STAT E O F T H E A RT R E V I E W

Increased cardiovascular risk in rheumatoid

arthritis: mechanisms and implications
Bryant R England,1 2 Geoffrey M Thiele,1 2 Daniel R Anderson,3 Ted R Mikuls1 2
1
Veterans Affairs (VA) Nebraska-
Western Iowa Health Care System, A B S T RAC T
Omaha, NE, USA
2
Division of Rheumatology and
Rheumatoid arthritis is a systemic autoimmune disease characterized by excess
Immunology, Department of morbidity and mortality from cardiovascular disease. Mechanisms linking
Internal Medicine, University of
Nebraska Medical Center, Omaha, rheumatoid arthritis and cardiovascular disease include shared inflammatory
NE, USA
3
mediators, post-translational modifications of peptides/proteins and subsequent
Division of Cardiology,
Department of Internal Medicine, immune responses, alterations in the composition and function of lipoproteins,
University of Nebraska Medical
Center, Omaha, NE, USA increased oxidative stress, and endothelial dysfunction. Despite a growing
Correspondence to: T R Mikuls understanding of these mechanisms and their complex interplay with conventional
tmikuls@unmc.edu
Cite this as: BMJ 2018;361:k1036 cardiovascular risk factors, optimal approaches of risk stratification, prevention, and
doi: 10.1136/bmj.k1036 treatment in the context of rheumatoid arthritis remain unknown. A multifaceted
Series explanation: State of the approach to reduce the burden posed by cardiovascular disease requires optimal
Art Reviews are commissioned
on the basis of their relevance to management of traditional risk factors in addition to those intrinsic to rheumatoid
academics and specialists in the US
and internationally. For this reason arthritis such as increased disease activity. Treatments for rheumatoid arthritis
they are written predominantly by
US authors
seem to exert differential effects on cardiovascular risk as well as the mechanisms
linking these conditions. More research is needed to establish whether preferential
rheumatoid arthritis therapies exist in terms of prevention of cardiovascular disease.
Ultimately, understanding the unique mechanisms for cardiovascular disease in
rheumatoid arthritis will aid in risk stratification and the identification of novel
targets for meaningful reduction of cardiovascular risk in this patient population.

Introduction controlled trials, and observational (excluding case

Rheumatoid arthritis is a systemic, autoimmune disease
that affects approximately 0.5-1.0% of the population.1
It is characterized by a symmetrical inflammatory polyar-
thritis, but extra-articular features are also common and
portend a poor prognosis. Because of its frequency and
relevance to patients’ morbidity and survival, cardiovas-
cular disease has been a topic of substantial research,
resulting in an improved understanding of the mecha-
nisms linking rheumatoid arthritis and cardiovascular
disease and supporting improved cardiovascular risk
reduction in rheumatoid arthritis patients. In this review,
we describe the scientific advancements elucidating the
mechanisms linking rheumatoid arthritis and cardiovas-
cular disease, the cardiovascular risk associated with spe-
cific drugs used to treat rheumatoid arthritis, and relevant
clinical management.
Sources and selection criteria
We searched PubMed for English language manuscripts
published from 1 January 2006 to 1 June 2017, using
the MeSH terms “rheumatoid arthritis” and “cardiovas-
cular disease” or “cardiovascular system”, identifying
2687 reports. We then searched reference lists of articles
selected through title, abstract, and full text review. We
selected systematic reviews, meta-analyses, randomized
reports and small case series (n<15)), translational, and
basic science studies from these sources, prioritized by
study quality and topic.
Burden of cardiovascular disease in rheumatoid arthritis
Cardiovascular disease accounts for the largest proportion
of excess mortality in rheumatoid arthritis, accounting for
39.6% of deaths in a review of 50 studies that included
91 618 patients and 33 250 deaths.2 In two large meta-
analyses that together contributed more than 150 000
patients, rheumatoid arthritis was associated with a 48%
increased risk of cardiovascular events (relative risk 1.48,
95% confidence interval 1.36 to 1.62) and a 50% higher
incidence of cardiovascular disease related mortality
(standardized mortality ratio 1.50, 95% confidence inter-
val 1.39 to 1.61) compared with the general population.3 4
Because atherosclerosis and congestive heart failure (CHF)
are the most frequent manifestations of cardiovascular
disease, the focus of this review reflects this.
Mechanisms linking rheumatoid arthritis and
cardiovascular disease
Traditional cardiovascular risk factors
The focus of this review is on rheumatoid arthritis related
factors contributing to cardiovascular risk, but it is cr­itical

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GLOSSARY OF ABBREVIATIONS
ABCA-1—aqueous diffusion, scavenger receptor B
ABCG-1—ATP binding cassette transporter G1
ACPA—anti-citrullinated protein antibodies
ACS—acute coronary syndrome
AIA—adjuvant induced arthritis
CCP—anti-cyclic citrullinated peptide
CHF—congestive heart failure
CIA—collagen induced arthritis
CRP—C reactive protein
DAS28—28 joint disease activity score
DMARD—disease modifying anti-rheumatic drug
eNOS—endogenous nitric oxide synthase
EPCs—endothelial progenitor cells
ESR—erythrocyte sedimentation rate
EULAR—European Union League Against Rheumatism
HDL—high density lipoprotein
hsCRP—high sensitivity C reactive protein
IL—interleukin
LDL—low density lipoprotein
MCP-1—monocyte chemoattractant protein-1
NSAID—non-steroidal anti-inflammatory drug
RCT—randomized controlled trial
RORA-AS—ROsuvastat in Rheumatoid Arthritis, Ankylosing
Spondylitis and other inflammatory joint diseases (trial)
ROS—reactive oxygen species
SAA—serum amyloid A
Tang—angiogenic T cells
TEAR—Treatment of Early RA (trial)
TNF-α—tumor necrosis factor α
to acknowledge the contribution of traditional cardiovas-
cular risk factors in rheumatoid arthritis patients. In a
prospective cohort study, hypertension, dyslipidemia,
and insulin resistance were observed to be more closely
related to surrogate markers of cardiovascular disease—
microvascular function, endothelial function, and carotid
intima media thickness—than were inflammatory mark-
ers in rheumatoid arthritis.5 Longitudinal analysis of cor-
onary artery calcium scores showed similar incidence and
progression between rheumatoid arthritis patients and
controls, with traditional risk factors, rather than char-
acteristics of rheumatoid arthritis, being most predictive.6
Traditional cardiovascular risk factors, including obesity,
diabetes, smoking, and hypertension, seem to be over-
represented in rheumatoid arthritis,7 8 findings that have
not been universally replicated.9 10 In contrast, smoking
has consistently been identified as a robust and shared
risk factor for the development of cardiovascular disease
and rheumatoid arthritis.11
Disease activity and inflammation
Mounting evidence suggests a central role of the immune
system in the pathogenesis of cardiovascular disease, and
pro-inflammatory cytokines implicated in rheumatoid
arthritis also enhance atherogenesis.12 Thus, the devel-
opment of “risk calculators” that adequately account for
disease activity will be critical to improve cardiovascular
risk assessment because conventional risk factors do not
fully explain the excess burden of cardiovascular disease
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in rheumatoid arthritis.13 Supporting this contention,
several observational studies have identified associations
between higher disease activity in rheumatoid arthritis and
cardiovascular outcomes. In a Swedish nested case-control
study of incident rheumatoid arthritis, higher disease activ-
ity was associated with increased odds of acute coronary
syndrome (ACS) based on acute phase response as well
as different composite measures of disease activity (odds
ratio 1.32 per unit increase in 28 joint disease activity score
(DAS28); odds ratio 1.61 for moderate and 2.59 for high
European Union League Against Rheumatism (EULAR) dis-
ease activity score compared with to low disease activity).14
Similar results were observed in a US cohort study, in
which time averaged disease activity in the remission range
was associated with a 53% lower risk of cardiovascular
events than in high disease activity, independent of tradi-
tional cardiovascular risk factors and rheumatoid arthritis
treatments.15 These observations were further corroborated
in the Nijmegen early rheumatoid arthritis cohort, in which
a 1 unit increase in time averaged DAS28, but not disease
duration, was associated with a 33% higher risk of car-
diovascular disease.16 Likewise, higher C reactive protein
(CRP) and erythrocyte sedimentation rates (ESR) were asso-
ciated with a significantly increased risk of cardiovascular
disease in two large US studies and a Spanish rheumatoid
arthritis cohort.17‑19 A population based cohort study of
incident rheumatoid arthritis showed that each six week
flare was associated with a 7% increase in risk of cardio-
vascular disease, whereas patients in remission had a risk
similar to that of non-rheumatoid arthritis controls.20
Disease activity and cardiac function
Rheumatoid arthritis disease activity is not only predic-
tive of cardiovascular events but also strongly correlates
with cardiac function. Using speckle-tracking echocar-
diography, greater left ventricular strain was observed in
rheumatoid arthritis patients than in controls and was
associated with disease activity.21 Similarly, higher rheu-
matoid arthritis disease activity is positively associated
with left ventricular global longitudinal strain,22 as well
as left ventricular wall thickness.23 Diastolic dysfunction
is also over-represented in rheumatoid arthritis patients
and is associated with higher circulating interleukin
(IL)-6 concentrations.24
Recognizing the aforementioned associations of dis-
ease activity, rheumatoid arthritis treatments that target
remission might be necessary to optimally preserve car-
diac function. Supporting this hypothesis, rheumatoid
arthritis patients in remission (Simplified Disease Activ-
ity Index <3.3) showed improved left ventricular func-
tion as assessed by stress corrected mid-wall shortening
and global longitudinal strain compared with those with
low, moderate, or high disease activity.25 Differences in
left ventricular function were independent of traditional
cardiovascular risk factors.25 Moreover, no differences
in left ventricular function were seen between healthy
controls and rheumatoid arthritis patients in remission.
Disease activity and surrogate markers
To better understand the contributions of inflammation,
several observational studies have examined the relation
 STAT E O F T H E A RT R E V I E W
of rheumatoid arthritis disease activity with surrogate
markers of cardiovascular disease. In a cross sectional
study using computed tomography-angiography, rheuma-
toid arthritis patients had higher coronary artery plaque
burden than controls and higher disease activity was
associated with the presence of unstable plaque,26 sug-
gesting that disease related inflammation contributes not
only to development of plaques but also to their vulner-
ability and rupture. Both swollen joint counts and CRP
were associated with the carotid plaque progression in
rheumatoid arthritis,27 and circulating IL-6 and tumor
necrosis factor α (TNF-α) concentrations were indepen-
dently associated with coronary artery calcification.28
Additionally, multivariable analyses accounting for
IL-6 and CRP concentrations attenuated the association
between rheumatoid arthritis and coronary artery calci-
fication, suggesting that inflammation mediates patho-
physiologic processes of stable and unstable plaque.29
Exploring how traditional and non-traditional risk fac-
tors together contribute to risk of cardiovascular disease,
a cohort study of rheumatoid arthritis patients undergo-
ing serial carotid ultrasonography over a span of three
years showed that systemic inflammation and traditional
risk factors both predicted progression of atherosclero-
sis.30 Importantly, risk related to systemic inflammation
seemed to be dependent on the number of traditional risk
factors present. Specifically, ESR values predicted athero-
sclerosis progression only in rheumatoid arthritis patients
with two or more conventional risk factors, suggesting an
interaction between traditional and rheumatoid arthritis
related cardiovascular risk factors.
Cellular mechanisms
Ex vivo and in vitro studies have begun to elucidate cel-
lular mechanisms by which rheumatoid arthritis related
inflammation drives cardiovascular disease. Aortic
adventitia from rheumatoid arthritis patients undergo-
ing coronary artery bypass grafting showed increased
TNF-α and IL-18 expression compared with controls, as
well as increased IL-33 and IL-33 ligand expression in
endothelial cells of the aortic adventitia vasa vasora.31
These findings suggest the existence of a unique pro-
inflammatory adventitial microenvironment in rheuma-
toid arthritis that fosters atherogenesis through linkage
of innate and adaptive immune responses, key roles of
IL-18 and IL-33. A cross sectional analysis of circulating
peripheral blood mononuclear cells taken from rheu-
matoid arthritis patients recently identified cell subsets
strongly associated with coronary artery calcification.32
Independent of traditional cardiovascular risk factors and
other features of rheumatoid arthritis, unique effector
memory CD4 T cell and monocyte subsets were associated
with coronary artery calcification, suggesting a potential
intrinsic link between immune subsets that are character-
istic of rheumatoid arthritis and cardiovascular disease.
In vitro, the addition of IL-17 and TNF-α to endothelial
cells induced a pro-inflammatory, pro-thrombotic, and
pro-coagulant state.33 TNF-α also cleaves VE-cadherin,34
an endothelium specific adhesion molecule important in
maintaining endothelial tight junctions. Cleavage of this
molecule could result in increased permeability, intersti-
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tial edema, and hemorrhage in vivo. Despite these intrigu-
ing findings, much more work is needed to elucidate the
pro-inflammatory networks bridging rheumatoid arthritis
and cardiovascular disease.
Oxidative stress
Oxidative stress, an imbalance of reactive oxygen species
(ROS) and antioxidants, is typically increased in the con-
text of inflammation and contributes to the development
of cardiovascular disease and rheumatoid arthritis,35 36
representing another potential shared pathway between
the diseases. Concentrations of malondialdehyde and
nitrotyrosine, two nitro-oxidative stress parameters, are
associated with increased myocardial strain in rheuma-
toid arthritis.37 Myeloperoxidase, a source of oxidants, is
increased in the serum of rheumatoid arthritis patients
relative to controls. Moreover, myeloperoxidase derived
oxidants seem to target and impair the function of high
density lipoproteins (HDL).38 Advanced glycosylation end
products, generated in the setting of hyperglycemia and
oxidative stress, are increased in rheumatoid arthritis rel-
ative to controls and inversely associated with endothelial
function.39
Serum and left ventricular tissues from rats with adju-
vant induced arthritis (AIA), an animal model of rheu-
matoid arthritis, had a higher concentration of oxidative
stress related aldehyde than controls.40 NADPH and glu-
tathione pools were 30% lower in left ventricular tissues
of AIA rats than controls, suggesting depletion of key anti-
oxidant system reserves related to inflammatory arthritis.
Showing both the complexity and the interconnectedness
of systems, renin-angiotensin activation in the AIA mouse
exacerbated vascular hypertrophy and oxidative stress,
whereas angiotensin II type-1 receptor blockade reduced
NADPH oxidase activity and oxidative stress in aortic tis-
sues and improved endothelial function.41
Endothelial dysfunction
The endothelium regulates vascular tone and homeo-
stasis, and its dysregulation is integral to atherogenesis.
Rheumatoid arthritis has been characterized by endothe-
lial dysfunction that seems to evolve throughout its natu-
ral course. A longitudinal study observed no differences
in endothelial function measured by endothelial depend-
ent, flow mediated dilatation in newly diagnosed rheu-
matoid arthritis cases compared with controls, although
cases showed increased carotid intima media thickness
over time.42 A case-control study found impaired coro-
nary flow reserve in early rheumatoid arthritis that was
inversely associated with asymmetric dimethylargi-
nine, an inhibitor of endogenous nitric oxide synthase
(eNOS),43 which is essential in regulating vascular tone,
leukocyte adhesion, and platelet aggregation. Reports
on the role of disease activity in endothelial function
have been conflicting. Effective disease modifying anti-
rheumatic drugs (DMARDs) can improve microvascular
endothelial function,44 and in the AIA model circulating
IL-1β, TNF-α, and MIP-1α concentrations were nega-
tively associated with endothelial function.45 In contrast,
endothelial function was not associated with rheumatoid
arthritis disease activity in at least one cross sectional
 STAT E O F T H E A RT R E V I E W
study but was associated with composite cardiovascu-
lar risk scores.46 Critical to endothelial function, repair,
and neovascularization are endothelial progenitor cells
(EPCs) and recently identified angiogenic T cells (Tang).
Relative to controls, EPCs and Tang are reduced in rheu-
matoid arthritis, with the lowest Tang counts noted among
patients with comorbid cardiovascular disease.47 48 Their
connection to rheumatoid arthritis is further established
through inverse associations with disease activity and
improved EPC counts after treatment with TNF inhibi-
tors.47 48
The complex interplay of mechanisms is further high-
lighted by the fact that endothelial function is also influ-
enced by oxidative stress. In vitro experiments using
endothelial cells from rheumatoid arthritis patients
showed that endogenous ligands and phospholipid
oxidation products activate endothelial cells through
NFkB pathways via toll-like receptor 4 signaling.49 The
AIA model was used to characterize downstream conse-
quences of systemic inflammation in rheumatoid arthri-
tis, showing that dysregulation of NADPH oxidases and
eNOS occurred and resulted in enhanced lipid peroxida-
tion, generation of vascular ROS, and impairment of aor-
tic endothelial function.50
Post-translational modifications and autoantibodies
Post-translational protein modifications, including cit-
rullination—the enzymatic conversion of the amino acid
arginine to citrulline—are hypothesized to contribute to
development of rheumatoid arthritis. Anti-citrullinated
protein antibodies (ACPA) are highly disease specific,
are detectable in most rheumatoid arthritis patients,
and portend more severe arthritis. Epidemiologic stud-
ies have reported varying results specific to autoantibody
associations with cardiovascular disease. Anti-cyclic
citrullinated peptide (CCP; a commercial ACPA meas-
ure) and rheumatoid factor positivity have been linked
to increased risk of ischemic heart disease and incident
CHF.17 51 52 In separate nested case-control and cohort
studies, however, seropositivity was not associated with
risk of ACS or with cardiovascular disease related morbid-
ity or mortality.14 53 Supporting a possible pathogenic role
of these autoantibodies, seropositivity was associated
with risk of cardiovascular disease even in the absence of
rheumatoid arthritis in the Multi-Ethnic Study of Athero-
sclerosis (rheumatoid factor and anti-CCP) and Northwick
Park Heart Study (anti-CCP).54 55
Several observational studies have characterized asso-
ciations between autoantibodies and cardiac function.
Anti-CCP antibody was associated with left ventricular
global longitudinal strain, impaired left ventricular relax-
ation, and lower left ventricular mass, stroke volume, and
end diastolic volume by cardiac magnetic resonance
imaging in rheumatoid arthritis.22 56 57 These findings
prompted investigation of the myocardium for the pres-
ence of citrullinated antigens acting as putative targets for
pathogenic autoantibodies. Compared with control speci-
mens, left ventricular tissues from rheumatoid arthritis
patients showed increased staining for citrullinated pro-
teins as well as peptidyl arginine deiminases (enzymes
catalyzing citrullination).58
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ACPA recognize a variety of citrullinated (cit-) peptides,
with data suggesting that antigen specificity could influ-
ence pathogenicity. For instance, higher circulating con-
centrations of anti-cit-fibrinogen and anti-cit-vimentin
antibody were associated with increased left ventricular
mass in independent rheumatoid arthritis cohorts free of
cardiovascular disease.59 This was not observed for anti-
bodies recognizing non-citrullinated (native) peptides/
proteins. In the same cohorts, higher concentrations of
anti-cit-histone H2B antibody (but not antibody to other
citrullinated or native antigens) were associated with cor-
onary artery calcium scores but not with coronary artery
calcium progression.60 In contrast, among rheumatoid
arthritis patients with comorbid cardiovascular disease,
investigators observed no evidence of associations between
rheumatoid factor, anti-cit-fibrinogen, anti-cit-Fibβ 36-52,
and anti-CCP antibody, or of rheumatoid factor with carotid
intima media thickness, carotid plaque, or coronary artery
calcium scores.61
A structural analog of citrulline and a result of car-
bamylation, homocitrulline is the antigenic target of
anti-carbamylated protein antibodies. These antibodies
were recently identified in rheumatoid arthritis patients
and were associated with subclinical cardiovascular dis-
ease.62 63 In addition, carbamylation has been shown to
be pro-atherogenic in other disease states.64 Malondial-
dehyde-acetaldehyde adducts represent an alternative
post-translational modification postulated to contribute
to both cardiovascular disease and rheumatoid arthri-
tis. Malondialdehyde-acetaldehyde adducts are gener-
ated under oxidative stress and lipid peroxidation, are
highly immunogenic, and unlike malondialdehyde are
highly stable.65 66 Circulating anti-malondialdehyde-
acetaldehyde antibody concentrations are increased in
rheumatoid arthritis compared with controls and corre-
late with disease activity, and IgG isotypes are associated
with comorbid cardiovascular disease.67 Moreover, anti-
malondialdehyde-acetaldehyde antibody concentrations
are higher among non-rheumatoid arthritis patients pre-
senting for cardiac care than in healthy controls, isotypes
vary markedly depending on coronary artery disease phe-
notype, and malondialdehyde-acetaldehyde adducts have
been detected in atherosclerotic human aortic tissue.68
Lipid perturbations
Quantitative lipoprotein alterations
In the general population, higher total cholesterol and
low density lipoprotein (LDL) concentrations confer
increased risk of cardiovascular disease. In rheumatoid
arthritis, however, this interpretation is overly simplistic.
For example, rheumatoid arthritis patients with moderate
LDL cholesterol concentrations (70-130 mg/dL) have been
observed to have the lowest risk of myocardial infarction,
with low and high LDL concentrations corresponding to
increased risk.18 Lower total cholesterol and LDL were
associated with increased cardiovascular events in a sep-
arate rheumatoid arthritis cohort 69; and in a study of US
Veterans with rheumatoid factor, LDL was not associated
with either myocardial infarction or stroke.17 These find-
ings have prompted the description of a “lipid paradox”
in rheumatoid arthritis,69 which is not a universal fin­ding
 STAT E O F T H E A RT R E V I E W
as higher LDL concentrations have portended higher risk
of cardiovascular disease in at least one large claims based
study.70 In contrast to reports for total cholesterol and LDL,
associations between HDL and cardiovascular events have
been relatively consistent and similar to the general popu-
lation, with higher HDL concentrations yielding lower car-
diovascular risk.17 18 70
Evidence suggesting the existence of this lipid paradox
in rheumatoid arthritis has led to several studies examin-
ing the effects of inflammation on lipids. In an observa-
tional study of rheumatoid arthritis patients with visits one
year apart, reductions in high sensitivity (hs)CRP of more
than 10 mg/dL were strongly associated with increases in
LDL, apolipoprotein A1, HDL, and HDL cholesterol efflux
capacity.71 No associations were seen with changes in
hsCRP and apolipoprotein B or atherogenic indices (total
cholesterol/HDL and apoliporotein B/A1). Others have
similarly found lipid ratios (such as total cholesterol/HDL
or LDL/HDL) to be less influenced by systemic inflamma-
tion and thus a preferred measure for cardiovascular risk
stratification in rheumatoid arthritis.72 Further support-
ing a link with inflammation are the changes in lipids that
occur as a consequence of rheumatoid arthritis treatments.
In the Treatment of Early RA (TEAR) trial, a two year, rand-
omized, placebo controlled, four arm trial in 755 patients
with early rheumatoid arthritis, starting DMARD treatment
resulted in significant increases in total cholesterol, HDL,
and LDL that correlated with improvements in CRP.73
Functional lipoprotein alterations
Although lipid concentrations are most often leveraged
for cardiovascular risk stratification, assessments of lipo-
protein function may be more relevant in the context of
rheumatoid arthritis. HDL acts as an antioxidant and regu-
lates cholesterol efflux. Under inflammatory conditions,
changes in HDL composition occur and lead to impaired
function.74 Rheumatoid arthritis disease activity and ero-
sions were independently associated with the presence
of pro-inflammatory HDL.74 Likewise, HDL function was
impaired in rheumatoid arthritis patients relative to con-
trols, with the lowest function in those with pro-inflam-
matory HDL. Proteomic profiling of HDL from patients
with rheumatoid arthritis showed that inflammatory HDL
contained increased acute phase proteins.75 The primary
component responsible for the antioxidant properties of
HDL is paroxonase-1. Paranoxase-1 activity is decreased
in rheumatoid arthritis compared with controls,76 which
is highly relevant as lower paranoxase-1 activity is associ-
ated with increased carotid plaque burden.77 Changes to
lipid composition in rheumatoid arthritis are not limited
to HDL. LDL from rheumatoid arthritis patients had higher
levels of glycated end products and was more oxidized
than LDL from controls.78 In vitro, LDL from rheumatoid
arthritis patients underwent enhanced phagocytosis by
macrophages, had higher fatty acid accumulation, and
induced approximately threefold greater oxidation.
HDL antioxidant function and cholesterol efflux capac-
ity are only moderately correlated, suggesting that these
properties might be influenced differentially in rheu-
matoid arthritis. HDL participates in reverse cholesterol
transport by removing cholesterol from cells in a process
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termed “cholesterol efflux.” HDL from rheumatoid arthritis
patients with high disease activity had reduced cholesterol
efflux capacity in vitro compared with HDL from patients
with low disease activity.79 Serum from rheumatoid arthri-
tis patients showed impaired ATP binding cassette trans-
porter G1 (ABCG-1) mediated cholesterol efflux capacity
compared with controls, which inversely correlated with
disease activity.80 Other mechanisms of cholesterol efflux
examined (ABCA-1, aqueous diffusion, scavenger recep-
tor B1) did not differ from controls. Naive THP-1 mac-
rophages exposed to plasma from rheumatoid arthritis
patients downregulated cholesterol efflux proteins (ABCA-
1, ABCG-1, 27-hydroxylase) and upregulated scavenger
receptors (CD36, LOX1, CXCL16) resulting in increased
uptake of oxidized LDL and foam cell formation.81 In vitro,
serum from rheumatoid arthritis patients increased mRNA
expression of scavenger receptors (SR-A, LOX-1, CD36) in
human arterial endothelial cells and increased oxidized
LDL induced monocyte chemoattractant protein-1 (MCP-1)
production, and IL-6 and TNF-α upregulated oxidized LDL
uptake through activation of SR-A and LOX-1, transform-
ing macrophages into foam cells.82 83 These processes were
attenuated with inhibition of IL-6 or TNF-α.
The collagen induced arthritis (CIA) animal model of
rheumatoid arthritis, which has a pro-atherogenic lipid
profile with lower HDL and higher oxidized LDL, has also
aided in defining lipid mechanisms.84 After exposing
murine peritoneal macrophages to serum from CIA mice,
accelerated cholesterol accumulation occurred without
changes in apolipoprotein A1 or HDL mediated intracellu-
lar cholesterol efflux. CD36 expression, a robust regulator
of lipid influx, was increased after exposure to CIA serum.
MCP-1, a pro-inflammatory cytokine upregulated in CIA,
did not affect lipid accumulation or CD36 expression.
However, serum with higher oxidized LDL and lower HDL
concentrations upregulated CD36 mRNA expression, an
effect that was reduced with administration of simvasta-
tin. Together, these findings suggest that the inflammation
of rheumatoid arthritis alters lipid composition/function,
enhances scavenger receptor expression, and amplifies
cholesterol influx and foam cell formation.
Interaction of traditional and rheumatoid arthritis related
cardiovascular risk factors
The relation between conventional risk factors and rheu-
matoid arthritis related mechanisms driving excess cardio-
vascular disease burden is complex and often bidirectional
(fig 1). Oxidative stress, for instance, characterizes sys-
temic inflammation in rheumatoid arthritis and promotes
insulin resistance, which in turn further exacerbates ROS-
antioxidant imbalance. Although obesity is a recognized
cardiovascular risk factor, an “obesity paradox” has been
observed in rheumatoid arthritis whereby greater body mass
is protective of cardiovascular disease mortality.85 Proposed
hypotheses include the inadequacy of commonly used body
composition measures, epidemiologic phenomena such as
index event bias,86 confounding by comorbidity,85 and lack
of consideration of weight trajectories.87 88 Adiposity itself
may contribute to systemic inflammation, insulin resistance,
and cardiovascular disease risk through the release of adi-
pokines or other pro-inflammatory mediators.89‑93
 STAT E O F T H E A RT R E V I E W

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Fig 1 |  Overview of mechanisms of cardiovascular disease (CVD) in rheumatoid arthritis (RA). Several mechanisms interact to amplify risk of CVD in RA. Higher RA
disease activity contributes to systemic inflammation and pro-inflammatory cytokine production. This inflammation causes quantitative and qualitative lipid
modifications resulting in perturbations of cholesterol transport and enhanced foam cell formation. Post-translational modifications of proteins serve as targets
of RA autoantibodies that may have deleterious effects on the cardiovascular system and enhance systemic/local inflammation. Oxidative stress, which results
from inflammation, contributes to post-translational modifications of proteins and directly affects endothelial function. These RA related mechanisms exacerbate
the pathogenicity of traditional CVD risk factors such as tobacco use, diabetes, hypertension, dyslipidemia, obesity, and chronic kidney disease. ACPA=anti-
citrullinated protein antibodies; HDL=high density lipoprotein; IL=interleukin; LDL=low density lipoprotein; oxLDL=oxidized LDL; MAA=malondialdehyde-
acetaldehyde; RF=rheumatoid factor; ROS=reactive oxygen species

Cardiovascular disease risk and RA treatments
Recent advances in rheumatoid arthritis management
have been accompanied by growing interest in under-
standing how these therapies might affect risk of cardio-
vascular disease. In the following section and figure 2,
we review clinical data on cardiovascular risk with rheu-
matoid arthritis treatment, as well as studies providing
insight into mechanistic pathways.
Methotrexate
Methotrexate, long considered a cornerstone of rheu-
matoid arthritis treatment, has garnered substantial
interest for its potential cardioprotective effects. In a sys-
tematic review and meta-analysis of observational and
controlled trials encompassing 28 studies and 236 525
rheumatoid arthritis patients, methotrexate was associ-
ated with a 28% reduction in cardiovascular events (rela-
tive risk 0.72, 95% confidence interval 0.57 to 0.91).94
Subsequent observational studies further supported the
beneficial effect of methotrexate on cardiovascular dis-
ease in rheumatoid arthritis with a 34-66% reduction in
cardiovascular events.128 129 Although few studies have
investigated CHF outcomes, methotrexate has looked
protective in cohort and nested case-control studies.52 130
In addition to its indirect effects mediated by reduc-
tions in rheumatoid arthritis disease activity, methotrex-
ate seems to exert other cardioprotective properties on
lipids and endothelium. Sera from rheumatoid arthritis
patients treated with methotrexate showed increased
cholesterol efflux capacity mediated by ABCG-1 and scav-
enger receptor class B type I,95 an effect that was absent
among those receiving adalimumab. In vitro, methotrex-

For personal use only 6 of 17

 STAT E O F T H E A RT R E V I E W

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Fig 2 |  Drugs used for treatment of rheumatoid arthritis and their cardiovascular risk. CHF=congestive heart failure; COX=cyclooxygenase; CVD=cardiovascular
disease; DMARDs=disease modifying anti-rheumatic drugs; HCQ=hydroxychloroquine; LDL=low density lipoprotein; MI=myocardial infarction; NSAID=non-
steroidal anti-inflammatory drug; RA=rheumatoid arthritis; RR=relative risk; TNF=tumor necrosis factor17 90 94-127

For personal use only 7 of 17

 STAT E O F T H E A RT R E V I E W
ate inhibits foam cell formation by promoting reverse
cholesterol transport through activation of adenosine A2
receptor and increases in cholesterol 27-hydroxylase and
ABCA-1.96 Methotrexate has direct beneficial effects on
vascular endothelium in vitro by inducing mitochondrial
antioxidant enzyme production.97 Additionally, it actively
scavenges superoxide radicals and prevents malondial-
dehyde-acetaldehyde-adduct formation in vitro, which is
important because malondialdehyde-acetaldehyde modi-
fication activates the immune system, impairs endothe-
lial function, and generates free radicals.98 Methotrexate
also scavenges intracellular free radicals generated by
malondialdehyde-acetaldehyde adduction.
Other conventional DMARDs and combination DMARD
therapies
Post hoc analysis of the TEAR trial showed that over two
years of follow-up, patients treated with triple therapy
(methotrexate, hydroxychloroquine, and sulfasala-
zine) had improved lipid profiles compared with those
treated with methotrexate monotherapy or methotrex-
ate plus etanercept.99 Triple therapy resulted in higher
HDL and lower LDL, total cholesterol, and total choles-
terol/HDL ratio.99 A follow-up study from the TEAR trial
showed that, whereas HDL function was similar between
treatment arms, triple therapy was associated with an
improved HDL inflammatory index and HDL associated
haptoglobin concentrations.90 Favorable lipid changes
have also been observed with hydroxychloroquine. Our
group has previously reported that use of hydroxychlo-
roquine for more than three months was associated with
improved total cholesterol, LDL, triglycerides, HDL/
LDL, and total cholesterol/HDL.100 Moreover, rheuma-
toid arthritis patients treated with hydroxychloroquine
were more likely to reach recommended lipid targets.
Similarly, in an observational study of incident rheuma-
toid arthritis, hydroxychloroquine use was associated
with decreases in LDL and total cholesterol, with trends
toward increased HDL and decreased triglycerides.101
Beyond favorable lipid changes, hydroxychloroquine
use has been associated with a significantly reduced risk
of diabetes and near 70% reduction in cardiovascular
events in rheumatoid arthritis.102 131
Biologic and small molecule DMARDs
TNF inhibitors
The aforementioned systematic review and meta-analy-
sis estimated a 30% reduction in risk of cardiovascular
events with TNF inhibitors in rheumatoid arthritis (rela-
tive risk 0.70, 0.54 to 0.90), with protective associations
specifically for myocardial infarction (0.59, 0.36 to 0.97)
and stroke (0.57, 0.35 to 0.92).94 TNF inhibitor use might
also influence outcomes after a cardiovascular event. In
a propensity score adjusted observational study, mortal-
ity after acute myocardial infarction was similar between
patients using TNF inhibitors and conventional DMARDs,
but those who stopped TNF inhibitor more than 90 days
before acute myocardial infarction had a threefold higher
risk of death.132 These cardioprotective benefits may not
apply to all patients receiving TNF inhibitors, as response
to treatment and length of follow-up may affect risk. In
For personal use only 8 of 17
a cohort study of rheumatoid arthritis patients starting
TNF inhibitor treatment, EULAR good responders had
similar rates of ACS to matched general population con-
trols, whereas EULAR moderate and non-responders had
2.5-fold higher rates.133 In a comparison of methotrexate
treated rheumatoid arthritis patients starting a TNF inhib-
itor with those receiving a non-biologic DMARD, TNF
inhibitor use was marginally associated with a 20-30%
reduction in composite cardiovascular events over the
first six months but not by 12 months.134 Because of failed
randomized controlled trials (RCTs) in CHF,135 136 concern
has been raised about TNF inhibitor use in patients with
this comorbidity. Not universally reported,94 137 TNF
inhibitor use has been associated with an increased risk
of hospital admission for CHF as well as increased mortal-
ity compared with methotrexate among older rheumatoid
arthritis patients.138
TNF inhibitor use has been associated with improved
surrogate markers of cardiovascular disease. In a series
of 48 consecutive female patients with rheumatoid arthri-
tis, treatment with etanercept led to significant improve-
ments in left ventricular mass index on echocardiography
over three to six months that correlated with improve-
ments in disease activity, a finding not observed with
methotrexate, leflunomide, or sulfasalazine.103 Post hoc
analyses of the BeSt trial showed improved blood pres-
sure with infliximab treatment independent of potential
confounders and treatment response.104 A three month
controlled trial of TNF inhibitor versus delayed treatment
in 60 patients with inflammatory arthritis (rheumatoid
arthritis, psoriatic arthritis, and ankylosing spondyli-
tis) found that TNF inhibitors reduced aortic stiffness
(change in aortic pulse wave velocity, −0.50 v 0.05 m/s;
P=0.002).105 In a substudy of the golimumab double
blind RCTs, golimumab failed to yield consistent effects
on carotid ultrasound indices of atherosclerosis.139
Underlying the associations between TNF inhibitors
and cardiovascular disease are quantitative and func-
tional changes in lipids as well as improvements in
endothelial dysfunction and oxidative stress. In a sys-
tematic review and meta-analysis including 13 studies
(n=702 patients) with lipid measurements before and
after the start of TNF inhibitor treatment, long term
TNF inhibitor use (22-52 weeks) was associated with
increased HDL (0.27 mmol/L), total cholesterol (0.26
mmol/L), and triglycerides (0.28 mmol/L); decreased
apolipoprotein B/A (0.30); and stable LDL and total cho-
lesterol/HDL.106 In double blind RCTs of golimumab (GO-
BEFORE, n=637; GO-FORWARD, n=444), increases in
total cholesterol, HDL, and LDL at 14 weeks were greater
for patients treated with golimumab plus methotrexate
than in patients receiving methotrexate alone, although
atherogenic indices (total cholesterol/HDL, apolipo-
protein B/A1) were similar.107 In rheumatoid arthritis
patients with active disease starting infliximab treatment,
PON-1 activity increased as did in vitro HDL total anti-
oxidative capacity.108 Early after infliximab was started,
improvements correlated with inflammatory markers, a
correlation that diminished after six months, suggesting
direct antioxidant properties. Adalimumab inhibited cho-
lesterol uptake in macrophages in vitro but did not affect
 STAT E O F T H E A RT R E V I E W
cholesterol efflux.95 Likewise, EPCs increased after TNF
inhibitor treatment and correlated with both improve-
ments in disease activity and asymmetric dimethyl argi-
nine reduction in a series of consecutive rheumatoid
arthritis patients.109 In a small trial comparing metho-
trexate monotherapy with methotrexate plus infliximab
in rheumatoid arthritis, both groups showed reductions
in superoxide production and trends toward improved
PON-1 activity.110 Combination treatment yielded addi-
tional improvements in HDL concentration and nitric
oxide bioavailability from baseline, possibly related to
greater improvements in disease activity.
Non-TNF biologic DMARDs and small molecule drugs
As part of regulatory trials, tocilizumab treatment was
noted to increase total cholesterol, HDL, LDL, and triglyc-
erides, prompting concern about increased cardiovascu-
lar risk.140‑143 Analysis of rheumatoid arthritis patients
receiving tocilizumab in subsequent safety registries
and extension studies, however, suggested that lipid
changes do not necessarily translate into an increase in
major adverse cardiovascular events.111 Furthermore,
a recent multi-database cohort study of 9218 patients
starting tocilizumab propensity matched to 18 810 start-
ing TNF inhibitor found a similar risk of cardiovascular
events (hazard ratio 0.84, 0.56 to 1.26).112 Ultimately,
closer inspection illustrated that lipid changes occur-
ring in the wake of different DMARD treatments likely
reflect improvement in inflammation rather than a unique
pro-atherogenic drug effect.144 Although reductions in
inflammation seem to have generic effects on lipid pro-
files, post hoc analysis of the ADACTA trial, a RCT of 326
rheumatoid arthritis patients comparing the efficacy of
tocilizumab and adalimumab, showed differing effects
of these biologics on lipids.113 After eight weeks of tocili-
zumab, greater increases were seen in total cholesterol,
HDL, LDL, triglycerides, and total cholesterol/HDL com-
pared with adalimumab. Although lipid concentrations
suggested a more atherogenic profile, functional lipid
modifications were actually more anti-atherogenic with
tocilizumab. HDL-serum amyloid A (SAA), secretory
phospholipase A2-IIa, and lipoprotein(a) all decreased
to a greater extent in the tocilizumab group. In a 24
week double blind RCT of tocilizumab versus placebo
in 132 rheumatoid arthritis patients with an inadequate
response to methotrexate (with an 80 week, open label
extension), characteristic increases in total cholesterol
(12.6%), LDL (10.6%), and triglyceride (28.1%) occurred
after 12 weeks, but no differences were seen in small LDL,
oxidized LDL, HDL, or apolipoprotein B/A1.114 Moreover,
improvements in qualitative and functional lipid parame-
ters were again observed with tocilizumab, including HDL
associated SAA (78% decrease), secretory phospholipase
A2-IIa (61% decrease), lipoprotein(a) (37% decrease),
and PON-1 (16% increase). In vitro, hepatic cells cultured
in IL-6 showed increased LDL receptor expression, sug-
gesting that altered hepatic clearance could represent
an alternative mechanism by which tocilizumab could
favorably affect lipids.115 Beyond lipid modifications,
tocilizumab also seems to improve endothelial function
and oxidative stress. A series of 20 rheumatoid arthritis
For personal use only 9 of 17
patients treated with tocilizumab for six months after fail-
ure of conventional DMARDs showed significant improve-
ments in endothelial function and decreased expression
of vascular cell adhesion molecule.116 Leukocyte gener-
ated peroxides and peroxynitrates were also reduced
with tocilizumab, and neutrophils collected after treat-
ment generated fewer neutrophil extracellular chromatin
traps. In a 24 week, open label RCT of 64 active, treat-
ment naive, rheumatoid arthritis patients comparing the
effects of monotherapy with tocilizumab, etanercept, or
adalimumab on arterial stiffness, tocilizumab improved
arterial stiffness to the same degree as etanercept and
adalimumab.117
Evaluation of the risk of cardiovascular disease with
other biologic and small molecule DMARDs has been lim-
ited. Small case series of rheumatoid arthritis patients
receiving rituximab showed transient improvement in
endothelial function and increased total cholesterol,
triglycerides, and apolipoprotein B/A1 ratios, although
lipid modulation occurred predominantly in those who
responded to treatment.118 119 Proteomic characterization
of HDL from responders to rituximab showed favorable
qualitative changes (for example, reduced SAA con-
tent).119 In an open label study with double blinded ator-
vastatin, total cholesterol, LDL, and apolipoprotein B
increased after the start of tofacitinib treatment, changes
that were attenuated with atorvastatin in the absence of
incremental toxicity.120
Few studies have compared the risk of cardiovascu-
lar events between biologic treatments in rheumatoid
arthritis. The aforementioned multi-database cohort
study found similar cardiovascular risk among patients
starting tocilizumab and TNF inhibitors.112 In a retro-
spective cohort study using Medicare data, rheumatoid
arthritis patients starting a TNF inhibitor (predominantly
etanercept and infliximab) had a 28% increased risk of
acute myocardial infarction compared with those start-
ing abatacept.121 However, this finding was not robust
to sensitivity analyses using a composite cardiovascular
disease outcome. In this same study, tocilizumab was
associated with a 36% lower risk than abatacept, but this
finding was observed only with the composite outcome.
Moreover, the number of patients starting tocilizumab
was limited and the findings narrowly met statisti-
cal significance. Certainly, further pharmacovigilance
studies of cardiovascular risk are needed, as the use of
non-TNF inhibitor biologics and small molecule DMARDs
increases.
Non-steroidal anti-inflammatory drugs and
glucocorticoids
With the removal of rofecoxib and valdecoxib from the
market owing to concerns about cardiovascular safety,
much attention has been paid to the cardiovascular risk
of other non-steroidal anti-inflammatory drugs (NSAIDs).
A recent systematic review and meta-analysis of observa-
tional studies and RCTs reporting cardiovascular events
among 236 525 rheumatoid arthritis patients identi-
fied an 18% increased risk of cardiovascular events
with NSAIDs (relative risk 1.18, 1.01 to 1.38).94 A Dan-
ish, nationwide cohort study assessed whether NSAIDs
 STAT E O F T H E A RT R E V I E W
confer similar risk in rheumatoid arthritis patients and
the general population. Although the association was
attenuated in rheumatoid arthritis compared with the
general population, NSAIDs were still associated with
a 22% increased risk of cardiovascular disease events
among rheumatoid arthritis patients.122 Risk was dose
dependent and primarily attributed to use of rofecoxib
and diclofenac. With a previous network meta-analysis
of RCTs including 116 429 patients suggesting the lowest
cardiovascular risk with naproxen use among NSAIDs in
the general population,145 the differential cardiovascular
risk of NSAIDs (celecoxib, ibuprofen, and naproxen) was
compared in a randomized, double-blind, non-inferiority
trial of 24 081 osteoarthritis and rheumatoid arthritis
patients at heightened cardiovascular risk with a mean
duration of follow-up of 34.1 months.123 Celecoxib was
non-inferior to ibuprofen (hazard ratio 0.85, 0.70 to 1.04)
and naproxen (0.93, 0.67 to 1.13) for the primary out-
come of time to first event meeting Antiplatelet Trialists
Collaboration criteria, although only 10% of participants
had rheumatoid arthritis and rheumatoid arthritis only
analyses were not done. Similarly, a pooled analysis
of three double blind RCTs comparing etoricoxib and
non-selective diclofenac in patients with osteoarthritis
(n=24 913) and rheumatoid arthritis (n=9787) showed
equivalent risk of composite cardiovascular events for
etoricoxib and diclofenac (hazard ratio 0.96, 0.79 to
1.16).124
Similar to NSAIDs, substantial attention has been
paid to glucocorticoid use in this domain. The afore-
mentioned meta-analysis of 236 525 rheumatoid
arthritis patients reported a 47% increased risk of all
cardiovascular events (relative risk 1.47, 1.34 to 1.60)
as well as elevated risk for myocardial infarction (1.41,
1.22 to 1.63), CHF (1.42, 1.10 to 1.82), and stroke (1.57,
1.05 to 2.35) with prednisone use.94 An observational
study examining a potential dose threshold for car-
diovascular risk with prednisone use in rheumatoid
arthritis observed that doses of 8 mg daily or above (and
cumulative doses above 40 g) were associated with an
increased risk of all cause and cardiovascular mortal-
ity independent of traditional risk factors and severity
of rheumatoid arthritis.125 Other observational studies
have linked even lower glucocorticoid doses with risk of
cardiovascular disease. Daily prednisone doses below
7.5 mg were associated with a 23-32% increased risk
for acute myocardial infarction in rheumatoid arthritis
patients enrolled in Medicare and the Veterans Affairs
Health System.17 121 In addition to dose, the timing of
corticosteroid use contributes to risk. In a large obser-
vational study of incident rheumatoid arthritis patients,
current glucocorticoid dose and cumulative duration of
exposure to glucocorticoid were independently associ-
ated with increased risk of myocardial infarction.126 Com-
plicating these analyses in observational studies is the
potential confounding by indication, as disease severity
prompts corticosteroid use, which is a potential expla-
nation for why glucocorticoid use was associated with
cardiovascular events only in rheumatoid factor positive
patients in a population based cohort study.146 Mecha-
nisms underlying these epidemiologic associations are
For personal use only 10 of 17
not entirely clear, although known glucocorticoid side
effects of weight gain, insulin resistance, dyslipidemia,
and elevated blood pressure are postulated pathways.
A recent cross sectional study identified a novel mecha-
nism potentially linking glucocorticoids to cardiovas-
cular disease in rheumatoid arthritis—impairment of
reverse cholesterol transport. Cholesteryl-ester transfer
protein mass and activity was reduced in rheumatoid
arthritis patients taking pr­ednisone compared with those
not taking pr­ednisone.127
Management and prevention of cardiovascular disease in
rheumatoid arthritis patients
Assessment of cardiovascular disease risk
Generally, the first step in preventing cardiovascular
disease is determining risk. However, traditional cardio-
vascular risk models including the Systematic Coronary
Risk Evaluation (SCORE), Framingham risk score (FRS),
Reynolds risk score (RRS), and 2013 American College of
Cardiology/American Heart Association CVD Risk Score
do not sufficiently stratify rheumatoid arthritis patients
according to risk.147‑149 Efforts have been made to develop
novel cardiovascular disease risk models for use in rheu-
matoid arthritis,150 151 or to modify existing models with
a correction factor for rheumatoid arthritis,152 but these
novel indices failed to outperform general population
models in limited external validation testing.151 153 Fur-
ther assessments of these models will be critical to deter-
mining the optimal risk model for regular clinical use.
In the meantime, we encourage the integration of car-
diovascular risk stratification with a risk model endorsed
by national guidelines into regular clinical care for rheu-
matoid arthritis patients.
Management of traditional cardiovascular risk factors
Despite accumulating data suggesting that rheumatoid
arthritis patients have high rates of cardiovascular dis-
ease, modifiable risk factors are suboptimally managed.
Assessment of adherence to cardiovascular disease qual-
ity indicators at two Canadian university clinics showed
low performance rates for several measures.154 Moreover,
rheumatoid arthritis patients are less likely than other
patients to have lipid measurements obtained,155 156 with
less than 50% of eligible rheumatoid arthritis patients in
the 5% random sample of Medicare receiving appropri-
ate lipid screening.157 Use of lipid lowering treatment for
rheumatoid arthritis patients fulfilling the National Cho-
lesterol Education Program’s Adult Treatment Panel III cri-
teria was suboptimal, with only 27% starting therapy.155
In a separate cross sectional study, 38% of rheumatoid
arthritis patients without previous cardiovascular dis-
ease were deemed at risk, and yet only 7% were receiving
statins.158 The underuse of lipid lowering treatment in
rheumatoid arthritis is in contrast to diabetes, for which
prescription rates were over 80%.159 Although the afore-
mentioned studies have reported suboptimal risk factor
management, a recent cohort study from the UK found
a higher likelihood of rheumatoid arthritis patients with
hyperlipidemia and hypertension receiving drug therapies
compared with matched controls,7 perhaps suggesting
that efforts to increase awareness of cardiovascular risk
 STAT E O F T H E A RT R E V I E W
and suboptimal screening/management of cardiovascular
risk factors in rheumatoid arthritis are leading to improve-
ments in quality of care.
Statins
Hydroxymethyl glutaryl coenzyme A reductase inhibi-
tors (statins) lead to marked reductions in cardiovascu-
lar events in the general population and seem to have
similar efficacy in patients with rheumatoid arthritis. In
a large, retrospective cohort study of patients with hyper-
lipidemia, primary prevention of cardiovascular disease
with statins was compared between rheumatoid arthritis
and controls (general population and osteoarthritis).8
A reduction in LDL after the start of statin treatment
was accompanied by a greater than 30% reduction in
cardiovascular events in rheumatoid arthritis, similar
to the risk reduction in both general and osteoarthritis
controls. In a retrospective analysis of the Incremen-
tal Decrease in End Points Through Aggressive Lipid
Lowering (IDEAL—an open label comparison between
atorvastatin 80 mg and simvastatin 20-40 mg in 8888
post-myocardial infarction patients) and Treating to
New Targets (TNT—a double blind RCT comparing ator-
vastatin 80 mg and 10 mg in 10 001 patients with coro-
nary artery disease) trials, patients with inflammatory
joint disease had similar decreases in atherogenic lipid
indices and cardiovascular events (20% reduction with
atorvastatin 80 mg) after statin treatment compared with
those without inflammatory arthritis.160 Further illustrat-
ing these potential benefits, discontinuation of statin has
been associated with a 67% increase in risk of acute myo-
cardial infarction, 60% increase in risk of cardiovascular
mortality, and 79% increase in risk of all cause mortal-
ity in patients with rheumatoid arthritis.161 162 Moreo-
ver, statins may improve cardiovascular disease risk in
rheumatoid arthritis through mechanisms independent
of lipid lowering. In an 18 month, open label study of
intensive lipid management with rosuvastatin (ROsuv-
astat in Rheumatoid Arthritis, Ankylosing Spondylitis
and other inflammatory joint diseases; RORA-AS), statin-
naive patients with inflammatory arthritis (64% rheu-
matoid arthritis) and prevalent atherosclerosis showed
improved arterial stiffness and significant reduction in
carotid plaque independent of LDL reduction.163 164 In
an AIA mouse model, fluvastatin reversed endothelial
dysfunction and inhibited NADPH oxidases, thus reduc-
ing vascular ROS production.165 Finally, statins may
reduce rheumatoid arthritis disease activity, with one
non-blinded, six month trial of 30 patients with early
rheumatoid arthritis reporting improved disease activity
(mean DAS28 improvement 2.19 v 0.92; P<0.001) with
atorvastatin 40 mg added to a regimen of methotrexate
and glucocorticoids.166
Physical activity
Despite the challenges that physical activity may pose to
patients with rheumatoid arthritis, the potential benefits
of exercise therapy warrant consideration. Similar to the
general population, physical activity is associated with a
favorable cardiovascular risk profile in rheumatoid arthri-
tis.167 In a six month trial of individualized aerobic and
For personal use only 11 of 17
resistance training compared with education alone in 40
rheumatoid arthritis patients with a mean DAS28 of 3.2,
exercise training significantly improved VO2 max, lipids
(mean change in total cholesterol/HDL −0.4 v 0.4), and
blood pressure (mean change −7.1 v 4.7 mm Hg systolic
and −3.1 v 3.5 mm Hg diastolic), as well as microvascular
and macrovascular endothelial function.168 169 Notably,
disease activity and physical function also improved sig-
nificantly in the exercise treatment group. Addressing
potential safety concerns with exercise interventions,
a two year RCT comparing high intensity exercise with
routine care in 309 rheumatoid arthritis patients failed
to find evidence of accelerated joint damage with high
intensity physical activity.170 Finally, as a shared risk fac-
tor for rheumatoid arthritis and cardiovascular disease,11
smoking cessation is critical in reducing cardiovascular
risk. This intervention may also pay dividends in terms
of rheumatoid arthritis disease activity, as smoking has
been linked to increased disease activity and inflam-
mation.171 172 Similarly, comorbid conditions adversely
affecting cardiovascular risk, including hypertension,
diabetes, and chronic kidney disease, should be aggres-
sively treated.
Management of rheumatoid arthritis
In previous work studying cause specific mortality in US
veterans, we found that the rate of cardiovascular disease
related mortality in rheumatoid arthritis patients in dis-
ease remission was similar to that of age and sex matched
controls from the general population, whereas rheuma-
toid arthritis patients with low to high disease activity
had increased cardiovascular mortality.173 Others have
shown similar cardiovascular disease risk stratifications
based on rheumatoid arthritis disease activity.174 In the
RORA-AS trial, lower rheumatoid arthritis disease activity
was associated with greater carotid plaque regression.164
Beyond reducing systemic inflammation, effective
rheumatoid arthritis treatments could mitigate cardiovas-
cular disease risk through other mechanisms. In the TEAR
trial, for instance, reductions in rheumatoid arthritis dis-
ease activity were accompanied by improved HDL func-
tion,90 and post hoc analyses from the BeSt trial showed
that rheumatoid arthritis patients in remission or low
disease activity had improved blood pressures compared
with those in moderate or high disease activity.104 Taken
together, these studies suggest that aggressively treating
rheumatoid arthritis toward remission should be the goal
for cardiovascular risk reduction with the understanding
that other comorbidities and patients’ preferences should
be considered. We advocate a multifaceted approach to
cardiovascular risk reduction in rheumatoid arthritis, tar-
geting both traditional and rheumatoid arthritis specific
cardiovascular risk factors, and both drug and non-drug
treatments, and involving a multidisciplinary team of
primary care providers, rheumatologists, and cardiolo-
gists (fig 3).
Emerging treatments
Several potentially high impact RCTs investigating car-
diovascular risk related to rheumatoid arthritis and/or
DMARD use are ongoing or recently completed. A Food
 STAT E O F T H E A RT R E V I E W

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Fig 3 |  Targeting cardiovascular disease (CVD) risk reduction in rheumatoid arthritis (RA). Targeting reduction of CVD in RA requires a multifaceted, team approach.
Key areas to target are tobacco use cessation, treating comorbid conditions (diabetes, hypertension, chronic kidney disease), assessing cardiovascular risk,
aggressively managing dyslipidemia, treating RA toward a goal of remission (or at least low disease activity), avoiding/limiting use of non-steroidal anti-
inflammatory drugs (NSAIDs) and corticosteroids, and potentially selecting disease-modifying antirheumatic drugs (DMARDs) with more favorable CVD risk
profiles. HCQ=hydroxychloroquine; MTX=methotrexate; TNFi=tumor necrosis factor inhibitor

and Drug Administration mandated open label RCT
comparing the risk of cardiovascular disease in 3080
rheumatoid arthritis patients receiving tocilizumab or
etanercept for up to five years was recently completed
(clinicialtrials.gov: NCT01331837) with preliminary
results suggesting no differences between treatments
in the occurrence of cardiovascular disease. An open
label, 24 week RCT comparing the effect of triple ther-
apy (methotrexate, hydroxychloroquine, and sulfasala-
zine) versus TNF inhibitor (etanercept or adalimumab)
in 200 rheumatoid arthritis patients with inadequate
response to methotrexate on change in vascular inflam-
mation assessed by fluorodeoxyglucose positron emission
tomo­graphy/computed tomography is actively recruiting

For personal use only 12 of 17

 STAT E O F T H E A RT R E V I E W
RESEARCH QUESTIONS
• How does rheumatoid arthritis related inflammation
interact with other cardiovascular risk factors to propagate
atherogenesis?
• How do post-translational modifications and subsequent
immune responses influence cardiovascular risk in
rheumatoid arthritis?
• What is the optimal goal of treatment in rheumatoid
arthritis for reduction of risk of cardiovascular disease?
• Should select rheumatoid arthritis immunomodulatory
therapies be preferentially used to prevent cardiovascular
disease in rheumatoid arthritis patients?
(clinicaltrials.gov: NCT02374021). The Trial of Atorvas-
tatin for the primary prevention of Cardiovascular Events
in Rheumatoid Arthritis (TRACE-RA, ISRCTN41829447),
a 2986 patient, double blind RCT comparing atorvastatin
40 mg daily with placebo was recently terminated early
owing to a lower than expected event rate. Finally, a pro-
spective, randomized, open label trial comparing a tar-
geted, intensified, multidimensional intervention against
conventional treatment of modifiable cardiovascular risk
factors in early rheumatoid arthritis is currently enrolling
patients.175
In the general population, several RCTs are under way
or have recently been completed that have implications for
management of rheumatoid arthritis. A six year, double
blind RCT of methotrexate for the secondary prevention of
cardiovascular disease in 7000 patients with type 2 diabe-
tes mellitus or metabolic syndrome is ongoing (Cardiovas-
cular Inflammation Reduction Trial, NCT01594333).176 In
a double blind RCT targeting the secondary prevention of
cardiovascular events among 10 061 patients with pre-
vious myocardial infarction and hsCRP above 2 mg/L,
canakinumab (monoclonal antibody to IL-1β) 150 mg,
but not the 50 mg dose, reduced cardiovascular events
by 15% (hazard ratio 0.85, 0.74 to 0.98) compared with
placebo.177 Whether the modest protective effect reported
with canakinumab translates to anakinra, the only IL-1β
targeted therapy currently approved in rheumatoid arthri-
tis, remains unclear.
Guidelines
EULAR commissioned a task force to propose recommen-
dations for management of cardiovascular risk in inflam-
matory arthritis in 2009,152 and a 2015/16 update was
recently published.178 Three overarching principles and
10 specific recommendations were provided, but the level
of evidence (range 2a-4) and strength of recommenda-
tions (range B-D) were generally low.
Conclusions
Patients with rheumatoid arthritis are at increased risk
of cardiovascular disease. Several mechanisms beyond
traditional cardiovascular risk factors confer this risk,
including heightened systemic inflammation and inflam-
matory mediators, post-translational modifications of
peptides/proteins and immune responses against these
antigens, oxidative stress, endothelial dysfunction, and
unique quantitative and qualitative lipid alterations.
Treating rheumatoid arthritis aggressively with DMARDs,
For personal use only 13 of 17
limiting use of corticosteroids and NSAIDs, and aggres-
sively managing traditional cardiovascular risk factors
are essential to reduce the substantial burden posed by
this common comorbidity.
Contributors: BRE did the literature review and prepared the initial draft of
the manuscript. All authors were involved in the conception, drafting, and
editing of the manuscript. TRM is the guarantor.
Funding: BRE is supported by a University of Nebraska Medical Center
(UNMC) internal medicine scientist development award, the UNMC
Mentored Scholars Program, and the UNMC College of Medicine Physician-
Scientist Training Program. TRM is supported by grants from the National
Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal
and Skin Diseases (P50AR060772), National Institute of Alcohol Abuse
and Alcoholism (R25AA020818), National Institute of General Medical
Sciences (U54GM115458), Veterans Affairs Office of Research and
Development (Merit Award, CX000896), Bristol Myers Squibb, and
Ironwood Pharmaceuticals. DRA is supported by the Harry R and Sarah
H Caspersen Coronary Artery Disease Research Fund and the Division of
Cardiovascular Medicine, Department of Internal Medicine, UNMC. GMT is
supported by grants from the Rheumatology Research Foundation and a
Bristol Myers Squibb investigator initiated grant.
Competing interests: We have read and understood the BMJ policy on
declaration of interests and declare the following interests: TRM serves as a
consultant for Pfizer.
Provenance and peer review: Commissioned; externally peer reviewed.
Patient involvement: No patients were involved in the creation of this
article.
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