Rheumatoid arthritis and cardiovascular disease

Cynthia S. Crowson, MS, a Katherine P. Liao, MD, MPH, b John M. Davis, III, MD, a Daniel H. Solomon, MD, MPH, b
Eric L. Matteson, MD, MPH, a Keith L. Knutson, PhD, a Mark A. Hlatky, MD, c and Sherine E. Gabriel, MD, MSc a
Rochester, MN; Boston, MA; and Stanford, CA

Background Rheumatic disease and heart disease share common underpinnings involving inflammation. The high
levels of inflammation that characterize rheumatic diseases provide a “natural experiment” to help elucidate the mechanisms
by which inflammation accelerates heart disease. Rheumatoid arthritis (RA) is the most common of the rheumatic diseases and
has the best studied relationships with heart disease.
Methods A review of current literature on heart disease and RA was conducted.
Results Patients with RA have an increased risk of developing heart disease that is not fully explained by traditional
cardiovascular risk factors. Therapies used to treat RA may also affect the development of heart disease; by suppressing
inflammation, they may also reduce the risk of heart disease. However, their other effects, as in the case of steroids, may
increase heart disease risk.
Conclusions Investigations of the innate and adaptive immune responses occurring in RA may delineate novel
mechanisms in the pathogenesis of heart disease and help identify novel therapeutic targets for the prevention and treatment of
heart disease. (Am Heart J 2013;166:622-628.e1.)

The role of inflammation in the development of heart
disease has only been recognized relatively recently.
Rheumatic disease can be viewed as a “natural
experiment” in the interplay between chronic inflam-
mation and heart disease, which could elucidate the
fundamental mechanisms by which inflammation accel-
erates the development of atherosclerosis and heart
disease. Rheumatoid arthritis (RA), systemic lupus
erythematosus, Sjögren syndrome, systemic scleroder-
ma, inflammatory myositis, and psoriatic arthritis are
characterized by chronic inflammation in various body
systems, most often the joints, skin, eyes, lungs, and
kidneys, but also in the heart and vascular system.
Rheumatoid arthritis is the most common and best
studied of the autoimmune rheumatic diseases and will
be the primary focus of this overview.
The immune underpinnings of heart disease and RA
share many similarities. In addition, circulating acute-
phase reactants, such as C-reactive protein (CRP), are
substantially elevated in RA and are risk markers for heart
disease in the general population. Understanding the
factors responsible for heart disease in patients with RA,
such as abnormal immunity and chronic inflammation,
may lead to novel therapeutic targets in the prevention of
heart disease.

Epidemiology of heart disease in RA

From the aMayo Clinic, Rochester, MN, bBrigham and Women's Hospital and Harvard
Medical School, Boston, MA, and cStanford University School of Medicine, Stanford, CA.
Ms Crowson has research funding from Pfizer and Roche/Genentech. Dr Liao is supported
by National Institutes of Health (NIH) K08 AR060257 and Katherine Swan Ginsburg Fund.
Dr Davis is a site primary investigator for industry-sponsored trials with UCB Pharma and
Roche. Dr Solomon is supported by NIH K24 AR 055989; receives research support from
Amgen, Lilly, and Abbott; serves as an epidemiologic consultant to CORRONA; and serves
in unpaid roles on 2 Pfizer sponsored trials. Dr Matteson has research funding from Pfizer
and is involved in an industry-sponsored trial with Roche/Genentech. Drs Knutson and
Hlatky reported that they have no relationships relevant to the contents of this manuscript to
disclose. Dr Hlatky is funded by the American Heart Association. Dr Gabriel is supported
by NIH R01 AR46849, receives research support from Pfizer, and serves as a consultant
for Roche/Genentech.
Submitted April 5, 2013; accepted July 1, 2013.
Reprint requests: Sherine E. Gabriel, MD, MSc, 200 First Street SW, Rochester, MN 55905.
E-mail: gabriel.sherine@mayo.edu
0002-8703/$ - see front matter
© 2013, Mosby, Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ahj.2013.07.010
Patients with RA have a 1.5- to 2.0-fold increased risk of
developing coronary artery disease (CAD) compared with
the general population, 1,2 similar in magnitude to the risk
imparted by diabetes mellitus. 3 This increased CAD risk is
evident even before the clinical recognition of RA: at
diagnosis, individuals with RA were more than 3 times as
likely to have had a prior myocardial infarction (MI) than
subjects without RA. 2 An expert committee of the
European League Against Rheumatism has recommended
that cardiovascular (CV) risk scores (eg, Framingham) be
multiplied by 1.5 in some patients with RA to reflect their
increased risk of heart disease. 4
Patients with RA also have twice the risk of developing
heart failure. 5 This risk is more pronounced in the
patients with RA who are rheumatoid factor positive than
American Heart Journal
Volume 166, Number 4
among seronegative patients. Patients with RA are less
likely to have typical signs and symptoms of heart failure,
tend to be managed less aggressively, and have poorer
outcomes. 6 Importantly, patients with RA and heart
failure are more likely to have a preserved ejection
fraction (N50%) and less likely to have clinical evidence of
CAD. Patients with RA may have a reduced likelihood of
developing heart failure after MI. 7 Collectively, these
findings suggest that patients with RA are more likely to
have heart failure caused by diastolic dysfunction, which
may be related to systemic inflammation.
The possible effect of RA on the risk of non-CV disease
is less clear. Some reports have noted increased risks of
cerebrovascular disease in RA, 8 whereas others have
not. 9 Overt and subclinical peripheral vascular disease
appears to be increased in patients with RA and is
associated with severity, particularly extra-articular
systemic disease. 10-12 The risk of venous thromboembo-
lism appears to be increased 2- to 3-fold in RA compared
with the general population. 9,13
Cardiovascular risk factor profile in RA
Patients with RA tend to have a different profile of
cardiac risk factors, including a higher frequency of
smoking and an altered lipid profile, compared with the
general population. The lipid profile in RA is character-
ized by suppression of total and low-density lipoprotein
(LDL) cholesterol levels during periods of high-grade
inflammation, with a proportionately greater suppression
of high-density lipoprotein (HDL) levels, yielding an
unfavorable ratio of total to HDL cholesterol. Lipid levels
have a paradoxical relationship with CAD risk in RA
because lower lipid levels are associated with more
severe systemic inflammation, which, in turn, is associ-
ated with increased CAD risk. 14 Inflammation in RA also
appears to alter lipoprotein structure and function 15; the
serum amyloid A load carried by HDL increases and
apolipoprotein A-I decreases, altering the usual anti-
atherogenic effects of HDL and resulting in proathero-
genic effects. 16
Patients with RA are more likely to have lower muscle
mass and low body mass index, which may result from
uncontrolled inflammation, limitations of physical activ-
ity, or both. Low body mass in RA appears to be
associated with a worsened prognosis. 17 Cachexia,
characterized by low muscle and fat mass, is now
uncommon in RA, but the combination of low muscle
mass and high fat mass is more prevalent in patients with
RA and may be even more problematic from a heart
disease perspective. 18 Visceral adiposity in RA is associ-
ated with insulin resistance, hypertension, metabolic
syndrome, and a greater inflammatory load. 18
Hypertension is common, and it appears to be under-
diagnosed and undertreated in RA. 19 Hypertension in RA
may be exacerbated by inflammation and medications.
Crowson et al 623
Increased risk of heart disease in patients with RA is
associated with elevation of inflammatory markers,
including CRP, erythrocyte sedimentation rate, rheuma-
toid factor, and anticitrullinated protein antibodies, and
with more active or severe RA. 20 Rheumatoid factor and
antinuclear antibodies have been associated with heart
disease and overall mortality, even in patients without
rheumatic diseases. 21
Heart disease management/outcome
in RA
Patients with RA are typically managed by several
physicians, and coordination of care may be suboptimal.
Smoking cessation and control of standard risk factors
are all indicated in patients with RA but may be
underused because of the understandable focus on
management of RA itself. Despite the well-understood
benefits of exercise on general and CV health, most
patients with RA do not pursue a regular exercise
program. 22,23 Both aerobic exercise training and resis-
tance exercise training for patients with RA have been
shown to be efficacious in improving overall well-being,
the muscle mass loss associated with RA, and markedly
improving physical function without exacerbating
disease activity and is likely to reduce CV risk and
should be part of routine care. 24-29
There is evidence that patients with RA are less likely to
receive both primary and secondary heart disease
preventions. Only 55% of patients with RA in one study
had lipid levels measured; management by rheumatolo-
gists was associated with less lipid screening. 30 Rheuma-
tologists were less likely to identify and treat cardiac risk
factors than primary care physicians. 31 Angina may also
be underdiagnosed, with chest pain attributed to RA
instead of CAD, perhaps because the increased risk of
CAD is not understood by treating physicians, and referral
to a cardiologist is less likely. Patients with RA and an
acute MI were less likely to receive reperfusion therapy
and secondary prevention medications, such as β-
blockers and lipid-lowering agents. 32 Patients with RA
were also less likely to undergo coronary artery bypass
grafting than patients without RA. 2
Effect of RA therapies on CV risk in RA
Rheumatoid arthritis therapies target inflammation, a
CV risk factor that is also important in patients without
rheumatic disease. Understanding how these therapies
also modify CV risk in RA may provide insight into the
inflammatory component of CV risk for all patients.
Glucocorticoids have been widely used in RA to
acutely control pain and inflammation associated with
RA flares. However, the beneficial anti-inflammatory
effects of glucocorticoids, which can improve mobility,
are also accompanied by adverse effects, including

624 Crowson et al
Figure 1
RR (95% CI)
0.79 (0.73, 0.87)
MTX use and CVD
0.46 (0.28, 0.77)
TNF iuse and CVD
0.1 1
Estimated relative risks (RRs) from meta-analyses on observational
data for CV risk in patients with RA associated with methotrexate
(MTX) use and CV risk associated with TNF inhibitor (TNFi) use
(adapted from Desai et al 31 and Hafstrom et al 34).
increasing CV risk factors and worsening heart disease
outcomes. Glucocorticoid use is associated with carotid
plaque and arterial stiffness, decreased insulin sensitiv-
ity, elevated lipid levels, and hypertension. 33,34 Patients
treated with high-dose steroids (N7.5 mg/d prednisone)
appear to have twice the risk of heart disease compared
with those who do not receive steroids. 35 Use of low-
dose glucocorticoids to treat active inflammatory disease
might have more benefits than harms, but this requires
further investigation.
The long-standing concern about CV risk with
nonsteroidal anti-inflammatory drugs (NSAIDs) use was
magnified after studies of the selective cyclooxygenase-2
inhibitors (coxibs). The VIGOR (Vioxx Gastrointestinal
Outcomes Research) study found an increased risk of
heart disease events with rofecoxib use, which led to its
removal from the market. 36 By contrast, another trial
found no differences in heart disease events among
subjects randomized to receive celecoxib or ibuprofen. 37
Finally, a network meta-analysis of 7 NSAIDs, including
4 coxibs, suggested that naproxen conferred the
lowest CV risk, whereas the remaining 6 NSAIDs
appeared to confer similar risk for CVD. 38 A large
trial currently enrolling patients, including those with
RA, will assess the differences between NSAIDs and risk
of heart disease. 39
Methotrexate, a first-line treatment of RA, has been
associated with lower CV risk. A recent meta-analysis
found that methotrexate use was associated with 21%
fewer CV events (Figure 1). 40 Methotrexate does not
appear to alter lipid profiles, 41 and there is insufficient
evidence about its effects on insulin resistance,
hypertension, or atherosclerotic plaque burden. Never-
theless, the apparent benefit of methotrexate in
reducing heart disease risk in RA and the strong
evidence that CRP is a risk factor for heart disease led
to the development of a large randomized trial
(ClinicalTrials.gov identifier: NCT01594333) designed
to determine whether low-dose methotrexate reduces
American Heart Journal
October 2013
heart disease risk in post-MI patients who have
metabolic syndrome or diabetes mellitus. 42
Tumor necrosis factor (TNF) inhibitors are frequently
used in patients with RA who do not achieve adequate
disease control with other therapies. Roughly 30% to 40%
of patients with RA in the United States received a TNF
inhibitor either as monotherapy or in combination with
other medications. Tumor necrosis factor inhibitor
therapy in patients with RA appears to be associated
with reduced risk of all heart disease events (Figure 1). 43
If this reduced CV risk is true, it may be mediated by
effects on controlling inflammation, rather than by
favorable modifications of CV risk factors. In general,
TNF inhibitors appear to elevate total and HDL choles-
terol, resulting in a stable atherogenic ratio. 44 In addition,
because RA disease activity appears to be inversely
correlated with HDL levels, treatments that control RA
activity may favorably affect HDL levels. 45 It is unclear,
however, whether TNF inhibitors exert a class effect on
lipids, or if specific TNF inhibitors achieve more
favorable lipid profiles. Tumor necrosis factor inhibitors
may improve endothelial function and insulin resistance;
their effect on arterial stiffness is unclear, with one study
showing improvement and another finding no change
with therapy. 44,46-48
There is insufficient evidence regarding the effect of
other disease-modifying antirheumatic drugs and heart
disease risk. Hydroxychloroquine is associated with a
decreased risk of diabetes mellitus in patients with RA 49
and may also improve lipid profiles, with evidence of
decreased LDL and total cholesterol/HDL ratios. 50
Tocilizumab, a humanized antibody that targets the
interleukin (IL)-6 receptor, increases LDL, HDL, and
triglyceride levels during clinical trials. 51 The long-term
clinical significance of these perturbations in lipid levels
remains unknown.
Effect of heart disease therapies in
patients with RA
There have been relatively few patients with rheumatic
diseases enrolled in major clinical trials of primary or
secondary prevention. Although commonly used CV
therapies are presumed to be effective in patients with
RA, there is little direct evidence of their efficacy.
Statins (hydroxymethylglutaryl CoA reductase inhibi-
tors) appear to reduce vascular inflammation and have
been tested for efficacy in the treatment of RA.
Atorvastatin treatment resulted in a small reduction in
RA disease activity compared with placebo, suggesting
that statins may reduce inflammation directly. 52 Small
studies in patients with RA have also shown improve-
ments in arterial stiffness and endothelial dysfunction
with atorvastatin. 53,54 Statin discontinuation for ≥3
months in patients with RA resulted in a 2% increased
risk of acute MI for each month of discontinuation. 55
American Heart Journal
Volume 166, Number 4
Figure 2
Why do patients with RA develop heart disease? Determinants of heart disease in patients with RA differ from the general population.
Notably, statin therapy has also been found to impair the
effectiveness of rituximab, 56 so drug interactions will be
important to consider in the clinical management of
patients with RA.
Aspirin was the mainstay of RA treatment until the
development of prescription NSAIDs in the 1970s.
Aspirin has been highly effective in secondary and
primary heart disease prevention, but few studies
included patients with rheumatic diseases. Aspirin
doses for heart disease prevention are far below those
used for RA treatment in the past (ranging from 2,600 to
4,800 mg/d). 57 Moreover, the gastrointestinal bleeding
risks of chronic aspirin use in patients with RA, who
frequently use NSAIDs and glucocorticoids, may shift the
balance away from CV benefit.
Mechanisms of RA pertinent to
CV disease
Emerging evidence suggests that T lymphocytes play a
crucial pathogenic role in both RA and heart dis-
ease. 58,59 The major risk gene for RA, HLA-DRB1,
predisposes to disease by promoting the selection and
Crowson et al 625
survival of autoreactive CD4 + T cells. HLA-DRB1 alleles
are also associated with increased risk of MI and various
forms of non–RA-associated heart disease. 60,61 As in
heart disease, T cells isolated from the joints of patients
with RA have enhanced production of interferon-γ and
interleukin-17, which presumably mediate chronic
inflammation. 62,63 The proven efficacy of antagonizing
T-cell costimulation is perhaps the most compelling
evidence that T cells are pathogenic in RA. 64 Similarly,
percutaneous stents that elute T-cell inhibiting drugs (eg,
sirolimus) prevent in-stent restenosis and repeat revas-
cularization in CAD. 65
In persons with either RA or heart disease, CD4 + T cells
characteristically lose the expression of the costimulatory
molecule, CD28, which ordinarily provides the “second
signal” required for T-cell activation. So-called CD28 null T
cells are believed to have undergone reprogramming,
leading to premature senescence. 66 Expansion of these
senescent T cells among persons with RA is associated
with extra-articular inflammatory manifestations, includ-
ing vasculitis and lung disease, as well as CAD. 67,68 In the
setting of heart disease, CD28 null T cells are identified in
atherosclerotic plaque, where they are believed to

626 Crowson et al
contribute to the inflammatory process by producing
cytokines and by killing vascular smooth muscle cells. 69
Interestingly, HLA-DRB1, the aforementioned RA-risk
gene, also predisposes to expansion of CD28 null T cells
in RA and in CAD. 61,70
Premature senescence of T cells in RA appears to be
caused by fundamental defects in the hematopoietic
system. CD34 + hematopoietic progenitor cells have
accelerated telomere erosion, a sign of senescence. 71
Naïve T cells in persons with RA also are prematurely
aged, with increased fragility and damage of their DNA
caused by insufficient activity of basic DNA repair
enzymes. 72,73 Similarly, telomere shortening in hemato-
poietic progenitor cells correlates with myocardial
dysfunction in patients with CAD. 74 The onset of both
RA and heart disease coincides with the loss of thymic
emigration of naïve T cells in the fifth decade, suggesting
that T-cell senescence may underlay the pathogenesis of
both of these age-associated conditions. In the foresee-
able future, rejuvenation of senescent T cells, using new
drugs that restore genomic repair and integrity, could
potentially be an effective strategy for the prevention and
treatment of CV disease. 75
Conclusion
Heart disease remains a major problem for patients
with RA. Systemic inflammation plays a major role,
through direct and indirect effects on the vasculature
(Figure 2). More research is needed to delineate the
disease mechanisms and to develop and evaluate risk
assessment tools, biomarkers, prevention strategies,
and treatments that are specific to RA. The CV risk in
patients with RA is not well recognized by practicing
physicians, and better recognition and control of
traditional risk factors in patients with RA is important.
Coordination of care among rheumatologists, cardiolo-
gists, and primary care physicians will be needed for
optimal management of CV risk in patients with RA.
Tight control of systemic inflammation among patients
with RA may also reduce CV risk. Symptoms suggestive
of CAD in patients with RA should be evaluated
promptly, and early referral to a CV specialist for
appropriate evaluation and treatment provides the best
chance of optimizing outcomes.
Disentangling the relationship between inflammation,
immune-modulating treatment, and CV risk in RA is
difficult. Specific disease-modifying drugs (eg, metho-
trexate and TNF inhibitors) effectively control inflamma-
tion in RA and also reduce CV risk. In contrast,
glucocorticoids increase CV risk because of their adverse
metabolic effects, which apparently outweigh their anti-
inflammatory benefits. Common treatments to reduce CV
risk (eg, statins) are likely to be effective in patients with
RA, but this supposition has little empirical support.
Currently enrolling trials such as one administering
American Heart Journal
October 2013
methotrexate (a first-line treatment of RA) to post-MI
patients without RA should provide insight regarding
whether reducing inflammation alone is associated with
reduced CV risk. 76
Finally, similar pathways in RA and heart disease
might be considered as therapeutic targets, such as T-
cell–directed or anticytokine therapies (IL-1, IL-6,
etc). 77,78 Indeed, an anti–IL-1β monoclonal antibody
(canakinumab) is being studied for heart disease
treatment. 79 These studies are anticipated to provide
valuable new insights into the pathophysiology and
treatment of heart disease. (See the online Appendix.)
Disclosures
No extramural funding was used to support this work.
The authors are solely responsible for the design and
conduct of this work, the drafting and editing of the
manuscript, and its final contents.
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Crowson et al 628.e1

Appendix article is not intended to be a systematic review or a meta-

The studies included in this review were identified by analysis. Articles cited in this review were selected based
searching PubMed using an extensive list of phrases on methodological strength, whereby evidence from
related to the topic of interest. The searches were randomized controlled trials and population-based stud-
restricted to full-text articles in the English language. This ies was preferred.
Reproduced with permission of the copyright owner. Further reproduction prohibited without
permission.