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Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is Associated with Disease Activity and Risk of Incident Cardiovascular Disease in Patients with Systemic Lupus Erythematosus

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Abstract—

To study the relationship of serum PCSK9 and disease activity and major adverse cardiovascular events (MACEs) in systemic lupus erythematosus (SLE). Consecutive patients who fulfilled ≥ 4 ACR criteria for SLE and consented for a biomarker study in 2009–2013 were included. Stored serum samples were assayed for PCSK9. PCSK9 levels were correlated with SLE disease activity scores. Patients were divided into two groups according to the median PCSK9 level and new MACEs over time were evaluated. The effect of PCSK9 level on MACEs and mortality was studied by Cox regression, adjusted for confounders. A total of 539 SLE patients were studied (93% women, age 41.9 ± 14.0 years). The median PCSK9 level at baseline was 220 ng/ml. Patients with higher PCSK9 (≥ 220 ng/ml; n = 269) had significantly higher SLE disease activity index (SLEDAI) than those with lower PCSK9 (< 220 ng/ml; n = 270). PCSK9 levels were significantly higher in patients with active renal than active non-renal SLE, which in turn were significantly higher than those with inactive SLE or healthy controls. PCSK9 level correlated with SLEDAI in the overall population (ρ = 0.30; p < 0.001). Over 91.3 ± 18.6 months, 29 patients developed 31 MACEs and 40 patients succumbed (25% for vascular events). The cumulative incidence of MACEs at 5 years was 4.8% in the higher PCSK9 and 1.1% in the lower PCSK9 group (HR2.51[1.11–5.70]; p = 0.03). Cox regression revealed higher PCSK9 was significantly associated with MACEs (HR1.003[1.000–1.005] per ng/ml; p = 0.02) independent of age, sex, renal function, baseline disease activity score, traditional atherosclerotic risk factors, antiphospholipid antibody and the use of aspirin/warfarin, statins and immunosuppressive drugs. PCSK9 level was also independently associated with all-cause (HR1.002[1.000–1.004] per ng/ml; p = 0.03) and vascular mortality (HR1.004[1.000–1.007]; p = 0.04). We concluded that serum PCSK9 level correlates with SLE disease activity. Higher serum PCSK9 levels are associated with increased risk of cardiovascular events and mortality in SLE.

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Acknowledgements

We would like to thank Miss Kylie Mak for her assistance in performing the PCSK9 assay and Miss Becky Fong for the clerical work during data collection. There were no commercial sources of support for this study.

Funding

This work was supported by a mini grant from the Hong Kong Society of Rheumatology.

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Authors and Affiliations

  1. Department of Medicine, Tuen Mun Hospital, Tsing Chung Koon Road, New Territories, Hong Kong SAR, China

    Chi Chiu Mok, Ling Yin Ho, Kar Li Chan & Sau Mei Tse

  2. Departments of Medicine, Pok Oi Hospital, Hong Kong, China

    Chi Hung To

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Contributions

CC Mok: Conceptualization, design, methodology, data collection and interpretation, writing. LY Ho: Conceptualization, design, data curation and interpretation, reviewing and editing. KL Chan: Conceptualization, data curation and interpretation, reviewing and editing. SM Tse: Conceptualization, data curation and interpretation, reviewing and editing. CH To: Conceptualization, methodology, data interpretation, reviewing and editing.

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Correspondence to Chi Chiu Mok.

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This study was approved by the Research and Ethics Committee of Tuen Mun Hospital.

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Written consent was obtained from all participants of this study.

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All authors (CC Mok, LY Ho, KL Chan, SM Tse and CH To) declare no conflict of interests.

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Highlights

• Serum PCSK9 levels correlate with SLE activity.

• Higher serum PCSK9 level at baseline is independently associated with new ischemic vascular events, all-cause and vascular mortality in patients with SLE.

• Serum PCSK9 is a potential biomarker for disease activity and cardiovascular risk in SLE and further validation is necessary.

Supplementary Information

Below is the link to the electronic supplementary material. Supplementary Figure 1: Cumulative incidence of major adverse cardiovascular events according to a history of lupus nephritis

Supplementary file1 (TIF 89 KB)

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Mok, C.C., Ho, L.Y., Chan, K.L. et al. Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is Associated with Disease Activity and Risk of Incident Cardiovascular Disease in Patients with Systemic Lupus Erythematosus. Inflammation 46, 1458–1470 (2023). https://doi.org/10.1007/s10753-023-01821-6

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