Cardiovascular
Complications of
Rheumatoid Arthritis:
Assessment, Prevention,
and Treatment
Mariana J. Kaplan, MD
THE IMPACT OF CARDIOVASCULAR DISEASE IN THE PROGNOSIS
OF PATIENTS WITH RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA), a chronic inflammatory disease that affects approximately
1% of the general population, is associated with increased mortality and reduced
life expectancy, with standardized mortality rates ranging from 1.28 to 3.0.1–7 Despite
remarkable improvements in RA treatment, there is evidence indicating that the
mortality gap between patients with this disease and the general population is not
closing. When patients in the Rochester RA cohort were grouped by the decade of
disease incidence when they first met American College of Rheumatology criteria,
no significant differences in survival were observed over four decades.8 Because
the control population showed decreases in mortality rate, these observations support
the notion that the mortality gap between patients with RA and healthy controls is
actually widening, particularly in patients who are seropositive for the rheumatoid
factor (RF).9
This increase in mortality in RA is predominantly caused by accelerated coronary
artery and cerebrovascular atherosclerosis, and to other cardiovascular (CV) complications, including heart failure.10–12 Indeed, cardiovascular disease (CVD)-associated
mortality risk is increased in men and women with seropositive RA.13 A recent metaanalysis indicated that the risk for CVD-associated death could be as much as 50%
higher among patients with RA compared with controls, with the risk for ischemic
Funding support: This work was supported by the National Institutes of Health through PHS
grant R01 HL086553.
Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical
School, 1150 West Medical Center Drive, 5520 MSRBI, Box 5680, Ann Arbor, MI 48109, USA
E-mail address: makaplan@med.umich.edu
KEYWORDS
Rheumatoid arthritis Atherosclerosis Heart failure
Inflammation Cardiovascular Cytokines
Rheum Dis Clin N Am 36 (2010) 405–426
doi:10.1016/j.rdc.2010.02.002 rheumatic.theclinics.com
0889-857X/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
heart disease and cerebrovascular diseases being elevated to a similar degree.14 RA
is an independent risk factor for multi-vessel coronary artery disease.15 The enhanced
vascular risk is not restricted to individuals with established RA, because increased
mortality in patients who are positive for the RF and have early inflammatory polyarthritis has been reported.13,16
In men and women with RA with disease onset in the 1980s and 1990s, CVD
mortality was significantly increased (standardized mortality rates of 1.36 and 1.93,
respectively). However, standardized admission rates for CV complications were
not raised in these patients, suggesting either that vascular disease in RA has a higher
case fatality than in the general population or that it often goes unrecognized before
the fatal event.17 Patients with RA also have substantially increased 30-day mortality
from all causes and from CVD following a first acute vascular event,18 and more
frequent recurrent ischemic events after acute coronary syndrome.19 RA extra-articular manifestations, usually related to uncontrolled inflammation, are also associated
with increased CV mortality,20 suggesting that processes intrinsic to RA pathogenesis
play important roles in CV damage and its clinical consequences.
CVD does not only impact mortality in RA but also leads to significant morbidity. CV
events occur approximately a decade earlier in RA than in controls21 and patients with
RA are twice as likely to suffer a myocardial infarction6,8,16 with the increased relative
risk for CV events being concentrated in younger patients with RA and individuals
without known prior CV events.22 However, in a population of male United States’
veterans older than 50 years, RA has also been associated with a higher risk for major
adverse CV events, particularly in patients with increased disease activity independent
of traditional risk factors.23
Patients with prolonged arthritis have more atherosclerosis than patients of the
same age with more recent disease onset, suggesting that atherogenesis accelerates
after the onset of RA.24,25 The odds ratio for the likelihood of having more severe coronary artery calcification in established RA has been determined at 3.42, after adjusting
for traditional CV risk factors.26 Further, an increased prevalence of severe subclinical
atherosclerotic findings in long-term treated patients who have RA without clinical
evidence of atherosclerotic disease has been reported.27 However, even patients
with early RA show evidence of increased subclinical atherosclerosis,28 as assessed
by carotid plaque, carotid intima media thickness, and coronary calcification. Patients
with RA also exhibit significantly increased arterial stiffness29 and young to middleaged patients who have RA with low disease activity and free from traditional CV
risk factors and overt CVD have altered endothelial reactivity.30
In many ways, CVD in RA shares similarities with CVD in diabetes mellitus (DM).
Preclinical atherosclerosis and the risk for CVD appears to be of equal frequency
and severity in RA and DM of similar duration.31 Compared with non-diabetic controls,
patients who are non-diabetic with RA and those with type 2 DM have comparable
hazard ratios for CVD: 2.16 (95% CI 1.28–3.63, P 5 .004) and 2.04 (95% CI 1.12–
3.67, P 5 .019), respectively.32 Further, similar to what occurs in DM, patients with
RA are less likely to report symptoms of angina and more likely to experience unrecognized myocardial infarction and sudden cardiac death.33 However, despite the
increased risk for vascular events, strategies to prevent CVD are similar among
women with and those without RA.34
Patients with RA are also at significantly higher risk for congestive heart failure (CHF)
compared with those without the disease. CHF risk precedes the diagnosis of RA and
cannot be explained by an increased incidence of traditional CV risk factors.35 RA is
associated with increased left ventricular mass, which is independently related to
disease duration, whereas systolic function is typically preserved.36 Abnormalities of
406 Kaplan
transmitral and pulmonary venous flow have been proposed as markers of altered diastolic function in patients who have long-standing RA with normal systolic function.37
The clinical presentation and the outcome of CHF differ significantly between RA and
control individuals. In the former, CHF presentation may be more subtle but mortality
from this complication is significantly higher.38 Even after adjusting for CV risk factors
and ischemic heart disease, patients with RA have almost twice the risk for developing
CHF than patients without arthritis. Again, this increase has been seen primarily in
patients who are seropositive for the RF.35 In addition, patients with RA are at
increased risk for death in the period immediately after CHF develops and this risk
remains elevated for 6 months.38
Previous studies have suggested that traditional CV risk factors do not fully account
for the increased propensity to vascular complications in RA39 and that immune dysregulation, inflammation, and metabolic disturbances observed in RA could play an
important role in accelerated atherogenesis and mortality. Indeed, histologic examination of coronary arteries in RA has revealed less atherosclerosis but greater evidence
of inflammation and instability.40
PATHOGENIC MECHANISMS INVOLVED IN PREMATURE CARDIOVASCULAR
DISEASE IN PATIENTS WITH RHEUMATOID ARTHRITIS
Over the past few years, striking similarities in the inflammatory and immunologic
responses in atherosclerosis and RA have been described.41 Although chronic inflammation can promote endothelial cell activation and vascular dysfunction, which leads
to decreased blood vessel compliance and atheroma formation, the reasons for the
dramatic increase in atherosclerotic disease in RA are not totally understood and
appear to be fairly complex (Fig. 1). It appears that variables that increase CV mortality
in RA are present very early during the natural history of the disease, because patients
with new onset RF positive inflammatory arthritis exhibit evidence of abnormal endothelial function, which is considered a good predictor of future development of atherosclerosis.42 RF as an independent risk factor for ischemic heart disease in the general
population has been suggested by some studies. Indeed, RF has been associated
dnE oth aile dl tcnufsy ion
and erp m ruta dVCe isea es
NSAIDS and steroids
T:senikotyC N 1-LI,F
IL-6, -LI 17
Acu et hp ase
tcaer tna :s C S,PR PA
Homocysteine
Impaired
vascular repair
Proinflammatory
HDL
CD4+CD28- cells
iL p di ep r xo di a ,noit
dyslipidemia
ecnatsisernilusnI
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Fig. 1. Putative mechanisms leading to endothelial dysfunction and vascular damage in RA.
Cardiovascular Complications of RA 407
with increased all-cause mortality and CV mortality after adjustment for traditional risk
factors, even among subjects without joint symptoms.43,44 Further, preliminary
evidence indicates that patients with RA who are positive for anti-cyclic citrullinated
peptide antibodies (Abs) (anti-CCP) have higher subclinical atherosclerosis than those
who are not.45 A recent study indicated that anti-CCP Abs in RA are independently
associated with the development of ischemic heart disease (odds ratio[OR] 2.8;
95% CI 1.19–6.56; P 5 .009).46 The precise role that autoantibodies (autoAbs) play
in premature CVD in RA, however, remains to be determined.
Traditional Cardiovascular Risk Factors
RA is associated with traditional and nontraditional CV risk factors.39,47–53 Therefore,
assessments based only on traditional risk factors are insufficient to capture the extent
of CV risk in RA. A higher Framingham risk score is independently associated to coronary calcification in RA.54 Age and hypertension correlate with increased CV risk RA,
but so do factors associated with inflammation, including neutrophil count and radiographic score.13 It also appears that physically inactive patients with RA have significantly worse CVD risk profile compared with those who are physically active.55
Although smoking is associated with RF and anti-CCP Abs production and is now
recognized as an independent risk factor for RA development,56,57 it does not appear
to predict CV events or cardiac-associated mortality in seropositive patients with
inflammatory arthritis.13,58 However, the prevalence and severity of coronary calcification in established RA has been linked in part to tobacco use.26 Indeed, a personal
history of ischemic heart disease, smoking, hypertension, and diabetes mellitus has
been found to contribute to CV death in RA.59
A proatherogenic lipid profile has been reported in patients with RA.60 Beyond the
abnormalities in plasma lipids, increased levels of small, dense LDL are common in
patients who are drug-naı¨ve with early RA. The role that these particles may play in
the atherogenic process in this disease is still unclear.61 AutoAbs recognizing oxidized
LDL are associated with atherosclerosis in the general population. These antibodies
are present in RA and correlate with inflammation but their role in CVD in RA remains
to be determined.62 Serum lipoprotein A is significantly increased and high-density
lipoprotein cholesterol (HDL) significantly decreased in women with RA. In addition,
HDL function is abnormal in RA, because this molecule is unable to protect LDL
from oxidation and is therefore considered proinflammatory.63 Proinflammatory
HDLs can contribute to oxidative damage and have been reported in approximately
20% of patients with RA.64 Further, a recent study indicates that proinflammatory
HDL in RA is associated with active disease and an altered protein cargo.65 A recent
study suggests that total cholesterol and LDL levels significantly decrease within 5
years before the diagnosis of RA. The mechanisms and significance of these findings
remains to be determined.66
Insulin Resistance, Body Weight, Homocysteine, and Thyroid Function
Other metabolic abnormalities that predispose to vascular disease in the general population (microalbuminuria, insulin resistance, and increased homocysteine) are prevalent in RA.67 Insulin resistance is an important risk factor for CVD, and tumor necrosis
factor (TNF)-a and other proinflammatory molecules directly affect insulin sensitivity.
Factors that lead to increased systemic oxidative stress and proinflammatory cytokine
overexpression may therefore promote insulin resistance. RA is associated with
a higher prevalence of the metabolic syndrome than control subjects, which was
present in about a third of patients with early disease and in 42% of patients with
long-standing disease.68 Patients with RA have evidence of impaired glucose
408 Kaplan
handling, which is secondary to peripheral insulin resistance mediated by the inflammatory response. Further, patients who have RA with carotid plaque have higher
insulin resistance.69 The precise role that corticosteroids play in insulin resistance
development in RA remains to be determined.70 Insulin resistance has been shown
to improve with the use of disease-modifying antirheumatic drugs (DMARDs) and biologics in RA.71,72 Increased trunk fat has been significantly and independently associated with increased arterial stiffness in patients who are postmenopausal with RA.73
High homocysteine levels have been linked to atherothrombosis in RA.67 A potential
role of thyroid function in the development of subclinical atherosclerosis in this disease
has also been proposed, because hypothyroidism in RA is an independent association
with carotid plaque and this is enhanced in patients who also have other traditional CV
risk factors or neutrophilia.74
Family History
A parental history of death from CVD is associated with a 70% increase in risk for fatal
CVD in RA and an increase in 10-year mortality from CVD from 5% to 10% in men and
from 2% to 4% in women aged 50 to 67 years.75
Genetic Influences
Functional polymorphisms that relate to major histocompatibility complex (MHC)
expression are associated with increased susceptibility to RA, myocardial infarction,
and multiple sclerosis.76 A 168A / G polymorphism in the type III promoter of the
MHC class II transactivator (MHC2TA) has been associated with increased susceptibility to these three diseases and with lower expression of MHC2TA after leukocyte
stimulation with interferon-g. These polymorphisms may result in differential MHC
molecule expression and could potentially be associated with susceptibility to
common complex diseases with inflammatory components.76 Shared epitope alleles
(HLA-DRB1 genotype), particularly compound heterozygotes, are associated with
death from all causes and from CVD, independently of autoAb status in RA. However,
the combination of shared epitope, smoking, and anti-CCP antibodies is associated
with a higher risk for premature death in patients with inflammatory polyarthritis and
RA.77 Other studies have also linked the shared epitope to ischemic heart disease
in RA.78,79 The exact mechanisms by which the presence of the shared epitope
may enhance premature vascular damage in RA remain to be determined.
A recent study suggests that the IL-6-174C-allele may associate with CVD in RA and
possibly exerts its effect via increased inflammation.80 Patients with RA who carry the
TNF-a-1031 T/C polymorphism have smaller LDL particles that have greater affinity for
extracellular matrix and higher susceptibility for oxidation.81 Other genetic polymorphisms that have been proposed to be associated to the development of CVD in
RA include plasminogen activator inhibitor I (PAI-1) and coagulation factor XIII.82 Polymorphisms in TNF receptor type II are associated with hypertension in Scandinavian
subjects with RA.83 In another recent Scandinavian study, no increased occurrence of
CVD before the onset of RA was detected. The authors then concluded that shared
risk factors or susceptibilities for RA and CVD likely contributed less than RA-related
factors to the increased occurrence of vascular complications in this disease.84
The Role of Inflammation in Cardiovascular Disease in Rheumatoid Arthritis
Recent evidence indicates that there is a close temporal correlation between inflammation and morphologic features of rapidly progressive carotid atherosclerosis, which
suggests that elevations in inflammatory biomarkers might help in predicting the
Cardiovascular Complications of RA 409
presence of atherosclerosis.85 Markers of systemic inflammation confer a statistically
significant additional risk for CV death among patients with RA, even after controlling
for traditional CV risk factors and comorbidities.59,86 Increased levels of proinflammatory mediators, including TNF; interleukin-6 (IL-6); interleukin-17 (IL-17); and others,
could be detrimental to the endothelium and myocardium and promote insulin resistance. Levels of these cytokines are increased in RA.87–89 The C-reactive protein
(CRP) concentration at baseline is an important predictor of subsequent death from
CVD in patients with new onset inflammatory polyarthritis, and is independent of other
factors of disease severity.90 High levels of CRP also correlate with carotid intima
media thickness.91 High sensitivity CRP and lower glomerular filtration rate have
been independently predictive of endothelial dysfunction in RA.92 Higher erythrocyte
sedimentation rate, small and large joint swelling, rheumatoid nodules, vasculitis
and rheumatoid lung have been independently associated with increased risk for
CV death.59 In a recent study comparing subjects with RA and controls, TNF-a and
IL-6 were significantly associated with the severity of coronary artery calcification in
RA, independent of Framingham risk score.93 Enhanced arterial stiffness in RA correlates with CRP and IL-6 levels.29 Similarly, in those subjects experiencing new onset
CHF, the proportion of subjects with high sedimentation rate was greatest in the 6
months preceding the diagnosis of cardiac dysfunction. This finding indicates that
an enhanced inflammatory process may promote the development of heart dysfunction in inflammatory arthritis94 The magnitude and chronicity of the inflammatory
response, as measured by circulating levels of inflammatory markers, correlates
with carotid atherosclerosis development in RA.91 Levels of adhesion molecules linked
to vascular damage, including soluble vascular cell adhesion molecule-1 (VCAM-1);
intercellular adhesion molecule-1; and endothelial–leukocyte adhesion molecule,
were higher in RA. VCAM-1 levels have been associated with carotid atherosclerosis
in RA.92
Although the exact role of IL-17 in premature vascular damage in RA remains to be
determined, recent work indicates that this cytokine may play a role in atherosclerosis
development in murine models of vascular disease95,96 and elevated circulating levels
of IL-17 have been reported in patients with acute coronary syndromes.97 IL-17 is
produced concomitantly with IFN-g by coronary artery-infiltrating T cells and these
cytokines act synergistically to induce proinflammatory responses in vascular smooth
muscle cells.98 IL-17 accelerates myocardial fibrosis in animal models of heart injury.99
However, there is recent evidence that IL-17 may also play a regulatory role in atherosclerosis100 and future studies should determine whether this cytokine plays a pivotal
role in vascular damage in RA.
T Cells
An expanded population of CD41CD28 T cells has been demonstrated in the peripheral blood of patients with RA,101 and clonal expansion of a similar T-cell subset has
been reported in the blood and atherosclerotic plaques of patients with unstable
angina.102 These cells can injure the endothelium and cause vascular damage.
Patients who have RA with persistent CD41CD28 expansion have presented with
increased preclinical atherosclerotic changes, including endothelial dysfunction and
carotid atherosclerosis, compared with those without expansion.102,103 TNF-a induces
downregulation of the CD28 molecule in CD41 T cells, suggesting a pathogenic mechanism for the development of these cells.104 Treatment with anti-TNF agents has been
found to downregulate this cell subset in patients with RA and in patients with unstable
angina and no RA.104,105 The precise role that these cells play in the development of
acute coronary events in RA requires further investigation.
410 Kaplan
Abnormalities in Vasculogenesis
An adequate balance between endothelium destruction and regeneration is needed to
maintain vascular health. Endothelial progenitor cells (EPCs) are present in the circulation of patients with different forms of vascular damage and are released from the
bone marrow during acute vascular injury.106 EPCs appear to be crucial in normal
revascularization after endothelium damage occurs. Furthermore, reduced EPC
numbers and abnormal EPC function correlate with increased incidence of atherosclerosis, impaired vasculogenesis after ischemia, and future CV events.106,107 Recent
reports 108,109 suggest that EPC numbers are decreased in the systemic circulation
of patients with active RA and that their functions are impaired. Potentially, this
phenomenon could contribute to atherosclerosis but further studies correlating
abnormal EPCs with functional markers of endothelial dysfunction in RA are needed.
Endothelial dysfunction in patients who have RA with low-grade inflammation was
associated with decreased EPC numbers and low-grade dysfunction of these cells.109
A single dose of infliximab significantly increases EPC numbers and improves their
functional properties in RA.110 Others have proposed that asymmetric dimethylarginine, a major endogenous inhibitor of nitric oxide synthase associated with atherosclerosis risk in the general population,111 may contribute to EPC depletion in RA via
depressed NO-dependent mobilization or survival of these cells.112
EPCs can contribute to synovial neovascularization in RA.113 Proinflammatory cytokines upregulate vascular endothelial growth factor, which increases synovial EPCs
and is essential to the pro-angiogenic process. The discrepancy observed between
decreased angiogenic responses in RA peripheral blood and enhanced angiogenesis
at the level of the synovium has not been clarified but may be related to differences in
EPC homing, perhaps driven by the proinflammatory milieu of the joint.113
EFFECT OF RHEUMATOID ARTHRITIS TREATMENT ON CARDIOVASCULAR
DISEASE RISK
The lack of a unifying explanation for accelerated CVD in RA is reflected by the confusion that still exists regarding possible preventive measures aimed at decreasing
atherogenic risk. There is still considerable uncertainty on how to manage patients
with RA effectively to reduce their risk for future CV events, because some of the medications used to treat RA might have dual effects on risk for CV morbidity. This risk is
exemplified by the use of corticosteroids, which on one hand may decrease CV complications in RA by decreasing inflammation but on the other hand increase it by promoting
pro-atherosclerotic lipid profiles, hypertension, and insulin resistance.114 Methotrexate
can promote hyperhomocysteinemia (usually corrected by folic acid supplementation)115 and cause endothelial damage.116 However, long-term follow-up of patients
with RA has suggested that methotrexate significantly reduces overall and CV
mortality.117 Furthermore, use of DMARDs is associated with reductions in risk for
hospitalization for congestive heart failure in RA.118 The author will now discuss the
role that various medications may play in CV risk or prevention in RA.
Nonsteroidal Antiinflammatory Drugs and Cardiovascular Complications
in Rheumatoid Arthritis
Current and new users of all classes of non-aspirin nonsteroidal antiinflammatory
drugs (NSAIDS), including patients with RA, have an elevated relative risk estimate
for myocardial infarction.119 Several patient characteristics increase the risk for CV
events among users of some NSAIDS, including increased age, hypertension,
previous myocardial infarction and CVD, chronic renal disease, chronic obstructive
Cardiovascular Complications of RA 411
pulmonary disease, and RA. This finding indicates that patients who have RA with
various comorbidities and advanced age may be particularly prone to developed CV
complications while on specific NSAIDS.120 However, a large case-control analysis
found that the risk for first-time myocardial infarction is increased for several weeks after
the cessation of NSAID therapy, an effect that is more pronounced in patients with RA or
lupus and in individuals who discontinue NSAID therapy after previous long-term
use.121 These findings suggest that NSAIDs might have a role in suppressing the risk
for myocardial infarction in patients with RA and other inflammatory conditions and
that, ideally, abrupt discontinuation of NSAIDS in these populations should be avoided.
Role of Corticosteroids in Cardiovascular Disease in Rheumatoid Arthritis
Corticosteroids can induce hypertension, insulin resistance, and disturbances in
blood lipids; they induce obesity and may enhance hypercoagulability.122 As
mentioned earlier, whether glucocorticoids promote accelerated atherogenesis in
RA is still a matter of debate. In one study, subjects exposed to glucocorticoids had
higher incidence of carotid plaque and arterial incompressibility, independent of CV
risk factors and RA clinical manifestations.123 A Scandinavian study reported that
treatment with low-dose prednisolone did not influence endothelial function or carotid
intima media thickness in RA, although it promoted higher levels of total cholesterol.124 An increased risk for CV events with high cumulative exposure to corticosteroids has been found in patients with RA who are seropositive for RF, but not on the
patients who are seronegative.125 However, in patients who have RA with a history of
ischemic heart disease, use of corticosteroids attenuated the risk for CV death.59
Disease-Modifying Antirheumatic Drugs
A recent study indicated that prolonged exposure to various DMARDS, including
methotrexate, leflunomide, and sulfasalazine, was associated with a reduction of
CV risk in RA, and similar trends were observed with corticosteroid use.126 Further
supporting a beneficial effect of methotrexate treatment in CVD prevention, this
drug reduced the incidence of vascular disease in veterans with psoriasis or RA.127
Low to moderate cumulative doses appeared to be more beneficial than higher doses.
In addition, a combination of methotrexate and folic acid led to a further reduction in
the incidence of CVD, suggesting that the latter did not decrease the efficacy of methotrexate. Furthermore, methotrexate use was associated with a significantly lower risk
for CV events in patients with RA compared with patients who had never used
DMARDs (OR 0.16). Methotrexate use has also been associated with a decreased
incidence of the metabolic syndrome, whereas corticosteroids or other DMARDS
did not show a protective effect.72 Adding additional DMARDS, such as sulfasalazine
and hydroxychloroquine, appears to provide additional CV protection.128 In a Canadian study, DMARD use was associated with a reduction in myocardial infarction
risk in patients with RA, whereas corticosteroids showed an increased risk and coxibs
did not change risk.129 In a recent cross-sectional analysis, drugs used to treat RA did
not have major adverse effects on CV risk factors and use of antimalarials was actually
associated with beneficial lipid profiles and lower blood pressure.130 As a potential
antiatherogenic mechanism of methotrexate (MTX), Reiss and colleagues131 have
shown that through adenosine A2A receptor activation, MTX promotes reverse
cholesterol transport and limits foam cell formation in macrophages.
Anti-tumor Necrosis Factor Therapy
The effects of TNF-a blockers on CVD in RA are complex because these drugs may
promote CHF and decrease heart compliance while controlling inflammation and
412 Kaplan
decreasing risk for plaque formation.132 Infliximab can improve endothelial function in
RA after 12 weeks of therapy,89 and anti-TNF therapy also reduces aortic stiffness to
a level comparable to that of healthy individuals by 4 and 12 weeks of treatment.133
Prolonged effects on endothelial function (18 months of therapy) were recently
reported with infliximab and adalimumab.134 It appears that the risk to develop first
CV events in RA is lower in patients treated with TNF blockers.135 However, prospective, long-term, longitudinal studies are required to evaluate the precise role of antiTNF therapy in atherosclerosis prevention. Anti-TNF therapy can also improve other
risk factors for accelerated atherosclerosis, including promoting a decrease in insulin
resistance,71 CRP, IL-6 and CD41CD28 T cells, and an increase in HDL.132,136
However, it appears that at least some of the beneficial effects of anti-TNF agents
on endothelial function are not sustained, have not been reported in all studies, and
are not seen in all patient populations (eg, in the case of patients with diabetes treated
with etanercept).137–139 In one study, although an initial improvement in RA endothelial
function was observed with infliximab, values returned to baseline 4 weeks after the
infusion in subjects followed for 1 year.138 Another report found that, although infliximab induces a transient increase in flow-mediated dilatation (FMD), the drug also
induces vasoconstriction and increases in wall shear stress.140 There is also evidence
that biologics may induce elevations in blood lipids with a deleterious shift in the
atherogenic index in RA.140 It is possible that the various TNF antagonists have
different effects on endothelial and smooth muscle cells and on vascular function.
Animal studies suggest a negative influence of TNF-a inhibitors on collateral artery
growth, and this observation deserves further investigation into the potential role of
this therapy in decreasing alternative mechanisms of cardiac perfusion in individuals
with impaired coronary circulation.141
Previous studies in the general population have shown that short-term TNF-a antagonism with infliximab does not improve and high doses (10 mg/kg) adversely affect the
clinical condition of patients with moderate-to-severe chronic heart failure.142 Despite
contraindication to the use of these agents in patients with moderate-severe heart
failure, epidemiologic studies in RA have not consistently substantiated this association.143,144 In fact, a recent German study has concluded that inhibition of TNF that
effectively reduces inflammatory activity in RA is more likely to be beneficial than
harmful with regards to CHF risk, especially when not combined with corticosteroids
of coxibs.145 Similarly, a recent study indicates that blocking TNF in patients who have
RA without evident heart failure decreases N-terminal pro-brain natriuretic peptide
pointing at no treatment-induced deterioration in cardiac function, and a potential
CV risk benefit.146 However, TNF-inhibitors may increase the risk for first hospitalization and exacerbation of CHF in elderly patients with RA.147 A recent study indicates
that, when compared with patients who have RA receiving MTX monotherapy, those
receiving biologic immunosuppressive agents had no changes in the risk for experiencing a CV event, whereas use of oral glucocorticoids and other cytotoxic immunosuppressive agents (leflunomide, azathioprine) was associated with significant
increases in the risk for CV events.148
Rituximab and Other Biologics
Preliminary data from various groups suggests that rituximab infusions exert early and
sustained favorable effects on endothelial dysfunction and plasma lipids.149,150 The
role of abatacept and anakinra in CV prevention in RA remains to be determined,
although there is some preliminary evidence that chronic inhibition of IL-1 actions
with anakinra improves left ventricle deformation in parallel with endothelial function
and nitro-oxidative stress in RA.151
Cardiovascular Complications of RA 413
RISK ASSESSMENT AND PREVENTION OF CARDIOVASCULAR DISEASE
IN RHEUMATOID ARTHRITIS
Ideally, preventive strategies to decrease CV risk in RA should start shortly after its
diagnosis. This statement is supported by observations that the factors that promote
premature CV mortality in this disease are present early on, maybe even before overt
clinical manifestations manifest. Clearly, a significant proportion of patients with RA
have suboptimal management of CV risk factors. Depending on the risk stratification
method used, it is considered that 2% to 26% of patients who have RA without overt
CVD have sufficiently high risk for requiring statin therapy, yet most of them remain
untreated.152 There is also evidence that target organ damage is highly prevalent in
patients with RA and associates independently with hypertension, arterial stiffness,
and heart rate.153 These observations indicate an urgent need for CV reduction strategies. However, specific guidelines that address the management of CV risk factors in
RA are not available and several important questions with regards to prevention
remain unanswered. It is unknown which levels of lipids or blood pressure should
prompt pharmacologic intervention in RA and whether these interventions can modify
CV risk. Although RA and DM have a comparable enhanced CV risk, it is unclear
whether guidelines similar to the ones developed for diabetes would lead to significant
CV risk reduction in RA. Similarly, it is unknown which patients with RA should be
considered as candidates for subclinical and clinical coronary artery and carotid artery
disease screening or for heart function screening.
The author suggests that CV assessment in RA should start by considering and
detecting the presence of other major comorbidities, including hypertension, tobacco
use, hyperglycemia, dyslipidemia, increased body mass index, central obesity, physical inactivity, and family history of CV disease. Proper identification of these factors is
crucial as a first step toward developing a plan for CV risk reduction in RA. It is unclear
whether the presence of RA should be used as an additional risk factor during stratification; however, there are strong indications from the literature that this should be the
case. Given the high prevalence of silent ischemia and decreased CV symptoms in
RA, future prospective studies should investigate whether effective strategies for
earlier detection of clinical CV disease will reduce morbidity and mortality in these
patients. For patients that are deemed to be at high risk (seropositive for RF or antiCCP Abs, aggressive erosive disease, extra-articular RA manifestations, and high
inflammatory markers) or for those with specific CV risk factors in addition to the
arthritis, specialized testing, including 24-hour monitoring of ambulatory blood pressure, stress test, or echocardiography, may be warranted. However, until clear guidelines are developed for CV prevention in this and other systemic autoimmune
diseases, the justification for these tests remains unclear.
Targeting Traditional Cardiovascular Risk Factors in Rheumatoid Arthritis
Optimal blood pressure should be targeted with weight maintenance, physical activity,
sodium control, judicious use of corticosteroids, and when indicated antihypertensive
drugs (Table 1). A recent study suggested that 10 mg/day of ramipril for 8 weeks in
combination with standard of care markedly improved endothelial function in patients
with RA154 and ACE inhibitors may be considered a good antihypertensive strategy in
this disease. Intensive strategies for smoking cessation should be initiated early and
aggressively. Weight loss and increased exercise are first-line strategies for reducing
insulin resistance and hyperglycemia and should be attempted in conjunction with
good control of the inflammatory response. The role of thiazolidinediones in the
improvement of insulin resistance and CVD in RA remains to be determined and is
414 Kaplan
currently being investigated in controlled clinical trials. These drugs have pleiotropic
effects on the endothelium that go beyond glucose control and may prove to have
a dual beneficial effect in CV prevention and control of joint inflammation. There are
hypothetical concerns with regards to thiazolidinedione use, specifically CHF and
increased risk for fracture in RA, that should be explored.
Statins can mediate modest but clinically apparent antiinflammatory effects in
RA.155 Atorvastatin, 20 mg/day for 12 weeks, resulted in significant improvements in
arterial stiffness in subjects with RA, particularly in subjects with active disease.156
Similarly, subjects with RA treated with 40 mg simvastatin for 4 weeks had a reduction
in proatherogenic lipids and markers of oxidative stress, and improvement in FMD.157
In another recent study, simvastatin 20 mg/day also improved FMD in RA. The drug
also lowered CRP and TNF-a concentrations.158 Ezetimibe and simvastatin treatment
for 6 weeks similarly reduced disease activity and inflammatory markers in RA, and
also reduced aortic pulse wave velocity and improved endothelial function.159
Although it is still unclear which levels of lipids are ideal for CV prevention in RA,
optimal LDL and HDL cholesterol levels should be sought. A recommended LDL level
of less than 100 mg/dL and HDL over 40 mg/dL, similar to what is recommended for
patients with other CV risk factors, is warranted until more specific information
becomes available for RA. Maximal dietary therapy should be tried with the addition
of drug therapy when necessary. The benefit of use of antiplatelet agents in RA is
unclear. A recent study indicated that statins may be protective for RA development
in individuals with dyslipidemia.160
Current and Future Strategies for Targeting Disease-Specific Cardiovascular Risk
Factors in Rheumatoid Arthritis
As mentioned earlier, various therapies used in the management of RA may have
a protective CV risk effect. In addition, patients with RA and prolonged exposure to
hydroxychloroquine have a reduced risk for developing diabetes.161 Studies have
Table 1
Managing cardiovascular risk factors in rheumatoid arthritis
Risk Factor Cardiovascular Prevention Strategies
Smoking Counseling, nicotine patches or gum, bupropion, varenicline
Hypertension Frequent blood pressure monitoring, diet, exercise, stress
management, antihypertensives, minimize NSAID and
corticosteroid use
Hyperlipidemia Diet, exercise, moderate alcohol use,a statins, minimize corticosteroid
use, antimalarialsa
Diabetes Counseling, diet, exercise, oral hypoglycemic agents or insulin
Insulin resistance Counseling, diet, control of inflammation (DMARDS/biologics), PPARagonistsa
Obesity Counseling, diet, exercise, minimize corticosteroid use
High homocysteine Folic acid supplementation with methotrexate/sulfasalazine use
Family history of CVD Counseling, monitoring risk factors
Inflammation DMARDS, biologics, NSAIDS, statins,a PPAR-agonistsa
Thrombotic risk Low dose aspirin, consider anticoagulation when other risk factors for
thrombosis are present
Abbreviation: PPAR, peroxisome proliferator activated receptor.
a Not enough evidence to suggest as standard of care.
Cardiovascular Complications of RA 415
also suggested that antimalarials could have a vasculoprotective effect in inflammatory diseases, at least in part mediated by beneficial effects on lipids.162 Further investigation is required to determine whether specific doses or duration of corticosteroid
use is beneficial or harmful to the vasculature in RA. The deleterious adverse effects
on the vasculature might be prominent in patients receiving over 7.5 mg per day of
prednisone for at least 6 months.163 There is some evidence that low-dose corticosteroids could have a beneficial effect on lipid profiles.48 Overall, as mentioned earlier,
exposure to DMARDS appears to be associated with decreased CV morbidity and
with decreased hospitalizations for heart failure.118,128 However, because the mortality
gap between RA and the general population appears to be widening, it is unclear that
the current use of DMARDS and biologics is effectively reducing CV risk. As new biologics become more widely available for use in clinical practice, assessment of their
role in CV prevention or damage in RA should become possible. These strategies
include anti-IL-6, anti-IL-17, other anti-B cell therapies, and so forth. Certainly, a better
understanding of the mechanisms that promote RA development and severity may
provide additional light into the most effective preventive strategies for vascular
damage in this disease.
SUMMARY
Given the serious impact of the increased risk for atherosclerosis in RA, future work
should focus on understanding the precise molecular mechanisms that lead to premature vascular damage in inflammatory arthritides and on assessing the individual
effects of various treatments on CVD in these patients by performance of rigorous
studies. Future studies should also focus on the development of effective screening
methods for the identification of those patients who are at the highest cardiovascular
risk and who would benefit from early intervention. Clearly, the development of guidelines for the management of CV risk factors in RA, similar to those that have been
developed for diabetes, is greatly needed. In the meantime, a combination of strategies that include appropriate control of the inflammatory cascade, immunologic diatheses, and metabolic changes observed in RA should be sought. Finally, an increased
awareness of the increased risk for silent ischemia, early myocardial infarction, heart
failure, and sudden death is warranted in this patient population.
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