Cardiovascular involvement in Rheumatoid Arthritis
RN Sarkar
INTRODUCTION
R heumatoid arthritis (RA) along with SLE and other
autoimmune inflammatory arthritides are associated
with increased cardiovascular morbidity and mortality
predominantly due to accelerated and premature
atherosclerosis 1. Thus both men and women with RA
are twice as likely to suffer from myocardial infarction
as compared to general population 2. The overall life
expectancy in RA is significantly reduced, with standardized
mortality rates ranging from 1.28 to 3.0 3.
Cardiovascular events occur approximately a decade earlier
in RA like that in diabetes mellitus. Moreover, like DM,
there is an independent association of RA and preclinical
and overt CV disease and most of the time it is silent with
unfavourable outcome 4. Another very important recent
finding is the increased prevalence of heart failure with
preserved ejection fraction and lack of typical symptom of
heart failure in RA patients compared to non RA patients
5
. In this study Davis et al found an increased incidence of
diastolic dysfunction and a 1.9 fold increased mortality.
In some way there is a close similarity between RA and DM.
Both RA and DM are independent risk factors for preclinical
as well as overt CV disease. Like diabetes, RA patients are
less likely to report symptoms of angina, have increased
incidence of unrecognized myocardial infarction and sudden
death6. There is also increased prevalence of heart failure
with preserved ejection fraction due to left ventricular
diastolic dysfunction related to disease duration as seen
in DM7.
Thus the various cardiovascular involvements in RA are -
1. Preclinical CV disease - which includes endothelial
dysfunction and structural cardiovascular remodelling.
2. Overt C. V. - which includes heart failure and cardiovascular
death.
3. Other morbid events like Pericarditis, myocarditis,
valvular regurgitation especially of aortic and mitral valve,
embolic events, rheumatoid nodule and atrioventricular
block.
In this review, I will focus mainly on the increased prevalence
of premature and subclinical atherosclerosis in RA and the
potencial role of disease modifying drugs and novel targeted
biologic therapies in preventing CV disease.
Epidemiological evidence
Deaths due to CAD have been reported in several RA
mortality study series.
Standard mortality ratios (SMRs) for patients with RA dying
from CV diseases ranges from 1.13 to 5.258. The most
striking finding of increased mortality in RA due to CAD have
been in young women aged 15-49years, where SMRs were
as high as 3.64 9. Solomon et al, in a prospective cohort
study, conducted among 114342 women participating in the
Nurses Health Study who were free of CV disease and RA at
baseline in 1976. At the end of the 10 years follow up an
incident diagnosis of RA in 527 women were made and there
were 2296 myocardial infarction and 1326 strokes. The age
adjusted risk of MI was two fold higher for patients with RA
than those without relative risk 10.
In another recently published population based cohort study,
266 Medicine Update-2011
patients with RA had a significantly higher risk of CVD than
non-RA patient. More than half of the newly diagnosed RA
aged 50-59 years and all those older than 60years had a
more than 10% increased risk of CVD within 10years of the
onset of RA 11.
Meta-analysis of observational studies showed that CV
disease mortality is increased by about 50% in patients who
have RA compared to the general population 12.
In the QUEST-RA study 13 which analysed the prevalence
of CV disease in 4363 patients with RA (78% female) and
its association with traditional CV risk factors, clinical
features of RA and the use of DMARDs in a multinational
cross - sectional chort of non-selected patients of RA. There
was an association between any CV event and age and male
gender and between extra articular disease and myocardial
infarction. Prolonged use of methotrexate, leflunomide,
salfasalazine, glucocorticoids and biological agents was
associated with a reduction of the risk of CV mortality 13.
Risk factors for premature atherosclerosis
R A is associated with both traditional and non-traditional
CV risk factors.11,14
Various studies has confirmed that markers of systemic
inflammation confer a statistically significant additional risk
for CV death among patients with RA, even after controlling
traditional risk factors like smoking, hypertension, obesity
and lipid abnormalities 12,15. Various non-traditional risk
factors are -
1. Genetic determinants - HLA DRB1 shared epitope allele16.
2. Elevated highly sensitive CRP
3. R F positivity and erosive disease
4. Extra-articular disease
5. Immunological/ Molecular markers-
TNF-alpha,IL-1 and IL-6 are all linked to severity of
subclinical atherosclerosis.
Adhesion molecules - intracellular adhesion molecule
1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-
1) and endothelial - leukocyte adhesion molecule
- are all higher in active RA patients. VCAM-1 levels
were associated with carotid atherosclerosis.
6. Cellular markers
CD-4+ and CD 28 null lymphocytes- clonal expansion
of these sub-set of T-lymphocytes have been reported
in the blood and atherosclerotic plaque of patients
with unstable angina as well as in patients with RA.
Toll-like receptor antagonists 2 and 4 which are involved
in innate immunity have been suggested to mediate
inflammation related premature atherosclerosis 18.
Endothelial progenitor cells (EPCs) - in the bone
marrow are the most important cells in endothelial
repair after vascular injury. Decreased levels of
circulating EPCs as well as impaired function of EPCs
has been noted19.
7. Increased procoagulant activity-
Antiphospholipid antibodies
Plasminogen activator Inhibitor-1(PAI-1)
Hyperhomocysteinaemia
8. Lipid abnormalities
Rheumatoid arthritis is associated with pro-atherogenic
lipid profiles. There is increased synthesis of LDL,
and serum lipoprotein (a) is found to be significantly
increased, high-density lipoprotein decreased and HDL
function abnormal as it is unable to protect oxidation of
LDL20,21.
Pathogenesis of Premature CV disease .
There are striking similarities between inflammatory and
immunological responses in atherosclerosis and RA. The
endothelial dysfunction is the earliest stage of atherosclerosis
and is an expression of systemic phenomenon. Chronic
inflammation can promote endothelial cell activation and
vascular dysfunction leading to atheroma formation.
Activated inflammatory cells, mostly macrophages and mast
cells release enzymes involved in collagen degradation.
There is upregulation of adhesion molecules such as
E-selectin, intracellular adhesion molecule-1 (ICAM-1),
vascular cell adhesion molecule-1 (VCAM-1) and endothelial
leukocyte adhesion molecule. The adhesion molecules bind
and recruit monocytes / macrophages and T-lymphocytes,
which migrate into the subendothelium where along with
oxidized LDL, they form the fatty streak. In the absence
of down regulation of this inflammatory process, the fatty
streak develops into a fibrous plaque which can rupture and
lead to an ischaemic event22.
Endothelial dysfunction and sub-clinical atherosclerosis
Endothelial dysfunction, which is being recognized as a
promoter of CAD progression and a trigger of CV events like
plaque rupture has been recently described in patients with
RA with high disease activity without evidence of clinical
atherosclerosis i.e. angina23,24.
Direct and indirect evidence of Atherosclerosis
Direct evidence: Warrington et al, at the Mayo clinic

analysed the angiogram data of 79 patients with RA and new
onset CAD. They also measured the pro-inflammatory CD
4+ and CD28 null T cells by flow cytometry. They observed
that patients with RA were more likely to have multivessel
coronary involvement at first coronary angiogram compared
to control (p=0.002). CD4+ and CD null T cell population
were significantly higher in patients with CAD and RA than
in controls with stable angina (p=0.001) and reached levels
found in acute coronary syndrome28.
Chung et al, observed that the prevalence and severity of
coronary calcification is more in long standing RA and is
related to inflammatory markers and smoking23.
Indirect evidence: There are two non invasive methods
of detecting subclinical atherosclerosis and endothelial
dysfunction- CIMT and FMV.
Flow mediated vasodilation( FMV)
This is an accurate and reproducible method for evaluating
endothelial function.
Altered function of arterial endothelium can be detected
ultrasonographically by determining arterial vasodilatation
after post occlusion reactive hyperaemia (FMV).
Vaudo et al demonstrated that young to middle aged patients
with RA and low disease activity, free from cardiovascular
risk factors and overt CV disease, have an altered endothelial
reactivity which indicates a higher susceptibility to the
development of atherosclerotic disease 24.
Wong M et al measured the small artery elasticity (SAE),
large artery elasticity (LAE) and Systemic Vascular Resistance
(SVR) in 43 patients of RA. Fifteen with CAD and 36 without
CAD and compared with 38, age and sex matched controls.
LAE was significantly lower and SVR was significantly higher
in RA patients than in controls. They also observed that
SAE and LAE values were inversely correlated with markers
of inflammation viz HsCRP, serum amyloid A and VCAM1.
The authors concluded that arterial elasticity inversely
associated with markers of inflammation 25.
Carotid Intima Media Thickness (CIMT)
Measurement of the CIMT and of carotid plaque non-
invasively by B-mode ultrasound using a high resolutions
7.5MHz transducer is an important tool for diagnosis early
sub-clinical atherosclerosis. The CIMT is strongly correlated
with the presence of coronary artery disease 26,27.
Medicine Update-2011 267
The CIMT assesses the atherosclerotic burdens and provides
information that is independent and incremental to that
provided by standard risk factors. It is a feasible, reliable,
valid and cost effective method for both population
studies and clinical trials of atherosclerosis progression
and regression, subsequent to DMARDs and statin therapy.
Our Experience
Carotid Ultrasound:
We did a small study on 30 seropositive RA patients
and compared with age, sex matched had they control.
Common carotid IMT were assessed with US doppler using
a high resolution 7.5MHz linear transducer common carotid
IMT was significantly higher in patients with RA. Carotid
atherosclerosis was present in 13.33% of RA patients and
was statistically significant carotid atherosclerosis was
present in 50% of smokers in RA group and showed significant
correlation with carotid IMT levels. Even though both
groups had similar lipid parameter distribution, CIMT was
significantly higher in RA patients compared to the control
group (0.626 0.124 Vs 0.455 0.5,p<0.0001). Among 30
RA patients, 4 (13.3%) patients had carotid artery plaque
on US which was statistically significant (p<0.0001). RA
patients with carotid artery plaque had higher mean ESR
and CRP values.
FMV
Another study to evaluate the influence of chronic
inflammatory state on endothelial function in patients with
RA was undertaken on 50 young to middle aged patients with
RA (age 18 to 55years) with DAS 3.2 and without overt
CV disease. This was compared with 50 age sex matched
control. FMV was assessed on the brachial artery in supine
position. The brachial artery was scanned longitudinally
just above the anticubital crease using a 10MHz transducer
probe. FMV was expressed as the relative increase in brachial
artery diameter during hyperaemia and defined as 100 (post
hyperaemia diameter - basal diameter / basal diameter). It
is expressed as percentage value. We observed that FMV of
the brachial artery was significantly lower in patients with
RA (4.03 1.9) compared to control (8.7 1.57) which was
statistically significant (p<0.0001). No significant difference
in brachial artery FMV was seen between patients with
and without serum rheumatoid factor, bone erosion, peri
articular osteopenia and deformity. Baseline FMV showed
an inverse correlation with CRP.
Early detection of CV disease in RA
Early detection of CV disease in RA is important and
268 Medicine Update-2011
advantageous for the prevention of long term morbidity
and mortality.
This can be effectively done by identifying subclinical
atherosclerosis by the use of biomarkers of vascular health
already described and endothelial dysfunction as measured
by surrogate methods like FMV and carotid CIMT.
Management of CV risk in RA and role of DMARDs
There is no treatment strategy with proven prognostic
significance and predictive accuracy for targeted control
of cardiovascular risk in RA as evidenced by higher CRP
levels - more than 3mg/L in 66% and more than 10mg/L in
10-14%, in RA patients on remission or mildly active disease
suggestive that well controlled RA may still be accompanied
by increased CV risk 29.
There are numerous evidence based studies highlighting
the cardioprotective effects of DMARDs particularly
methotraxate and biologics. Choi et al, have demonstrated
that methotrexate-treated patients had a 70% reduction
in CV mortality compared with those who did not receive
DMARD30. The role of corticosteroids is controversial.
Though there are reports of increased incidence of carotid
plaque and arterial stiffness with prolonged use of steroids,
Davies et al found no association between corticosteroid
exposure and CV events in RA patients followed for a median
period of 15 years. In fact low dose steroids may confer
some beneficial effect on lipid profile and inflammatory
mechanism31. QUEST-RA study has shown the beneficial
effect of MTX, leflunamide, sulfasalazine and biologics 13.
In addition to this the cardioprotective effect of statins is
well established in RA after the TARA Trial32. Statins appear
to be underutilized in RA Patients33.
The new ongoing cardiovascular inflammation reduction
trial (CIRT) proposes to test the effect of a very low dose
methotrexate therapy versus placebo in the secondary
prevention of cardiovascular events in the general
population. This will test the inflammatory hypothesis of
atherothrombosis. If successful, the results of this trial would
increase the understanding of the impact of inflammation
in atherothrombosis and offer novel approaches for the
targeted cardioprotective treatment in RA34.
EULAR - recommendations 35.
Based on the extensive data on CV disease in RA, European
League Against Rheumatism (EULAR) multidisciplinary
expert committee has given recommendations for CV
risk management in RA, Psoriatic arthritis and ankylosing
spondylitis. The ten recommendations are
1. RA should be regarded as a condition associated with
higher risk for CV disease. This may apply also to AS and
PSA. The increased risk appears to be due to both an
increased prevalence of traditional risk factors and the
inflammatory burden.
2. Adequate control of disease activity is necessary to lower
the CV risk
3. CV risk assessment is recommended in all RA patients
as well as PSA and AS.
4. Risk score models should be adapted for RA patients by
introducing a 1.5 multiplication factor - when disease
duration is more then 10years, RF or anti CCP positivity
and presence of certain extra-articular manifestations.
5. TC/HDL cholesterol ratio should be used when the SCORE
model is used
6. Intervention should be carried out according to national
guidelines
7. Statins, ACEI / AT II blockers are preferred to treat HTN.
8. The role of COXIBs and most NSAIDS regarding CV risk
is not well established and needs further investigation.
Need to be cautious while prescribing COXIBs in patients
with documented CV disease or presence of CV risk
factors
9. Corticosteroids - use the lowest dose possible
10. Recommended smoking cessation
CONCLUSION
Evidence continue to accumulate indicating that patients
with RA present an increased risk of CV mortality and
morbidity. The factors involved in the pathogenesis of
increased CV disease are complex and multi-factorial
involving complex inflammatory mechanism leading to
accelerated and premature atherosclerosis. Apart from
traditional risk factors, there are some risk factors like clonal
expansion of CD 4+ T cells,interleukins, adhesion molecules,
atherogenic lipids and abnormal vasculogenesis (neo-
angiogenesis) which come into play in the atherogenesis.
Similar to diabetes , premature development of CV disease
is silent with unfavourable outcome. Apart from accelerated
atherosclerosis there is also diastolic dysfunction leading to
heart failure with preserved ejection fraction.
There is now a growing body of opinion regarding early
detection and prevention of CV disease. Apart from early use
of DMARDs, statins lipid lowering and vasculotropic effect
should be fully utilized. Role of anti TNF therapies and other
biologics in CAD prevention in RA has been validated but
needs further well controlled studies.

As CRP has a strong correlation with disease activity in
RA, monitoring the patients CRP level is necessary to
assess the level of inflammatory burden as well as CV risk.
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