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Current Vascular Pharmacology, 2020, 18, 000-000 1
REVIEW ARTICLE
1570-1611/20 $65.00+.00 © 2020 Bentham Science Publishers
Cardiovascular Disease in Systemic Lupus Erythematosus: Recent Data on
Epidemiology, Risk Factors and Prevention
Myrto Kostopoulou1, Dionysis Nikolopoulos1, Ioannis Parodis2 and George Bertsias3,4,*
14th Department of Internal Medicine, Attikon University Hospital, Joint Rheumatology Program, National and Kapo-
distrian University of Athens Medical School, Athens, Greece; 2Division of Rheumatology, Department of Medicine
Solna, Karolinska Institutet and Rheumatology, Karolinska University Hospital, Stockholm, Sweden; 3Department of
Rheumatology, Clinical Rheumatology and Allergy, University of Crete Medical School, Iraklio, Greece; 4Laboratory of
Rheumatology, Autoimmunity and Inflammation, Institute of Molecular Biology and Biotechnology-FORTH, Iraklio,
Greece
A R T I C L E H I S T O R Y
Received: July 19, 2019
Revised: November 20, 2019
Accepted: December 12, 2019
DOI:
10.2174/1570161118666191227101636
Abstract: Systemic Lupus Erythematosus (SLE) is associated with increased risk for accelerated athe-
rosclerosis and cardiovascular (CV) events including coronary heart disease, cerebrovascular and pe-
ripheral artery disease. CV events occur both early and late during the disease course, with younger
patients being at much higher risk than age-matched counterparts. The risk cannot be fully accounted for
by the increased prevalence of traditional atherosclerotic factors and may be due to pathophysiologic
intermediates such as type I interferons and other inflammatory cytokines, oxidative stress, activated
granulocytes and production of extracellular chromatin traps, antiphospholipid and other autoantibodies
causing dysfunction of lipoproteins, altogether resulting in endothelial injury and pro-atherogenic
dyslipidaemia. These mechanisms may be further aggravated by chronic intake of prednisone (even at
doses <7.5 mg/day), whereas immunomodulatory drugs, especially hydroxychloroquine, may exert anti-
atherogenic properties. To date, there is a paucity of randomized studies regarding the effectiveness of
preventative strategies and pharmacological interventions specifically in patients with SLE. Neverthe-
less, both the European League Against Rheumatism recommendations and extrapolated evidence from
the general population emphasize that SLE patients should undergo regular monitoring for atheroscle-
rotic risk factors and calculation of the 10-year CV risk. Risk stratification should include disease-
related factors and accordingly, general (lifestyle modifications/smoking cessation, antihypertensive and
statin treatment, low-dose aspirin in selected cases) and SLE-specific (control of disease activity, mini-
mization of glucocorticoids, use of hydroxychloroquine) preventive measures be applied as appropriate.
Further studies will be required regarding the use of non-invasive tools and biomarkers for CV assess-
ment and of risk-lowering strategies tailored to SLE.
Keywords: Autoimmune disease, type I interferon, antiphospholipid antibodies, glucocorticoids, dyslipidaemia, ischemic heart
disease, cerebrovascular disease, statin.
1. INTRODUCTION
Systemic Lupus Erythematosus (SLE) is the prototype
systemic autoimmune disease that can affect any organ [1].
SLE usually starts in early or mid-adulthood and affects
more women than men [1]. Its pathogenesis is complex and
involves an interaction between genetic and environmental
factors, which results in the activation of innate and adaptive
*Address correspondence to this author at the Department of Rheumatology,
Clinical Rheumatology and Allergy, University of Crete Medical School,
71003 Voutes, Iraklio, Greece; Tel: (+30) 2810 394635;
E-mail: gbertsias@uoc.gr
immune pathways and the production of autoantibodies di-
rected against nuclear and other self-antigens [1]. Despite
advances in the treatment and overall management, patients
with SLE still suffer from increased morbidity and mortality
as compared with the general population, and an increased
burden of comorbid conditions including metabolic and car-
diovascular (CV) disease (CVD) [2, 3]. This has been further
augmented by the fact that life expectancy for SLE patients
has increased considerably over the last decades [4]; thus,
patients live long enough to manifest such complications.
In this review, we summarize the evidence on the epide-
miology and risk factors of CVD in SLE. We discuss the
2 Current Vascular Pharmacology, 2020, Vol. 18, No. 00 Kostopoulou et al.
major pathophysiologic drivers of atherosclerosis in the con-
text of the disease, as well as the existing modalities in risk
assessment and stratification. We conclude based on the evi-
dence-based use of preventative measures and some practical
considerations in the routine management of SLE.
2. DEFINITIONS
Atherosclerosis is a chronic inflammatory state character-
ized by the accumulation of lipids and immune cells in the
sub-endothelial arterial wall, resulting in inflammation-
driven plaque formation [5]. It is the main contributor to the
clinical burden of CVD and subclinical forms of atheroscle-
rosis constitute a risk for and are predictive of future cardio-
vascular events (CVE) [6]. However, there are patients with
atherosclerosis who never develop CVE, and, conversely,
there are patients with CVE without any evidence of sub-
clinical atherosclerosis [7]. The complexity of this interplay
becomes more prominent in SLE, where inflammatory me-
diators may independently contribute to the formation of
atherosclerotic plaques and subsequent CVE [5, 8, 9].
In most epidemiologic studies on SLE outcomes, CVD
comprises coronary heart disease (CHD; myocardial infarc-
tion (MI), angina pectoris and/or heart failure), cerebrovas-
cular disease (a stroke or transient ischemic attack) and pe-
ripheral artery disease (intermittent claudication and critical
limb ischemia) [10]. To this end, study designs on survival
outcomes require large patient cohorts and long-term follow-
up. As a result, most studies investigate subclinical athero-
sclerosis rather than actual CVE rates. The former is defined
by the presence of plaque, however, a number of surrogate
markers are commonly used, particularly carotid intima me-
dia thickness (cIMT) and coronary artery calcium (CAC)
[11]. Other non-invasive assessments of endothelial function
and vascular stiffness such as flow-mediated vasodilation
and pulse wave velocity (PWV) are also used due to their
feasibility and established correlation to CVD risk in the
general population [12-14]. Given the heterogeneity and sub-
jectivity of the techniques used to assess CVD, results may
not always be generalized.
3. EPIDEMIOLOGY OF CVD IN SLE
The impact of CVD on SLE mortality was first docu-
mented in the 1970’s by Urowitz et al. who described a bi-
modal mortality pattern where an early peak (within 1 year of
diagnosis) attributed to disease activity and infections, was
followed by a later one (>5 years after diagnosis) due to CVD
[15]. Since then, death related to lupus activity has been mark-
edly decreased due to the introduction of new treatments and
improved overall management. However, CV mortality re-
mains unchanged and is considered one of the main causes of
death in SLE, especially during late disease stages [16, 17].
In recent studies, the overall prevalence of CVE in SLE
varies between 4% and 20% depending on the definitions
used and the ethnic and age variation [18-22]. According to a
recent meta-analysis including 17,187 SLE patients, CVE
occurrence had a pooled estimate of 25.4% in a median fol-
low-up of 8 years [23]. SLE patients have a 2- to 10-fold
increased risk of clinical CVD compared with the general
population, even after adjustments for traditional risk factors
[21, 24-27]. This risk is even more pronounced among
younger women, as illustrated in the Framingham Offspring
Study, where premenopausal women with SLE were over
50-times more likely to suffer an MI than age- and sex-
matched controls [28]. Notably, the risk of CV morbidity is
increased since the early stages of the disease. In two studies
examining CVE risk during the first and second year after
SLE diagnosis, the adjusted hazard ratios (HR) were 3.8 and
6.0, respectively [25, 29].
As in the general population, subclinical atherosclerosis
in SLE is more prevalent than clinical CVD. A recent study
found the risk of subclinical atherosclerosis in SLE patients
to be comparable to that in matched patients with diabetes
mellitus (DM) and rheumatoid arthritis, suggesting compara-
ble cardiovascular burden [30]. In two autopsy series, athe-
rosclerotic coronary plaques were seen in up to 40% of the
tissue segments of SLE patients [31, 32]. The premature on-
set and the accelerated nature of atherosclerosis have also
been documented in several cross-sectional and prospective
studies [9, 33-37]. Thus, both cIMT and carotid plaques were
more frequent in SLE patients than age- and sex-matched
controls [9, 38]. In a meta-analysis of 80 studies, SLE pa-
tients had a greater cIMT and a 2-fold increased prevalence
of carotid plaques compared with controls [39]. Although
data connecting subclinical atherosclerosis to the incidence
of CVEs in SLE are sparse, one prospective study with a
mean follow-up of 8 years showed that women with cIMT or
carotid plaque at baseline had an increased incidence of
CVD (HR 1.35 and 4.26, respectively) [40].
Traditional atherosclerotic risk factors contribute to in-
creased risk but cannot fully explain the accelerated CVD in
SLE. In a retrospective study of 263 SLE patients, there was a
marked difference between the observed and expected (as-
sessed according to the Framingham risk score) incidence of
CHD, resulting in a 7.5-fold increased risk [27]. In another
prospective study of CHD in patients with SLE and matched
controls followed over a median of 8 years, SLE per se was an
independent risk factor even after correcting for traditional
atherosclerotic risk factors [41]. What accounts for this excess
risk remains elusive, but studies suggest that it can be partly
attributed to disease and treatment-related factors (Table 1).
Specifically, among various SLE-specific factors that have
been found to correlate with CVD (i.e. disease activity and
duration, cumulative damage, presence of antiphospholipid
(aPL) antibodies, lupus nephritis, and various treatments), data
on disease duration are more robust, indicating as expected,
longer duration as an independent predictor for both CVE and
accelerated atherosclerosis [40, 42-45]. Thus, in a cohort of
392 women with SLE, disease duration at enrolment correlated
with the incidence of CVE in age-adjusted Cox regression
models (HR: 1.04 per 1-year) [40]. Higher organ damage (as-
sessed by the Systemic Lupus International Collaborating
Clinics/American College of Rheumatology Damage Index)
was also significantly associated with CVE and subclinical
atherosclerosis [22, 23, 46]. Conversely, data on the impact of
disease activity on atherosclerosis are less consistent in the
literature [21, 28, 47-49], with several studies failing to dem-
onstrate significant associations [39, 50, 51].
4. PATHOGENESIS OF ACCELERATED CVD IN SLE
At an early stage, endothelial injury caused by oxidized
low-density-lipoprotein (oxLDL) induces the expression of
Cardiovascular Disease in Lupus Current Vascular Pharmacology, 2020, Vol. 18, No . 00 3
endothelial cell adhesion molecules and recruitment of
monocytes, which differentiate into macrophages [52]. In-
gestion of oxLDL by these macrophages transforms them
into cholesterol-laden “foam cells” [52]. The subsequent
production of growth factors and cytokines leads to the pro-
liferation of vascular smooth muscle cells and plaque devel-
opment [53]. To this end, although the pathogenesis of ac-
celerated atherosclerosis in SLE is not thoroughly under-
stood, systemic inflammatory response, together with the
early appearance of traditional risk factors, is believed to
exacerbate the atherogenic process [54].
4.1. The Role of Pathophysiology Intermediates
4.1.1. Inflammatory Cytokines
Several studies have implicated type I interferons (IFNs)
in premature atherosclerosis in murine and human SLE [55-
58]. Patients with SLE have an increased expression of type I
IFN-regulated genes (so-called ‘interferon signature’),
which play important roles in the pathogenesis of this disease
[59]. Notably, these IFNs may hamper vascular repair and
inhibit angiogenesis by decreasing endothelial progenitor
cells and suppressing neo-vascularization in sites of endothe-
lial injury [55]. In addition to their anti-angiogenic role, type
I IFNs may also contribute to the atherogenic process by
enhancing foam cell formation [60], promoting platelet acti-
vation, impairing smooth muscle cell maturation, and leading
to plaque rupture [61, 62]. In a study that evaluated type I
IFNs in relation to subclinical atherosclerosis in SLE, en-
hanced serum IFN activity was associated with increased
cIMT and severity of CAC in SLE patients but not in con-
trols [57]. Another cytokine, tumour necrosis factor (TNF)-α
also contributes to endothelial injury by stimulating mono-
cyte differentiation into macrophages and foam cells. Al-
though high levels of TNF-α in SLE have been associated
with high triglyceride and low high density lipoprotein cho-
lesterol (HDL-C) levels [63], their actual impact on subclini-
cal atherosclerosis remains uncertain [9, 64]. Other impli-
cated cytokines include interleukin (IL)-6 and IL-17, with
circumstantial evidence suggesting a possible link between
their increased levels and atherosclerosis is SLE [65-67].
4.1.2. Oxidized Low-Density Lipoproteins (oxLDL)
Low-density lipoproteins (LDL) trapped in the subendo-
thelial space and exposed to active reactive oxygen species
(ROS) result in the formation of oxLDLs. Next, chemokines
and proinflammatory cytokines released by endothelial cells,
promote monocytes infiltration to the subendothelial space
where they differentiate into macrophages [52]. The oxLDLs
are phagocytosed by macrophages, which transform into
foam cells [52]. In SLE patients, circulating oxLDLs are
increased and have been correlated with measures of sub-
clinical atherosclerosis [68]. This might be due to the higher
levels of proinflammatory high-dense lipoprotein (pi-HDL)
observed in SLE, which, in contrast to normal HDL, does not
prevent LDL oxidation [69]. Moreover, antibodies against
HDL (anti-HDL) or against apolipoprotein A1 (the main
constituent of HDL) impair the anti-oxidant activity of nor-
mal HDL, therefore enhancing LDL oxidation [70]. OxLDL
may also create complexes with anti-β2-glycoprotein I (anti-
β2-GPI) autoantibodies, which are encountered in a propor-
tion of SLE patients, and induce an antibody-mediated
phagocytosis by neighbouring macrophages, thus accelerat-
ing the atherogenic process [71].
4.1.3. Neutrophils and Neutrophil Extracellular Traps
(NETs)
Neutrophils have been recently implicated in the patho-
genesis of atherosclerosis. Their role in innate immune re-
sponse is well-described and encompasses mechanisms such
as phagocytosis and intracellular degradation, degranulation,
the release of ROS and formation of NETs, all physiologi-
cally induced following a pathogen insult [72]. However,
some of these mechanisms may be triggered by endogenous
molecules such as cytokines [73]. In lupus, the co-existence
of a specific subset of proinflammatory neutrophils, known
as low density granulocytes (LDGs), and atherosclerosis has
been shown to be pathogenic [74]. In a recent study, vascular
Table 1. SLE-related risk factors with significant associations with cardiovascular diseases and atherosclerosis.
CVD
Subclinical Atherosclerosis
Risk Factor
OR
No. Studies
OR
No. Studies
Disease activity
1.21
3
7
Disease duration
1.01
5
2.30 – 3.16
12
Cumulative damage
1.38
2
1.7
5
a-PL (any)
1.57 – 5.00
12
5.2
1
Renal involvement
1.12 – 2.41
7
2.16
3
GCs
2.46
8
0.33 – 2.93
7
HCQ
0.06 – 0.34
8
3
CYC
0.31
1
AZA
2.33 – 2.58
4
CVD, cardiovascular disease; OR, odds ratio; a-PL, anti-phospholipid antibodies; GCs, glucocorticoids; HCQ, hydroxychloroquine; CYC, cyclophosphamide; AZA, azathioprine.
4 Current Vascular Pharmacology, 2020, Vol. 18, No. 00 Kostopoulou et al.
damage and non-calcified plaque burden (an indicator of
plaque vulnerability assessed by computed tomography an-
giography) correlated with the proportion of circulating
LDGs in SLE subjects. Interestingly, the Framingham risk
score did not correlate with non-calcified plaque burden,
suggesting an independent role of LDGs in plaque formation
and instability [75]. To this end, LDGs have been linked to
increased type I IFN production and endothelial damage via
NETosis [76]. NETosis represents a unique type of cell
death, different from apoptosis and necrosis, that causes ex-
ternalization of fibrous networks (NETs) consisting of nu-
clear chromatin, antimicrobial components including mye-
loperoxidase, neutrophil elastase and human cathelecidin
(LL-37) [77]. The mechanism that connects NETs to athero-
sclerosis in the SLE population has yet to be defined. None-
theless, in a study in paediatric SLE patients, NET content
was shown to be capable of inducing IFN-α by plasmacytoid
dendritic cells [78], while in another study, excess of NETs
resulted in vascular leakage and endothelial-to-mesenchymal
transition, thus jeopardizing vascular integrity [79].
4.1.4. Autoantibodies
Several autoantibodies and immune complexes have been
linked to vascular damage and atherosclerosis in lupus. aPL
antibodies including lupus anticoagulant, anticardiolipin and
anti-β2-GPI antibodies, represent a strong risk factor for
thrombotic events driven by immune-mediated mechanisms
rather than atherosclerosis [80]. aPL antibody positive SLE
patients, especially patients with moderate to high serum
antibody levels, are at increased risk of venous and arterial
thrombotic events compared with aPL-negative counterparts
[81]. Although the underlying mechanism that links the pres-
ence of aPL antibodies to endothelial injury in lupus is not
clear, possible pathways include the anti-β2-GPI binding to
β2-GPI and the subsequent endothelial cell activation [82]
and enhanced formation of foam cells induced by a complex
of ox-LDL/β2-GPI/anti-β2-GPI [83]. Conversely, IgM
autoantibodies against phosphorylcholine and malondialde-
hyde have been recently found to play a protective role
against atherosclerosis in SLE, probably by increasing the
clearance of apoptotic cells and by reducing oxidative stress
[84, 85].
4.2. Increased Prevalence of Traditional CVD Risk Fac-
tors
The increased CVD burden in SLE can be partly attrib-
uted to the increased prevalence and deleterious effect of
traditional risk factors (Table 2). In a study from the Toronto
Table 2. Summary of the recent studies reporting on traditional cardiovascular risk factors in patients with SLE.
CVD Risk
Atherosclerosis Risk
(cIMT/Carotid Plaque)
Risk Factor
Significant
Associations
Non-Significant
Associations
Significant
Associations
Non-Significant
Associations
Comments
10 studies
3 studies
12 studies
3 studies
Hypertension
(HR 2.3–18.05)
(OR 1.4–4.8)
High level of evidence
4 studies
4 studies
6 studies
2 studies
DM
OR: 7.07-61.8
Inconsistent results
8 studies
3 studies
12 studies
6 studies
Dyslipidemia
OR: 2.18-5.37
OR: 1.52-3.4
Great heterogeneity under the term
dyslipidemia
2 studies
1 study
Metabolic syndrome
HR: 3.88
OR: 3.11
Low level of evidence
7 studies
4 studies
7 studies
4 studies
Smoking
OR: 1.48-3.25
OR: 1.05-5.89
Heterogeneity regarding the expo-
sure variable (ever/current/no
smoking, pack-years)
4 studies
2 studies
Homocysteine
OR: 1.24
No study with CVE as outcome
1 study
3 studies
3 studies
Obesity
OR: 4.09
Low level of evidence
4 studies
3 studies
4 studies
4 studies
CKD
OR: 1.002-2.26
(creatinine levels)
Heterogeneity regarding the out-
comes (creatinine levels, eGFR,
definition of CKD)
CVD, cardiovascular disease; cIMT, carotid intima media thickness; HR, hazard ratio; OR, odds ratio; DM, diabetes mellitus; CKD, chronic kidney disease; eGFR, estimated glome-
rular filtration rate.
Cardiovascular Disease in Lupus Current Vascular Pharmacology, 2020, Vol. 18, No . 00 5
Lupus Cohort, women with SLE had increased prevalence of
hypertension, DM, premature menopause and sedentary life-
style compared to their age-matched counterparts [86]. How-
ever, SLE subjects have increased CVD risk even after ac-
counting for these factors, which explains why risk assess-
ment models used in the general population (e.g. the
Framingham risk score) underestimate the actual hazard in
SLE [27]. Age and gender are the most robust, non-
modifiable risk factors for CVD both in the general popula-
tion and in patients with SLE [22, 87]. Specifically, higher
age and male sex have been associated with multiple meas-
ures of subclinical atherosclerosis and increased incidence of
CVE, yielding an up to 3-fold increase in CVD events in
SLE [88-90]. Among modifiable factors, arterial hyperten-
sion, dyslipidaemia, and smoking have consistently been
reported as predictors of CVD in SLE, whereas data on DM,
metabolic syndrome and homocysteinaemia are less robustly
associated. In a recent meta-analysis of 32 studies, hyperten-
sion (OR 3.5) and dyslipidaemia (OR 3.9) were significant
predictors of CVE [23], while other studies have reported
similar associations even after adjusting for possible con-
founding variables [21, 44, 51, 90-93]. Smoking has also
been associated with an increased risk for CVD (HR ranging
from 1.9 to 8.6) and subclinical atherosclerosis [46, 89, 94,
95].
4.3. The Role of Treatment
4.3.1. Glucocorticoids
Lupus patients are frequently treated with immunosup-
pressive agents and glucocorticoids (GCs) for prolonged
time periods. The use of GCs, in particular, has been linked
to an increased risk for atherosclerosis and higher rates of
CVEs [21]. However, the association between GCs and CVD
may be confounded by many factors intrinsic to active dis-
eases such as vascular inflammation and certain comorbid-
ities. Several studies have evaluated the impact of GCs both
on CVEs and subclinical atherosclerosis with inconsistent
results [9, 30, 96-98]. The discrepancies may be partly ex-
plained by the difference in the assessment of drug exposure
(current dose, cumulative dose, duration of treatment) and
differences in the sampled population (e.g. lupus nephritis).
Both higher cumulative GC intake and longer duration of
treatment have been strongly associated with accelerated
atherosclerosis [30, 96, 97]. Lupus patients treated with ≥10
mg of prednisone equivalent daily for 10 years had substan-
tially increased CVE risk, which was further augmented
when the daily dose exceeded 20 mg [21]. In contrast, Roma
et al. showed that a higher progression of carotid plaque was
associated with a lower average dose of GCs, pointing out a
possible atheroprotective effect [9]. Notably, a study con-
ducted in a paediatric SLE population revealed a decreased
cIMT in patients treated with moderate doses of GCs com-
pared with those treated with low or high GC doses [98].
GCs have multiple effects on immune-mediated path-
ways which are commonly involved in the pathogenesis of
atherosclerosis. However, little is known about the endothe-
lial modifications in response to GCs, especially in the con-
text of SLE. In experimental models, normal mice treated
with GCs exhibited increased endothelial dysfunction [99,
100]. A possible explanation involves endothelial nitric ox-
ide synthase, a molecule with an atheroprotective profile. In
this model, increased ROS production induced by GCs
down-regulated endothelial nitric oxide synthase mRNA and,
consequently, reduced its bioavailability [101]. An interest-
ing study demonstrated that the deletion of macrophage-
specific GC receptor reduced vascular calcification without
affecting atherosclerotic lesion size [102], highlighting the
role of GCs on vascular calcification. On the other hand,
GCs may have presumed atheroprotective effects by inhibit-
ing the expression of adhesion molecules, mainly Intercellu-
lar Adhesion Molecule 1 (ICAM-1) and vascular cell adhe-
sion molecule-1 (VCAM-1), resulting in decreased cell mi-
gration at the side of plaque [103]. Moreover, GCs inhibit
the nuclear factor kappa B (NF-κB) [102]; a molecule, which
is activated at different stages of atherosclerosis participating
in underlying pathogenesis [104]. Another group treated an
atherosclerotic murine model with dexamethasone, and ob-
served inhibition of proliferation and recruitment of macro-
phages along with decreased aortic foam cell formation
[105].
Although the effect of GCs per se on atherosclerosis re-
mains to be better defined, the long-term exposure to GCs
culminates in the accumulation of various comorbidities in-
cluding hypertension, dyslipidaemia, glucose intolerance and
central obesity [106]. Thus, most of the pro-atherogenic ef-
fects of GCs may be driven by the aggregation of such co-
morbidities.
4.3.2. Antimalarials
Hydroxychloroquine (HCQ) is the cornerstone of lupus
care due to its multiple beneficial effects including decreased
CVD risk and protection against both arterial and venous
thrombosis along with a lower burden of atherosclerotic
plaques [107-109]. Several clinical studies have reported on
the atheroprotective role of HCQ [4]. Its main effects are
mediated by anti-inflammatory and lipid-lowering properties
as well as its ability to control the glycaemic profile [110-
112]. A study utilising lupus-prone mice (NZB/NZW F1
strain), demonstrated that early administration of HCQ in-
creases nitric oxide availability and improves the function of
endothelium via reduction of ROS [113]. Moreover, antima-
larials have been shown to reduce type I IFN production by
plasmacytoid dendritic cells [114], which may represent an-
other atheroprotective mechanism as IFN is a mediator of
vascular damage in lupus [55]. Another positive effect of
HCQ on prevention of CVD may be mediated by the im-
pediment to NET formation [115], as NETs contribute to
plaque development [116]. Interestingly, HCQ has been
shown to inhibit platelet activation and aggregation induced
by aPL antibodies, suggesting an antithrombotic role [117].
4.3.3. Mycophenolate Mofetil (MMF)
The direct effect of MMF on atherosclerotic lesions has
been evaluated in mice and human studies. Specifically, in
Ldlr–/– lupus-prone mice that are prone to atherosclerosis, the
administration of MMF resulted in inhibition of T-cell infil-
tration and activation in atherosclerotic plaques [118].
Moreover, in non-lupus atherogenic mice, treatment with
MMF has been shown to reduce atherosclerosis [119]. One
study in SLE patients who underwent carotid endarterectomy
demonstrated a reduced number of infiltrated activated T-
6 Current Vascular Pharmacology, 2020, Vol. 18, No. 00 Kostopoulou et al.
cells along with elevated levels of regulatory T-cells at the
atherosclerotic lesion [120]. Furthermore, there was also a
reduced metalloproteinase and pro-inflammatory genes ex-
pression. Nevertheless, Kiani et al. failed to detect any bene-
ficial effect of MMF on either progression of subclinical
atherosclerosis or coronary calcification in a longitudinal
SLE cohort study [121]. In addition, Sazliyana et al. did not
find any significant decrease in cIMT in association with the
duration of treatment or the cumulative dose of MMF [122].
4.3.4. Other Immunosuppressive Drugs
Methotrexate has been evaluated for the prevention of
atherosclerotic events in healthy individuals without yielding
positive results [123]. However, methotrexate seems to be
protective against atherosclerosis in rheumatoid arthritis,
which represents another chronic autoimmune inflammatory
disorder. A meta-analysis has underscored its putative
atheroprotective role in rheumatoid arthritis patients by 21%
reduction in the overall incidence of CVD and in particular,
an 18% reduction in the risk of MI [124]. Several studies
have shown that use of azathioprine is associated with an
increased CV burden [93, 98, 122, 125, 126]. However, these
findings may reflect the systemic inflammation in these pa-
tients. In contrast, one study demonstrated that the use of
cyclosporine may be beneficial in reducing atherosclerosis
progression as measured by cIMT [122, 127]. Furthermore,
carotid plaque formation has been negatively correlated with
the use of cyclophosphamide, thus highlighting a possible
atheroprotective effect, presumably through reduction of the
systemic inflammation burden [9].
4.3.5. Biologic Drugs
Rituximab, an anti-CD20 monoclonal antibody targeting
B-cells, has been introduced as an off label option in the
therapeutic armamentarium of severe and refractory lupus
[128]. Rituximab seems to be protective against premature
atherosclerosis by affecting the total cholesterol/HDL-C ra-
tio, HDL-C and levels of tissue factor [129]. These findings
may reflect the attenuation of systemic inflammation medi-
ated by B-cell depletion. An interesting study conducted in
atherosclerosis-prone mice (apoE−/− and Lldlr−/− strains)
treated with a CD20-specific monoclonal antibody [130],
demonstrated significantly decreased atherosclerosis along
with decreased titers of anti-oxLDL antibodies. Moreover,
reduced numbers of infiltrating B-cells, T-lymphocytes and
macrophages were detected in atherosclerotic lesions in the
aforementioned mice.
Belimumab is a monoclonal antibody against B-cell acti-
vated factor (BAFF), inhibiting B-cell maturation and sur-
vival, and is approved for the management of SLE [131].
Two interesting studies conducted in hyperlipidemic apoE−/−
mice showed that both the treatment with antibodies directed
against the BAFF receptor (BAFF-R) and BAFF-R defi-
ciency (Baffr−/− mice) led to reduced atherosclerosis [132,
133]. BAFF-R inhibition neutralizes the B2 cells subtype,
which is atherogenic, while preserving the B1 cells that are
considered atheroprotective [131, 133]. Furthermore, be-
limumab may exert a protective role against aPL syndrome
development [134]. It is worth noting that aPL seroconver-
sion from positive to negative levels has been observed in
SLE patients treated with belimumab [135]. These data sug-
gest that belimumab might be beneficial in the prevention of
aPL-medicated thrombotic events and accelerated atheroscle-
rosis. Nevertheless, belimumab efficacy has been shown to
be weakened in patients with previous thrombotic events
[136-138], necessitating further survey of the impact of be-
limumab use on primary and secondary CVD prevention
separately.
Anifrolumab, a monoclonal antibody against type I IFN
receptor [139], may be a promising agent in preventing sub-
clinical atherosclerosis in view of the pro-atherogenic prop-
erties of type I IFNs. To this end, other biologics such as
anti-TNF and anti-IL6 are under investigation as atheropro-
tective agents in patients with rheumatoid arthritis [140].
5. SELECTED CVD MANIFESTATIONS IN PA-
TIENTS WITH SLE
5.1. Coronary Heart Disease (CHD)
In recent studies, the prevalence of clinically significant
CHD in SLE varies from 2-14% [20, 141-143]. Incidence
rates of MI are significantly raised in lupus patients confer-
ring at least a 2-fold risk compared with the general popula-
tion. In a study that comprised 4,863 individuals with SLE,
the adjusted HR for MI was 2.61 compared to non-SLE con-
trols [29]. This risk was even more marked during the first
year of diagnosis and in younger women, highlighting the
premature onset of atherosclerosis [28, 29, 90]. Race and
ethnic variation may contribute to discrepant MI rates across
different lupus cohorts. In a recent study including 65,788
cases of SLE with wide race and ethnic distribution, there
was a reduced MI risk among Hispanics and Asians com-
pared with Caucasian SLE patients (HR: 0.61 and HR: 0.57,
respectively) [144]. Notably, the increased risk seen in SLE
patients seems to be extended to long-term poorer outcomes
and increased cause-specific mortality. Although in-hospital
post-MI outcomes do not differ between SLE patients and
controls [145, 146], patients with SLE are more likely to
experience a new MI or require repeat percutaneous coro-
nary intervention within 1 year after the initial event [147].
Moreover, long-term data suggest that SLE patients with MI
are at least 2.6 times more likely to die than non-SLE pa-
tients with the same coronary event [148, 149].
5.2. Cerebrovascular Disease
Individuals with SLE have an increased risk for cere-
brovascular disease compared with the general population
[29, 150, 151]. In a recent meta-analysis of 5 studies, the
pooled relative risk of stroke in SLE patients was 2.53 [152].
Similar to CHD, the risk of cerebrovascular disease is high-
est early during the course of the disease and amongst indi-
viduals younger than 50 years [29, 150-153]. Race and eth-
nicity seem to modify the risk with Blacks and Hispanics
being more susceptible to the development of stroke com-
pared with Caucasian SLE patients (HR 1.31) [144]. Studies
on immediate post-ischemic stroke mortality failed to prove
a significant difference between SLE and non-SLE subjects
[145, 154]. However, Rossides et al. recently reported an
increased late mortality risk (after the first month of an
ischemic stroke) (HR 1.85) and an even greater risk of death
in cases of haemorrhagic stroke expanded even before the
Cardiovascular Disease in Lupus Current Vascular Pharmacology, 2020, Vol. 18, No . 00 7
first month from the occurrence of the event (HR 2.30)
[154].
5.3. Peripheral Artery Disease
The prevalence of peripheral artery disease in SLE as-
sessed by the ankle-brachial index ranges between 21% and
33% [155-157]. In a population-based cohort study of 10,144
patients with SLE and 10,144 controls, the risk of peripheral
artery disease was higher amongst the former (HR 9.39)
even after adjustment for traditional risk factors and GC use.
In the same study, younger (≤34 years old) and newly diag-
nosed SLE patients had a strikingly increased risk compared
to age-matched controls (HR 47.6 and 32.0, respectively)
[158]. Moreover, age seems to modify the effect of tradi-
tional risk factors on peripheral artery disease risk, thus ex-
plaining the discordance between studies evaluating predic-
tors of the disease in different age groups.
6. ASSESSMENT OF CVD RISK IN PATIENTS WITH
SLE
6.1. Traditional CVD Risk Factors and Risk Stratifica-
tion Scores
There are several validated risk prediction tools (e.g.
Framingham Risk Score, Systematic COronary Risk Evalua-
tion (SCORE), QRISK which uses multiple risk factors) that
quantify CVD risk and guide preventive measures in the
general population. However, their performance in SLE pa-
tients is considered suboptimal due to underestimating the
actual risk [27, 41, 46, 159, 160]. Modifications on the
aforementioned “conventional” risk tools, either by incorpo-
rating SLE as a separate risk factor [161] or by introducing
“multipliers” to increase the calculated score [162, 163],
have been suggested to provide a more accurate risk esti-
mate. An additional data-driven risk equation designed by
Petri et al. [164] used SLE-specific predictors of CVEs from
the Hopkins Lupus Cohort to formulate a more oriented tool.
Although extensive validation studies are lacking, a recent
comparative assessment between different risk scores in
1,887 SLE patients, showed that the modified (multiplied by
a factor of 2) Framingham risk score outperformed in terms
of both usability and sensitivity/specificity (46% and 83%,
respectively) [160].
6.2. Non-Invasive Methods for CVD Assessment
6.2.1. Coronary Artery Assessment
CAC assessed by electron beam or multislice computed
tomography, is an indicator of coronary atherosclerosis and
is associated with increased CVD risk in the general popula-
tion [165]. The prevalence of CAC is higher in SLE subjects
compared with age-matched healthy controls, even after ad-
justment for traditional risk factors [166]. In SLE subjects
followed over a 2-year period, CAC progression correlated
with age, smoking and total cholesterol levels [167].
Whether the CAC progression rate is more accelerated in
SLE and its link to future CVE has yet to be defined.
Other modalities of CV imaging such as Single Photon
Emission Computerized Tomography (SPECT) and Mag-
netic Resonance Imaging (MRI) have been used to detect
perfusion defects and coronary atherosclerosis in SLE pa-
tients [168]. Plazak et al. compared echocardiography, CAC
and SPECT findings in 50 SLE patients and found that
SPECT could reveal myocardial perfusion defects even in
patients without evident CAC. This discrepancy could be due
to that SPECT may additionally show ischemia caused by
thrombosis or vasculitis, which cannot be detected by CAC
[169]. Similarly, Varma et al. in a study evaluating cardiac
magnetic resonance (cMR) found that SLE patients had a
diffuse contrast enhancement pattern indicative of both in-
flammation and atherosclerotic plaque stability [170].
6.2.2. Carotid Plaques and cIMT
The most frequently used modality for assessing and
monitoring subclinical atherosclerosis in SLE is carotid ul-
trasound. Risk stratification through ultrasound focuses on
the detection of carotid plaques and measures of cIMT.
While these indices have been linked to increased CVD haz-
ard both in the general and the SLE population [40, 171], the
presence of plaques is generally considered a powerful pre-
dictor of future CVEs [162]. The higher prevalence of ca-
rotid plaques and increased cIMT in SLE patients has been
verified in a series of studies and meta-analyses [39, 172,
173]. Interestingly, even SLE patients without CVD history
have been shown to have significantly elevated measures of
subclinical atherosclerosis in agreement with a higher CVD
risk [40].
6.2.3. Endothelial Dysfunction and Vascular Stiffness
Endothelial dysfunction, a potentially reversible loss of
vascular homeostasis, is an early event in the atherogenic
process and precedes the formation of atherosclerotic
plaques [174]. Impairment of endothelial integrity is difficult
to be detected through non-invasive techniques, however,
endothelial-dependent flow-mediated vasodilation, measured
in the brachial artery by high-resolution ultrasound is fre-
quently used for the assessment of endothelial dysfunction
[175]. In SLE patients, the flow-mediated vasodilation is
significantly lower compared with matched controls as a
result of both traditional and disease-related risk factors
[176, 177]. In a recent meta-analysis of 25 case-control stud-
ies, the presence of DM, higher diastolic blood pressure and
renal involvement were all associated with impaired vasodi-
lation in SLE subjects [177]. Unlike the assessment of cIMT
and plaques, the validity of flow-mediated vasodilation as a
prognostic tool has not been tested in prospective cohorts,
therefore limiting its usefulness in CVD risk assessment.
In the general population, arterial stiffness measured by
PWV has been associated with an increased risk of CVD and
serves as an indicator of vascular damage [162]. Many stud-
ies have reported higher PWV measurements in SLE pa-
tients, however, absolute values may vary depending on the
modality used and the sampled population [110, 178, 179].
Although the predictive value of PWV regarding CVD in
SLE is still unknown, a recent cross-sectional study reported
that patients with higher measurements of PWV had an in-
creased CVD risk [180].
6.3. Novel Biomarkers
A number of soluble molecules associated with CVD in
SLE can potentially serve as predictive biomarkers. A com-
8 Current Vascular Pharmacology, 2020, Vol. 18, No. 00 Kostopoulou et al.
prehensive review identified >20 biomarkers associated with
CVEs, CVD mortality and premature atherosclerosis in pa-
tients with SLE (Table 3) [116]. In addition, the hypothesis
that an accurate risk stratification would probably require a
combination of molecules rather than a single biomarker has
recently been tested. In 2014, McMahon et al. found that a
panel of biomarkers comprising 4 inflammatory (inflamma-
tory HDL, leptin, homocysteine and TNF-like weak inducer
of apoptosis) and 2 traditional (age and diabetes) risk factors
yielded a better predictive value than individual biomarkers
and traditional risk factors on detecting subclinical athero-
sclerosis in SLE patients (for high-risk patients positive pre-
dictive value was 64%, negative predictive value was 94%,
sensitivity was 89%, and specificity was 79%) [181].
Moreover, a number of immune mediators found to be inde-
pendently associated with both CVD and SLE are currently
under investigation as surrogate predictive biomarkers for
atherosclerosis in SLE patients [182]. Certain circulating
immunometabolites found to be increased in SLE, promote
the activation of the inflammasomes (large multiprotein
complexes that serve as key signalling platforms) [183]. Fol-
lowing activation, inflammasomes cause the activation of
caspase-1 resulting in aberrant IL-1β production [184].
However, inhibition of the latter has been associated with
lower CVD risk in the general population [183]. Therefore,
immunometabolites could serve as putative biomarkers for
further stratification of SLE patients.
Since neutrophils are known to play a central role in the
pathogenesis of both atherosclerosis and SLE, proteins se-
creted from activated neutrophils (i.e. S100A8, A9, A8/9,
and A12) may also be considered candidate biomarkers of
CVD development in patients with SLE; these proteins have
been shown to be associated with atherosclerosis and in-
flammation [182, 185]. Similarly, follicular helper T-cells
have been shown to be implicated in the pathogenesis of
both atherosclerosis and SLE [186]. Polymorphisms of
OX40L, a trigger that promotes the activation of these cells,
have also been associated with increased susceptibility to
lupus and atherosclerosis [187]. Additional studies may
promote the utilisation of these gene polymorphisms as
novel biomarkers. Although these candidate biomarkers
might be promising, further investigations are needed to
validate these hypotheses.
7. CVD PREVENTION IN PATIENTS WITH SLE
The increased CV burden seen in SLE patients empha-
sizes the need for primary and secondary prevention strate-
gies. However, to date, there is no high-quality evidence to
guide CVD risk management. The majority of prevention
trials on SLE population have used repeated measures of
subclinical atherosclerosis and modifications of traditional
CVD risk factors as primary outcomes rather than the actual
CVD incidence, which is a clear limitation to be corrected in
future trial design. That would necessitate joint multicentre
efforts.
7.1. Non-Pharmacological Interventions and Counselling
Smoking cessation, avoidance of sedentary life and main-
tenance of a normal body mass index have all been associ-
ated with a better cardiovascular risk profile in the general
Table 3. Novel biomarkers and associations with cardiovascu-
lar disease (CVD) in patients with SLE.
Biomarker
Association with CVD
PC4d
Mortality and CVEs
CRP
Mortality and CVEs
Asymmetric dimethyl-arginine
CVEs and atherosclerosis
Homocysteinemia
CVEs and atherosclerosis
VEGF
CVEs and atherosclerosis
Whole blood viscosity
CVEs and atherosclerosis
TWEAK
CVEs and atherosclerosis
Type I interferon
CVEs
VWf
CVEs
Interleukin-6
CVEs
sCD40L
CVEs
Annexin A5
Atherosclerosis
AntiapoAI
Atherosclerosis
C3 complement
Atherosclerosis
Endocan
Atherosclerosis
Eselectin
Atherosclerosis
Fattyacidbinding protein 4
Atherosclerosis
ICAM1
Atherosclerosis
piHDL
Atherosclerosis
VCAM-1
Atherosclerosis
PC4d, Platelets bearing complem ent protein C4d; CVE, cardiovascular event; CRP, C-
reactive protein; VEGF, vascular endothelial growth factor; sCD40L , soluble CD40
ligand; TWEAK, tumor necrosis factor-like weak inducer of apoptosis; Anti-apoA-I,
anti- apolipoprotein A1; ICAM1, intercellular adhesion molecule 1; piHDL, pro-
inflammatory high-density lipoprotein; VCAM, vascular cell adhesion molecule-1.
population. In SLE patients, data regarding the effect of
smoking cessation on CVD hazards are indirect and mostly
extrapolated from studies identifying smoking as a CVD risk
factor [188]. Similarly, indirect evidence from studies on
surrogate markers of CVD suggests that physical exercise
and dietary supplementation with low-dose omega-3-
polyunsaturated fatty acids may reverse endothelial dysfunc-
tion [189, 190].
7.2. Pharmacological Interventions
7.2.1. Statins
Statins are potent inhibitors of the biosynthesis of choles-
terol that have been widely used for CVD management. In
addition to their lipid-lowering effect, they have several plei-
otropic and anti-inflammatory properties. Therefore, it was
reasonably hypothesized that SLE patients could benefit
from their dual effect both on atherosclerosis and disease
activity [191]. However, studies in SLE patients have pro-
vided inconsistent results and the protective role of statins
Cardiovascular Disease in Lupus Current Vascular Pharmacology, 2020, Vol. 18, No . 00 9
against CVD has been disputed. To date, there are no high
quality randomized controlled trials (RCTs) that have tested
or currently test the long-term effect of statins on hard out-
comes such as MI, stroke and CVD mortality in SLE. Re-
sults from 2 longitudinal studies (1 retrospective and 1 small
post-hoc analysis of an RCT) suggested a protective effect of
statins against CVEs and mortality in SLE patients [192,
193]. In line with the previous findings, patients treated with
atorvastatin had a lower rate of progression of atherosclero-
sis in 2 RCTs [194, 195]. In contrast, in a double-blinded
RCT of 200 SLE patients who were randomized to receive
atorvastatin or placebo, the progression of CAC, cIMT or
carotid plaque did not differ in the 2 groups at the end of a 2-
year follow up [167]. Similar results were obtained from
another RCT where the administration of rosuvastatin was
not found to reduce cIMT progression, and no significant
differences were observed between the treatment and control
arms [196].
7.2.2. Aspirin
There are no prospective studies of SLE patients that
examine the effect of aspirin on CVD management. How-
ever, in a retrospective study of 291 SLE patients followed
over a period of 8 years, aspirin use was found to be benefi-
cial regarding CVD prevention (HR: 0.24) [50]. For the sub-
group of SLE patients with aPL antibody positivity, a recent
meta-analysis found a significant protective effect of aspirin
against thrombotic events (pooled OR: 0.55) [197]. Given
the lack of robust evidence and the increased bleeding haz-
ard, aspirin use is recommended only for selected SLE pa-
tients with a high-risk aPL profile as defined by Tektonidou
et al. [128, 198].
7.2.3. Hydroxychloroquine (HCQ)
HCQ has been associated with a decreased clinical and
subclinical CVD hazard in a series of SLE cohorts [50, 51,
90, 109, 199]. In a recent retrospective study of SLE patients
without previous CVEs, long-term HCQ use (>5 years) was
protective against thrombosis (HR: 0.27) even after adjust-
ment for other treatments [50]. Moreover, there is increasing
evidence for a metabolic beneficial effect both in SLE and
rheumatoid arthritis patients. In a recent meta-analysis of 717
SLE patients, HCQ use was associated with a significant
decrease in total cholesterol, triglycerides, LDL-C and very-
low-density lipoprotein (VLDL) [200]. A similar effect on
lipid profile and a lower incidence of DM in HCQ users has
been recently reported in another meta-analysis of 16 studies
in patients with rheumatoid arthritis [201]. Taken together,
current evidence indicates a possible beneficial effect of
HCQ on CVD burden. However, additional trials are war-
ranted in order to validate the role of HCQ in primary and
secondary CVD prevention. An ongoing RCT
(NCT02648464) that has randomized 2500 patients with MI
to receive HCQ or placebo will compare CVE rates and de-
termine the atheroprotective role of HCQ on a wider scale.
8. RECOMMENDATIONS FOR CLINICAL PRAC-
TICE
Despite growing recognition of the CVD burden in SLE,
there is a paucity of well-designed controlled evidence to
guide management in everyday clinical practice. The 2019
update of the European League Against Rheumatism rec-
ommendations on the management of SLE underscore that
patients should be regularly assessed for both traditional and
disease-related risk factors, particularly disease activity and
duration, aPL antibodies and chronic use of glucocorticoids
[128]. Renal involvement, in particular, active nephritis typi-
cally evidenced by increased proteinuria, reduced glomerular
filtration rate, anaemia, hypalbuminaemia and hypertension,
represents a strong risk factor for accelerated atherosclerosis.
A second statement [128] in SLE recommendations under-
lines the possible use of low-dose aspirin and lipid-lowering
agents according to individual CVD risk profiles. Still, a
number of pertinent issues remain to be defined in SLE pa-
tients, such as the appropriate timing, frequency and means
for CVD risk assessment, the indications of such evaluations
and interpretation of non-invasive tools to detect subclinical
atherosclerosis, as well as optimal thresholds for traditional
atherosclerotic risk factors (e.g. LDL-C levels).
Until such data become available, one might extrapolate
from the existing recommendations for the general popula-
tion [202] while taking into consideration specific disease-
associated ‘risk enhancers’ [203]. In this respect, screening
for traditional atherosclerotic risk factors should begin early
during the disease course since many CVD events tend to
occur within the first few years due to high inflammatory
burden. Individual 10-year risk should be calculated accord-
ing to one of the existing tools (e.g. SCORE); however, ro-
bust validation in SLE patients is missing. The risk may be
further modified depending on the presence or not of lupus-
specific (e.g. chronic exposure to glucocorticoids) or other
risk-enhancing factors (e.g. family history of premature
CVD) (Fig. 1). Pending confirmation in large prospective
studies, the majority of SLE patients should be considered as
“moderate” or “high” risk patients and thus, preventative
strategies should be applied accordingly. Similar to the gen-
eral population, these include lifestyle modifications (e.g.
tobacco cessation, physical exercise), blood pressure control,
lipid-lowering agents and in selected cases (e.g. aPL-positive
patients with moderate/high CVD risk), and/or low-dose
aspirin. Although the effectiveness of these strategies in re-
ducing CVD events has not been established for SLE pa-
tients specifically, it is reasonable to assume they are equally
efficacious as in the general population. In case of uncer-
tainty over the benefit/risk ratio of pharmacological interven-
tions, non-invasive methods of CVD assessment (e.g. coro-
nary artery calcium) may be helpful for risk stratification.
Finally, focus should be directed on inflammation control
targeting to remission or the lowest achievable disease activ-
ity, use of HCQ (unless contraindicated), along with mini-
mizing (or completely withdrawing) glucocorticoids (Fig. 1).
CONCLUSIONS
Patients with SLE are at a substantially (2- to 10-fold)
increased risk for the development of CVD events, which
may occur both early and later during the course of the dis-
ease and contribute to increased morbidity and mortality.
This risk is driven by both general and disease-specific fac-
tors such as inflammatory mediators, autoantibodies and the
deleterious effects of glucocorticoids. Accordingly, SLE
10 Current Vascular Pharmacology, 2020, Vol. 18, No. 00 Kostopoulou et al.
patients warrant a regular assessment of their CV risk and
continuous consideration of general and disease-specific
risk-lowering strategies. Importantly, the collaboration be-
tween different disciplines (rheumatologists, internists, car-
diologists, nephrologists and general practitioners) is desir-
able to fine-tune risk stratification and optimize pharmacol-
ogical treatments. We anticipate the emergence of new data
pertaining to the indications and interpretation of non-
invasive tools and biomarkers for CVD risk assessment, as
well as the efficacy of risk-lowering strategies tailored to
SLE.
LIST OF ABBREVIATIONS
Anti-β2-GPI = Anti-β2-Glycoprotein I
aPL = Antiphospholipid
CAC = Coronary Artery Calcium
CHD = Coronary Heart Disease
CV = Cardiovascular
CVD = Cardiovascular Disease
Fig. (1). Cardiovascular risk assessment, stratification and preventative measures in patients with SLE. A1C, glycosylated haemoglobin
A1C; CKD, chronic kidney disease; CVD, cardiovascular disease; FRS, Framingham Risk Score; GC, glucocorticoids; HCQ, hydroxy-
chloroquine; hsCRP, high-sensitivity C-reactive protein; LDA, low disease activity; LDL-C, Low-density lipoprotein cholesterol; LPa, lipo-
protein-a; OGTT, oral-glucose tolerance test; PG, plasma glucose; SCORE, Systematic COronary Risk Evaluation; T2DM, Type 2 diabetes
mellitus. (A higher resolution / colour version of this figure is available in the electronic copy of the article).
Cardiovascular Disease in Lupus Current Vascular Pharmacology, 2020, Vol. 18, No . 00 11
CVE = Cardiovascular Event
DM = Diabetes Mellitus
GC = Glucocorticoid
HDL-C = High-Density Lipoprotein Cholesterol
HR = Hazard Ratios
HCQ = Hydroxychloroquine
ICAM-1 = Intercellular Adhesion Molecule 1
IFN = Type I Interferon
MI = Myocardial Infarction
NETs = Neutrophil Extracellular Traps
NF-κB = Nuclear Factor Kappa B
oxLDL = Oxidized Low-Density-Lipoprotein
PWV = Pulse Wave Velocity
ROS = Reactive Oxygen Species
SLE = Systemic Lupus Erythematosus
TNF-α = Tumour Necrosis Factor-α
VCAM-1 = Vascular Cell Adhesion Molecule-1
VLDL = Very Low Density Lipoprotein
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
None.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
Declared none.
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