Abstract
Cardiovascular disease (CVD) is a leading cause of mortality in patients with juvenile-onset systemic lupus erythematosus (JSLE) associated with atherosclerosis. The interplay between dyslipidaemia and inflammation—mechanisms that drive atherosclerosis—were investigated retrospectively in adolescent JSLE patients using lipoprotein-based serum metabolomics in patients with active and inactive disease, compared to healthy controls (HCs). Data was analysed using machine learning, logistic regression, and linear regression. Dyslipidaemia in JSLE patients was characterised by lower levels of small atheroprotective high-density lipoprotein subsets compared to HCs. These changes were exacerbated by active disease and additionally associated with significantly higher atherogenic very-low-density lipoproteins (VLDL) compared to patients with low disease activity. Atherogenic lipoprotein subset expression correlated positively with clinical and serological markers of JSLE disease activity/inflammation and was associated with disturbed liver function, and elevated expression of T-cell and B-cell lipid rafts (cell signalling platforms mediating immune cell activation). Finally, exposing VLDL/LDL from patients with active disease to HC lymphocytes induced a significant increase in lymphocyte lipid raft activation compared to VLDL/LDL from inactive patients. Thus, metabolomic analysis identified complex patterns of atherogenic dyslipidaemia in JSLE patients associated with inflammation. This could inform lipid-targeted therapies in JSLE to improve cardiovascular outcomes.
Highlights
Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by loss of immune cell regulation and the presence of autoantibodies against multiple nuclear and non-nuclear antigens, resulting in chronic inflammation and multiple organ damage
This study provides an in-depth analysis of dyslipdaemia in a large cohort of adolescent patients with juvenileonset systemic lupus erythematosus (JSLE) compared to age matched healthy donors
Three key points arise from this work; firstly, NMR metabolomics identified early dyslipidaemia in JSLE patients despite no significant difference observed in the lipid profile routinely used in clinical care, which was characterised by reduced small high density lipoproteins (HDL) subsets; secondly, increased clinical disease activity in JSLE exacerbated reductions in HDL subsets and was associated with elevated atherogenic lipoprotein subsets compared to age-matched healthy donors; and very-low-density lipoproteins (VLDL)/LDL lipoprotein levels correlated positively with T-cell and B-cell plasma membrane lipid rafts and in vitro culture of VLDL/LDL isolated from patients with clinically active disease increased lymphocye lipid raft expression
Summary
Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by loss of immune cell regulation and the presence of autoantibodies against multiple nuclear and non-nuclear antigens, resulting in chronic inflammation and multiple organ damage. Between 15–20% of all patients with SLE have juvenile-onset disease (JSLE) [1]. Cardiovascular disease (CVD) as a serious long-term complication of SLE and JSLE [3] and is mediated by atherosclerosis, a chronic inflammatory disease of the large arteries, characterised by defects in lipid homeostasis (dyslipidaemia) [4]. Patients with JSLE have an increased risk of mortality due to CVD [5,6]. This indicates that the atherosclerotic process which is known to begin in childhood or adolescence and is accelerated in JSLE patients due to the prolonged exposure to inflammation [7,8]
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