Neutrophil subsets and their gene signature associate with vascular inflammation and coronary atherosclerosis in lupus

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Abstract

BACKGROUND. Systemic lupus erythematosus (SLE) is associated with enhanced risk of atherosclerotic cardiovascular disease not explained by Framingham risk score (FRS). Immune dysregulation associated to a distinct subset of lupus proinflammatory neutrophils (low density granulocytes; LDGs) may play key roles in conferring enhanced CV risk. This study assessed if lupus LDGs are associated with in vivo vascular dysfunction and inflammation and coronary plaque. METHODS. SLE subjects and healthy controls underwent multimodal phenotyping of vascular disease by quantifying vascular inflammation ( 18 F-fluorodeoxyglucose–PET/CT [ 18 F-FDG–PET/CT]), arterial dysfunction (EndoPAT and cardio-ankle vascular index), and coronary plaque burden (coronary CT angiography). LDGs were quantified by flow cytometry. Cholesterol efflux capacity was measured in high-density lipoprotein–exposed (HDL-exposed) radioactively labeled cell lines. Whole blood RNA sequencing was performed to assess associations between transcriptomic profiles and vascular phenotype. RESULTS. Vascular inflammation, arterial stiffness, and noncalcified plaque burden (NCB) were increased in SLE compared with controls even after adjustment for traditional risk factors . In SLE, NCB directly associated with LDGs and associated negatively with cholesterol efflux capacity in fully adjusted models. A neutrophil gene signature reflective of the most upregulated genes in lupus LDGs associated with vascular inflammation and NCB. CONCLUSION. Individuals with SLE demonstrate vascular inflammation, arterial dysfunction, and NCB, which may explain the higher reported risk for acute coronary syndromes. The association of LDGs and neutrophil genes with vascular disease supports the hypothesis that distinct neutrophil subsets contribute to vascular damage and unstable coronary plaque in SLE. Results also support previous observations that neutrophils may disrupt HDL function and thereby promote atherogenesis. TRIAL REGISTRATION. Clinicaltrials.gov NCT00001372 FUNDING. Intramural Research Program NIAMS/NIH (ZIA AR041199) and Lupus Research Institute A distinct subset of neutrophils are independently associated with vascular inflammation and coronary atherosclerosis in lupus.

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Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus.

E. Baechler, F Batliwalla, G Karypis … (2003)

Systemic lupus erythematosus (SLE) is a complex, inflammatory autoimmune disease that affects multiple organ systems. We used global gene expression profiling of peripheral blood mononuclear cells to identify distinct patterns of gene expression that distinguish most SLE patients from healthy controls. Strikingly, about half of the patients studied showed dysregulated expression of genes in the IFN pathway. Furthermore, this IFN gene expression "signature" served as a marker for more severe disease involving the kidneys, hematopoetic cells, and/or the central nervous system. These results provide insights into the genetic pathways underlying SLE, and identify a subgroup of patients who may benefit from therapies targeting the IFN pathway.

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Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus.

Mary Roman, Beth-Ann Shanker, Adrienne L Davis … (2003)

Although systemic lupus erythematosus is associated with premature myocardial infarction, the prevalence of underlying atherosclerosis and its relation to traditional risk factors for cardiovascular disease and lupus-related factors have not been examined in a case-control study. In 197 patients with lupus and 197 matched controls, we performed carotid ultrasonography, echocardiography, and an assessment for risk factors for cardiovascular disease. The patients were also evaluated with respect to their clinical and serologic features, inflammatory mediators, and disease treatment. The risk factors for cardiovascular disease were similar among patients and controls. Atherosclerosis (carotid plaque) was more prevalent among patients than the controls (37.1 percent vs. 15.2 percent, P<0.001). In multivariate analysis, only older age, the presence of systemic lupus erythematosus (odds ratio, 4.8; 95 percent confidence interval, 2.6 to 8.7), and a higher serum cholesterol level were independently related to the presence of plaque. As compared with patients without plaque, patients with plaque were older, had a longer duration of disease and more disease-related damage, and were less likely to have multiple autoantibodies or to have been treated with prednisone, cyclophosphamide, or hydroxychloroquine. In multivariate analyses including patients with lupus, independent predictors of plaque were a longer duration of disease, a higher damage-index score, a lower incidence of the use of cyclophosphamide, and the absence of anti-Smith antibodies. Atherosclerosis occurs prematurely in patients with systemic lupus erythematosus and is independent of traditional risk factors for cardiovascular disease. The clinical profile of patients with lupus and atherosclerosis suggests a role for disease-related factors in atherogenesis and underscores the need for trials of more focused and effective antiinflammatory therapy. Copyright 2003 Massachusetts Medical Society

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Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus.

J Esdaile, M. Abrahamowicz, T Grodzicky … (2001)

The frequency of coronary heart disease (CHD) and stroke are increased in systemic lupus erythematosus (SLE), but the extent of the increase is uncertain. We sought to determine to what extent the increase could not be explained by common risk factors. The participants at two SLE registries were assessed retrospectively for the baseline level of the Framingham study risk factors and for the presence of vascular outcomes: nonfatal myocardial infarction (MI), death due to CHD, overall CHD (nonfatal MI, death due to CHD, angina pectoris, and congestive heart failure due to CHD), and stroke. For each patient, the probability of the given outcome was estimated based on the individual's risk profile and the Framingham multiple logistic regression model, corrected for observed followup. Ninety-five percent confidence intervals (95% CIs) were estimated by bootstrap techniques. Of 296 SLE patients, 33 with a vascular event prior to baseline were excluded. Of the 263 remaining patients, 34 had CHD events (17 nonfatal MIs, 12 CHD deaths) and 16 had strokes over a mean followup period of 8.6 years. After controlling for common risk factors at baseline, the increase in relative risk for these outcomes was 10.1 for nonfatal MI (95% CI 5.8-15.6), 17.0 for death due to CHD (95% CI 8.1-29.7), 7.5 for overall CHD (95% CI 5.1-10.4), and 7.9 for stroke (95% CI 4.0-13.6). There is a substantial and statistically significant increase in CHD and stroke in SLE that cannot be fully explained by traditional Framingham risk factors alone.