Cardiovascular Involvement in Autoimmune Diseases

Abstract

Autoimmune diseases (AD) represent a broad spectrum of chronic conditions that may afflict specific target organs or multiple systems with a significant burden on quality of life. These conditions have common mechanisms including genetic and epigenetics factors, gender disparity, environmental triggers, pathophysiological abnormalities, and certain subphenotypes. Atherosclerosis (AT) was once considered to be a degenerative disease that was an inevitable consequence of aging. However, research in the last three decades has shown that AT is not degenerative or inevitable. It is an autoimmune-inflammatory disease associated with infectious and inflammatory factors characterized by lipoprotein metabolism alteration that leads to immune system activation with the consequent proliferation of smooth muscle cells, narrowing arteries, and atheroma formation. Both humoral and cellular immune mechanisms have been proposed to participate in the onset and progression of AT. Several risk factors, known as classic risk factors, have been described. Interestingly, the excessive cardiovascular events observed in patients with ADs are not fully explained by these factors. Several novel risk factors contribute to the development of premature vascular damage. In this review, we discuss our current understanding of how traditional and nontraditional risk factors contribute to pathogenesis of CVD in AD.

Full text

Review Article
Cardiovascular Involvement in Autoimmune Diseases
Jenny Amaya-Amaya,1,2 Laura Montoya-Sánchez,1,2 and Adriana Rojas-Villarraga1,2
1Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario,
Carrera 24 No. 63C-69, 11001000 Bogot´
a, Colombia
2Mederi, Hospital Universitario Mayor, Calle 24 No. 29-45, 11001000 Bogot´
a, Colombia
Correspondence should be addressed to Adriana Rojas-Villarraga; adrirojas@gmail.com
Received  March ; Accepted  May ; Published  July 
Academic Editor: Miguel A. Gonz´
alez-Gay
Copyright ©  Jenny Amaya-Amaya et al. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Autoimmune diseases (AD) represent a broad spectrum of chronic conditions that may aict specic target organs or multiple
systems with a signicant burden on quality of life. ese conditions have common mechanisms including genetic and epigenetics
factors, gender disparity, environmental triggers, pathophysiological abnormalities, and certain subphenotypes. Atherosclerosis
(AT) was once considered to be a degenerative disease that was an inevitable consequence of aging. However, research in the last
three decades has shown that AT is not degenerative or inevitable. It is an autoimmune-inammatory disease associated with
infectious and inammatory factors characterized by lipoprotein metabolism alteration that leads to immune system activation
with the consequent proliferation of smooth muscle cells, narrowing arteries, and atheroma formation. Both humoral and cellular
immune mechanisms have been proposed to participate in the onset and progression of AT. Several risk factors, known as classic
risk factors, have been described. Interestingly, the excessive cardiovascular events observed in patients with ADs are not fully
explained by these factors. Several novel risk factors contribute to the development of premature vascular damage. In this review,
we discuss our current understanding of how traditional and nontraditional risk factors contribute to pathogenesis of CVD in AD.
1. Introduction
Autoimmune diseases (ADs) represent a broad spectrum
of chronic conditions that may aict specic target organs
or multiple systems with a signicant burden on quality of
life. ese conditions have common mechanisms including
genetic and epigenetic factors, gender disparity, environmen-
tal triggers, pathophysiological abnormalities, and certain
subphenotypeswhicharerepresentedbytheautoimmune
tautology [–]. Atherosclerosis (AT) was once considered to
be a degenerative disease that was an inevitable consequence
of aging. However, research in the last three decades has
shown that AT is not degenerative or inevitable. It is an
autoimmune-inammatory disease associated with infec-
tious and inammatory factors characterized by lipoprotein
metabolism alteration that leads to immune system acti-
vation with the consequent proliferation of smooth mus-
cle cells, narrowing arteries, and atheroma formation [].
Both humoral and cellular immune mechanisms have been
proposed to participate in the onset and progression of
atheromatous lesions [].
In recent years, many reports have focused on the
immunological background of AT, and there is no longer
any doubt that it shares several autoimmune pathways [,].
erefore, it is not surprising to nd an accelerated AT in
quite a lot of ADs. Several risk factors, known as classic
risk factors, have been described since the Framingham
heartstudy.Overtime,theseleadtoendothelialdysfunc-
tion, subclinical AT, and cardiovascular (CV) events [–].
Interestingly, the excessive CV events observed in patients
with ADs are not fully explained by these factors. Several
novel risk factors contribute to the development of premature
vascular damage. Sarmiento-Monroy et al. [],basedona
model of rheumatoid arthritis (RA), proposed a classication
for nontraditional risk factors in ADs, which divided them
into genetic determinants, AD-related, and miscellaneous
[,]. erefore, a complex interaction between traditional
and disease-specic traits leads to a premature AT process in
Hindawi Publishing Corporation
BioMed Research International
Volume 2014, Article ID 367359, 31 pages
http://dx.doi.org/10.1155/2014/367359

BioMed Research International
autoimmunity. All of these pathways may possibly converge
into a shared proatherogenic phenotype []. While ADs
are characterized by a high degree of cardiovascular disease
(CVD), there are several subphenotypes such as arterial
hypertension (HTN); coronary artery disease (CAD): angina,
ischemic heart disease (IHD), and myocardial infarction
(MI);congestiveheartfailure(CHF);peripheralvascular
disease (PVD); le ventricular diastolic dysfunction (LVDD);
cerebrovascular disease (cerebrovascular accidents (CVAs);
transient ischemic attacks (TIAs)); thrombosis: deep vein
thrombosis (DVT), pulmonary embolism (PE); and subclin-
ical AT.
In this paper, we discuss our current understanding of
how traditional and nontraditional risk factors contribute
to pathogenesis of CVD in ADs. It has become evident
over the last few years that some ADs are characterized by
common pathogenic mechanisms and high rates of morbidity
and mortality that are mainly CVD-related. e increased
CV mortality in the  rheumatic disorders studied the
most (i.e., RA, systemic lupus erythematosus (SLE), and
antiphospholipid syndrome (APS)) appears to be caused by
vascular damage secondary to accelerated AT. However, the
burden of CV involvement in other ADs (Sj¨
ogren’s syndrome
(SS) and systemic sclerosis (SSc)) appears to be lower and it
is characterized by specic risk factors in addition to those
shared with the general population.
2. Methods
Studies were identied via a MEDLINE search using the
following medical subject heading (MeSH) terms: “Arthri-
tis, Rheumatoid” OR “Lupus Erythematosus, Systemic” OR
“Antiphospholipid Syndrome” OR “Sj¨
ogren’s Syndrome” OR
“Scleroderma, Systemic” AND “Cardiovascular Diseases.”
Each group was cross-referenced with the following MeSH
terms/key words: “risk factors,” “traditional risk factors,” “clas-
sic risk factors,” “nontraditional risk factors,” and “novel risk
factors.” Each term was counted for the greatest number of
results. Limits regarding language (i.e., English), age (i.e.,
adults), and humans were taken into account. Assessment for
inclusion of studies was done independently by two blinded
reviewers (JAA-LMS). Disagreements between them were
resolved by consensus using predened eligibility criteria,
from inception up to February .
2.1. Study Selection, Data Extraction, and Quality Assessment.
Abstracts and full-text articles were reviewed in search of
eligible studies. A study was included if (a) the abstract was
available, (b) it contained original data, (c) it used accepted
classication criteria for each AD, (d) it measured CV risk
factors, and (e) it examined clinical endpoints. Articles
were excluded from the analysis if they dealt with juvenile
pathologiesorweredoneonanimalmodels.Studieswerealso
excluded if they were reviews or case reports, if they discussed
topics not related to CVD in AD, if they did not meet the
inclusion criteria, if they had insucient data, or if they had
results that showed lack of statistical signicance. Likewise,
the two blinded reviewers (JAA, LMS) looked for duplicates,
excluded them, and organized selected articles. Only novel
and classic risk factors [,] with statistical signicance
were included.
3. Results
ere were , articles identied in PubMed. Of these,
, were identied as duplicates, lacking data or signif-
icant statistical associations. A total of  full-text arti-
cles were assessed for eligibility. Only  articles were
included for methodological analysis. Finally,  articles
that had interpretable data and fullled the eligibility criteria
were included. Several traditional cardiovascular risk factors
such as dyslipidemia, hyperhomocysteinemia, smoking, and
TDM had been reported. Many studies were associated
with nontraditional risk factors such as genetic markers,
autoantibodies, duration of the diseases, markers of chronic
inammation, polyautoimmunity, and familial autoimmu-
nity. ese factors and their associations are depicted in
Tables ,,,,andandinFiguresand .
3.1. Rheumatoid Arthritis. A broad spectrum of subpheno-
types and mortality due to CVD, including stroke, HTN, IHD,
intima-media thickness (IMT), CAD, MI, PVD, thrombosis,
and LVDD were described in RA, and the general prevalence
range is %–% [–]. Table  shows the main traditional
and nontraditional risk factors associated with CVD in RA,
and Figure  exemplies these associations.
3.2. Systemic Lupus Erythematosus. CVDisatleastdou-
bled among SLE patients compared to other populations
and mortality is also increased []. CVD burden in SLE
includes carotid plaques, MI, angina, CHF, stroke, IMT, PVD,
pericarditis, and others discussed below [,–]. Tab l e 
shows traditional and nontraditional risk factors associated
with CVD in SLE.
3.3. Antiphospholipid Syndrome. e prevalence of CVD
ranges from . to %, and it could increase up to % in
patients with antiphospholipid antibodies (APLA). On the
otherhand,theprevalenceofCVDinasymptomaticAT
reaches % compared to % in SLE patients and % in
normal controls [,]. In the Euro-Phospholipid cohort,
MI was the presenting manifestation in .% of the patients,
anditappearedduringtheevolutionofthediseasein.%of
the cohort []. Cardiac manifestations may be found in up to
%, but signicant morbidity appears in only –% of these
patients. Most of these manifestations are explicable on the
basis of thrombotic lesions either in the coronary circulation
or on the valves []. Tabl e  shows the main traditional and
nontraditional risk factors associated with CVD in APS.
3.4. Sj¨
ogren’s Syndrome. CV events occurred in –.% with
stroke, MI, CVA, DVT, and arrhythmias [–]being
the most frequent. Furthermore, tricuspid regurgitation,
injured mitral and aortic valves, pulmonary hypertension,
and increased le ventricular mass have also been reported

BioMed Research International 
T : Traditional and nontraditional risk factors associated with CVD and RA.
Risk factor Comments References
Traditional risk factors
Obesity
(i) Insulin resistance due to release of inammatory cytokines such as TNF-𝛼.
(ii) Increased coronary calcication due to insulin resistance.
(iii) ↑Abdominal fat.
[,,]
Dyslipidemia (i) ↓HDL and ↑LDL and TAG.
(ii) Induces higher risk of IHD. [,,,–]
Advanced age
(i) Old age prompts structural and functional deterioration in the heart and
vessels structure.
(ii) Senescent immune system is normally associated with phenotypical and
functional changes.
[,]
Family history of CVD Heritable factors: HTN and familial hypercholesterolemia. [,,]
TDM
(i) Coexistence of TDM and RA increases three times the risk of developing
CVD.
(ii) Abdominal obesity, antihypertensive medication, disease activity, and use of
GCs aect glucose metabolism in RA patients.
[,,]
Hyperhomocysteinemia
(i)ItisconsideredasbiomarkerforATandariskfactorrelatedtoCADand
CVA.
(ii) ere is still controversy about whether hyperhomocysteinemia is a causative
agent of cardiovascular damage or only an epiphenomenon of inammation.
(iii) A high prevalence of this biomarker had a statistical association with male
gender and higher radiological damage.
[,,–]
Metabolic syndrome
(i) Alteration in the production of cytokines and proinammatory adipokines
leads to an increasing activity of RA and an accelerating AT.
(ii) It was related to pain and functional status, suggesting disease activity
(iii) Increased prevalence of waist circumference, blood pressure, and fasting
glucose (i.e., worse prognosis).
(iv)Increasedepicardialadiposetissuevolume.
[,,,,
–]
Sedentary lifestyle
(i) Patients are less physically active than controls due to pain, stiness,
deformity, and impaired mobility.
(ii) Impairment of altered lipid pattern.
[,,]
Hypertension Increases the risk of IHD and CVA with important impact on mortality. [,,]
Male gender Cardiovascular disease is more frequent in male gender. [,,–]
Smoking
(i) Smokers with RA have worse prognosis than nonsmokers RA patients in
terms of RF titers, disability, radiological damage, CVD, and treatment response.
(ii) Premature CVD mortality.
[,,]
Nontraditional risk factors
Genetic
HLA-DRB SE
(i) Its alleles are related to chronic inammation, high disease activity, EAMs,
endothelial dysfunction, increasing CV events, AT plaque, and premature
mortality. Some of them are independent of autoantibody status.
(ii) Being a carrier of a single copy of HLA-DRB SE was signicantly associated
with an increased risk of atherosclerotic plaque in RA Colombian patients.
[,,–]
Non-HLA
(i) Polymorphisms in endothelin-1, MTH-FR, TRAF1/C5, STAT4, factor XIIIA,
PAI -1, TNFR-II, LT-A, LGALS2, TGF-𝛽,GSTT1,ACP1,andNF-𝜅𝛽1genes may be
contributed to CVD risk and adverse outcome.
(ii) Interaction between smoking and polymorphism in the VEGFA gene is
associated with IHD and MI in RA patients.
(iii) e IL6-174 gene polymorphism may play a role in the development of
subclinical atherosclerosis in patients with RA.
(iv) TNFA rs (G>A) gene polymorphism is associated with
predisposition to CV complications in RA patients. is predisposition seems to
be restricted to individuals carrying the SE.
(v) Genetically determined high serum levels of MBL and high serum levels of
agalactosylIgGareassociatedwithincreasedriskofIHD,MI,andpremature
death.
[,,–]

BioMed Research International
T : C ont i n u e d .
Risk factor Comments References
RA per se
(i) Independent factor for developing MI and accelerated AT.
(ii) It represents a broad spectrum of conditions related with the autoimmune
nature of the disease.
[,,]
Familial
autoimmunity
(i) It confers additional susceptibility to CVD in RA patients, as well as presence
of atherosclerotic plaque, radiographic progression, high disease activity, and
persistent inammation.
(ii) Increased frequency of HLA-DR.
[,]
Glucocorticoids
(i) It targets inammation but its adverse eects include carotid plaques, arterial
stiness, decreased insulin sensitivity, elevated lipid levels, hypertension, and
CVD.
(ii) Patients that are treated with a daily dose >.  m g / d a y a p p e a r e d t o h a v e t w i c e
as the risk of heart disease as patients that are in nonsteroidal treatment.
(iii) e increased mortality in patients under low-dose oral GC for more than 
years has been related mainly to CVD.
[,,,,,
–]
Long duration of
disease
(i) Disease duration over  years was signicantly associated with increased risk
of atherosclerotic plaque in Colombian population.
(ii) Patients with prolonged RA have more atherosclerosis than patients of the
same age with more recent disease onset. ey have more extensive subclinical
atherosclerosis or CAC, independent of other CHD risk factors.
(iii) RA duration is independently associated with LVDD suggesting the impact
of chronic autoimmune inammation on myocardial function.
[,,,,
–]
Polyautoimmunity It was associated with CVD in Colombian population. []
RA-
associated Autoantibodies
(i) Immune complexes from RF can be deposited in the endothelium generating
endothelial dysfunction and AT through inammatory reactions.
(ii) RF-positive patients were at increased risk of CV events following exposure
to GC.
(iii) RF titers were independently predictive of endothelial dysfunction and
increased mortality in RA.
(iv) Anti-CCP and RF-IgM were related to impaired endothelial function
independent of other CV risk factors, and they are independently associated with
impaired le ventricular relaxation and development of IHD.
(v) Anti-ox-LDL, ACLA, APLA, and anti-ApoA- are associated with early
atherosclerotic changes and future thrombotic events.
(vi) e presence of ACLA and an altered lipid prole may represent an
important risk factor for thrombotic events in patients aected by RA. Anti-PC,
anti-HSP /, and anti-MDA-LDL may have independent roles in subclinical
AT.
(vii) Anti-ox-LDL was strongly related with the degree of inammation and
carotid plaque and may predispose to a higher risk for CVD, as they were
independently associated with subclinical atherosclerosis.
(viii) High levels of anti-MCV and LDL-immune complexes are risk factors for
increased AT and are associated with inammation.
[,,,–
]
Chronic
proinammatory
state
(i) It may accelerate atherogenic processes and microvascular dysfunction:
accentuation of known pathways of plaque formation.
(ii) Inammatory stimuli may be involved in the initiation of CHF among
patients with RA.
(iii) Markers of chronic inammation (i.e., current and cumulative
inammation) such as CRP, ESR, TNF-𝛼, IL-, IL-, and haptoglobin are present
in endothelial activation and increased in carotid IMT, carotid plaque, CAD, CV
complications, and mortality.
(iv) Both established CV risk factors and manifestations of RA inammation
contribute signicantly to carotid atherosclerosis in RA and may modify one
another’s eects.
[,,,,,
,,–]
High disease
activity
(i) Higher activity index is associated with CV events and mortality.
(ii) DAS- was a signicant predictor of major adverse CV events and mortality.
(iii) e occurrence of new CV events in very early RA was explained by
traditional CV risk factors and was potentiated by high disease activity.
[,,,,
,]

BioMed Research International 
T : C ont i n u e d .
Risk factor Comments References
EAMs
(i) Increases three times the risk of having CVD and these patients, also present
greater IMT.
(ii) CVD is considered a severe EAM of the disease.
(iii) Severe EAM manifestations are associated with an increased risk of CVD
events. Systemic EAM disease is a major determinant of CVD morbidity.
[,,,,
–]
Household duties Employed women are somewhat less physically disabled than their unemployed
counterpart (including housework). [,,]
Hypothyroidism Fourfold higher risk of CVD even aer adjustment for other traditional CV risk
factors. [,,]
Others rombogenic and
other factors
(i) State of hypobrinolysis is associated with CVD progression and levels of von
Willebrand factor, PAI-, and tissue type plasminogen
(ii) Other biomarkers have been related to CVD: OPG, OPN, sPTX-,
periodontal disease, hepcidin, seric uric acid, para-articular bone loss, and MBL.
[,,,,
–]
Rheumatoid
cachexia
Associated with high levels of LDL, low levels of atheroprotective anti-PC, and
high frequency of HTN in RA patients.
Patients with RA experience a .% increase in body fat mass for a given BMI
compared to healthy individuals.
[,,,]
ACP: acid phosphatase locus; anti-ApoA-: anti-apolipoprotein A- antibodies; ACLA: anticardiolipins antibodies; anti-𝛽GPI: anti-𝛽 glycoprotein I
antibodies; anti-CCP: anti-cyclic citrullinated peptide antibodies; anti-HSP: anti-heat shock proteins antibodies; anti-MCV: anti-modied citrullinated
vimentin antibodies; anti-MDA-LDL: anti-malondialdehyde modied LDL antibodies; anti-oxLDL: anti-oxidized low-density lipoprotein antibodies; APLA:
antiphospholipid antibodies; AT: atherosclerosis; BMI: body mass index; CAC: coronary artery calcication; CAD: coronary artery disease; anti-PC: anti-
phosphorylcholine antibodies; CRP: c-reactive protein; CV: cardiovascular; CVA: cerebrovascular accident; CVD: cardiovascular disease; DAS: disease
activity index; EAM: extra-articular manifestations; ESR: erythrocyte sedimentation rate; GCs: glucocorticoids; GSTT-: glutathione S-transferase, HDL: high-
density lipoprotein; HTN: hypertension; IHD: ischemic heart disease; IMT: intima-media thickness; LDL: low-density lipoprotein; LGALS: galectin-; MBL:
mannose-binding lectin; MI: myocardial infarction; LT-A: lymphotoxin-A; MTH-FR: methylene tetrahydrofolate reductase; NF𝜅B: nuclear factor of kappa
light polypeptide gene enhancer in B-cells ; NO: nitric oxide; OPG: osteoprotegerin; OPN: osteopontin; PAI-: plasminogen activator inhibitor type-; IL:
interleukin ; activator inhibitor type-; RA: rheumatoid arthritis; RF: rheumatoid factor; SE: shared epitope; sPTX-: serum pentraxin-; STAT:signal
transducer and activator of transcription ; TDM: type  diabetes mellitus; TAG: triglycerides; TGF-𝛽: transforming growth factor beta; TNF-𝛼:tumor
necrosis factor-𝛼; TNFR-II: tumor necrosis factor receptor II; TRAF/C: TNF receptor-associated factor ; VEGF-A: vascular endothelial growth factor A.
[]. Table  shows the main traditional and nontraditional
risk factors associated with CVD in SS.
3.5. Systemic Sclerosis. A broad spectrum of subphenotypes
and mortality due to CVD have been described. Mortality
in patients with SSc caused by CVD is between  and %
and, despite being similar to the general population, it occurs
a decade earlier (). CV symptoms are found in % of
theSScpatientswhileasymptomaticpatientswithcoronary
artery calcication (CAC) accounted for approximately .%
in diuse SSc and % in limited SSc [–]. However,
Doppler results have shown that % of the patients have
carotid stenosis, compared to % of the control patients [].
Arrythmias, coronary spasm, MI, PVD, CVA, CAD, LVDD,
and myocardial brosis [,,,–] are also dened.
Table  shows the main traditional and nontraditional risk
factors associated with CVD in SSc.
4. Discussion
is review adds further evidence about high frequency of
CVD in patients with ADs and their traditional (i.e., dys-
lipidemia, abnormal BMI, and male) and nontraditional risk
factors (i.e., steroids, household duties, and autoantibodies)
[,]. It also highlights the impact on public health and the
need to develop new strategies in prediction, prevention, and
treatment. rough the review, several factors and outcomes
related to CVD were also identied.
4.1. Physiopathology of Atherosclerosis in AD. AT is a multi -
factorial, chronic, and inammatory disease that had been
traditionally viewed as a lipid-based disorder aecting the
vessel walls. Nowadays, this theory has been modied, and
itisknownthatallarmsoftheimmunesystemtakepart
in atheroma formation. e increased understanding of the
mechanisms promoting vascular damage has recently led
to a sharper focus on proinammatory pathways, which
appear to play a key role in the development and propagation
ofthedisease.us,someofthemechanismsthatdrive
atherosclerotic plaque formation, and therefore CVD, are
shared with several ADs although each disease may have
particular immunological aberrations that provide specic
proatherogenic pathways [–,,,–]. is process is
characterizedbytheaccumulationoflipidparticles,immune
cells, autoantibodies, autoantigens, and the multiple pro-
duction of inammatory cytokines such as tumor necrosis
factor-𝛼(e.g.,TNF-𝛼). All these components lead to a gradual
thickening of the intima layer, thus causing a decrease in
elasticity, narrowing of the arterial lumen, reduction of
bloodow,plaquerupture,and,nally,theCVevent[,
]. e systemic inammatory response that characterizes
AT also involves acute-phase reactants such as erythrocyte

BioMed Research International
T : Traditional and nontraditional risk factors associated with CVD and SLE.
Risk factor Comments References
Traditional risk factors
Hypertension
(i)ItismorefrequentamongSLEpatientsthanpeoplewith
noninammatory disorders
(ii) It acts as CVD subphenotype as well as a risk factor and also
inuences the risk of death by CVD. It increases the risk of thrombosis
and it is more prevalent among SLE patients with atherosclerotic plaque.
(iii) Lupus patients with abnormal myocardial scintigraphic ndings and
hypertension, as risk factor for CAD, had a higher risk of abnormal
ndings on coronary angiography.
[,,–]
TDM
(i) TDM has inuence on abnormal myocardial perfusion in
asymptomatic patients with SLE.
(ii) Alterations in glycemic prole were associated with traditional risk
factors for CHD and lupus characteristics, including CVD, damage
index, and renal involvement.
(iii) Patients with SLE and TDM were at increased risk of thrombosis,
atherosclerotic plaque, and CAC. is risk remains elevated throughout
the course of the disease.
[,,–
,,,,]
Dyslipidemia
(i) e main risk factor for death in SLE was heart involvement, which
was inuenced by dyslipidemia. e inammatory context of SLE leads
to dysregulation of lipid metabolism pathways →increased risk of
atherosclerotic disease and thrombotic events.
(ii) Alterations in lipid prole were a risk factor for endothelial
dysfunction, myocardial perfusion abnormalities, and premature CAC
and CAD in young women.
[,,,–
,,,,
–]
Male gender
(i) Male gender was a risk factor for developing severe organ damage
(CVD) and mortality in SLE patients.
(ii) Males with SLE were at increased risk of thrombosis and CAC. is
risk remains elevated throughout the course of the disease.
(iii) Patients had more peripheral vascular and gonadal involvement.
[,,,,,
,,]
Metabolic syndrome
(i) SLE patients had a high prevalence of MetS that directly contributes
to increasing inammatory status and oxidative stress.
(ii) MetS were associated with traditional risk factors for CAD and lupus
characteristics, including CVD, damage Index, and renal involvement.
(iii) HCQ use proved to be protective against MetS.
(iv) Insulin sensitivity and intima-media thickness are altered in SLE
patients, especially those with MetS comorbidity with an associated
increase in disease activity and damage
(v) Renal lupus, higher corticosteroid doses, Korean and Hispanic
ethnicity are associated with MetS in SLE patients
[,,,–
]
Obesity
(i) Patients with SLE who had excess weight present distinct
clinical-laboratory ndings, sociodemographic characteristics, and
treatment options when compared to normal weight patients. Excess
weight is associated with SLE poor prognosis.
(ii) Increased weight has inuence on abnormal myocardial perfusion in
asymptomatic SLE patients.
(iii) SLE patients with high BMI have increased QT interval parameters,
presence of CAD, and carotid plaque. is prolongation may lead to an
increased CV risk.
[,,,,,
,,,–
]
Smoking
(i) Smoking is an important determinant in the occurrence of
thrombotic (central and/or peripheral, arterial and/or venous) events in
SLE patients, due to atherosclerotic plaque and thrombosis
(ii) Smoking habits inuence abnormal myocardial perfusion in
asymptomatic SLE patients.
(iii) Smoking was a risk factor for premature CAC and CAD in young
women with SLE.
[,,–
,,,,
,,,]

BioMed Research International 
T : C ont i n u e d .
Risk factor Comments References
Advanced age Several traditional risk factors, including age, appear to be important
contributors to atherosclerotic CV damage.
[,,,,
]
Menopausal status
(i) High percentage of SLE patients with abnormal angiographic ndings
was in postmenopausal status.
(ii) ere is high prevalence of premature menopausal status as risk
factor for CVD.
(iii) Postmenopausal status was a risk factor for premature CAC in
young women with SLE.
(iv) Postmenopausal women had a higher prevalence of subclinical AT
and abnormal myocardial perfusion in asymptomatic patients with SLE.
[,,,–
,,,]
Family history of CVD
(i) Familial history of CVD was an independent risk factor for
atherosclerotic process and premature CAC in women with SLE.
(ii) Family history of CVD inuences abnormal myocardial perfusion in
asymptomatic SLE.
[,,,,,
]
HRT
HRT use was not associated with the occurrence of vascular arterial
events in the LUMINA patients. HRT use in women with SLE should be
individualized, but data suggest its use may be safe if APLA are not
present or vascular arterial events have not previously occurred.
[]
Hyperhomocysteinemia (i) Hyperhomocysteinemia was a risk factor for CAC in SLE patients.
(ii) e presence of polyautoimmunity and hyperhomocysteinemia was
a risk factor for thrombotic events.
[,]
Nontraditional risk factors
Genetic
determinants
Ancestry
ere are several dierences regarding clinical (including CVD),
prognostic, socioeconomic, educational, and access to medical care
features in GLADEL cohort according to ancestry (White, Mestizo, and
African-LA).
[,,]
Non-HLA
(i) A SNP in FGG rs demonstrated association with arterial
thrombosis risk in Hispanic American patients with SLE.
(ii) e CRP GT20 variant is more likely to occur in African-American
and Hispanic SLE patients than in Caucasian ones, and SLE patients
carrying the GT allele are more likely to develop vascular arterial
events (LUMINA multiethnic cohort).
(iii) TRAF3IP2 may aect disease phenotype and, particularly, the
occurrence of pericarditis.
(iv) ere is a considerable genetic component for CAD with IRF8 as a
strong susceptibility locus.
[,–]
Polyautoimmunity
(i) e presence of APS and its characteristic antibodies was the major
independent contributor to the development of thrombotic events and
severe organ damage.
(ii) Polyautoimunity (e.g., APS) may suggest concerted pathogenic
actions with other autoantibodies in the development of thrombotic
events.
[,,,–]
SLE per se
(i) SLE diagnosis is associated with carotid plaque formation and
development of CV event.
(ii) High percentage of patients with abnormal angiographic ndings
had higher ACR criteria number for SLE.
(iii) Endothelial dysfunction is associated with traditional and
SLE-specic risk factors, and early data suggest reversibility of
endothelial dysfunction with therapy.
[,,,]
Autoantibodies
(i) One of the independent predictors of vascular events in a multiethnic
US cohort (LUMINA) was the presence of any APLA.
(ii) Anti-𝛽GPI antibodies were strongly associated with thrombosis.
e decrease of anti-𝛽GPI levels at the time of thrombosis may indicate
a pathogenic role.
[,,,,–
]

BioMed Research International
T : C ont i n u e d .
Risk factor Comments References
(iii) e higher frequency of aPT found in thrombosis may suggest
concerted pathogenic actions with other autoantibodies in the
development of thrombotic events.
(iv) Patients with ACLA seem to be at an increased risk for arterial and
venous thrombotic events and showed an association with
echocardiographic abnormalities.
(v) ere was correlation between lupus anticoagulant and thrombotic
events in Brazilian lupus patients.
Immune cells
aberrations
(i) Complement xing activity of ACLA seems to be relevant in
thrombotic venous events.
(ii) Activation of endothelial MMP- by MMP- contained in NETs as
an important player in endothelial dysfunction and MMP- as a novel
self-antigen in SLE. ese results further support that aberrant NET
formation plays pathogenic roles in SLE.
[,]
Inammatory
markers
(i) Increased ESR and CRP were independently associated with MetS
and vascular events in lupus patients. [,,]
Endogenous
dyslipidemia
(i) HDL distribution and composition (−HDLb, +HDLb, and
+HDLc) were abnormal in SLE patients.
(ii)LowHDLlevelsandincreasedTAGlevelswereassociatedwithAT
by cIMT measurement.
(iii) SLE pattern of dyslipoproteinemia may increase the risk of
developing CAD.
[–]
SLE-associated Disease activity
(i) Disease activity (SLAM) is an important determinant in the
occurrence of thrombotic (central and/or peripheral, arterial and/or
venous) events in the LUMINA cohort.
(ii) SLEDAI scores were positively correlated with abnormal BMI and
WC.
(iii) Higher disease activity (i.e., SLEDAI and SLICC) is a predictor of
CAC and it was independently associated with MetS, myocardial
perfusion abnormalities, and thrombosis. Higher score of SDI was
associated with atherosclerotic plaque in Brazilian SLE patients.
(iv) SLE patients have a lipid prole abnormality which is aggravated by
disease activity and may reside in a defect of VLDL metabolism.
(v) ere is a close link between MeTS and SLICC/ACR score with
increased aortic stiness.
[,,,,
,,,–
]
Organ damage
(i) Baseline and accrued damage increase mortality risk (including due
to CVD).
(ii) Measured by SDI, patients had more peripheral vascular
involvement.
(iii) MetS was associated both with traditional risk factors for CHD and
with lupus characteristics including damage index.
(iv) ere was a correlation between IMT and revised damage index
(SLICC).
(v) Atherosclerotic CV damage in SLE is multifactorial, and
disease-related factors (including CRP levels and SDI at baseline) appear
to be important contributors to such an occurrence.
[,,,,
,]
Long duration
(i) Longer duration of SLE was associated with atherosclerotic plaque
and CV events.
(ii) A correlation between IMT and duration of the disease was found in
SLE patients.
(iii) Disease duration was an independent predictor for premature CAC
in young women with SLE.
[,,,]
Medications
(i) PDN > mg/day was independently associated with MetS and IMT
in SLE patients.
(ii) IHD was observed in SLE patients: those with long term steroid
therapy and those with frank episodes of vasculitis.
[,,]

BioMed Research International 
T : C ont i n u e d .
Risk factor Comments References
Vascul opathy
(i) Current vasculitis was associated with abnormal myocardial
scintigraphy.
(ii) Patients with SLE and RP seem to be at increased risk for arterial and
venous thrombotic events. IHD was observed in SLE patients: those with
long term steroid therapy and those with frank episodes of vasculitis.
[,,]
Renal involvement
MetS were associated with traditional risk factors for CHD and lupus
characteristics, including damage index and renal involvement
(nephritic syndrome).
[]
BMD Decreased BMD was an independent predictor for premature CAC. []
Miscellaneous Sociodemographic
factors A low education and monthly income were associated with MetS. []
(OH) levels Lower baseline (OH) vitamin D levels are associated with higher risk
for CVD and more active SLE at baseline. [,,]
(OH) vit D: -hydroxy vitamin D; ACLA: anticardiolipins antibodies; ACR: American College of Rheumatology; anti-𝛽GPI: anti-beta  glycoprotein 
antibodies; aPT: antiprothrombin antibodies; APLA: antiphospholipid antibodies; APS: antiphospholipid syndrome; AT: atherosclerosis; BMD: bone mineral
density; BMI: body mass index; CAC: coronary artery calcication; CAD: coronary artery disease; cIMT: carotid intima-media thickness; CRP: C-reactive
protein; CV: cardiovascular; CVD: cardiovascular disease; ESR: erythrocyte sedimentation rate; GLADEL: Grupo Latino Americano De Estudio de Lupus;
HDL: high-density lipoprotein cholesterol; HRT: hormone replacement therapy; IHD: ischemic heart disease; IMT: intima-media thickness; IRF: interferon
regulatory factor ; LA: Latin America; LDL: low-density lipoprotein cholesterol; LUMINA: Lupusin Minorities: Nature versus Nurture cohort; MetS:metabolic
syndrome; MMP: matrix metalloproteinases; NETs: netosis bo dies; PDN: prednisolone; RP: Raynaud’s phenomenon; TAG: triglycerides; TRAF: tumor necrosis
factor receptor-associated factors; TDM: type  diabetes mellitus; SDI: SLE damage index; SLAM: systemic lupus activity measure; SLE: systemic lupus
erythematosus; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index; SLICC: Systemic Lupus International Collaborating Clinics score; SDI: SLICC
damage index; SNP: single-nucleotide polymorphism; VLDL: very low-density lipoprotein cholesterol; WC: waist circumference.
sedimentation rate (ESR) and c-reactive protein (CRP) [–
].
Endothelial dysfunction is the rst step leading to AT and
has been associated with both traditional and nontraditional
risk factors related to several ADs. Other factors involved
are high concentrations of angiotensin II, increased smooth
muscle hypertrophy, peripheral resistance, and oxidation of
low-density lipoprotein cholesterol (LDL) as well as ele-
vated plasma homocysteine concentrations and genetic alter-
ations [–]. us, the dierent forms of injury increase
endothelium adhesiveness for leukocytes or platelets as well
as endothelium permeability with the expression of multi-
ple vascular cell adhesion molecules (VCAM), intercellular
adhesion molecules- (ICAM-), selectins, and chemokines
[,,]. In addition to their dierentiation, macrophages
(M𝜙) are associated with upregulation of toll-like receptors,
which enhances a cascade of M𝜙activation and release of
vasoactive molecules such as nitric oxide (NO), reactive
oxygen, endothelins, and proteolytic enzymes. All of them
lead to the plaque destabilization and the increased risk for
rupture [,,–].
T cells, predominantly lymphocyte T helper  (),
are also recruited to the subendothelial space.  cells
dominate over lymphocyte T helper  () as well as
their anti-inammatory mediators (i.e., IL-, -, and -).
is kind of reaction is greater in several ADs with a high
production of TNF-𝛼, IL-, IL-, IL-, and so forth, which,
in combination, activates T cells even more and favors
smooth muscle cell migration, proliferation, and foam cell
formation [,,,]. Furthermore, activated M𝜙express
human leukocyte antigen (HLA) II that allows them to
present antigens to T lymphocytes. Smooth muscle cells from
the lesions also have class II HLA molecules on their surfaces
and can also present antigens to T cells such as ox-LDL
and heat shock proteins (HSP) / [,]. e immune
regulatory molecule CD ligand and its receptor CD are
expressed by M𝜙, T cells, endothelium, and smooth muscle.
Both are upregulated in lesions of AT and thus provide
further evidence of immune activation [,]. As ox-LDL
is a macromolecule with many potential autoantigens, it is
possible that antioxidized low-density lipoprotein antibodies
(anti-oxLDL) represent a family of autoantibodies against
dierent autoantigens involved in CVD. us, the clinical
impact of these autoantibodies might vary. However, there
are reports showing that elevated anti-oxLDL titers have been
detected in patients with early-onset PVD, severe carotid
AT,CHF,CAD,MI,anddeath[,]. is suggests a
proatherogenic role for these autoantibodies and supports a
key role for them in the progression of AT [,,].
Beta- glycoprotein- (𝛽GPI) is considered to be an
autoantigen in APS. Moreover, it is abundantly expressed
within the subendothelial regions and in the intima-media
layers at the border of atherosclerotic plaque. Both IgM
and IgG anti-𝛽GPI levels are elevated in patients with AT
and other inammatory conditions []. 𝛽GPI is the actual
autoantigen for most anticardiolipin antibodies (ACLA), a
group of antibodies with procoagulant activity. e associ-
ation between APLA, AT, and thrombosis can also be seen
outside the setting of autoimmunity. us, ACLA promote
AT by attracting monocytes into the vessel wall and inducing
monocyte adherence to endothelial cells. All of this is medi-
ated by adhesion molecules such as ICAM-, VCAM-, and E-
selectin [,]. e APLA should be considered more than an
AT marker since they can enhance AT and are proatherogenic

 BioMed Research International
T : Traditional and nontraditional risk factors associated with CVD and APS.
Risk factor Comment Reference
Traditional risk factors
Metabolic syndrome
e most common risk factors are
hypertriglyceridemia, low HDL levels, and visceral
obesity.
[,]
Hyperlipidemia High levels of APLA may be a marker for earlier
endothelial damage caused by hyperlipidaemia. [,]
TDM
It is associated with cardiovascular disease among APS
patients. It did not show any dierence between APS
patients and the general population.
[,]
Smoking CVD risk factor increases risk of AT. [,]
Obesity Increases the risk of insulin resistance and MetS. [,]
HTN Increases risk of ischemic events and CVD. [,]
Sedentary lifestyle Increases risk of obesity and comorbidities, propending
CVD. [,]
Nontraditional risk factors
APS per se
Patients with primary APS have a high prevalence of
carotid IMT and a decreased lumen diameter. IMT in
primary APS may be associated with stroke. Patients
with primary APS with IMT must be considered as
carriers of atherosclerosis.
[]
Autoantibodies
(i) ACLA are associated with a higher risk of venous
thrombosis and arterial thrombosis.
(ii) Lupus anticoagulant is a major risk factor for
arterial thrombotic events.
(iii) Immunoinammatory mechanisms, primarily
APLA,haveanoutstandingroleinAPS-related
vasculopathies.
(iv) Patients having APLA and AT may have greater
risk for ischemic events than patients with the same
degree of AT but without APLA.
(v) 𝛽GPI is abundantly present in the atherosclerotic
plaque.
(vi) Anti-𝛽GPI and ACLA may be involved in CAD
and stroke.
(vii) CAD and PVD occurred more oen in patients
with elevated serum levels of IgG or IgM APLA,
including ACLA or anti-𝛽GPI.
[,,,–]
ACLA: anticardiolipins antibodies; anti-𝛽GPI: anti-𝛽 glycoprotein I antibodies; APLA: antiphospholipid antibodies; APS: antiphospholipid syndrome; AT:
atherosclerosis; 𝛽GPI: 𝛽 glycoprotein I; CAD: coronary artery disease; CVD: cardiovascular disease; HDL: high-density lipoprotein; HTN: hypertension;
IMT: intima-media thickness; MetS: metabolic syndrome; PVD: peripheral vascular disease; TDM: type  diabetes mellitus.
[,]. Likewise, serum from patients with CVD shows a
high prevalence of antibodies against HSP, which mediate
lysis of stressed endothelial cells [,,].
4.2. Rheumatoid Arthritis. In addition to diarthrodial joints,
RA can damage virtually any organ thus leading to potential
extra-articular manifestations (EAMs). CVD is considered an
EAMandrepresentsthemajorpredictorofpoorprognosis
and the main cause of death in this population [,,,
]. ere is evidence that vascular damage accrual begins
prior to the diagnosis of RA and accelerates as the disease
progresses. RA patients present with endothelial dysfunction
and increased subclinical AT compared to age-matched
controls [–]. Endothelial function, assessed by brachial
artery ow-mediated vasodilation, also worsens with disease
duration []. e CV mortality is higher in RA and life
expectancy of patients with RA is three to ten years less than
that of the general population [,]. CVD is known to
appear earlier and . times more frequently than in the
general population [,,]. us, CVD is the leading
cause of death for RA patients around the world [,].
Currently, IHD secondary to AT is the most prevalent cause
of death associated with CVD in RA patients []. Almost all
mortality studies have been done on populations of European
origin, and there is limited information on other ethnic
groups. A meta-analysis of  RA mortality studies, published
between  and , reported a weighted combined all-
cause standardized mortality ratio (meta-SMR) of . with
similar increases in mortality risk apparent from the ratios
for IHD (meta-SMR .) and for CVA (meta-SMR .)

BioMed Research International 
T : Traditional and nontraditional risk factors associated with CVD and SS.
Risk factor Comment Reference
Traditional risk factors
Dyslipidemia
(i) High prevalence of hyperlipidemia and low HDL are
associated with CVD and rst-degree heart block.
(ii) SS patients showed .-fold higher prevalence of
hypertriglyceridemia.
[,–,,]
TDM It is associated with CV compromise in SS patients. []
Advanced age Age is a predictor for valve compromise []
Nontraditional risk factors
Systemic
compromise
Articular, renal, liver, peripheral neuropathy, CNS, joint
and gastrointestinal involvement, and parotid
enlargement are associated with stroke, IHD and lower
ow-mediated vasodilation
.
[,,]
Polyautoimmunity SS patients with APS were signicantly associated with
APLA in thrombotic events. []
SS-associated Autoantibodies
(i)SS-Aisassociatedwithstroke,IHD,andcarotid
thickening.
(ii) SS-B is related to rst-degree heart block, valve
compromise, and lower nitrate mediated vasodilation.
(iii) APLA and lupus anticoagulant are associated with
thrombotic events.
(iv) ACLA IgG is associated with arrhythmias
(v) RF is related to lower nitrate mediated vasodilation.
(vi) Anti-HDL.
[,–,,,]
Long duration of
disease
Longer duration of the disease is associated with stroke
and IHD. [,]
Chronic
proinammatory
state
Elevated CRP is associated with stroke and IHD [,]
Glucocorticoids
(i) Steroid use is associated with stroke and IHD
(ii) Patients with GCs showed a higher frequency of
HTN, TDM, and elevated TAG.
[,]
Others Hematological
alterations
(i) Hypogammaglobulinemia, leukopenia,
thrombocytopenia, and s-VCAM- are associated with
thrombotic events and lower nitrate mediated
vasodilation.
(ii) Low C and cryoglobulinemia are predictors for
valve injury
[,,,,,]
ACLA: anticardiolipins antibodies; anti-HDL: anti-high-density lipoprotein antibodies; APLA: antiphospholipid antibodies; APS: antiphospholipid syndrome;
CNS: central nervous system; CRP: c-reactive protein; CV: cardiovascular; CVD: cardiovascular disease; GCs: glucocorticoids; HDL: high-density lipoprotein
cholesterol; HTN: hypertension; IHD: ischemic heart disease; RF: rheumatoid factor; SS-A: anti-Ro/SSA antibodies; SS-B: anti-La/SSB antibodies; SS: Sj˜
ogren’s
syndrome; s-VCAM: soluble vascular cellular adhesion molecules; TAG: triglycerides; TDM: type  diabetes mellitus.
[]. RA patients with CVD frequently experience “silent”
IHD with no symptoms before a sudden cardiac death.
Indeed, sudden cardiac deaths are almost twice as common
in patients with RA as in the general population [].
According to the above, the Rochester Epidemiology Project
[]showedthatpatientswithRAhadagreaterriskofMI
than controls of equivalent age and sex. Recently, Sarmiento-
Monroy et al. [] did a systematic literature review of CVD
in the Latin American (LA) population. A wide range of
prevalence for CVD has been reported (.–.%) for
this population. e highest prevalence was indicated in
Puerto Rican patients (.%) by Santiago-Casas et al. [],
while for Brazil [,], Colombia [,,,], and
Argentina [,], a similar prevalence was reported (.,
., and .%, resp.). However, the mortality in RA patients
has been poorly evaluated in this population. Acosta et al.
[] demonstrated a mortality rate of .% in a six-year
follow-up. For both, the most frequent cause of death was
CVD in .% and .% of the cases, respectively. Table 
and Figure  give a summary of the main ndings related
to traditional and nontraditional CVD risk factors in RA
patients. In the Colombian population, Amaya-Amaya et al.
[] found that the traditional risk factors including male
gender, hypercholesterolemia, and an abnormal body mass
index (BMI) were associated with CVD. Nevertheless, the
increasedprevalenceofCVeventsinRAisnotfullyexplained

 BioMed Research International
T : Traditional and nontraditional risk factors associated with CVD and SSc.
Risk factor Comments References
Traditional risk factors
Dyslipidemia
(i) e alteration of lipid prole has been described,
givenbytheincreasedlevelsofLDLandlipoproteinA,
which are related to the reduction in the brinolysis
and thrombotic and coronary events.
(ii) Decreased levels of HDL are related to
anticentromere antibodies positivity.
(iii) ere is elevation of TAG, total cholesterol, and
LDL and decrease in HDL levels.
[,,–]
TDM It is associated with CV events in SSc patients. [,]
Hypertension Its prevalence increased with the age, and it is
correlated with MI. []
Hyperhomocysteinemia Increased levels are related to AT and endothelial
dysfunction. []
Nontraditional risk factors
SSc per se It is an independent risk factor for MI []
Autoantibodies
(i) oxLDL/𝛽GPI and anti-oxLDL/𝛽GPI complex:
these are considered proatherogenic.
(ii) anti-ox-LDL: higher levels are correlated with AT
and thrombosis.
(iii) anti-LPL: its presence is related to TAG elevated
and AT and CV events.
(iv) AECA may also contribute to an increased risk of
early AT in SSc
(v) Others: anticentromere, anti-HSP/, and APLA.
[,,,–]
Chronic inammation
Increase of CRP levels and intercellular adhesion
molecule- may also contribute to an increased risk of
early AT in SSc.
[,]
AECA: anti-endothelial cell antibodies; anti-HSP: anti-heat shock proteins antibodies; anti-LPL: anti-lipoprotein lipase antibodies; an anti-oxLDL/𝛽GPI
complex: anti-oxidized low-density lipoprotein/𝛽 glycoprotein I antibodies; APLA: antiphospholipid antibodies; AT: atherosclerosis; CRP: c-reactive protein;
CV: cardiovascular; CVD: cardiovascular disease; HDL: high-density lipoprotein cholesterol; LDL: low-density lipoprotein; oxLDL/𝛽GPI complex: oxidized
low-density lipoprotein/𝛽 glycoprotein I; SSc: systemic sclerosis; TAG: triglycerides; TDM: type  diabetes mellitus.
by these classic risk factors. Both nontraditional RA risk
factors and traditional risk factors act together to develop
CVD (Figure ).
Regarding CV risk screening and management, strategies
have been developed for the general population and are
basedonCVriskscorecalculatorssuchastheFramingham
score and the Systematic Coronary Risk Evaluation (SCORE)
model, but the accuracy of these models has not been
adequately evaluated in inammatory arthritis []. Recent
studies have shown that the SCORE underestimates the actual
cardiovascular risk of patients with RA. In this regard, a
study showed a high frequency of carotid plaques in the
group of individuals included in the category of moderate
risk according to SCORE risk charts []. e major strategy
is to develop healthy life styles as a way to maintain control
of classical risk factors. Statins can eectively lower total
cholesterol in RA patients and signicantly improve the
rates of CV-related and all-cause mortality when used for
primary prevention of vascular events [,]. Similarly,
ACE inhibitors and angiotensin II blockers may also have
a favorable eect on inammatory markers and endothelial
function in RA [,]. Regarding novel risk factors,
it is necessary to establish an adequate management of
the disease []. e main goal of the treatment should be to
reduce the disease activity, and, therefore, decrease the CV
burden []. Both conventional []andbiologicaldisease
modifying antirheumatic drugs (DMARDs) are used for this
purpose. Some studies have shown greater disease control
with nonconventional DMARDs such as anti-TNF agents,
which lower CRP and IL- levels, increase HDL levels, and
improve endothelial function [–]. Eective treatment
mayalsoresultinimprovedphysicalactivitywhichsubse-
quently leads to a decreased risk of hypertension, obesity, and
diabetes, all important determinants of CV disease []. e
antimalarial (AMs) drugs have been associated with a better
CV outcome, enhanced glycemic control, improved lipid pro-
les, a decreased thrombosis risk, and a reduced probability
of developing TDM in patients with RA [,,]. e
glucocorticoids (GC) should be used prudently to minimize
CV risk secondary to their eects on metabolic parameters
and blood pressure. Altogether, there is no clear evidence that
low doses of GC contribute signicantly to an enhanced CV
risk in inammatory arthritis in contrast to high doses. GCs
rapidly and eectively suppress inammation in RA and their
use might be justied for short-term treatment, for example,
for “bridging therapy” in the period between initiation

BioMed Research International 
GeneticRA-relatedOthers
Obesity
Dyslipidemia
Advanced age
Family history of CVD
Type 2 diabetes mellitus
Hyperhomocysteinemia
Metabolic syndrome
Inadequate lifestyle
Hypertension
Male gender
Smoking
Polymorphisms
(HLA and non-HLA genes)b
Familial autoimmunityc
Long duration of RA (over 10 years)
Polyautoimmunityd
Autoantibodiese
Chronic proinflammatory statef
High disease activity
Extra-articular manifestations
Other medicationsg
Household dutiesh
Rheumatoid cachexia
Hypothyroidism
rombogenic factorsi
Miscellaneousj
Glucocorticoids
Traditional risk factors
Nontraditional risk factors
Endothelial
dysfunction
Subclinical
atherosclerosis
Accelerated
atherosclerosis
Early IMT
increased
Impaired
endothelial
function
High mortality
(30–50%)
Tunica
adventitia
Tunica
media
Clot
Plaque
Clot
Plaque
Other
antibodies
Cytokines
Macrophage
RF
Endothelium
CVD
manifest
F : Traditional and nontraditional risk factors for cardiovascular disease in rheumatoid arthritis. AD: autoimmune disease; CVD:
cardiovascular disease; IMT: intima-media thickness; RA: rheumatoid arthritis; RF: rheumatoid factor. aCVDincludesabroadspectrumof
subphenotypes: stroke/transient ischemic attack, coronary artery disease, myocardial infarction, angina, congestive heart failure, arrhythmias,
ventricular diastolic dysfunction, hypertension, pulmonary embolism, deep vein thrombosis, and peripheral arterial/venous disease. bMainly
HLA-DRB∗ shared epitope alleles. ce presence of any diagnosed AD in rst-degree relatives of proband. de presence of two
concomitant AD in a single patient on the basis of international criteria. eRheumatoid factor, anti-cyclic citrullinated peptides antibodies,
anti-oxidized low-density lipoprotein, anticardiolipins, anti-phosphorylcholine, anti-modied citrullinated vimentin, anti-apolipoprotein
A-, and anti-cytokeratin  antibodies. fHigh levels of c-reactive protein and erythrocyte sedimentation rate. gMethotrexate, leunomide,
and nonsteroidal anti-inammatory drugs. hPatients (females and males) with RA working on household duties. ivon Willebrand factor,
plasminogen activator inhibitor-, and tissue plasminogen activator. jHypothyroidism, periodontal disease, and other markers such as
mannose-binding lectin, serum pentraxin , osteopontin, osteoprotegerin, and seric uric acid.
and response to DMARD treatment, although the debate
does not appear to be settled yet. erefore, a conservative
approachwaschoseninwhichtheuseofthelowestdose
for the shortest period possible was recommended [,,
,]. Reports indicate that anti-TNF is independently
associated with a lower CV risk due to the fact that it
reduces CV events in young patients by improving the lipid
prole, insulin resistance, endothelial function, and aortic
compliance and decreasing progression rates of subclinical
AT [,–]. Other biological therapy also produces the
same eect. A good example of that was the improvement of
endothelial function following rituximab therapy in patients
with RA that had been refractory to anti-TNF-alpha drugs
[,]. Finally, data about other biologics are conicting
and preliminary; as such, randomized, controlled studies are
needed to identify their CV risk reduction role [,].
4.3. Systemic Lupus Erythematosus. SLE occurs most oen
in young women of child-bearing age, the same population
that is at the highest relative risk of subclinical AT [,
]. Classically, there is a bimodal mortality pattern among
SLE patients with an early peak in the rst  years aer
diagnosis due to active disease, infections, and nephritis and
a second peak with deaths occurring – years aer SLE
diagnosis due to CVD as described by Urowitz et al. [].
Although the overall mortality rate for SLE patients has
improved over the past  years, mortality due to CVD (i.e.,
–%) has remained the same [–]. ere is strong
epidemiologic evidence that CVD risk among SLE patients
compared to the general population is at least doubled [].
Carotid plaque is prevalent in % of SLE patients under
age  and in up to % of those over age  [].
e increased risk of MI and angina among SLE patients

 BioMed Research International
VCAM/ICAM-1 HSP 60/65
LDL
Myocyte
Monocy te
Pathogen
Cytokine
Auto-Ab
CIC
Neutroph il
Macrophage Foam cell
Calcium
Cl
assic ris
k
f
actor
s
Novel risk factors
CVD
event
Traditional and autoimmune-related mechanisms of CVD in SLE and APS
Proatherogenic
cycle
Management
strategies
Icons
SLE-specic factors
SLE per se
Genetic determinants
Proinammatory markers
Circulating ICs
Hyperprolactinemia
SLE disease activity and duration
Organ damage
Lupus nephritis
Endogenous dyslipidemia
Premature menopause
Medications
Miscellaneous
Common risk factors
Polyautoimmunity
Antiphospholipid antibodies
Endothelial adhesion molecules
Vasc u l o p a thy
APS-specic factors
Other autoantibodies
Immune cells aberrations
MetS
Obesity
Smoking
Dyslipidemia
Advanced age
Menopausal status
Family history of CVD
Hyperhomocysteinemia
Sedentary lifestyle
Renal impairment
Hypertension
Male gender
T2DM/IR
HRT
∙Aggressive treatment of SLE activity, immunomodulatory drugs (AMs, CYC, and MMF)
∙Anticoagulation therapy; thromboprophylactic treatment
∙Monitoring and treatment of CVD risk factors (traditional and nontraditional)
∙Other medications: aspirin, statins, IECAs, and AT II blockers
Subclinical atherosclerosis
Early increase of intima-media thickness
Impaired endothelial
function
Endothelial dysfunction
oxLDL/𝛽2GPI complex
CD4+ T cell
Accelerated
atherosclerosis
F : Traditional and autoimmune-related mechanisms of cardiovascular disease in systemic lupus erythematosus and antiphospholipid
syndrome. A complex interaction between traditional and disease-specic traits leads to premature atherosclerosis process. Several risk
factors (le) have been described since the Framingham heart study, known as classic risk factors, which over time conduce to endothelial
dysfunction, subclinical atherosclerosis, and CV event manifest. In the autoimmune setting (right), several novel risk factors contribute
to development of premature vascular damage. is damage is represented by impaired endothelial function and early increase of intima-
media thickness, which are surrogates of the accelerated atherosclerosis process. ese associations are even more pronounced in this
case of polyautoimmunity (SLE and APS in the same individual), where risk factors have additive eects and atherosclerosis develops
earlier. e cornerstone of management of CV risk includes an aggressive treatment of disease activity, the continuous monitoring and
treatment of modiable CV risk factors, and the use of other medications in order to diminish the CV burden. ACE-I: angiotensin-
converting enzyme inhibitors; AMs: antimalarials; APS: antiphospholipid syndrome; AT-II blockers: angiotensin II receptor blockers; Auto-
Ab: autoantibodies; AZA: azathioprine; CIC: circulating immune complex; CYC: cyclophosphamide; CVD: cardiovascular disease; HDL:
high-density lipoprotein; HRT: hormone replacement therapy; IR: insulin resistance; MetS: metabolic syndrome; MMF: mycophenolate
mofetil; oxLDL/𝛽GPI complex: oxidizedlow-density lipoprotein/ glycoprotein I; SLE: systemiclupus eryt hematosus; TDM: type  diabetes
mellitus.
has been well characterized in a number of population-
based studies [,–]. Bengtsson et al. []further
corroborated these results in their population-based Swedish
study where they demonstrated that the risk of CVA and/or
MI in the total SLE population was .-fold higher than
that in the general population, but among women with SLE
aged–,itwas-foldhigheroverthe-yearfollow-up
period. Several research groups have reported prevalence
rates in SLE cohorts. In the Systemic Lupus International
Collaborating Clinics-Registry for Atherosclerosis (SLICC-
RAS) cohort, there were  cases of PVD among , patients
during a -year period []. In the Lupus in Minorities:
Nature versus Nurture study (LUMINA), .% of  patients
developed PVD over a mean follow-up of . years [].
In a recent meta-analysis, Schoenfeld et al. []showedthat
epidemiological data strongly support the hypothesis that
SLE patients are at an elevated relative risk of CVD. e
variabilityregardingtherelativeimportanceofriskfactorsfor
CVD among SLE patients in past epidemiological studies is
likely due, in part, to dierent design methods and dierent
patient and comparison groups. Independent predictive risk
factors (from multivariate analysis) for CV events have been
assessed in ve large prospective cohorts of patients with
SLE, including the Baltimore [], Pittsburg [], LUMINA
[], Toronto [], and SLICC-RAS []cohorts.emain
results are discussed in Table  and Figure .DiverseSLE
cohortshaveshowntheinuenceofadvancedage,dyslipi-
demia, obesity, HTN, and hyperhomocysteinemia as classical

BioMed Research International 
risk factors for CVD in the lupus population [,–].
ere is strong epidemiological evidence that traditional
CVD risk factors also elevate CVD risk among SLE patients
(Figure ). Amaya-Amaya et al. [] recently added further
evidence of the high frequency of CVD in  consecutive
patients with SLE (.%). eir ndings on traditional risk
factors (i.e., dyslipidemia, smoking), plus the conrmation
that coee consumption is another risk factor, showed that,
in combination, they contribute to this complication in the
LA population. It is well known that while traditional CVD
risk factors are undoubtedly important in increasing the CVD
risk among SLE patients, these do not fully account for the
elevated risk of CVD in this population. Esdaile et al. []
evaluated risk factors for CAD in two Canadian lupus cohorts
by means of the Framingham multiple logistic regression
model and found a high risk of developing CAD aer
removing the inuence of these risk factors. erefore, SLE-
associated factors play an important role in the premature
AT process characteristic of those patients [,–].
Hence, there is an increasing interest in identifying novel
risk factors that might explain the development of accelerated
AT in these populations. e proposal has been made that
SLE be managed the same way that TDM is—as a “CVD
equivalent”—with lower lipid goals, more aggressive aspirin
use, and potentially more aggressive monitoring [,].
Recent studies have started to address the question of
whether traditional treatment regimens may prevent or slow
AT in SLE patients []. ere are several new mechanisms
of action described for AMs, many of which have benecial
eects in the management of CV risk in patients with SLE
[,]. ere is evidence that AM drugs reduce LDL
levels, elevate HDL, and, when taken concomitantly with
steroids, can reduce TC []. In addition, benecial eects
of HCQ on thrombosis formation have also been described
[–]. Ruiz-Irastorza et al. [,]foundthatHCQuse
conferred a –% decrease in the risk of CVD. Otherwise,
the recent randomized controlled Lupus Atherosclerosis
Prevention Study by Petri et al. []suggeststhatatorvastatin
did not in fact slow progression of subclinical AT in 
SLE patients over  years. However, in other studies, it
has been demonstrated that statins do reduce CD levels
in vivo and in vitro and, therefore, interfere with CD-
CD ligand interactions in both SLE and AT []. As
inammation is one of the targets of therapy in SLE, several
other immunosuppressant drugs and biological therapies
currently employed in SLE could also be considered such as
potential new antiatherogenic agents [,].
4.4. Antiphospholipid Syndrome. e APS is a prothrombotic
state that can aect both the venous and arterial circulations.
e deep veins of the lower limbs and cerebral arterial
circulation are the most common sites of venous and arterial
thrombosis, respectively []. e heterogeneity of APS
clinical manifestations is likely linked to the varied eects
that APLA can induce on endothelial cells []. rom-
botic events are the clinical hallmark of APS, occurring in
venous and arterial circulations with a high recurrence rate
of arterial involvement. ey can be expressed as carotid
disease, CVA, CAD, and PVD due to thrombus formation
or AT [–]. Further, other cardiac manifestations may
include irregular thickening of the valve leaets due to
deposition of immune complexes that may lead to vegetation
and valve dysfunction, which are frequent and may be
asignicantriskfactorforstroke[–]. Tab l e  and
Figure  show the main traditional and nontraditional risk
factors associated with APS and CVD. Early diagnosis of APS
through examination of the heart and aggressive control of
all traditional risk factors through lifestyle modications and
pharmacotherapy, probably anti-inammatory treatment,
and close follow-up of APS patients may help to minimize
CV risk in these individuals [,]. e APS coagulopa-
thy in these patients requires careful and judicious use of
appropriate antiaggregant and anticoagulant therapy [].
Specically targeted therapies that exert anti-inammatory
or immunomodulatory eects become important therapeutic
tools in APS. In order to achieve benecial eects, these
drugs should primarily antagonize the pathogenic eects
of APLA. Moreover, these treatments should also control
atheroma,whichisoneofthemajorcausesofCVmortalityin
this pathology []. For instance, AM drugs may exert evi-
dent antiatherogenic properties [,]. Statins also have
pleiotropic characteristics, which include antiatherosclerotic
(i.e., preventing endothelial dysfunction), anti-inammatory
(i.e., reducing CRP levels), antioxidant, immunomodulatory,
and antithrombotic eects [–]. Likewise, aspirin has
been used in primary and secondary prevention in APS
patients particularly for its inhibitory eects on platelet
aggregation [,]. In addition to their anticoagulant
eects, unfractionated heparins and low molecular weight
heparins also have anti-inammatory properties. us, hep-
arins may represent another anti-inammatory therapeutic
tool even though the mechanisms of action responsible for
their anti-inammatory eects are not yet fully understood
[]. Recent improvements in the understanding of the
pathogenic mechanisms have led to the identication of novel
potential targets and therapies that might be used as new
potential immunomodulatory approaches in APS and CVD
such as B-cell targeted therapies, complement inhibition,
inhibition of costimulation, intracellular pathway inhibition,
and anticytokine therapies [].
4.5. Sj¨
ogren’s Syndrome. is is an autoimmune epithelitis
that aects the exocrine glands with a functional impairment
that usually presents as persistent dryness of the eyes and
mouth [,]. Its clinical spectrum extends from an
autoimmune exocrinopathy to a systemic involvement with
vasculitis and diverse extraglandular systemic manifesta-
tions (–%). is includes CVD although with lower
prevalence as mentioned above [,]. Chronic systemic
inammation is a risk factor for developing AT, however,
and contrary to what is expected, the prevalence of CVD
associated with AT is not appreciably increased in patients
with SS. is probably is characterized by chronic but milder
inammation as Ramos-Casals et al. showed []. In fact,
Akyel et al. [] found endothelial dysfunction in SS patients
although their carotid IMT was comparable to the healthy

 BioMed Research International
control group. It should be noted that the CV risk in patients
withSSisrisingasaresultofthepopulationaectedbythe
disease (i.e., postmenopausal women) [,]. Vaudo et al.
[] found a high rate of subclinical AT due to changes in
the carotid arterial wall studied/seen by femoral and carotid
ultrasonography. All these ndings (i.e., Table )suggestthat
a functional impairment of the arterial wall may sustain early
phases of atherosclerotic damage in SS. A combined eect
of disease-related chronic inammatory and immunological
factors appears to support dysfunction of endothelium and
vascular smooth muscle cells, respectively. Table  contains
the most frequent traditional and nontraditional risk factors
relatedtoCVDandSS.emanagementofCVDinSS
patients must be directed toward rigorous intervention of
modiable risk factors as well as nontraditional risk factors,
warranting a routine evaluation of autoantibodies and other
SS-related factors. P´
erez-De-Lis et al. []foundaprotective
role of AMs in CVD and SS patients since these drugs show
an association with a lower frequency of HTN, TDM, and
dyslipidemia. So, in the future, it will be necessary to analyze
theincidenceofCVDandtheroleofthedierentriskfactors
listed in Table  prospectively for the development of such
complications.
4.6. Systemic Sclerosis. ere are two major disease presen-
tations: the microvascular and macrovascular involvement.
e vasculopathy of SSc typically aects the small arteries
and capillaries (i.e., microvascular occlusive disease with
vasospasm and intimal proliferation) while macrovascular
disease has been demonstrated by carotid ultrasonography,
ankle brachial blood pressure index, and peripheral angiog-
raphy [,,] due to brosis, thickening, and chronic
proliferation of the intimal layer as well as transmural lym-
phocytic inltrate without evidence of atherosclerotic plaque
[,]. However, recently, the evidence has demonstrated
increased atherosclerosis, including CAC, higher prevalence
of subclinical CAD, and higher carotid IMT [,]. Patchy
brosis is the most important feature in the myocardium,
especially when it is localized in subendocardial regions.
is brosis usually accompanies LVDD [,], but it is
symptomatic in % of the cases []. ere have been
reported MI or myocardial perfusion defects with coro-
nary arteries which suggests that the etiology of infarction
may be due to microvascular disease rather than coronary
AT although we must recognize that the latter is higher
in patients with SSc [,]. Patients with SSc have a
reduced coronary ow reserve [,], which is associated
with higher coronary events [,]. Other authors have
reported ectasia, spasm, and coronary artery stenosis [,].
Arrhythmias and conduction disturbances are characteristic
of cardiac involvement in SSc as hypertrophy and heart failure
contractility [,] have been reported. Ultrasonography
evaluation is also used to evaluate the carotid arteries and
has been proven to be a useful marker for the assessment
of subclinical AT and a strong predictor of subsequent
MI and CVA [,,].Inaddition,onceSSchas
been diagnosed and established, attention to treatment of
the vascular component is critical. While the traditional
approach has been solely to use vasodilator therapy, new
investigations are underway to develop novel therapies, to
prevent further vascular injury, and to stimulate vascular
repair. Some of the current treatment approaches include
the following: prostacyclin analogs, endothelin antagonists,
phosphodiesterase inhibitors, immunosuppressive therapy,
and tyrosine kinase inhibitors [].
4.7. Spondyloarthropathies. Since spondyloarthropathies are
also chronic autoimmune-autoinammatory diseases asso-
ciated with accelerated atherosclerosis, the patients with
spondyloarthropathies also have a higher risk of cardio-
vascular disease than the general population. Ankylosing
spondylitis has been associated with increased mortality rate
compared to the general population, which is, in great part,
theresultofcardiovascularcomplications.Also,subclinical
atherosclerosis, manifested by the presence of endothelial
dysfunction and increased carotid intima-media wall thick-
nessandcarotidplaques,hasbeenobservedinpatientswith
psoriatic arthritis and ankylosing spondylitis. In patients with
ankylosing spondylitis, TNF-alpha blockade was associated
with improvement of insulin resistance, markers of metabolic
syndrome, and biomarkers of endothelial dysfunction [–
].
5. Conclusions
AT and ADs share several mechanisms. e excessive CV
events observed in patients with ADs are not fully explained
by classic risk factors. Several novel risk factors contribute
to development of premature vascular damage. erefore, a
complex interaction between traditional and disease-specic
traits converges into a shared proatherogenic phenotype
in this population. Until additional research and disease-
specic risk prediction tools are available, current evidence
supports aggressive treatment of disease activity and careful
screening for and management of modiable traditional risk
factors in patients with ADs. e nding and understanding
of complex interactions between predisposing factors (i.e.,
genetic, environmental factors, and ADs per se) will allow
us to better describe and assess the broad spectrum of CV
subphenotypes in ADs and their treatments.
Conflict of Interests
e authors have indicated that they have no conict of
interests regarding the content of this paper.
Acknowledgments
e authors thank their colleagues at the Center for Autoim-
mune Diseases Research (CREA), for fruitful discussions.
is work was supported by the School of Medicine and
Health Sciences, Universidad del Rosario, Bogota, Colombia.

BioMed Research International 
References
[] J.-M. Anaya, A. Rojas-Villarraga, and M. Garc´
ıa-Carrasco, “e
autoimmune tautology: from polyautoimmunity and familial
autoimmunity to the autoimmune genes,” Autoimmune Dis-
eases, vol. , Article ID ,  pages, .
[]J.M.Anaya,J.Castiblanco,A.Rojas-Villarragaetal.,“e
multiple autoimmune syndromes. A clue for the autoimmune
tautology,” Clinical Reviews in Allergy and Immunology,vol.,
no. , pp. –, .
[] J-M. Anaya, “e diagnosis and clinical signicance of polyau-
toimmunity,” Autoimmunity Reviews,vol.,no.-,pp.–
, .
[]G.K.Hansson,I.Kriszbacher,M.Kopp
´
an, and J. B´
odis,
“Inammation, atherosclerosis, and coronary artery disease,”
e New England Journal of Medicine,vol.,pp.–,
.
[] C. Blasi, “e autoimmune origin of atherosclerosis,”
Atherosclerosis,vol.,no.,pp.–,.
[] R.R.S.Packard,A.H.Lichtman,andP.Libby,“Innateandadap-
tive immunity in atherosclerosis,” Seminars in Immunopathol-
ogy,vol.,no.,pp.–,.
[] L. J. Jara, G. Medina, O. Vera-Lastra, and M.-C. Amigo,
“Accelerated atherosclerosis, immune response and autoim-
mune rheumatic diseases,” Autoimmunity Reviews,vol.,no.,
pp. –, .
[] C. Gonzalez-Juanatey, J. Llorca, J. Martin, and M. A. Gonzalez-
Gay, “Carotid intima-media thickness predicts the development
of cardiovascular events in patients with rheumatoid arthritis,”
Seminars in Arthritis and Rheumatism,vol.,no.,pp.–
, .
[] H.M.M.S.Ahmed,M.Youssef,andY.M.Mosaad,“Antibodies
against oxidized low-density lipoprotein are associated with
subclinical atherosclerosis in recent-onset rheumatoid arthri-
tis,” Clinical Rheumatology,vol.,no.,pp.–,.
[] A.Karrar,W.Sequeira,andJ.A.Block,“Coronaryarterydisease
in systemic lupus erythematosus: a review of the literature,”
Seminars in Arthritis and Rheumatism,vol.,no.,pp.–
, .
[] J. J. Belch, S. McSwiggan, and C. Lau, “Macrovascular disease in
systemic sclerosis: the tip of an iceberg?” Rheumatology,vol.,
supplement , pp. v–v, .
[] R. Gerli, G. Vaudo, E. B. Bocci et al., “Functional impairment
of the arterial wall in primary Sj¨
ogren’s syndrome: Combined
action of immunologic and inammatory factors,” Arthritis
Care and Research,vol.,no.,pp.–,.
[] J.C.Sarmiento-Monroy,J.Amaya-Amaya,JS.Espinosa-Serna,
C. Herrera-D´
ıaz, J. M. Anaya, and A. Rojas-Villarraga, “Cardio-
vascular disease in rheumatoid arthritis: a systematic literature
review in latin america,” Arthritis,vol.,ArticleID,
 pages, .
[] J. Amaya-Amaya, J. C. Sarmiento-Monroy, R. Mantilla, R.
Pineda-Tamayo, A. Rojas-Villarraga, and J. M. Anaya, “Novel
risk factors for cardiovascular disease in rheumatoid arthritis,”
Immunologic Research,vol.,no.-,pp.–,.
[] J.Amaya-Amaya,J.C.Sarmiento-Monroy,J.Caro-Morenoet
al., “Cardiovascular disease in latin American patients with
systemic lupus erythematosus: a cross-sectional study and a
systematic review,” Autoimmune Diseases,vol.,ArticleID
,pages,.
[] J. M. Kahlenberg and M. J. Kaplan, “Mechanisms of premature
atherosclerosis in rheumatoid arthritis and lupus,” Annual
Review of Medicine,vol.,pp.–,.
[] A.Sandoo,J.J.C.S.VeldhuijzenvanZanten,G.S.Metsios,D.
Carroll, and G. D. Kitas, “Vascular function and morphology in
rheumatoid arthritis: a systematic review.,” Rheumatology,vol.
,no.,pp.–,.
[] S.Corrao,S.Messina,G.Pistone,L.Calvo,R.Scaglione,andG.
Licata, “Heart involvement in Rheumatoid Arthritis: Systematic
review and meta-analysis,” International Journal of Cardiology,
vol. , no. , pp. –, .
[] C. S. Crowson, K. P. Liao, J. M. Davis III et al., “Rheumatoid
arthritis and cardiovascular disease,” American Heart Journal,
vol. , no. , pp. .e–.e, .
[] E.A.R.Khan,L.K.Stamp,J.L.O’Donnell,andP.T.Chapman,
“Cardiovascular morbidity in rheumatoid arthritis patients
in North Canterbury, New Zealand –,” International
Journal of Rheumatic Diseases,vol.,no.,pp.–,.
[] M. Holmqvist, E. Gr¨
ansmark, ¨
A. Mantel et al., “Occurrence and
relative risk of stroke in incident and prevalent contemporary
rheumatoid arthritis,” Annals of the Rheumatic Diseases,vol.,
no. , pp. –, .
[] K. Yiu, M. Mok, S. Wang et al., “Prognostic role of coronary
calcication in patients with rheumatoid arthritis and systemic
lupus erythematosus,” Clinical and E xperimental Rheumatology ,
vol.,no.,pp.–,.
[]C.D.Popa,E.Arts,J.Fransen,andP.L.C.M.vanRiel,
“Atherogenic index and high-density lipoprotein cholesterol as
cardiovascular risk determinants in rheumatoid arthritis: the
impact of therapy with biologicals,” Mediators of Inammation,
vol. , Article ID ,  pages, .
[] A.Solomon,G.R.Norton,A.J.Woodiwiss,andP.H.Dessein,
“Obesity and carotid atherosclerosis in African black and Cau-
casian women with established rheumatoid arthritis: a cross-
sectional study,” Arthritis Research and erapy,vol.,no.,
article R, .
[]H.G.Raterman,H.Levels,A.E.Voskuyl,W.F.Lems,B.
A. Dijkmans, and M. T. Nurmohamed, “HDL protein com-
position alters from proatherogenic into less atherogenic and
proinammatory in rheumatoidart hritis patients responding to
rituximab,” Annals of the Rheumatic Diseases,vol.,no.,pp.
–, .
[] A. M. van Sijl, K. van den Hurk, M. J. L. Peters et al., “Dierent
typeofcarotidarterialwallremodelinginrheumatoidarthritis
compared with healthy subjects: a case-control study,” e
Journal of Rheumatology,vol.,no.,pp.–,.
[]S.R.Schoenfeld,S.Kasturi,andK.H.Costenbader,“e
epidemiology of atherosclerotic cardiovascular disease among
patients with SLE: a systematic review,” Seminars in Arthritis
and Rheumatism,vol.,no.,pp.–,.
[] M. A. Petri, A. N. Kiani, W. Post, L. Christopher-Stine, and
L. S. Magder, “Lupus atherosclerosis prevention study (LAPS),”
Annals of the Rheumatic Diseases,vol.,no.,pp.–,
.
[] L. S. Magder and M. Petri, “Incidence of and risk factors for
adverse cardiovascular events among patients with systemic
lupus erythematosus,” e American Journal of Epidemiology,
vol. , no. , pp. –, .
[]A.N.Kiani