomarkers, Statens Serum Institut, Copenhagen, Denmark. Division of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. This work was supported by the Lupus Research Alliance (grant number 519414) and the Institute of Translational Health Sciences (ITHS). Address correspondence to Christian Lood, PhD, University of Washington, Division of Rheumatology, 750 Republican Street, Room E-545, Seattle, WA, 98109, USA. Email: Loodc@uw.edu>
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Anders A. Bengtsson
Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA. Department of Autoimmunity and Biomarkers, Statens Serum Institut, Copenhagen, Denmark. Division of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. This work was supported by the Lupus Research Alliance (grant number 519414) and the Institute of Translational Health Sciences (ITHS). Address correspondence to Christian Lood, PhD, University of Washington, Division of Rheumatology, 750 Republican Street, Room E-545, Seattle, WA, 98109, USA. Email: Loodc@uw.edu>
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Christian Lood
Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA. Department of Autoimmunity and Biomarkers, Statens Serum Institut, Copenhagen, Denmark. Division of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. This work was supported by the Lupus Research Alliance (grant number 519414) and the Institute of Translational Health Sciences (ITHS). Address correspondence to Christian Lood, PhD, University of Washington, Division of Rheumatology, 750 Republican Street, Room E-545, Seattle, WA, 98109, USA. Email: Loodc@uw.edu>
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Abstract

Objective Neutrophil extracellular traps (NETs) are essential in host defense, but are also linked to inflammation and autoimmunity, including systemic lupus erythematosus (SLE). We recently described that immune complexes (ICs) induce NET formation, promoting lupus-like disease in mice. In the current study, we investigated, for the first time, the role of NETs in human SLE and their association with disease activity and severity.

Methods Levels of NETs (MPO-DNA complexes) were analyzed in plasma from four crosssectional SLE cohorts (n=44-142), one longitudinal SLE cohort (n=47), and healthy individuals (n=100) using ELISA. Type I interferon (IFN) activity was determined using a cell reporter system.

Results SLE patients had elevated levels of NETs in circulation compared to healthy controls (p<0.01). NET levels identified patients with a severe disease phenotype characterized by ICdriven nephritis (p<0.05). Though not associated with current disease activity (p=0.20), levels of NETs were associated with future increase in SLEDAI within three months (OR=1.75, p=0.01), as well as an overall heightened SLEDAI over one year (p<0.01). Finally, levels of NETs were associated with arterial events (OR=5.0, p=0.02) and endothelial cell activation (p<0.001).

Conclusion NET levels are elevated in SLE patients, associated with IC-driven disease. NET levels provide significant clinical value in identifying patients at risk of active disease and/or severe disease, including nephritis and cardiovascular disease, which may allow for early interventions.

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Accepted manuscript
Neutrophil extracellular traps identify patients at risk of increased disease activity and cardiovascular comorbidity in systemic lupus erythematosus
Stanley Moore, Hsin-Hsuan Juo, Christoffer T. Nielsen, Helena Tyden, Anders A. Bengtsson, Christian Lood
The Journal of Rheumatology Dec 2019, jrheum.190875; DOI: 10.3899/jrheum.190875

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Accepted manuscript
Neutrophil extracellular traps identify patients at risk of increased disease activity and cardiovascular comorbidity in systemic lupus erythematosus
Stanley Moore, Hsin-Hsuan Juo, Christoffer T. Nielsen, Helena Tyden, Anders A. Bengtsson, Christian Lood
The Journal of Rheumatology Dec 2019, jrheum.190875; DOI: 10.3899/jrheum.190875
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