Cardio en Reuma

REVIEWS
Cardiovascular comorbidity in rheumatic

diseases
Michael T. Nurmohamed, Maaike Heslinga and George D. Kitas
Abstract | Patients with rheumatoid arthritis (RA) and other inflammatory joint diseases (IJDs) have an
increased risk of premature death compared with the general population, mainly because of the risk of
cardiovascular disease, which is similar in patients with RA and in those with diabetes mellitus. Pathogenic
mechanisms and clinical expression of cardiovascular comorbidities vary greatly between different rheumatic
diseases, but atherosclerosis seems to be associated with all IJDs. Traditional risk factors such as age,
gender, dyslipidaemia, hypertension, smoking, obesity and diabetes mellitus, together with inflammation,
are the main contributors to the increased cardiovascular risk in patients with IJDs. Although cardiovascular
risk assessment should be part of routine care in such patients, no disease-specific models are currently
available for this purpose. The main pillars of cardiovascular risk reduction are pharmacological and
nonpharmacological management of cardiovascular risk factors, as well as tight control of disease activity.
Nurmohamed, M. T. etal. Nat. Rev. Rheumatol. advance online publication 18 August 2015; doi:10.1038/nrrheum.2015.112
Introduction
Amsterdam
Rheumatology and
Immunology Center,
VUUniversity Medical
Center, PO Box7057,
1007MB Amsterdam,
Netherlands (M.T.N.).
Amsterdam
Rheumatology and
Immunology Center,
Reade, PO Box58271,
1040HG Amsterdam,
Netherlands (M.H.).
Department of
Rheumatology and
Research &
Development
Directorate, Dudley
Group NHS Foundation
Trust, Russells Hall
Hospital, Clinical
Research Unit,
DudleyDY1 2HQ, UK
(G.D.K.).
Correspondence to:
G.D.K.
kitas@dgh.nhs.uk
Compared with the general population, patients with

rheumatic diseases are at increased risk of developing
several comorbid conditions, of which cardiovascular
comorbidities are the most common and have the greatest
effect on mortality.1 The epidemiology and pathogenesis
of cardiovascular comorbidities in inflammatory joint
diseases (IJDs) are particularly well-studied for rheum
atoid arthritis (RA), but have also been investigated for
rheumatic diseases such as ankylosing spondylitis (AS)
and systemic lupus erythematosus (SLE). Growing
awareness of this increased cardiovascular risk has led
to several efforts to unravel the underlying mechanisms,
especially in RA. The elevated risk is only partly explained
by increased prevalence of traditional cardiovascular
risk factors such as age, gender, dyslipidaemia, hyper
tension, smoking, obesity and diabetes mellitus; systemic inflammation, genetic factors and treatment effects
might also have important roles (Figure1). Pathogenic
mechanisms and clinical expression of cardiovascular
comorbidities vary greatly between different rheumatic
diseases, but atherosclerosis seems to be a shared factor
in all IJDs. However, not all cardiovascular comorbidity
and mortality can be attributed to atherosclerosis: non
ischaemic heart failure (HF), microvascular dysfunction, cardiac autonomic neuropathy and arrhythmias
are emerging as major contributors to the cardiovascular
Competing interests
M.T.N. has received honoraria for lectures or advisory boards
from Abbvie, BMS, Janssen, Merck, Pfizer and Roche, and
unrestricted educational grants from Abbvie, BMS, Pfizer and
Roche. G.D.K. has received honoraria for lectures or advisory
boards, as well as hospitality, from Abbvie, BMS, Lilly, Novartis,
Pfizer, Roche and UCB, and unrestricted educational grants
fromPfizer. M.H. declares no competing interests.
burden, and medications to treat the rheumatic disease

can influence cardiovascular risk positively or nega
tively. Some cardiac manifestations show a degree of
disease specificityconduction disturbances and aortic
insufficiency, for example, are associated withAS.2
In this Review we focus on cardiovascular comorbid
ities resulting largely from atherosclerosis, with RA as
the predominant model. Additional (nonatherosclerotic)
mechanisms occurring in other autoimmune diseases,
particularly SLE, are also considered. A logical conse
quence of the increased awareness of cardiovascular
comorbidity in rheumatic disease is a shift from its recog
nition towards prevention and treatment. Development
of cardiovascular risk assessment models in patients with
IJD is being attempted, and more evidence is emerging of
the effects of rheumatological and cardiovascular treat
ments on cardiovascular risk and outcomes. However,
despite these advances, much remains to be learned in
thisfield.
IJD and cardiovascular disease burden

RA
Patients with RA have an increased risk of premature
death compared with the general population.3 The main
cause for this increase in mortality is cardiovascular
disease. Several observational cohort studies have examined the magnitude of the increased risk by studying the
occurrence of cardiovascular events in patients with rheu
matic diseases (generally RA). In a meta-analysis1 that
pooled study results from different parts of the world, an
overall 48% (pooled RR1.48, 95%CI 1.361.62) increased
risk for incident cardiovascular disease was observed
in patients with RA, compared with the general popu
lation. The results of a prospective study of a Dutch RA
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Key points
Patients with inflammatory joint diseases (IJDs) have an increased burden
ofcardiovascular disease compared with the general population
Inflammation and traditional risk factors contribute to the cardiovascular
riskassociated with IJDs
IJDs and atherosclerosis are thought to have a common, inflammatory
pathogenesis
Cardiovascular risk management is unsatisfactory in patients with IJD
The main pillars of cardiovascular management in IJD are pharmacological
andnonpharmacological approaches to reduce cardiovascular risk factors,
along with tight control of disease activity
Coordination of care between rheumatologists, internists, cardiologists and
primary-care physicians should be increased to optimize management of
cardiovascular risk in patients with IJD
Inflammation
+
Traditional risk factors
Tobacco smoking
Exercise
Blood pressure
Lipid profile
Gender
Age
Diabetes
Medication effects
DMARDs
Glucocorticosteroids
NSAIDs and COXIBs
Cardiovascular
disease
Figure 1 | Contributors to cardiovascular risk in IJDs.Nature

Patients
with IJDs
have
Reviews
| Rheumatology
increased risk of cardiovascular disease compared with the general population,
mainly resulting from traditional risk factors and inflammation. Traditional
cardiovascular risk factors include age, gender, dyslipidaemia, hypertension,
smoking, obesity, lack of exercise and diabetes mellitus. Medication can affect
cardiovascular risk by targeting inflammation, but can also have undesired
effectsglucocorticosteroids, for example, are associated with dyslipidaemia
andhypertension. Inflammation can modify some traditional risk factors, the
best-known example being the influence on lipid profile. Abbreviations: COXIB,
cyclooxygenase2 selective inhibitor; IJD, inflammatory joint disease.
cohort suggested that the magnitude of the cardiovascular

risk increase in RA (around twofold) is similar to that
observed in patients with diabetes mellitus.4 This finding
was corroborated by the results of a Danish nationwide
study 5 and attributed to a similar rate of acceleration of
atherosclerosis in these two conditions.6
In patients with RA, relative to unaffected indivi
duals, the increased risk of myocardial infarction (MI)
is greater (around 68%) than that of cerebrovascular
accident (around 41%).79 In one study,10 compared with
unaffected controls, an 87% increased risk of congestive
HF in RA was observed, mostly in rheumatoid-factorpositive patients, but whether this level of risk would
exist in contemporary RA cohorts is unclear. Evidence
derived from observational studies suggests that effective control of inflammationeither with biologic or
nonbiologic DMARDs, particularly anti-TNF agents
and methotrexateis associated with reduction of
cardiovascular disease risk. Although developments in
therapeutic strategies in the past couple of decades are
reflected by a decline in mortality rates,11 the mortality
gap between patients with RA and the general population
has not improved, demonstrating that cardiovascular

disease is still of major importance in these patients.12
Reports of studies in this field focus on the incidence of
atherosclerotic and ischaemic events rather than non
ischaemic cardiovascular disease. However, patients
with RA and other IJDs are not just at increased risk
for ischaemic cardiovascular disease: a range of cardiac
manifestations can present during the course of rheumatic disease (Table1). Classic cardiac complications
of RA owing to inflammation, such as pericarditis and
endocarditis, or long-term development of amyloid
osis are rare and seldom cause clinically overt disease
nowadays.13 However, recent developments in cardiac
imaging suggest that microvascular disease and myo
carditis are common,14 as is cardiac autonomic neuro
pathy,15,16 particularly during active phases of the disease.
The effects of these pathologies on cardiac function and
risk of sudden cardiac death need to be further evaluated.
Spondylarthropathies
Available data on spondylarthropathies indicate that,
compared with unaffected individuals, patients with
psori atic arthritis and AS have an increased cardio
vascular risk,17,18 which approaches the magnitude seen
in RA. A meta-analysis assessing the occurrence of MI or
stroke in patients with AS showed significant increases in
MI (OR1.60, 95%CI 1.321.93) and in stroke (OR1.50,
95%CI 1.391.62) relative to control groups.19 For psor
iatic arthritis, compared with the general population, a
meta-analysis showed an increased risk of MI (OR1.57,
95%CI 1.082.27) and inconclusive results for stroke;
pooled results included all patients with psoriasis and
did not focus on patients with psoriatic arthritis.20 As
with RA, not all cardiovascular morbidity and mortality in spondylarthropathies can be attributed to athero
sclerosis. In patients with AS, aortitis involving the aortic
root and the ascending aorta (leading to valvular insufficiency) can occur, but it rarely does so nowadays.21
The fibrosis that occurs with aortitis can extend into the
cardiac tissue and cause conduction abnormalities.
SLE
In SLE, cardiac comorbidities are also common. SLE is
associated with a bimodal mortality distribution, and
cardiovascular disease is by far the most important
contributor to the second (late) peak in mortality.22 In
fact, amongst rheumatic diseases, SLE is associated with
the greatest increase in cardiovascular disease risk, and
theresults of an epidemiological study showed that
women 4450years old with SLE have a 50-fold increased
risk of MI compared with women of similar age in the
general population.23 The cause of the increased cardio
vascular disease risk in SLE is multifactorial (more so
than in IJDs). Traditional risk factors and inflammation are important, but other mechanisms of endothelial
damage, such as the prothrombotic environment wherein
autoantibodies against phospholipids and endothelial
cells contribute to a vulnerable plaque phenotype also
add to the cardiovascular disease burden.24 In addition,
treatment can lead to substantial corticosteroid exposure.
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Table1 | Cardiac involvement in inflammatory joint diseases
Cardiovascular disease
Inflammatory joint disease

Rheumatoid arthritis
Ankylosing spondylitis
Systemic lupus
erythematosus
Atherosclerotic
cardiovascular disease
Increased risk of
myocardialinfarction,
cerebrovascular accident
Increased risk of
myocardialinfarction,
cerebrovascular accident
Risk is mainly increased

inyoung women
Pericarditis
Increased prevalence, usually

ofno clinical significance
Rare
Common, often asymptomatic
Myocarditis
Rare, associated with

activedisease
Rare
High prevalence in autopsy

studies, often subclinical
Heart failure
Common, mostly diastolic

heartfailure
Unknown
Increased risk, mainly

inyoungwomen
Valvular heart disease
Rare, mostly not

clinicallysignificant
Aortic root disease and aortic

regurgitation, rare nowadays
Rare, possible association with

antiphospholipid antibodies
Conduction abnormalities
Uncommon, mostly
atrioventricular block or RBBB
Common, association
withHLAB27
Uncommon, mostly
sinustachycardia
Cardiac manifestations that can occur during the course of rheumatic disease. Increase in risk is relative to the general population. Abbreviation: RBBB, right
bundle branchblock.
Some of the mechanisms that increase cardiovascular

risk are specific for SLE and differ from those in other
IJDs.25 An example is lipid metabolismin SLE, auto
antibodies might alter the metabolism of lipoproteins
involved in atherogenesis and thereby contribute to
atherosclerosis. For instance, low levels of HDL can be
caused by the presence of high levels of antibodies to
HDL and apolipoproteinA1 in patients with SLE and
coronary ischaemia.26 Furthermore, IFN is involved
in the pathophysiology of SLE and causes the uptake of
lipids by macrophages and their transformation into foam
cells, linking it to plaque formation in patients with SLE.27
These findings suggest that the management of cardio
vascular risk factors in SLE should have stricter targets for
dyslipidaemiaand possibly for hypertensionthan the
targets used in the general population.28
Contributions of known risk factors
Traditional risk factors are important contributors to the

cardiovascular risk in the general population as well as
in patients with IJD. Despite this fact, when adjusting for
traditional risk factors, the absolute cardiovascular risk
for patients with RA is still increased when compared
with the general population. As such, RA (and possibly other IJDs) is an independent risk factor for cardio
vascular disease.29 Traditional cardiovascular risk factors
contribute to the excess cardiovascular disease seen in
IJD, albeit in a different way than in the general population. In patients with RA, for example, smoking, male
gender and history of cardiovascular disease confer proportionately less to the risk of developing cardiovascular
disease than in the general population,29 but this disparity
is because of the presence of additional risk factors rather
than lesser importance of traditional risk factors inIJD.
Cholesterol
Cholesterol is an example of a risk factor with specific
characteristics in patients with RA. Hypercholesterolaemia
is an important risk factor for cardiovascular disease in the
general population. However, assessment of cholesterol
is complicated in patients with RA. Several studies have

evaluated lipid profiles in patients with IJDs, especially
RA,30,31 and the overall consensus is that active inflammation in RA leads to a decline in levels of total cholesterol,
LDL cholesterol, and HDL cholesterol compared with
individuals without RA.32 The greatest suppression occurs
in levels of HDL cholesterol, leading to an unfavourable
lipidprofile. This lipid paradox, whereby a reduction
inlipid levels is associated with higher cardiovascular
risk, has also been reported in other inflammatory diseases as well as in sepsis.33,34 However, the results are not all
consistent, and levels of HDL cholesterol have been both
positively 35 and negatively 36 associated with cardiovascular
disease risk in studies of patients with RA.
The lipid paradox in RA could be explained by modification of lipids by inflammation, which not only lowers
lipid levels, but also alters lipid structure and function,
changing the usual antiatherogenic effects of HDL
cholesterol into proatherogenic effects.37 At the genetic
level, polymorphisms traditionally associated with poor
rheumatological outcome in RA are also associated
with dyslipidaemia.38 A potential explanation for the
abnormal lipid profile observed in RA is that the low
cholesterol levels detected in patients with active RA
are driven by high cholesterol ester fractional catabolic
rates.39 Insupport of this hypothesis, in patients with RA,
treatment with a Janus-kinase inhibitor reduces chol
esterol ester catabolism, thereby increasing levels of HDL
cholesteroland LDL cholesterol relative to pretreatment
levels.39 In the context of cardiovascular risk assessment
in patients with RA, measurement of the ratio of total
cholesterol to HDL cholesterol is recommended in clinical practice, and it might be reasonable to suggest that
lipid measurements during inactive stages of the disease
are the most representative of the overall situation in a
given patient.37,33 Evidence suggests that lipid-lowering
(statin) therapy is substantially underutilized in patients
with RA who fulfill even the general population thresholds for this treatment.40 This unmet need for management of dyslipidaemia is also seen in patients with other

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IJDs,41 and could have adverse consequences in terms
ofcardiovascular outcome.
Body weight and physical inactivity

Another factor that seems paradoxical in patients with RA
is BMI. In the general population, high BMI increases the
cardiovascular risk compared with normal-to-low BMI,
which seems to be protective. In a study involving African
women with established RA, BMI was positively associated
with carotid artery intimamedia thickness (cIMT) and
waist-to-hip ratio was positively associated with the presence of carotid artery plaque, but only in Caucasian women
from a developed population.42 However, patients with
RA and low BMI (<20kg/m2) can also have higher risk of
cardiovascular death than individuals without RA and with
normal BMI (2030kg/m2).43 A reason for this disparity
might be the considerable differences in body composition
between individuals with and without RA, as a combination of physical inactivity and activation of inflammatory
pathways in RA can lead to low muscle mass combined
with a high percentage of fat (rheumatoid cachexia).44
Visceral adiposity in RA is associated with insulin resistance, hypertension, metabolic syndrome and inflammatory load.44 Physical inactivity is common in patients with
RA and is associated with an adverse cardiovascular risk
profile,45 whereas evidence is emerging that structured
exercise therapy has beneficial cardiovascular effects in
these individuals, at least in the short-to-medium term.4648
Diabetes and insulin resistance
The association between RA and insulin resistance is
strongly supported by the results of many studies,4951
andis most likely mediated by inflammation, because
insulin resistance correlates with levels of markers of
inflammation and disease activity. Insulin resistance often
precedes diabetes, but an association between RA and diabetes is not evident.52 Control of inflammation with potent
anti-inflammatory therapies, such as anti-TNF agents,
seems to reverse insulin resistance only in patients with
RA who are not obese, suggesting that inflammation and
BMI are both important contributors to insulin resistance
in this population.53 Anti-inflammatory agents can also be
effective in preventing diabetes, and in a study of patients
with RA or psoriasis, the risk of newly recorded diabetes
was lower for individuals initiating therapywith a TNF
inhibitor or hydroxychloroquine compared withother
nonbiologic DMARDs.54
Cigarette smoking
Smoking is a known environmental risk factor for RA,
and a higher prevalence of smokers has been observed in
patients with RA than in matched controls without RA,55
but the relationship between smoking and cardiovascular
disease is less well-established in patients with RA than
in the general population.29 In RA, smoking is associated
with factors that are predictive of cardiovascular outcome,
such as rheumatoid factor and anti-citrullinated protein
antibody (ACPA) positivity,56,57 rheumatoid nodules,56
response to anti-TNF treatment 58,59 and rheumatoid
cachexia.60 These interacting mechanisms make it difficult
to determine the contribution of smoking to cardio

vascular risk in this population, raising the question of
whether population-based risk-prediction models are also
applicable to patients withIJD.
Hypertension
Hypertension has one of the strongest associations with
cardiovascular disease in the general population and
might also have an important role in patients with IJD.
The reported prevalence of hypertension in patients with
RA is 473%,61 although a meta-analysis determined
no difference in its prevalence between 2,956 patients
with RA and 3,713 matched controls (OR1.09, 95%CI
0.911.31).62 By contrast, in a study designed to evaluate hypertension associated with RA, the prevalence of
hypertension was substantially higher in individuals with
RA than in matched controls.63 The results of the inter
national, cross-sectional COMORA study 64 showed that
hypertension is prevalent in 40.4% of patients with RA,
although interpretation of this value is hindered by the
lack of a control population.
Several mechanisms could contribute to the develop
ment of hypertension in RA, including the use of anti
rheumatic drugs, the presence of specific genetic
polymorphisms,6567 and activation of inflammatory
pathways that lead to increased peripheral vascular resistance.68 Some evidence suggests that anti-TNF therapy
can reduce blood pressure in this population69 by reducing peripheral resistance.70 However, hypertension is both
underdiagnosed and undertreated in patients with RA.
In a cross-sectional study,71 hypertension was present in
70.5% of 400 consecutive secondary-care patients with
RA, but only 60.6% of those received antihypertensive
therapy, mostly with suboptimal blood-pressure control,
whereas the condition was undiagnosed and untreated in
the remaining 39.4% of individuals with hypertension.
Hyperhomocysteinaemia
In the general population, hyperhomocysteinaemia is
associated with increased risk of cardiovascular disease
relative to normal levels of homocysteine.72 In auto
immune diseases, homocysteine can act as a proinflammatory agent by stimulating the immune system and,
in turn, high-grade inflammation can promote upregu
lation of homocysteine levels. Hyperhomocysteinaemia
is common in patients with IJD and is probably caused
by methotrexate administration, because this folic acid
antagonist influences homocysteine metabolism.73 Folic
acid or folinic acid supplementation of methotrexate
therapy prevents the increase in homocysteine levels,74
but the use of folic acid to lower homocysteine levels has
not been shown to prevent cardiovascular events in the
general population.75 Methylenetetrahydrofolate reductase (MTHFR) is the rate-limiting enzyme in the conversion of homocysteine to methionine. Polymorphisms in
the MTHFR gene can result in production of MTHFR
variants with reduced activity compared with the
wild-type enzyme, thereby increasing levels of homo
cysteine. These polymorphisms are possible markers for
cardiovasculardisease.76
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Plaque composition
Stable plaque
Unstable, ruptured plaque
Accelerated
atherosclerosis
with RA, polymorphisms have also been linked to dyslipi

daemia,38,84,85 hypertension6567 and biomarkers of endothelial function such as asymmetric dimethylarginine.86
Some of these associations might be modified by lifestyle factors, such as obesity or smoking. These studies
of genetic risk factors suggest new avenues of scientific
enquiry in this field.
Inflammation and cardiovascular risk

Inflammation
Prothrombotic state
Nonischaemic
cardiovascular disease
Figure 2 | Contribution of inflammation to cardiovascular

Naturedisease.
ReviewsRheumatic
| Rheumatology
inflammation is thought to be a major contributor to accelerated atherosclerosis.
IJD is associated with frequency, severity and vulnerability of coronary plaques.
Patients with IJD have higher risk of infarction after plaque rupture than individuals
without IJD, because of a hypercoagulable state induced by inflammation.
Nonischaemic heart disease like myocarditis, heart failure and myocardial
dysfunction also contributes to the burden of cardiovascular disease in IJD.
Abbreviation: IJD, inflammatory joint disease.
Thyroid disease
Autoimmunity is often a cause of hypothyroidism, and
the coexistence of these two diseases can affect cardio
vascular risk.77 Among patients with RA, those with
hypothyroidism have an increased cardiovascular risk
compared with those having normal thyroid function.
This effect of hypothyroidism has traditionally been
attributed to impaired vascular endothelial function,
hypertension and adverse effects on lipid profiles. In
patients with RA, the presence of thyroid peroxidase antibodies, which is strongly predictive of autoimmune hypothyroidism, is associated with greater cIMT progression
than in the absence of such antibodies.78 This association
suggests that assessment of thyroid function is important in the context of cardiovascular risk management in
patients with IJD.
Genetic factors
Genetic factors have a potential role in the link between

atherosclerosis and IJDs, in particular RA. Several
polym orphisms at loci both inside and outside the
MHC region of the genome are associated with sub
clinical atherosclerosis and cardiovascular events.7981
In this regard, associations have been found between
HLA-DRB1*04 shared epitope alleles and endothelial
dysfunction80 or cardiovascular morbidity.79 In the presence of the shared epitope, the TNF308 (rs1800629)
polymorphism predisposes patients with RA to cardio
vascular disease.81 Polymorphisms at loci outside the
MHC region seem to be associated with the risk of
cardiovascular events independently of the presence
oftraditional cardiovascular risk factors.76,82,83 In patients
In addition to traditional risk factors, inflammation is

an important independent contributor to cardiovascular
risk. The link was first established in the general population, in which Creactive protein (CRP) levels are associated with cardiovascular risk.87 In patients with IJD,
markers of active inflammation, including levels of CRP,
erythrocyte sedimentation rates, numbers of affected
joints and disease activity scores, as well as disease severity or cumulative inflammation (estimated by radiographic scores), have all been linked to cardiovascular
risk.79,8892 IJDs and atherosclerosis are considered to
have an inflammatory pathogenesis, in which the mechanisms of formation, progression, instability and rupture
of the atherosclerotic plaque resemble the mechanisms
observed in synovitis.93 Although high-grade systemic
inflammation seems to be central to the cardiovascular
risk in patients with IJD (Figure2), the interaction
between inflammation, traditional risk factors, genetic
factors and medication effects has not yet been elucidated.
Effects on vascular function and morphology

The striking similarities between the inflammatory processes in blood vessels and in joints of individuals with
IJDs, together with the links between markers of inflammation and cardiovascular disease in the general population, have led to the hypothesis that inflammation is
a major contributor to accelerated atherosclerosis.94
The pathways by which rheumatic inflammation leads
to accelerated atherosclerosis are not completely clear.
The endothelium has a key role in vascular function as
an endocrine organ, producing vasoactive factors that
control vasomotor tone, homeostasis and interactions
between the vessel wall and circulating blood cells. Nitric
oxide is one of the most important of these factors, and
inflammation can disrupt the equilibrium between the
production of nitric oxide and other vasoactive factors,
leading to endothelial-cell dysfunction, which in turn is
associated with atherosclerosis.95
Noninvasive techniques for the assessment of peripheral vascular function and morphology, which correlate
with coronary circulation, provide the means to assess
vascular health without compromising patient safety.96
Endothelial function can be assessed by testing the ability
of endothelial cells to release nitric oxide in response to
various stimuli, which is determined by quantification
of vessel dilation. Assessment of pulse-wave velocity
and pulse-wave analysis provide information on arterial
stiffness as an outcome of functional and morphological
changes in the vasculature. Structural changes resulting from advanced atherosclerosis can be assessed by
measurement of cIMT.

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Vascular function and morphology are both affected
in patients with RA, but a clear association with inflammation has not been demonstrated. 97 The results of
examinations of the effects of antirheumatic treatment
on vascular function and morphology are inconsistent,
possibly owing to variation in patients clinicalresponses.
Effects on plaque composition

In addition to accelerated atherosclerosis, the compo
sition of the atherosclerotic plaque has a role in the
incidence of cardiovascular disease in patients with IJD.
In patients with RA and no history of cardiovascular
disease, compared with matched controls without RA,
coronary plaques are more frequent (71% versus 45%),
more severe and more prone to rupture.98 Plaque vulner
ability is associated with rheumatic disease activity,
demonstrating a link between inflammation and plaque
composition.98,99 Plaques in patients with RA who have
active disease are more vulnerable than in those with RA
in clinical remission.99 Compared with matched controls
without RA, patients with RA have worse outcomes after
acute coronary syndrome, with increased deaths and
increased and earlier recurrence of MI.100 The histo
logical features of coronary artery disease in patients with
RA include vascular inflammation and unstable plaque
composition with higher frequency than in controls,
suggesting that the mechanisms responsible for cardio
vascular morbidity and mortality are different in patients
with RA compared with the generalpopulation.101
Effects on prothrombotic phenomena
In addition to accelerated atherosclerosis and unstable
plaques with increased chance of rupture, patients with
IJD have higher risk of infarction after plaque rupture
than individuals without IJD, owing to a hypercoagulable
state induced by inflammation in IJD.102 The immune and
coagulation systems are closely linked:102 inflammatory
cytokines induce expression of tissue factor, inhibit the
protein C system and act as inhibitors of fibrinolysis,
promoting a hypercoagulable state. Platelets are important factors in normal homeostasis and also have a role
in inflammation with the release of a range of thrombotic
and inflammatory molecules; the adhesion and aggregation of platelets are key tothe processes that occur
at the onset of MI after plaque rupture.103,104 Although
data relating to venous thrombotic events in IJDs are
scarce, it seems that the risks of pulmonary embolism
and deep-vein thrombosis are increased in patients
with RA when compared with the general population.105
Hypercoagulability is of particular interest in SLE because
antiphospholipid autoantibodies are highly prevalent in
this disease (and to a lesser extent in RA), so patients with
SLE have a high risk of (venous)thrombosis.106,107
Nonischaemic cardiovascular disease
In addition to atherosclerotic ischaemic heart disease,
myocarditis and myocardial dysfunction also contribute to the burden of cardiovascular disease in IJD.
Myocarditis is common in RA, with a reported post
mortem incidence of 1150%,108 but other inflammatory
pathologies, such as cardiac tamponade or constrictive

pericarditis, are very rare. Myocarditis has been linked
to HF,109 but is not always recognized as a cause of HF
in patients with RA because myocarditis is not detected
by echocardiographycardiovascular magnetic reson
ance (CMR) might be a better tool for this purpose but
requires prospective evaluation.110 HF is more common
in patients with RA than in the general population, with a
twofold higher incidence.10 Affected patients present with
diastolic dysfunction but preserved left ventricle ejection
fraction, reflecting the influence of chronic inflammation on the myocardium, which induces hypertrophy and
fibrosis and causes impairment in contractility.110,111 Left
ventricular diastolic dysfunction and pulmonary hypertension have been observed in patients with longstanding
RA without history of cardiovascular events and without
classic cardiovascular risk factors.112 Not only do patients
with RA and HF present differently from those without
HF, their prognoses are also worse, with significantly
highermortality.113
Predicting cardiovascular risk in IJD

Risk-prediction models
The well-established cardiovascular risk in patients
with RA, and to a lesser extent with other IJDs, implies
that cardiovascular risk assessment should be part of
routine care in such patients. Clinicians should be able
to identify those patients at highest risk, to adapt their
management accordingly. Unfortunately, cardiovascular
risk in patients with RA is still underestimated in clinical practice,114 and despite improvements in the understanding of the risk and the recommendations given by
the European League Against Rheumatism (EULAR)
Task Force, the management of cardiovascular risk
remainsunsatisfactory.63,115
In the past 12years, several algorithms have been
developed to aid the prediction of risk for cardio
vascular disease, such as the Framingham Risk Score,116
the Reynolds Risk Score,117,118 QRISK2 (EMIS and the
University of Nottingham, UK)119 and SCORE.120 These
risk models are largely based on longitudinal cohort
studies performed in the general population, raising the
question of whether they can also be of use in patients
with IJD. QRISK2 was developed in a population that
included patients with RA, and RA is an independent
risk factor in the algorithm. The Reynolds Risk score
incorporates CRP levels, but not within the range seen
in high-grade inflammatory diseases. None of these risk
models takes account of the influence of inflammation
and antirheumatic medication on lipids and other classic
risk factors, nor considers systematic differences between
IJD populations (which are predominantly female, with
restricted age ranges) and the general population. Some
attempts have been made to address these problems.
For instance, the EULAR Task Force has recommended
adapting risk models when calculating cardiovascular
risk in patients with RA by incorporating a multiplication
factor of 1.5 when a patient meets two or more of the
following three criteria: disease duration longer than
10years, positivity for rheumatoid factor or ACPA and
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presence of extra-articular manifestations.121 The 2012
ESC guidelines,122 as well as QRISK2, incorporate RA as
an independent cardiovascular risk factor in their models,
although in the ESC recommendations the presence of
RA has no influence on clinical management, in contrastto QRISK2. However, neither of these approaches
seems to improve accuracy in estimates of cardiovascular
risk in patients with IJD relative to models that do not
include RA,123,124 and risk-stratification models for this
group of patients require improvement. The 2013 guidelines of the joint task force of the American College of
Cardiology (ACC) and American Heart Association
(AHA) used the novel Pooled Cohort Equations to calculate the 10-year risk of atherosclerotic cardiovascular
disease.125 Compared with previous guidelines, in patients
with RA, this calculation considerably increased the
number who would be recommended for cholesterollowering statin treatment, but did not improve prediction
of cardiovascularrisk.126,127
Patients with RA often suffer from asymptomatic
atherosclerosis and silent ischaemic disease in the presence of an unstable plaque, which can lead to sudden
death.128 An early diagnosis of atherosclerosis, before
the onset of clinically evident cardiovascular disease,
can enable earlier and more aggressive primary prevention measures. Imaging studies and specific biomarkers
could potentially help with early diagnosis. Alternatively,
IJD-specific risk-prediction models might not be necessary if an approach of blanket primary prevention of
specific lipid and blood-pressure targets was taken in all
patients with IJD, similar to the practice associated with
diabetes.122 Whereas such an approach would be simpler
than developing specific models, its safety, effectiveness
and cost-effectiveness in these populations would need
to be formally assessed.
Imaging techniques
The underestimation of the cardiovascular risk in RA
might occur partly because of the high prevalence of
asymptomatic atherosclerosis in this group of patients.
Carotid ultrasonography is a noninvasive technique used
to detect atherosclerotic plaques in the carotid artery. The
presence of carotid atherosclerosis can be used as a surro
gate for coronary atherosclerosis. In addition, carotid
ultrasonography provides measurements of the cIMT.
InRA, cIMT is increased compared with individuals
without RA,129 and this increase is associated with a higher
incidence of cardiovascular events.130 In the 2012 ESC
guidelines,122 the presence of carotid plaques was recognized to be equal to having cardiovascular disease,which
implies that the addition of ultrasonography to risk
assessment would result in the classification of more
patients as being at high risk than current models without
imaging. In a study of the use of carotid ultrasonography
in patients with RA, this technique led to the categorization of 39% of patients into the group with high risk of
cardiovascular disease, whereas only 7% were estimated
to be at high risk with the Framingham Risk Score.92
Similarly, in patients with RA, compared with the modified EULAR SCORE alone, addition of the findings of
carotid ultrasonography improves the sensitivity in the

high cardiovascular-risk group.131 In patients with psoriatic arthritis, ultrasonographic assessment of individuals
stratified by Framingham Risk Score results in reclassification of a considerable number of patients into higher
cardiovascular risk categories.132 Although these results
suggest that the addition of carotid ultrasonography could
improve cardiovascular risk assessment in patients with
IJD, it has not yet been demonstrated that this inclusion
would ultimately lead to decreased cardiovascular risk.
Issues of feasibility, accessibility and cost relating to the
use of carotid ultrasonography also need to be addressed
before it can be recommended.
Biomarkers
In addition to imaging techniques, the value of a number
of biomarkers in cardiovascular-risk prediction has
been investigated, at least in the general population.
These biomarkers include genetic factors, markers of
inflammation, immunological markers and markers
ofendothelial function.6 For example, levels of the cytokine receptor osteoprotegerin (also known as tumor
necrosis factor receptor superfamily member 11B) are
associated with the presence of cardiovascular disease
in patients withRA,133 possibly through an association
with endothelial activation and carotid atherosclerosis.134
Angiopoietin2 is another marker of endothelial function
that correlates with cardiovascular disease in patients
with RA.135 Researchers have also evaluated the utility of
Btype natriuretic peptide as a marker for cardiovascular
risk in the presence of rheumatic disease.136 Serum uric
acid levels have associations with hypertension,137 renal
dysfunction138 and cardiovascular disease139 in patients
with RA, in the general population and in other at-risk
populations, but it remains unclear whether they reflect
specific pathogenic pathways or are epiphenomena.140
Microalbuminuria141 and mean platelet volume142 are
associated with hypertension in patients with RA, but
the utility of these factors in the prediction of cardio
vascular risk is not known. Asymmetric dimethylarginine
and symmetric dimethylarginine are potential biomarkers of cumulative inflammatory vascular damage and
cardiovascular disease inRA.143145
The use of biomarkers in risk-prediction models to
improve cardiovascular risk stratification was demonstrated in a large European population wherein additional measurement of the combination of Nterminal
pro-brain natriuretic peptide, CRP and troponin I led
to an improved 10year-risk estimation, compared with
a conventional-risk-factor model alone.146 The value
of these biomarkers for risk prediction in the presence
of IJDs is not known. A difficulty in the assessment of
this value is that the influence of IJD activity and treatment on biomarker levels has not yet been determined.
Another issue is that, whereas in the general population
large sample sizes are available, IJD cohorts are much
smaller, making it more difficult to validate biomarkers
against specific end points (such as MI), meaning that
international collaborations are likely to be required in
thisfield.

REVIEWS
Control of
disease activity
Early diagnosis
Nonpharmacological
management of
risk factors
Smoking cessation
Physical activity
Healthy diet
Antirheumatic therapy
Nonbiologic DMARDs
Biologic DMARDs
NSAIDs
Pharmacological
management
of risk factors
Statins
Antihypertensives
Cardiovascular risk management
Nature Reviews | Rheumatology

Figure 3 | Principles of cardiovascular risk management by rheumatologists.
Fromthe perspective of the rheumatologist, the management of cardiovascular
comorbidity of patients with IJD has three main principles. Pharmacological
management of cardiovascular risk factors includes medication to control blood
pressure and lipid levels. Nonpharmacological management of cardiovascular risk
factors includes lifestyle interventions such as cessation of tobacco smoking and
engagement in regular physical activity. Control of disease activity consists of
strategies to control the chronic systemic inflammation in IJD, by means of
DMARDs, NSAIDs, cyclooxygenase2 selective inhibitors and glucocorticosteroids.
Abbreviation: IJD, inflammatory joint disease.
Cardiovascular risk management
Risk assessment provides opportunities for disease prevention. From the perspective of the rheumatologist, the
management of cardiovascular comorbidity of patients
with IJD has three main principles: pharmacological
management and nonpharmacological management of
cardiovascular risk factors, and tight control of disease
activity (Figure3). Unfortunately, the risk of cardio
vascular disease in patients with RA is still not fully recognized, and these patients receive preventive measures
less often than the general population.
Lifestyle interventions
Lifestyle interventions should be the first steps in cardio
vascular risk management, and patients should be advised
to quit tobacco smoking and to engage in regular physical activity. Evidence pertaining to lifestyle interventions
demonstrates that exercise has several cardiovascular
benefits in patients with RA. 46 Structured exercise
therapy improves microvascular and macrovascular
function and cardiorespiratory fitness, and decreases
cardiovascularrisk.46,47
Pharmacological interventions
In the general population, and also in patients with diabetes, preventive measures such as lowering blood pressure and lipid levels are effective in reducing the burden of
cardiovascular disease.147 Whether these measures are also
beneficial for patients with IJD has not yet been studied
sufficiently, although, notably, it seems that statins have a
moderate anti-inflammatory effect in RA.148 Large, randomized, controlled trials are necessary to compare the
effects of preventive measures, with cardiovascular disease
outcomes as end points. Such trials require large numbers
of patients and several years of follow-up observation, and
are very difficult to conduct in populations of patients with
IJDs. Despite the limited availability of evidence relating
to the management of traditional risk factors in patients
with rheumatic diseases, wide-ranging support exists for
the practice of offering cardiovascular risk management
to all patients meeting the criteria set for risk reduction in
the general population. This strategy would require that
all patients with IJD are screened regularly, and when an
increase in risk is identified, patients should be managed
accordingly. However, a key question remains regarding
who is responsible for the preventive care of this group of
patients. In most countries, primary-care physicians carry
out cardiovascular risk management. Currently, awareness of the high risk in this group of patients is inadequate
among all health-care professionals, from primary-care
physicians to cardiologists and even rheumatologists.
Therefore, achieving adequate awareness is an important
objective, which should lead to appropriate cardiovascular
risk screening and preventivemeasures.
Control of disease activity

Tight disease control is thought to improve all outcomes
in IJDs, including cardiovascular outcomes, although randomized trials investigating cardiovascular outcomes in
this disease management approach are lacking. Chronic
systemic inflammation contributes substantially to the
cardiovascular risk associated with IJDs, and adequate
suppression of disease activity is necessary to reduce this
risk. This goal can be achieved by early diagnosis and
treatment of IJDs. However, from the cardiovascular point
of view, the best way to control inflammation is unknown.
Several DMARDs are available for treatment of IJDs, and
although they might all decrease cardiovascular risk by
reducing inflammation, other possible cardioprotective
or deleterious properties are also important to consider.
The influence of antirheumatic therapies on lipid levels
has received particular attention because of the inter
action between lipids and inflammation, although the
clinical relevance of this influence is uncertain. Notably,
all the available evidence relating to the effects of anti
rheumatic therapy on cardiovascular disease is derived
from observational studies, and caution is required when
making conclusions on the basis of this evidence, because
of potential sources of bias.
NSAIDs and cyclooxygenase2 inhibitors
Although the development of synthetic and biologic
DMARDs has led to substantial reductions in the chronic
use of NSAIDs and cyclooxygenase2 selective inhibitors (COXIBs) in the treatment of IJDs, these agents still
have important roles in disease management. However,
the use of NSAIDs and COXIBs is associated with cardio
vascular risk in the general population.149 Subgroup ana
lysis150 identified patients with RA as a cardiovascular-risk
group, but only in association with the use of rofecoxib
REVIEWS
and valdecoxib, both of which have now been withdrawn
from the market. A systematic review and meta-analysis,151
published in 2015, also identified cardiovascular risk in
patients with IJDs, which was largely associated with
the use of rofecoxib, and not with NSAIDs or celecoxib.
Notably, treatment with NSAIDs and COXIBs can have
beneficial effects in many patients with RA, perhaps by
reduction of inflammation and improvement of physical activity. The risks and benefits resulting from these
anti-inflammatory treatments in patients with IJDs
requireclarification.
Glucocorticosteroids have a complex and controversial
relationship with cardiovascular risk. They are very
effective at treating inflammation, which is associated
with cardiovascular risk. However, glucocorticosteroid
treatment can increase insulin resistance from baseline
levels, induce hypertension and cause metabolic syndrome, thereby increasing cardiovascular risk. Longterm use of high-dose glucocorticosteroids (>7.5mg of
prednisolone equivalent daily) is associated with mortality in patients with RA, but the net cardiovascular effect
of limiting glucocorticosteroid exposure needs to be
furtherelucidated.152
Nonbiologic DMARDs
Studies examining the effect of nonbiologic DMARDs on
cardiovascular risk have mainly focused on methotrexate, which is the cornerstone of RA therapy. In patients
with RA, methotrexate treatment seems to reduce cardio
vascular risk relative to patients without methotrexate, but
the mechanisms responsible for this protective property
are not clear.151 In terms of the activity of methotrexate,
suppression of inflammation seems to be the most important pathway for lowering cardiovascular morbidity and
mortality. Currently, this inflammatory hypothesis is being
tested by administration of low doses of methotrexate to
patients with prior MI and persistently elevated CRP,
todetermine whether methotrexate can have a role in the
prevention of secondary cardiovasculardisease.153
Biologic DMARDs
Inhibitors of TNF are utilized in the treatment of IJDs.
Anti-TNF therapy reduces inflammation and is associated
1.
2.
3.
4.
Avina-Zubieta, J.A., Thomas, J., Sadatsafavi, M.,

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Nurmohamed, M.T., van der HorstBruinsma, I.
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with cardiovascular risk reduction, compared with nonbiologic DMARDs, in patients with RA.151,154 Anti-TNF
therapy in patients with RA also modifies lipid levels from
baseline, increasing total cholesterol, HDL cholesterol, tri
glycerides and possibly LDL cholesterol.155 These changes
probably reflect a normalization of lipid levels by suppression of inflammation. Moreover, the antiatherogenic
properties of HDL cholesterol seem to be restored by TNF
blockade.85 Lipid changes are also frequently reported in
clinical trials of tocilizumab, a humanized monoclonal
antibody against the IL-6 receptor that inhibits the IL6
signalling pathway. A meta-analysis identified an effect
in patients with RA of treatment with tocilizumab (and
also tofacitinib, but not anti-TNFs), with increased levels
of total cholesterol, HDL cholesterol and LDL cholesterol
compared with placebo.156 The greater effect of tocilizumab on lipid levels relative to other biologic agents is
not a complete surprise, because IL6 affects serum lipid
levels by fatty acid mobilization into peripheral tissues.157
Conclusion and future perspectives
The body of evidence relating to cardiovascular disease

in IJDs is growing, but the mechanisms underlying the
increased cardiovascular risk in patients affected by these
conditions compared with the general population are not
yet clear. The results of further research could delineate
specific mechanisms in the pathogenesis of ischaemic
heart disease and address other pathologies, such as
microvascular dysfunction and autonomic neuropathy.
This knowledge will help to identify novel therapeutic
targets for the prevention and treatment of heart disease
in patients with IJDs. Existing models for the prediction
of cardiovascular risk are not sufficiently accurate in
these patients, and the development of disease-specific
approaches is necessaryalthough very challenging.
Prospective clinical trials are needed to assess the roles
of antirheumatic therapies, pharmacological control
of traditional risk factors and lifestyle-modification
strategies in the potential reduction of cardiovascular
risk in IJDs. In the meantime, systematic screening for
cardiovascular risk and coordination of care between
rheumatologists, internists, cardiologists and primarycare physicians is imperative to achieve optimal management of cardiovascular risk and cardiovascular disease in
patients with IJDs.
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Author contributions
All authors contributed equally to discussion of
content, writing the article and reviewing and editing
the manuscript before submission.

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REVIEWS

Cardiovascular comorbidity in rheumatic

Compared with the general population, patients with

burden, and medications to treat the rheumatic disease

IJD and cardiovascular disease burden

NATURE REVIEWS | RHEUMATOLOGY

ADVANCE ONLINE PUBLICATION | 1

Figure 1 | Contributors to cardiovascular risk in IJDs.Nature

cohort suggested that the magnitude of the cardiovascular

has not improved, demonstrating that cardiovascular

2 | ADVANCE ONLINE PUBLICATION

Inflammatory joint disease

Risk is mainly increased

Increased prevalence, usually

Common, often asymptomatic

Rare, associated with

High prevalence in autopsy

Common, mostly diastolic

Increased risk, mainly

Valvular heart disease

Rare, mostly not

Aortic root disease and aortic

Rare, possible association with

Some of the mechanisms that increase cardiovascular

Contributions of known risk factors

Traditional risk factors are important contributors to the

is complicated in patients with RA. Several studies have

NATURE REVIEWS | RHEUMATOLOGY

ADVANCE ONLINE PUBLICATION | 3

Body weight and physical inactivity

to determine the contribution of smoking to cardio

4 | ADVANCE ONLINE PUBLICATION

with RA, polymorphisms have also been linked to dyslipi

Inflammation and cardiovascular risk

Figure 2 | Contribution of inflammation to cardiovascular

Genetic factors have a potential role in the link between

In addition to traditional risk factors, inflammation is

Effects on vascular function and morphology

NATURE REVIEWS | RHEUMATOLOGY

ADVANCE ONLINE PUBLICATION | 5

Effects on plaque composition

pathologies, such as cardiac tamponade or constrictive

Predicting cardiovascular risk in IJD

6 | ADVANCE ONLINE PUBLICATION

carotid ultrasonography improves the sensitivity in the

NATURE REVIEWS | RHEUMATOLOGY

ADVANCE ONLINE PUBLICATION | 7

Cardiovascular risk management

Nature Reviews | Rheumatology

Cardiovascular risk management

Control of disease activity

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Avina-Zubieta, J.A., Thomas, J., Sadatsafavi, M.,

Conclusion and future perspectives

The body of evidence relating to cardiovascular disease

Investigation. Ann. Rheum. Dis. 68, 13951400

NATURE REVIEWS | RHEUMATOLOGY

Levy, L., Fautrel, B., Barnetche, T.

ADVANCE ONLINE PUBLICATION | 9

32. Robertson, J., Peters, M.J., McInnes, I.B.

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3nitrotyrosine in rheumatoid arthritis patients.

81. Rodrguez-Rodrguez, L. etal. TNFA 308

NATURE REVIEWS | RHEUMATOLOGY

2 | ADVANCE ONLINE PUBLICATION

4 | ADVANCE ONLINE PUBLICATION

6 | ADVANCE ONLINE PUBLICATION

8 | ADVANCE ONLINE PUBLICATION

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