Review

J Indian Rheumatol Assoc 2005 : 13 : 16 - 20

ACCELERATED ATHEROSCLEROSIS IN RHEUMATOLOGY- CURRENT

UNDERSTANDING AND THERAPEUTIC DIRECTIONS
Liza Rajasekhar
Abstract The purpose of this article is to review current evidence highlighting the fact that morbidity
and mortality due to atherosclerotic disease in cohorts of rheumatology patients occurs earlier than the
general population or those with traditional atherosclerotic risk factors. Why rheumatologic diseases
such as RA, SLE and vasculitis accelerate atherosclerosis is also considered. How these changes
occurring in the endothelial bed can be detected, whether they can be reversed acutely or chronically
by using standard lipid lowering therapy or by drugs directed at controlling the basic disease is also
discussed.
Keywords: accelerated atherosclerosis, statin, coronary
Evidence For Clinical Accelerated Atherosclerosis
In Rheumatology cohorts

persistence in the first three years of disease,

hypertension, and lupus itself as important risk factors
for the development of accelerated atherosclerosis in
these patients4. In rheumatoid arthritis (RA, there is a
decrease of 1015 years in life expectancy compared
with the general population, particularly in severe
disease5. 50% of unselected RA patients aged 40 70
have definitive evidence of cardiac ischaemia, compared
with 27% of controls matched for all classical cardiac
risk factors. This occurs approximately a decade earlier
in the RA cohort suggesting RA itself (or pathogenic
processes associated with it), are independent risk
factors for earlier ischaemic heart disease, probably due
to accelerated atherosclerosis6. It is however interesting
to note that symptoms of angina are not more common
in patients with rheumatoid arthritis. In view of the
overwhelming evidence of reduced life expectancy in
patients with RA with the majority of deaths being due
to cardiovascular disease, it is reasonable to assume
that absence of symptoms leads to an underestimation
of myocardial ischemia in patients with rheumatoid
arthritis. In primary vasculitis there is less evidence from
cohort studies demonstrating increased death from
atherosclerotic disease. Most of the evidence for
atherosclerosis in this group comes from studies
demonstrating the presence of diffuse endothelial
dysfunction in primary vasculitis7.

Mortality rates in SLE though significantly better

in the last two decades, remain three times that of age
and sex matched general population. Though survival
has increased, causes of death have changed. There is
more proportionate mortality from vascular
events1.Results of studies at several centers show that
SLE is associated with at least a fivefold increased risk
of coronary artery disease (CAD), which is accelerated
at its onset and seems to abolish a female
premenopausal protection against CAD2,3. Two
hundred and sixty three patients participating in two
SLE registries were evaluated for vascular outcomes.
After controlling for common risk factors at baseline
they demonstrated a 10 fold increase in relative risk for
non-fatal myocardial infarction and a 8 fold increase in
risk for stroke3. Observational cohort studies in SLE
identified hypercholesterolemia and particularly its
Dr Liza Rajaekhar, Associate Professor, Department of
Rheumatology, Nizams Institute of Medical Sciences,
Hyderabad
Address for correspondence
Plot No. 17, Wellington Enclave, Rukmini Devi Colony Phase
II, West Marredpally, Secunderabad 500026. E-mail:
lizarajasekhar@yahoo.com
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Liza Rajasekhar

Evidence For Subclinical atherosclerosis In

Rheumatology cohorts

to autoimmune diseases. Probably the first manifestation

of atherosclerosis is reduced nitric oxide dependent
vasodilatation of the endothelium. Endothelial injury
activates the endothelial cells, enhancing the expression
of adhesion molecules. Recruitment and proliferation
of smooth muscle cells and inflammatory cells like
macrophages in the subintimal space lead to plaque
initiation. This chronic inflammatory process in the
arterial wall is also influenced by other risk factors. One
of them is changes in the lipd sub fractions in patients
with autoimmune disease, others being smoking,
sedentary life style and change in the circulating cytokine
milieu. High levels of VLDL-C and triglycerides and
low levels of HDL-C are believed to be the lupus
lipid pattern14. In another study also lupus patients who
had higher incidence of subclinical atherosclerosis had
higher triglyceride and homocysteine levels but not
elevated LDL12. Increased levels of antibodies to
oxidized LDL, phospholipids, beta-2 glycoprotein and
prothrombin also have been shown in patients with
lupus15. These may play a role in accelerated
atherosclerosis in lupus by making the endothelium more
vulnerable to oxidation injury which in turn elicits a
cellular and humoral response contributing to plaque
progression and instability16. Even in non-autoimmune
subjects antibodies to oxidized LDL predict myocardial
infarction and progression of carotid atherosclerosis17.
In pediatric lupus population higher disease activity
indices were associated with higher levels of small dense
LDL molecules.

Extensive studies in atherosclerotic heart disease

have shown that imaging modalities reliably predict
myocardial infarctions or strokes in asymptomatic or
symptomatic populations8,9. Evidence of subclinical
atherosclerotic disease demonstrated by non invasive
imaging modalities is higher in autoimmune population.
The techniques used include myocardial perfusion
imaging, ultrasound imaging of carotid arteries for
thickness and presence of plaque and presence of
coronary calcifications by electron beam computerized
tomography. In addition, measuring changes in the
thickness of the carotid wall (CIMT) has been a reliable
tool to measure the impact of lipid lowering therapy on
the vessel wall in large multi-center studies of individuals
with symptomatic and asymptomatic atherosclerotic
heart disease10. In a study involving 197 lupus patients
and 197 age matched controls, patients had a
significantly higher incidence of plaques. Risk factors
associated with higher incidence of plaques included
older age, presence of lupus and higher cholesterol
levels. In the patient group those with plaques were
older, had longer duration of disease and higher damage
index11.This study used carotid ultrasonography for
detection of carotid plaques. In another study in the
lupus population, using electron beam tomography to
measure coronary artery calcification with age, race and
sex matched healthy controls, patients had a higher
incidence of coronary artery calcification. More patients
with calcification were older and male, however disease
activity indices were similar in both groups of patients12.
In RA similar data exists showing the presence of
increased carotid wall thickening in RA patients and
accelerated progress of this thickening over a 18-36
month follow- up period compared to a group who
had no RA but equivalent cardiovascular risk factors13.

In animal models, blockers of the inflammatory

cytokine pathway appear to block mononuclear cell
binding to arterial plaque. C-reactive protein (CRP),
an acute phase reactant, produced from hepatocytes
in response to circulating TNF- alpha and IL-6, may
also play a proinflammatory role in activating monocyte
chemotactic protein. CRP levels are being increasingly
recognized as authentic surrogate biomarkers for
atherosclerosis in the general population. These levels
may however not be so reliable in the lupus population
since CRP levels are not consistently elevated in lupus

Atheroma is an inflammatory process

The following model explains the process of
atherosclerosis and attempts to extrapolate the same
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Accelerated Atherosclerosis in Rheumatology- Current Understanding and Therapeutic Directions

patients with active disease. Antiatherosclerotic drugs

may exert some of their beneficial effects by inhibiting
the harmful effects of CRP18.

atherosclerosis shares important ideological concepts

with synovial inflammation in RA interest has been
generated in the role of statins in patients with RA and
lupus also. Numerous cholesterol-independent effects
of statins that may limit atherosclerosis are probably
involved: improved vasoreactivity, mostly through
increased NO bioavailability; decreased expression of
proinflammatory cytokines (interleukin-6, interleukin1 beta, tumor necrosis factor alpha), C-reactive protein,
chemokines, matrix metalloproteinases, and tissue factor
with the subsequent inhibition of thrombin generation;
reduced platelet activity; increased thrombomodulin
expression; enhanced fibrinolysis, regulation of
angiogenesis and immunomodulation20. While
constitutively only a limited number of specialized cell
types express MHC-II molecules, numerous other cells
become MHC-II positive upon induction by IFN
gamma. Statins act as direct inhibitors of this effect of
IFN-gamma in several cell types, including primary
human endothelial cells (ECs) and monocytemacrophages. This unexpected effect provides a
scientific rationale for using statins as
immunosuppressors22. The clinical benefit of this therapy
in the autoimmune disease population however needs
to be established in longitudinal studies.

Links in immunologic processes occurring in

general and rheumatologic population
Interferon gamma (IFN-gamma) is now generally
accepted as directly promoting atherosclerosis. IFN
gamma production induced by T- cell dysfunction
resulting from expansion of a unique population of
CD28- T cells has been demonstrated in unstable
angina, a condition pathologically associated with an
unstable plaque19. In active lupus there is increased
production of IFN gamma. In RA patients with
persistent expansion of this population of CD4 CD 28T cells, there was a greater increase in intimal thickness
of carotid artery and stronger decrease of brachial
artery flow mediated vasodilatation demonstrated over
18-36 months13. In patients with primary vasculitis,
endothelial dysfunction has been demonstrated at sites
distant from the vasculitic process. The current belief is
that inflammatory cytokines, especially TNF- alpha
and IL-6 contribute to this distant endothelial
dysfunction20.
Therapeutic directions

In a study on seven patients with RA who were

receiving infliximab currently for at least more than a
year, improvement in endothelial function was
demonstrated 2 days post infusion but return to
preinfusion levels was noted at 4 weeks23. In patients
with RA having a marked increase in carotid intimal
thickness, blockade of tumor necrosis factor-alpha led
to a partial reappearance of the CD28 molecule on the
CD4+ cell surface24 suggesting that TNF-alpha
blockade could be investigated for its effect in reversing
athrosclerosis risk factor in RA patients.

In a study using carotid ultrasound,

echocardiography and assessment of risk factors for
cardiovascular disease lupus patients were compared
to age and sex matched controls. Lupus patients with
plaques when compared to patients without carotid
plaques were more likely not to have been treated with
cyclophosphamide and hydroxychloroquine and were
more likely to have received lower doses of
prednisolone11. This suggests that therapy directed at
reversing the immune abnormalities in lupus may
succeed in reversing the risk of accelereated
atherosclerosis.

Two recent studies have demonstrated that

reduction in CRP levels were associated with reduction
in the incidence of myocardial events in patients treated
with statins following a myocardial infarction19,25. It is
therefore possible that patients with elevated CRP due

In two recent studies in patients with acute coronary

syndromes greater reduction in LDL levels with
aggressive statin therapy lead to significantly lesser
subsequent cardiovascular events 19. Since
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Liza Rajasekhar

to autoimmune rheumatic diseases may achieve

reduction in the risk of atherosclerosis by remission
induction and maintenance.

Rheum Dis Clin North Am 2000;26:257-78.

Esdaile JM, Abrahamowicz M, Grodzicky T, Li Y,
Panaritis C, du Berger R, et al. Traditional
Framingham risk factors fail to fully account for
accelerated atherosclerosis in systemic lupus
erythematosus. Arthritis Rheum 2001;44:2331-7.
4. Urowitz MB, Gladman DD. Accelerated atheroma
in lupusbackground. Lupus 2000;9:161-5.
5. Wallberg-Jonsson S, Johansson H, Ohman ML,
Rantapaa-Dahlqvist S. Extent of inflammation
predicts cardiovascular disease and overall mortality
in seropositive rheumatoid arthritis. A retrospective
cohort study from disease onset. J Rheumatol
1999;26:2562-71.
6. Banks MJ FJ, Bacon PA, Kitas GD. Expression
and prevalence of ischaemic heart disease in
rheumatoid arthritis. Arthritis Rheum 1998;41:S209.
7. Raza K, Thambyrajah J, Townend JN, Exley AR,
Hortas C, Filer A, et al. Suppression of inflammation
in primary systemic vasculitis restores vascular
endothelial function: lessons for atherosclerotic
disease? Circulation 2000;102:1470-2.
8. Guerci AD, Arad Y. Potential use of Ca++ scanning
to determine the need for and intensity of lipidlowering therapy in asymptomatic adults. Curr
Cardiol Rep 2001;3:408-15.
9. Mukherjee D, Yadav JS. Carotid artery intimalmedial thickness: indicator of atherosclerotic burden
and response to risk factor modification. Am Heart
J 2002;144:753-9.
10. Espeland MA, Craven TE, Riley WA, Corson J,
Romont A, Furberg CD. Reliability of longitudinal
ultrasonographic measurements of carotid intimalmedial thicknesses. Asymptomatic Carotid Artery
Progression Study Research Group. Stroke
1996;27:480-5.
11. Roman MJ, Shanker BA, Davis A, Lockshin MD,
Sammaritano L, Simantov R, et al. Prevalence and
correlates of accelerated atherosclerosis in systemic
lupus erythematosus. N Engl J Med 2003;349:2399406.
12. Asanuma Y, Oeser A, Shintani AK, Turner E,
Olsen N, Fazio S, et al. Premature coronary-artery
atherosclerosis in systemic lupus erythematosus.
N Engl J Med 2003;349:2407-15.
3.

Raza et al have demonstrated in a longitudinal study

using flow mediated brachial artery vasodialatation that
remission induction in patients with primary systemic
vasculitis reversed endothelial dysfunction7.
Conclusion
It is now established beyond doubt that reduced
life expectancy seen in the rheumatic disease population,
and in a very large proportion of them the cause of
death is from vascular events. In the lupus patients, older
age, higher damage indices, hypertriglyceridemia have
been established as risk factors for developing evidence
of atherosclerosis. In RA population, longer and more
severe disease contributes to risk. Common
immunologic events between the synovial inflammatory
response and the intimal inflammatory response have
been shown. In primary vasculitis, endothelial
dysfunction at sites distant from the vasculitic damage
has been demonstrated. Reversal of this dysfunction
with therapy directed at remission induction has been
demonstrated in short term studies. CRP, has been
authenticated as a marker in the general atherosclerotic
opulation and in patients with rheumatoid arthritis.
Statins have been shown to reduce atherosclerotic
events by their lipid and nonlipid effects in the general
population.
Longitudinal studies are needed to demonstrate
whether the effect of disease specific drugs and others
like statins and reduce the prevalence of asymptomatic
and symptomatic atherosclerotic disease in patients with
lupus, rheumatoid arthritis and primary vasculitis.
References:
1.

2.

Borchers AT, Keen CL, Shoenfeld Y, Gershwin

ME. Surviving the butterfly and the wolf: mortality
trends in systemic lupus erythematosus. Autoimmun
Rev 2004;3:423-53.
Bruce IN, Gladman DD, Urowitz MB. Premature
atherosclerosis in systemic lupus erythematosus.
19

Accelerated Atherosclerosis in Rheumatology- Current Understanding and Therapeutic Directions

20. Buckley CD, Ed Rainger G, Nash GB, Raza K.

Endothelial cells, fibroblasts and vasculitis.
Rheumatology (Oxford) 2005 (In press).
21. Undas A, Celinska-Lowenhoff M, Kaczor M,
Musial J. New nonlipid effects of statins and their
clinical relevance in cardiovascular disease. Thromb
Haemost 2004;91:1065-77.
22. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a
newly recognized type of immunomodulator. Nat
Med 2000;6:1399-402.
23. Gonzalez-Juanatey C, Testa A, Garcia-Castelo A,
Garcia-Porrua C, Llorca J, Gonzalez-Gay MA.
Active but transient improvement of endothelial
function in rheumatoid arthritis patients undergoing
long-term treatment with anti-tumor necrosis factor
alpha antibody. Arthritis Rheum 2004;51:447-50.
24. Gerli R, Schillaci G, Giordano A, Bocci EB, Bistoni
O, Vaudo G, et al. CD4+CD28- T lymphocytes
contribute to early atherosclerotic damage in
rheumatoid arthritis patients. Circulation
2004;109:2744-8.
25. Ridker PM, Cannon CP, Morrow D, Rifai N, Rose
LM, McCabe CH, et al. C-reactive protein levels
and outcomes after statin therapy. N Engl J Med
2005;352:20-8.

13. Nagata-Sakurai M, Inaba M, Goto H, Kumeda Y,

Furumitsu Y, Inui K, et al. Inflammation and bone
resorption as independent factors of accelerated
arterial wall thickening in patients with rheumatoid
arthritis. Arthritis Rheum 2003;48:3061-7.
14. Borba EF, Bonfa E. Dyslipoproteinemias in systemic
lupus erythematosus: influence of disease, activity,
and anticardiolipin antibodies. Lupus 1997;6:5339.
15. Alves JD, Ames PR. Atherosclerosis, oxidative
stress and auto-antibodies in systemic lupus
erythematosus and primary antiphospholipid
syndrome. Immunobiology 2003;207:23-8.
16. Jara LJ, Medina G, Vera-Lastra O, Shoenfeld Y.
Atherosclerosis and antiphospholipid syndrome.
Clin Rev Allergy Immunol 2003;25:79-88.
17. Vaarala O. Antibodies to oxidised LDL. Lupus
2000;9:202-5.
18. Yeh ET. CRP as a mediator of disease. Circulation
2004;109(21 Suppl 1):II11-4.
19. Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T,
Sasiela WJ, Tsai J, et al. Statin therapy, LDL
cholesterol, C-reactive protein, and coronary artery
disease. N Engl J Med 2005;352:29-38.

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