1450 Current Pharmaceutical Design, 2012, 18, 1450-1456

Rheumatoid Arthritis: Cardiovascular Manifestations, Pathogenesis, and Therapy

William M. Mellana, Wilbert S. Aronow*, Chandrasekar Palaniswamy, and Sahil Khera

Department of Medicine, Division of Cardiology, Westchester Medical Center, New York Medical College, Valhalla, New York, USA

Abstract: Rheumatoid Arthritis (RA) is a chronic progressive inflammatory joint disorder that affects 0.5% – 1% of the general popula-
tion. This review article discusses cardiovascular manifestations of rheumatoid arthritis, pathogenesis of these manifestations, and ther-
apy. This disease not only affects the joints, but it also involves other organ systems. The majority of these patients suffer significant
morbidity and mortality from cardiovascular disease. Cardiovascular manifestations of RA include predilection for accelerated athero-
sclerosis and endothelial dysfunction resulting in coronary artery disease (CAD), stroke, congestive heart failure, and peripheral arterial
disease. Some studies have shown that the risk of developing CAD in RA patients is the same as for patients with diabetes mellitus.
These patients should be treated with aggressive medical therapy such as disease modifying antirheumatic drugs, tumor necrosis factor
alpha inhibitors, and corticosteroids and with appropriate control of risk factors such as smoking, dyslipidemia, hypertension, and obe-
sity. Other manifestations include pericarditis, myocarditis, and vasculitis.

Keywords: Rheumatoid arthritis, cardiovascular disease, coronary artery disease.

INTRODUCTION RHEUMATOID ARTHRITIS AS AN INDEPENDENT CAR-

Rheumatoid arthritis (RA) is a progressive inflammatory joint
disease which affects 0.5 – 1 % of the general population [1]. This
review article discusses cardiovascular manifestations of rheuma-
toid arthritis, pathogenesis of these manifestations, and therapy. RA
is a chronic inflammatory disorder that affects females more than
males. Even pre-menopausal, female RA patients have accelerated
atherosclerosis [2]. The diagnosis is made clinically when the pa-
tient meets four out of the seven American College of Rheumatol-
ogy (ACR) criteria [3]. Patients with RA have reduced life expec-
tancy, and the majority of the deaths can be attributed to cardiovas-
cular disease (CVD) [4]. Several studies have shown that coronary
artery disease (CAD) risk is approximately 1.5 – 2 fold greater in
RA patients. The mechanism for this increased risk may be multi-
factorial, but inflammation is one of the most important factors in
promoting premature atherogenesis. Factors implicated in athero-
genesis in RA and other rheumatic diseases are discussed in a re-
view by Gasparyan et al [5]. More research is necessary to uncover
the exact mechanisms for excess cardiovascular risk in patients with
RA [6]. Platelet biomarkers are involved in inflammation, athero-
sclerosis, and thrombosis [7]. Evidence suggests that disease modi-
fying anti-rheumatic drugs reduce platelet activity [7].
CVD risk begins early in the course of the disease. A recent
analysis from the Minnesota residents’ cohort has suggested that as
early as 2 years before the fulfillment of the ACR criteria, patients
with RA are three times more likely to be hospitalized with acute
myocardial infarction (MI) and nearly six times more likely to ex-
perience a silent MI [8]. These patients are less likely to present
with angina, and more likely to present with a higher incidence of
congestive heart failure (CHF) and sudden cardiac death [9].
Autopsied causes of death in RA patients indicate that CAD in RA
patients often remains unrecognized [10]. Studies comparing the
CVD risk in diabetes mellitus type 2 and RA to the general popula-
tion concluded that the risk of CVD in RA is almost equal to that of
diabetes mellitus [11, 12]. RA then can be regarded as a CAD
equivalent like diabetes, although these data came from an observa-
tional study [13].
*Address correspondence to this author at the Cardiology Division, New
York Medical College, Macy Pavilion, Room 138, Valhalla, NY, 10595,
USA; Tel: +914-493-5311; Fax: +914-235-6274;
E-mail: wsaronow@aol.com
DIOVASCULAR RISK FACTOR
The risks of sudden death and MI appear to be increased in
patients with RA [14-16]. Although a higher prevalence of tradi-
tional cardiac risk factors may be present in patients with RA than
in the general population, epidemiologic data suggest that RA is an
independent risk factor for CAD [17]. CVD is a major contributor
to increased mortality among patients with RA.
CORONARY ARTERY DISEASE
Several studies have shown that RA patients have a higher inci-
dence of CAD. This has prompted some experts to consider it as a
CAD equivalent [13]. A population-based cohort study was done in
Olmsted county, Minnesota to assess the ten year risk of cardiovas-
cular disease in newly diagnosed RA patients [18]. This study re-
vealed that patients with RA have a 10 year absolute cardiovascular
risk comparable to that of non- RA patients 5-10 years older. This
study was retrospective but has provided an impetus for further
studies in the future that may now incorporate RA as one of the
clinical risk predictors of developing CVD.
The risk of developing CAD in RA patients is similar to that of
diabetic patients. In a population based cross-sectional study of 353
randomly selected outpatients with RA, the prevalence of CVD was
5.0% in the non-diabetic group, 12.4% in the type 2 diabetic group,
and 12.9% in those with RA. The authors concluded that the preva-
lence of CVD in RA is increased to an extent that is at least compa-
rable to that of diabetes [11]. These diseases may share some
mechanisms that increase the risk of developing CAD. The proin-
flammatory cytokine tumor necrosis factor alpha which is elevated
in RA causes insulin resistance [19]. Consequently, treatment with
tumor necrosis factor alpha inhibitors improves insulin resistance
[19].
Elderly patients with RA have more severe CAD compared to
elderly patients without RA [20]. In a study of 102 age-matched
and sex-matched patients with and without RA who underwent
coronary angiography for suspected CAD, patients with RA had a
higher prevalence of three-vessel CAD (30%) than patients without
RA (8%) (p < 0.001) and a greater need for coronary revasculariza-
tion (70% versus 23%, p < 0.001) [20]. Elderly RA patients were
also found to have higher incidence of heart failure (30%) than
patients without RA (2%) (p < 0.005) and a left ventricular ejection
fraction of 40% or less (23% versus 7%, p< 0.001) [20].

1873-4286/12 $58.00+.00 © 2012 Bentham Science Publishers

Rheumatoid Arthritis
Pathogenesis
The etiology of atherosclerosis in patients with RA was thought
to be secondary to the accumulation of classical CVD risk factors.
There is a higher prevalence of smoking, insulin resistance, dyslipi-
demia, obesity, hypertension, and physical inactivity in patients
with RA. Obesity may be a result of physical inactivity due to ar-
thritis. Chronic steroid treatment can also cause hypertension and
insulin resistance [21]. Previous studies have shown that steroid use
was associated with increased cardiovascular morbidity [22-24]. A
study performed by Davis et al [25] showed that only those patients
who were seropositive for the rheumatoid factor were at increased
risk for cardiovascular events when they were treated with steroids.
Those patients who were negative for the rheumatoid factor were
not at increased risk for cardiovascular events, regardless of the
dose and duration of steroid use [25].
Body mass index is not a good predictor of increased cardio-
vascular risk in RA patients as they may also have rheumatoid
cachexia [26]. These patients may have a normal to low body mass
index but have a high fat content as there is a loss of lean body
mass and gain of body fat as result inflammation [27-29]. RA pa-
tients have an increase in visceral fat areas which may be associated
with an increased risk of cardiovascular events. RA patients with
rheumatoid cachexia have increased disease activity with increased
inflammation which makes them at higher risk of cardiovascular
events [30, 31].
Low- grade inflammation in the general population has been
implicated as a cause of increased coronary events. The causality of
this as part of the atherogenic process has been debated, and its role
remains uncertain [32]. Some investigators argue that the inflamma-
tion was brought about by the entry of atherogenic low-density
lipoprotein (LDL) cholesterol into the vessel wall. The elevated
systemic inflammatory biomarkers are then secondary to diseased
blood vessels. The link between low- grade inflammation and CVD
has not been fully established.
There has been evidence that atherosclerosis is an inflammatory
disorder which has common pathways that drive rheumatoid arthri-
tis [33]. The same molecular and cellular mediators drive localized
inflammation of the synovium as well as the arterial wall [34]. The
atherosclerotic plaque is characterized by vascular smooth muscle
cells that have migrated to the intima. This is accompanied by mye-
loid cells, the migration of which is made possible through endothe-
lial dysfunction. The accumulation of lipid as well as matrix deposi-
tion leads to atheroma formation. Rupture of the fibrous cap would
lead to thrombus formation and eventual MI. Unstable coronary
lesions have plaques which have an abundance of inflammatory
moieties and immune cells at the shoulder region, with erosion of
the collagen cap that separates the atheromatous material of the
plaque from the lumen. This appears similar to the inflammation of
the synovium in RA. Systemic inflammation acts as an important
mediator of endothelial dysfunction which is an early event in CVD
pathogenesis. Several studies measuring vascular function such as
pulse wave analysis, flow-mediated vasodilation, and venous occlu-
sion plethysmography confirm endothelial dysfinction in RA pa-
tients.
Patients with RA have been proven to have an expanded popu-
lation of a particular T cell subset, namely CD4+CD28- [35, 36].
These are the same type of T cells that have been noted in the blood
and atherosclerotic plaques of patients with unstable angina [37].
These cells can damage the vessel wall leading to endothelial dys-
function. RA patients with clonal expansion of these T cell subsets
have presented with increased preclinical atherosclerotic changes
compared to those without clonal expansion of these T cells.
The systemic inflammatory response in RA can adversely affect
other risk factors for CVD besides its effect on endothelial dysfunc-
tion. RA patients have a low serum high-density lipoprotein (HDL)
cholesterol, an increased serum lipoprotein a, and a greater prepon-
Current Pharmaceutical Design, 2012, Vol. 18, No. 11 1451
derance of smaller atherogenic serum LDL cholesterol [38]. The
serum HDL cholesterol function is also abnormal and is unable to
protect LDL cholesterol from oxidation. This proinflammatory
HDL cholesterol can contribute oxidative damage and has been
reported in approximately 20 % of patients with RA [39]. Inflam-
matory cytokines such as tumor necrosis factor alpha decreases
both serum total cholesterol and serum HDL cholesterol, but it af-
fects the serum HDL cholesterol to a greater degree, thereby yield-
ing an unfavorable serum total cholesterol/HDL cholesterol ratio.
Serum lipid levels are not good predictors of CVD risk in RA pa-
tients. These patients may have low serum LDL cholesterol or total
cholesterol values but still remain at high risk of developing CVD
[40]. Recent data show that serum triglycerides may be a good pre-
dictor of cardiovascular disease risk [41].
Endothelial progenitor cells are bone marrow derived cells that
are released from the marrow during acute vascular injury. These
calls have a significant role in vasculogenesis after an injury [42].
These cells maintain a balance between endothelial destruction and
regeneration, a process which is important to maintain vascular
health. Higher concentrations of these cells may be protective, but
this still has to be proven. A study has shown that patients with
higher disease activity scores have lower concentrations of these
cells [42].
In patients with RA and CAD, there is less histologic evidence
of atherosclerosis but greater evidence of inflammation and insta-
bility than in control patients with CAD but without RA [43]. Re-
current ischemic events and death occur more often in patients with
RA and an acute coronary syndrome than in case matched controls
with an acute coronary syndrome but without RA [8].
Risk Assessment
Traditional CVD risk assessment should be performed on all
RA patients early on in their disease. These patients have a higher
incidence of sudden cardiac death, CHF, and silent ischemia with a
greater 30-day case fatality rate after a cardiovascular event [44].
The Framingham score underestimates the risk of cardiovascular
events in patients with chronic medical conditions [45, 46].
The European League Against Rheumatism (EULAR) has
made new recommendations on risk assessment in RA patients
[47]. One of their recommendations was to multiply the risk score
by a factor of 1.5. This multiplication factor can only be used if a
patient meets two out of three criteria which are the following: dis-
ease duration of more than 10 years, rheumatoid factor or anti –
cyclic citrullinated peptide (CCP) positive, and presence of extra-
articular manifestations. In the United States, the Framingham score
has been used for assessment of cardiovascular risk while the Sys-
temic Coronary Risk Evaluation (SCORE) model has been used in
Europe [48]. A significant number of RA patients require statin
therapy, but a lot of them are untreated. CVD risk factors should be
properly identified and managed aggressively.
Traditional risk factors for cardiovascular disease include
smoking, hypertension, increased serum total cholesterol and low-
density lipoprotein cholesterol, diabetes mellitus, obesity, and
physical inactivity. Emerging risk factors include low serum high-
density lipoprotein cholesterol, increased serum triglycerides, C-
reactive protein, and seropositivity to rheumatoid factor. Fig. (1)
shows risk factors predisposing to endothelial dysfunction and car-
diovascular disease.
Therapy
Disease modifying antirheumatic drugs (DMARD) have been
shown to decrease the risk of CAD in RA patients [49, 50].
Methotrexate reduced overall mortality in RA patients by 60%
through its reduction in CAD mortality [50-52]. Methotrexate also
reduced the incidence of metabolic syndrome. This drug may also
have favorable effects against atherogenesis by promoting reverse
cholesterol transport thereby limiting foam cell formation [53].
1452 Current Pharmaceutical Design, 2012, Vol. 18, No. 11 Mellana et al.

Smoking

Impaired Vascular Repair E C

Vascular Injury N A
D R
Dyslipidemia O D
T I
Lipid Peroxidation
H O
Pro-inflammatory HDL V
E
Adhesion molecules: A
L
VCAM-1 S
I
Cytokines: C
A
IL1,IL6,TNF,IL17 U
L
CD4+CD28- Cells L
D A
C-Reactive Protein/Acute
Phase Reactants Y R
S
Homocysteine D
F
I
U
Hyperglycemia S
N
Insulin Resistance E
C
A
Glucocorticoids T
S
I
E
Hypertension O
Fluid Retention N

Fig. (1). Risk Factors Predisposing to Endothelial Dysfunction and Cardiovascular Disease
HDL = high-density lipoprotein; VCAM-1 = vascular cell adhesion molecule-1; IL = interleukin; TNF = tumor necrosis factor

Hydroxychloroquine use was also associated with improvement
in dyslipidemia by decreasing serum LDL cholesterol, serum total
cholesterol, serum LDL/HDL cholesterol, and serum total choles-
terol/ HDL cholesterol [54]. This drug may be useful in controlling
dyslipidemia. Hydroxychloroquine was also associated with lower
fasting glucose in women with RA [55].
Tumor necrosis factor alpha antagonists can be used in patients
with RA. There has been some concern about its use in worsening
heart failure. A study showed that patients with asymptomatic heart
failure treated with tumor necrosis factor alpha antagonists had
reductions in N-terminal pro-BNP levels [56]. In another study,
long term use of tumor necrosis factor alpha antagonists did not
show an increase incidence of CVD events and in fact showed a
decreased risk of CVD events in patients younger than 63 years of
age [57]. Surrogate endpoints such as endothelial function and aor-
tic stiffness were improved in patients given this class of drugs
[57].
Glucocorticoids should be used at the lowest effective dose.
These drugs control inflammation which can attenuate the risk of
CVD but at the expense of inducing insulin resistance, hyperten-
sion, and dyslipidemia which are all risk factors for CVD [58].
Statins should be used early in the course of RA when appro-
priate and have been underutilized in patients with RA. Statins not
only exert beneficial effects through its effects on serum lipids but
also has anti-inflammatory effects [59, 60]. The Trial of Atorvas-
tatin in Rheumatoid Arthritis study revealed that statins had modest
improvements in disease activity scores as well as marked reduc-
tions in C-reactive protein and erythrocyte sedimentation rate,
which are both markers of inflammation [61].
Traditional CVD risk factors such as obesity, smoking, and
hypertension should be aggressively addressed in RA patients.
Obese patients should be counseled on the importance of diet and
exercise, and steroid use should be minimized. Smoking cessation
should be advised with referral to a smoking cessation program.
Blood pressure should be monitored and treated appropriately as
per guidelines [62].
HEART FAILURE
RA patients have an increased incidence of CHF compared to
the general population [63]. The cause behind this increased risk is
thought to be secondary to inflammation [64]. These patients may
have CHF associated with systolic or diastolic dysfunction [65, 66].
RA patients have a higher incidence of left ventricular systolic
dysfunction [17, 20]. One study revealed that RA patients are 3.0
times more likely to have left ventricular systolic dysfunction even
after adjustments for traditional CVD risk factors [17]. RA patients
also have an increased incidence of left ventricular hypertrophy
(LVH), which is a common cause of diastolic heart failure and of
diastolic dysfunction [67]. In a study comparing RA patients to
healthy matched controls, the prevalence of LVH was significantly
greater in patients with RA [68]. Mortality from CHF in RA pa-
tients with CHF is significantly higher than from CHF patients
without RA [69].
Rheumatoid Arthritis
Pathogenesis
The increased incidence of heart failure in patients with RA
may be attributed to inflammation, CAD, RA therapy, and amyloi-
dosis. In one cohort study of 575 RA patients who were followed
longitudinally for 15 years, 29.9% developed CHF [70]. The eryth-
rocyte sedimentation rate was followed serially in these patients,
and the value was higher six months preceding the onset of CHF
[70].
Randomized trials have not shown that tumor necrosis factor
alpha inhibitors are beneficial for RA patients with CHF [71-73].
However, these drugs may be beneficial in the majority of RA pa-
tients without heart failure. The populations tested were RA pa-
tients who had class II – IV CHF with a left ventricular ejection
fraction less than 31% [71, 72] or class III-IV CHF and a left ven-
tricular ejection fraction less than 35% [73]. The Randomised Etan-
ercept North American Strategy to Study Antagonism of Cytokines
(RENAISSANCE) trial compared patients who were treated with
placebo, etanercept 25mg twice weekly, and etanercept 25mg three
times a week [72, 73]. The mortality rates were 14%, 17.9%, and
19.8%, respectively, with a trend towards a higher mortality rate in
the etanercept- treated groups [71, 72].
In the Research into Etanercept Cytokine Antagonism in Ven-
tricular dysfunction (RECOVER) trial, the treatment groups were
placebo, etanercept 25 mg once a week, and etanercept twice a
week [71, 72]. The mortality rates and composite clinical function
score were not significantly different between the treatment groups
[71, 72].
The anti-TNF Therapy Against Congestive Heart Failure (AT-
TACH) trial tested infliximab in RA patients with CHF [73]. One
hundred and fifty patients were randomized to placebo, infliximab
5mg/kg, and infliximab 10mg/kg. The combined risk of all-cause
mortality or hospitalization for CHF through 28 weeks was signifi-
cantly increased 2.84 times (p = 0.043) by the higher dose of in-
fliximab and not improved by the low dose of infliximab [73].
Non-steroidal anti- inflammatory drugs (NSAIDs) cause exac-
erbation of preexisting CHF by increasing afterload through its
vasoconstrictive effect. These drugs should not be used in patients
with CHF because they precipitate and aggravate CHF, precipitate
acute renal failure in patients with CHF and with chronic kidney
disease, increase blood pressure, interfere with the antihypertensive
action of most antihypertensive drugs, and increase cardiovascular
events [74]. Treatment of CHF is the same for patients with and
without RA. NSAIDS should be avoided in these patients [74].
Therapeutic use of glucocorticoids have been associated with an
increased risk of CHF [75]. The increased risk is dose dependent
and is higher in patients taking glucocorticoids continuously rather
than intermittently [75]. RA patients who are taking corticosteroids
were at higher risk only if they were rheumatoid factor positive
[76]. Rheumatoid factor might interact with corticosteroids to
modulate the occurrence of CHF. Low-dose corticosteroids may be
used in some patients with RA.
Long standing inflammation can cause secondary amyloidosis
[77]. The most common manifestation is renal disease such as the
nephrotic syndrome, but secondary amyloidosis also causes a re-
strictive cardiomyopathy.
RA patients have a higher incidence of CAD which is the most
common cause of CHF in these patients. Large doses of aspirin can
interfere with the efficacy of angiotensin-converting enzyme inhibi-
tors in the treatment of CHF [74].
PERICARDITIS
Pericardial involvement occurs in up to 30% of RA patients
[78]. Most of these patients are asymptomatic [76]. The few pa-
tients who have pericarditis have a positive rheumatoid factor and
other extra-articular manifestations. Treatment of the disease should
Current Pharmaceutical Design, 2012, Vol. 18, No. 11 1453
control the symptoms. Glucocorticoids may be used if the pericardi-
tis does not respond to NSAIDS.
MYOCARDITIS
Myocarditis is a rare occurrence in RA patients and may be
granulomatous or interstitial. The granulomatous form is more spe-
cific for RA [79], while the interstitial form is more common with
systemic lupus erythematosus [74]. Endomyocardial biopsy may be
done to diagnose the disease [80]. Pulse methylprednisolone plus
oral prednisone may be used to treat rheumatoid myocarditis [81].
VASCULITIS
RA can cause vasculitis which may involve small to medium
sized arteries. RA vasculitis may be manifested as visceral arteritis,
distal arteritis, cutaneous ulceration, and neurovascular involvement
leading to sensory neuropathy [82].
PERIPHERAL ARTERIAL DISEASE
Peripheral arterial disease (PAD) is more prevalent in RA pa-
tient than in patients without RA. In a study that compared 234 non-
smoking patients with RA to 102 non-smoking healthy persons,
PAD occurred in 19% of patients with RA compared to 5% in the
control group [83]. The presence of extraarticular manifestations is
an independent risk factor for the development of PAD.
The pathogenesis of PAD in patients with RA involves acceler-
ated atherosclerosis caused by the prevalent cardiovascular risk
factors and a greatly augmented inflammatory status. A study by
Stametelopoulos et al [84] on subclinical PAD in patients with RA
without traditional cardiovascular risk factors studied the femoral
intimal medial plaque presence and vulnerability and femoral inti-
mal medial thickness (IMT) in 80 patients with RA with no overt
cardiovascular risk factors. These investigators also compared the
femoral plaque and IMT development to carotid artery IMT and
plaque presence and vulnerability. Although their study demon-
strated that atherosclerotic activity in the carotid artery was more
than in the femoral artery, the subclinical atherosclerosis in the
femoral arteries was more pronounced in the patients with RA than
with age-matched controls. This observation warrants primary pre-
vention strategies for PAD in patients with RA. If patients with RA
present with PAD, they should receive treatment for their PAD
[85]. Immunosuppressive agents may delay the progression of PAD
[86].
STROKE
RA patients have an increased incidence of ischemic stroke
[38]. A meta-analysis showed that the risk of death from stroke in
patients with RA was 1.52 times higher (95% CI, 1.40 – 1.67) than
in patients without RA [14]. In the AMORIS study, patients with
RA had an increased risk of ischemic stroke independent of their
serum total cholesterol levels [38].
CONCLUSION
RA patients have a significant increase in cardiovascular mor-
bidity and mortality than patients without RA. Inflammation is the
common link between CAD and RA. Aggressive treatment of RA
to control the inflammatory process with drugs such as hydroxy-
chloroquine, methotrexate, and tumor necrosis factor alpha antago-
nists may attenuate the risk of developing CVD. Risk assessment
for CVD should be performed in RA patients as early as possible.
Traditional risk factors should be identified and modifiable risk
factors treated. Traditional risk factors for cardiovascular disease
include smoking, hypertension, increased serum total cholesterol
and low-density lipoprotein cholesterol, diabetes mellitus, obesity,
and physical inactivity. Emerging risk factors include low serum
high-density lipoprotein cholesterol, increased serum triglycerides,
C-reactive protein, and seropositivity to rheumatoid factor. The new
EULAR recommendations have suggested multiplying the CVD
1454 Current Pharmaceutical Design, 2012, Vol. 18, No. 11 Mellana et al.

risk factors by a factor of 1.5, which would make the goals of sectional study, the CARRE Investigation. Ann Rheum Dis 2009;
treatment in these patients different when compared to the general 68: 1395-1400.
population, especially in the management of dyslipidemia. [12] Stamatelopoulos KS, Kitas GD, Papamichael CM, et al. Athero-
sclerosis in rheumatoid arthritis versus diabetes: a comparative
CONFLICT OF INTEREST study. Arterioscler Thromb Vasc Biol 2009; 29: 1702-08.
[13] John H, Toms TE, Kitas GD. Rheumatoid arthritis: is it a coronary
None. heart disease equivalent? Curr Opin Cardiol 2011; 26: 327-33.
[14] Aviña-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile
ABBREVIATIONS JM, Lacaille D. Risk of cardiovascular mortality in patients with
ACR = American College of Rheumatology rheumatoid arthritis: a meta-analysis of observational studies. Ar-
thritis Rheum 2008; 59: 1690-97.
ATTACH = Anti-TNF Therapy Against Congestive [15] Myllykangas-Luosujärvi RA, Aho K, Isomäki HA. Mortality in
Heart Failure rheumatoid arthritis. Semin Arthritis Rheum 1995; 25: 193-202.
CAD = Coronary artery disease [16] Wallberg-Jonsson S, Ohman ML, Dahlqvist SR. Cardiovascular
morbidity and mortality in patients with seropositive rheumatoid
CCP = Cyclic citrullinated peptide arthritis in Northern Sweden. J Rheumatol 1997; 24: 445-51.
CHF = Congestive heart failure [17] Gabriel SE, Crowson CS, O'Fallon WM. Comorbidity in arthritis. J
Rheumatol 1999; 26: 2475-9.
CVD = Cardiovascular disease [18] Maradit Kremers H, Crowson CS, Gabriel SE. Rochester Epidemi-
EULAR = European League Against Rheumatism ology Project: a unique resource for research in the rheumatic dis-
HDL = High-density lipoprotein eases. Rheum Dis Clin North Am 2004; 30: 819-34.
[19] Gonzalez-Gay MA, Gonzalez-Juanatey C, Vazquez-Rodriguez TR,
IMT = Intimal medial thickness Miranda-Filloy JA, Llorca J. Insulin resistance in rheumatoid ar-
LDL = Low-density lipoprotein thritis: the impact of the anti-TNF-alpha therapy. Ann NY Acad Sci
2010; 1193: 153-9.
LVH = Left ventricular hypertrophy [20] Yalamanchili K, Aronow WS, Kilaru R, et al. Coronary artery
MI = Myocardial infarction disease is more severe in older persons with rheumatoid arthritis
than in older persons without rheumatoid arthritis. Cardiol Rev
NSAIDs = Nonsteroidal anti-inflammatory drugs 2006; 14: 55-6.
PAD = Peripheral arterial disease [21] Wei L, MacDonald TM, Walker BR. Taking glucocorticoids by
prescription is associated with subsequent cardiovascular disease.
RECOVER = Research into Etanercept Cytokine An- Ann Intern Med 2004; 141: 764-70.
tagonism in Ventricular dysfunction [22] Maxwell SR, Moots RJ, Kendall MJ. Corticosteroids: do they
RENAISSANCE = Randomised Etanercept North American damage the cardiovascular system? Postgrad Med J 1994; 70: 863-
Strategy to Study Antagonism of Cytoki- 70.
nes [23] Kumeda Y, Inaba M, Goto H, et al. Increased thickness of the
arterial intima-media detected by ultrasonography in patients with
SCORE = Systemic Coronary Risk Evaluation rheumatoid arthritis. Arthritis Rheum 2002; 46: 1489-97.
[24] Solomon DH, Avorn J, Katz JN, et al. Immunosuppressive medica-
REFERENCES tions and hospitalization for cardiovascular events in patients with
[1] Lawrence RC, Helmick CG, Arnett FC, et al. Estimates of the rheumatoid arthritis. Arthritis Rheum 2006; 54: 3790-8.
prevalence of arthritis and selected musculoskeletal disorders in the [25] Davis JM 3rd, Maradit Kremers H, Crowson CS, et al. Glucocorti-
United States. Arthritis Rheum 1998; 41: 778-99. coids and cardiovascular events in rheumatoid arthritis: a popula-
[2] Pahor A, Hojs R, Gorenjak M, Rozman B. Accelerated atheroscle- tion-based cohort study. Arthritis Rheum 2007; 56: 820-30.
rosis in pre-menopausal female patients with rheumatoid arthritis. [26] Summers GD, Metsios GS, Stavropoulos-Kalinoglou A, Kitas GD.
Rheumatol Int 2006; 27: 119-23. Rheumatoid cachexia and cardiovascular disease. Nat Rev Rheu-
[3] Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheuma- matol 2010; 6: 445-51.
tism Association 1987 revised criteria for the classification of [27] Stavropoulos-Kalinoglou A, Metsios GS, Panoulas VF, et al. Asso-
rheumatoid arthritis. Arthritis Rheum 1988; 31: 315-24. ciations of obesity with modifiable risk factors for the development
[4] Prior P, Symmons DP, Scott DL, Brown R, Hawkins CF. Cause of of cardiovascular disease in patients with rheumatoid arthritis. Ann
death in rheumatoid arthritis. Br J Rheumatol 1984; 23: 92-9. Rheum Dis 2009; 68: 242-5.
[5] Gasparyan AY, Stavropoulos-Kalinoglou A, Mikhailidis DP, Toms [28] Giles JT, Allison M, Blumenthal RS, et al. Abdominal adiposity in
TE, Douglas KM, Kitas GD. The rationale for comparative studies rheumatoid arthritis: association with cardiometabolic risk factors
of accelerated atherosclerosis in rheumatic diseases. Curr Vasc and disease characteristics. Arthritis Rheum 2010; 62: 3173-82.
Pharmacol 2010; 8: 437-49. [29] Stavropoulos-Kalinoglou A, Metsios GS, Koutedakis Y, Kitas GD.
[6] Kitas GD, Gabriel SE. Cardiovascular disease in rheumatoid arthri- Obesity in rheumatoid arthritis. Rheumatology (Oxford) 2011; 50:
tis: state of the art and future perspectives. Ann Rheum Dis 2011; 450-62.
70: 8-14. [30] Munro R, Capell H. Prevalence of low body mass in rheumatoid
[7] Gasparyan AY, Stavropoulos-Kalinoglou A, Mikhailidis DP, arthritis: association with the acute phase response. Ann Rheum
Douglas KM, Kitas GD. Platelet function in rheumatoid arthritis: Dis 1997; 56: 326-9.
arthritic and cardiovascular implications. Rheumatol Int 2011; 31: [31] Helliwell PS, Jackson S. Relationship between weakness and mus-
153-64. cle wasting in rheumatoid arthritis. Ann Rheum Dis 1994; 53: 726-
[8] Douglas KM, Pace AV, Treharne GJ, et al. Excess recurrent car- 8.
diac events in rheumatoid arthritis patients with acute coronary [32] Emerging Risk Factors Collaboration, Kaptoge S, Di Angelantonio
syndrome. Ann Rheum Dis 2006; 65: 348-53. E, et al. C-reactive protein concentration and risk of coronary heart
[9] Maradit-Kremers H, Crowson CS, Nicola PJ, et al. Increased un- disease, stroke, and mortality: an individual participant meta-
recognized coronary heart disease and sudden deaths in rheumatoid analysis. Lancet 2010; 375: 132-40.
arthritis: a population-based cohort study. Arthritis Rheum 2005; [33] Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med
52: 402-11. 1999; 340: 115-126.
[10] Koivuniemi R, Paimela L, Suomalainen R, et al. Causes of death in [34] Pasceri V, Yeh ET. A tale of two diseases: atherosclerosis and
patients with rheumatoid arthritis autopsied during a 40-year pe- rheumatoid arthritis. Circulation 1999; 100: 2124-6.
riod. Rheumatol Int 2008; 28: 1245-52. [35] Martens PB, Goronzy JJ, Schaid D, Weyand CM. Expansion of
[11] van Halm VP, Peters MJ, Voskuyl AE, et al. Rheumatoid arthritis unusual CD4+ T cells in severe rheumatoid arthritis. Arthritis
versus diabetes as a risk factor for cardiovascular disease: a cross- Rheum 1997; 40: 1106-14.
Rheumatoid Arthritis
[36] Gerli R, Schillaci G, Giordano A, et al. CD4+CD28- T lympho-
cytes contribute to early atherosclerotic damage in rheumatoid ar-
thritis patients. Circulation 2004; 109: 2744-8.
[37] Liuzzo G, Biasucci LM, Trotta G, et al. Unusual CD4+CD28null T
lymphocytes and recurrence of acute coronary events. J Am Coll
Cardiol 2007; 50: 1450-8.
[38] Lorber M, Aviram M, Linn S, Scharf Y, Brook JG. Hypercholes-
terolemia and abnormal high-density lipoprotein in rheumatoid ar-
thritis. Br J Rheumatology 1985; 24: 250-5.
[39] McMahon M, Grossman J, FitzGerald J, et al. Proinflammatory
high-density lipoprotein as a biomarker for atherosclerosis in pa-
tients with systemic lupus erythematosus and rheumatoid arthritis.
Arthritis Rheum. 2006; 54: 2541-9.
[40] Semb AG, Kvien TK, Aastveit AH, et al. Lipids, myocardial in-
farction and ischaemic stroke in patients with rheumatoid arthritis
in the Apolipoprotein-related Mortality RISk (AMORIS) Study.
Ann Rheum Dis 2010; 69: 1996-2001.
[41] Innala L, Möller B, Ljung L, et al. Cardiovascular events in early
RA are a result of inflammatory burden and traditional risk factors:
a five year prospective study. Arthritis Res Ther 2011; 13: R131.
[42] Grisar J, Aletaha D, Steiner CW, et al. Depletion of endothelial
progenitor cells in the peripheral blood of patients with rheumatoid
arthritis. Circulation 2005; 111: 204-11.
[43] Aubry MC, Maradit-Kremers H, Reinalda MS, Crowson CS, Ed-
wards WD, Gabriel SE. Differences in atherosclerotic coronary
heart disease between subjects with and without rheumatoid arthri-
tis. J Rheumatol 2007; 34: 937-42.
[44] Symmons DP, Gabriel SE. Epidemiology of CVD in rheumatic
disease, with a focus on RA and SLE. Nat Rev Rheumatology
2011; 7: 399-408.
[45] Weiner DE, Tighiouart H, Elsayed EF, et al. The Framingham
predictive instrument in chronic kidney disease. J Am Coll Cardiol
2007; 50: 217-24.
[46] McEwan P, Williams JE, Griffiths JD, et al. Evaluating the per-
formance of the Framingham risk equations in a population with
diabetes. Diabet Med 2004; 21: 318-23.
[47] Peters MJ, Symmons DP, McCarey D, et al. EULAR evidence-
based recommendations for cardiovascular risk management in pa-
tients with rheumatoid arthritis and other forms of inflammatory ar-
thritis. Ann Rheum Dis 2010; 69: 325-31.
[48] Conroy RM, Pyörälä K, Fitzgerald AP, et al. Estimation of ten-year
risk of fatal cardiovascular disease in Europe: the SCORE project.
Eur Heart J 2003; 24: 987-1003.
[49] Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F.
Methotrexate and mortality in patients with rheumatoid arthritis: a
prospective study. Lancet 2002; 359: 1173-7.
[50] Naranjo A, Sokka T, Descalzo MA, et al. Cardiovascular disease in
patients with rheumatoid arthritis: results from the QUEST-RA
study. Arthritis Res Ther 2008; 10: R30.
[51] Salliot C, van der Heijde D. Long-term safety of methotrexate
monotherapy in patients with rheumatoid arthritis: a systematic lit-
erature research. Ann Rheum Dis 2009; 68: 1100-4.
[52] Westlake SL, Colebatch AN, Baird J, et al. The effect of
methotrexate on cardiovascular disease in patients with rheumatoid
arthritis: a systematic literature review. Rheumatology (Oxford)
2010; 49: 295-307.
[53] Reiss AB, Carsons SE, Anwar K, et al. Atheroprotective effects of
methotrexate on reverse cholesterol transport proteins and foam
cell transformation in human THP-1 monocyte/macrophages. Ar-
thritis Rheum 2008; 58: 3675-83.
[54] Morris SJ, Wasko MC, Antohe JL, et al. Hydroxychloroquine use
associated with improvement in lipid profiles in rheumatoid arthri-
tis patients. Arthritis Care Res (Hoboken) 2011; 63: 530-4.
[55] Penn SK, Kao AH, Schott LL, et al. Hydroxychloroquine and gly-
cemia in women with rheumatoid arthritis and systemic lupus
erythematosus. J Rheumatol 2010; 37: 1136-42.
[56] Peters MJ, Welsh P, McInnes IB, et al. Tumour necrosis factor
{alpha} blockade reduces circulating N-terminal pro-brain natri-
uretic peptide levels in patients with active rheumatoid arthritis: re-
sults from a prospective cohort study. Ann Rheum Dis 2010; 69:
1281-5.
[57] Cacciapaglia F, Navarini L, Menna P, Salvatorelli E, Minotti G,
Afeltra A. Cardiovascular safety of anti-TNF-alpha therapies: Facts
and unsettled issues. Autoimmun Rev 2011; 10: 631-5.
[58] Sholter DE, Armstrong PW. Adverse effects of corticosteroids on
the cardiovascular system. Can J Cardiol 2000; 16: 505-11.
Current Pharmaceutical Design, 2012, Vol. 18, No. 11 1455
[59] Palaniswamy C, Selvaraj DR, Selvaraj T, Sukhija R. Mechanisms
underlying pleiotropic effects of statins. Am J Ther 2010; 17: 75-8.
[60] Toms TE, Panoulas VF, Douglas KM, et al. Statin use in rheuma-
toid arthritis in relation to actual cardiovascular risk: evidence for
substantial undertreatment of lipid-associated cardiovascular risk?
Ann Rheum Dis 2010; 69: 683-8.
[61] McCarey DW, McInnes IB, Madhok R, et al. Trial of Atorvastatin
in Rheumatoid Arthritis (TARA): double-blind, randomised pla-
cebo-controlled trial. Lancet 2004; 363: 2015-21.
[62] Aronow WS, Fleg JL, Pepine CJ, et al. ACCF/AHA 2011 Expert
Consensus Document on Hypertension in the Elderly. J Am Coll
Cardiol 2011; 57: 2037-2114.
[63] Nicola PJ, Crowson CS, Maradit-Kremers H, et al. Contribution of
congestive heart failure and ischemic heart disease to excess mor-
tality in rheumatoid arthritis. Arthritis Rheum 2006; 54: 60-7.
[64] Mann DL. Inflammatory mediators and the failing heart: past,
present, and the foreseeable future. Circ Res 2002; 91: 988-98.
[65] Bhatia GS, Sosin MD, Patel JV, et al. Left ventricular systolic
dysfunction in rheumatoid disease: an unrecognized burden? J Am
Coll Cardiol 2006; 47: 1169-74.
[66] Myasoedova E, Crowson CS, Nicola PJ, et al. The Influence of
Rheumatoid Arthritis Disease Characteristics on Heart Failure. J
Rheumatol 2011; 38: 1601-6.
[67] Liang KP, Myasoedova E, Crowson CS, et al. Increased prevalence
of diastolic dysfunction in rheumatoid arthritis. Ann Rheum Dis
2010; 69: 1665-70.
[68] Rudominer RL, Roman MJ, Devereux RV, et al. Independent asso-
ciation of rheumatoid arthritis with increased left ventricular mass
but not with reduced ejection fraction. Arthritis Rheum 2009; 60:
22-9.
[69] Davis JM 3rd, Roger VL, Crowson CS, Kremers HM, Therneau
TM, Gabriel SE. The presentation and outcome of heart failure in
patients with rheumatoid arthritis differs from that in the general
population. Arthritis Rheum 2008; 58: 2603-11.
[70] Maradit-Kremers H, Nicola PJ, Crowson CS, et al. Raised erythro-
cyte sedimentation rate signals heart failure in patients with rheu-
matoid arthritis. Ann Rheum Dis 2007; 66: 76-80.
[71] Anker SD, Coats AJ. How to RECOVER from RENAISSANCE?
The significance of the results of RECOVER, RENAISSANCE,
RENEWAL and ATTACH. Int J Cardiol 2002; 86: 123-30.
[72] Mousa SA, Goncharuk O, Miller D. Recent advances of TNF-alpha
antagonists in rheumatoid arthritis and chronic heart failure. Expert
Opin Biol Ther 2007; 7: 617-25.
[73] Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT. anti-
TNF Therapy Against Congestive Heart Failure Investigators. Ran-
domized, double-blind, placebo-controlled, pilot trial of infliximab,
a chimeric monoclonal antibody to tumor necrosis factor-alpha, in
patients with moderate-to-severe heart failure: results of the anti-
TNF Therapy Against Heart Failure (ATTACH) trial. Circulation
2003; 107: 3133-40.
[74] Aronow WS. Treatment of heart failure in older persons. Dilemmas
with coexisting conditions: diabetes mellitus, chronic obstructive
pulmonary disease, and arthritis. Congestive Heart Fail 2003; 9:
142-7.
[75] Wei L, MacDonald TM, Walker BR. Taking glucocorticoids by
prescription is associated with subsequent cardiovascular disease.
Ann Intern Med 2004; 141: 764-70.
[76] Dhawan SS, Quyyumi AA. Rheumatoid arthritis and cardiovascu-
lar disease. Curr Atheroscler Rep 2008; 10: 128-33.
[77] Silva L, Sampaio L, Terroso G, et al. Amyloidosis secondary to
rheumatic diseases - 16 cases. Acta Reumatol Port 2010; 35: 518-
23.
[78] Guedes C, Bianchi-Fior P, Cormier B, Barthelemy B, Rat AC,
Boissier MC. Cardiac manifestations of rheumatoid arthritis: a
case-control transesophageal echocardiography study in 30 pa-
tients. Arthritis Rheum 2001; 45: 129-35.
[79] Ferrans VJ, Rodriguez ER. Cardiovascular lesions in collagen-
vascular diseases. Heart Vessels Suppl 1985; 1: 256-61.
[80] Slack JD, Waller B. Acute congestive heart failure due to the arteri-
tis of rheumatoid arthritis: early diagnosis by endomyocardial bi-
opsy: a case report. Angiology 1986; 37: 477-82.
[81] Tsuji M, Douwaki C, Yamada A, et al. [Acute congestive heart
failure due to malignant rheumatoid arthritis]. Kokyu To Junkan
1991; 39: 617-21. [Article in Japanese]
[82] Myasoedova E, Crowson CS, Turesson C, Gabriel SE, Matteson
EL. Incidence of extraarticular rheumatoid arthritis in Olmsted
1456 Current Pharmaceutical Design, 2012, Vol. 18, No. 11 Mellana et al.

County, Minnesota, in 1995-2007 versus 1985-1994: a population-
based study. J Rheumatol 2011; 38: 983-9.
[83] del Rincon I, Haas RW, Pogosian S, Escalante A. Lower limb
arterial incompressibility and obstruction in rheumatoid arthritis.
Ann Rheum Dis 2005; 64: 425-32.
[84] Stamatelopoulos KS, Kitas GD, Papamichael CM, et al. Subclinical
peripheral arterial disease in rheumatoid arthritis. Atherosclerosis
2010; 212: 305-9.
[85] Aronow WS. Office management of peripheral arterial disease. Am
J Med 2010; 123: 790-2.
[86] Henke PK, Sukheepod P, Proctor MC, Upchurch GR Jr, Stanley
JC. Clinical relevance of peripheral vascular occlusive disease in
patients with rheumatoid arthritis and systemic lupus erythemato-
sus. J Vasc Surg 2003; 38: 111-5.

Received: December 16, 2011 Accepted: January 10, 2012