Accelerated Atherosclerosis in Autoimmune Diseases

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Accelerated Atherosclerosis in Autoimmune
Diseases
Yaniv Sherer, MD
Department of Medicine B Center of Autoimmune
Diseases Sheba Medical Center Sackler Faculty of
Medicine Tel-Aviv University, Israel
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Atherosclerosis in Autoimmune Diseases
Autoimmune rheumatic diseases are associated with
higher rates of cardiovascular morbidity and
mortality, primarily secondary to accelerated
atherosclerosis
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Atherosclerosis in Autoimmune Diseases
Atherosclerosis is a multifactorial process which
is increasingly considered an immunemediated
process of the vascular system
Both cellular and humoral factors of the immune
system have a role in atherogenesis
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ATHEROSCLEROSIS- NON-INVASIVE METHODS
ACCELERATED ATHEROSCLEROSIS IN AUTOIMMUNE DISEASES
MECHANISMS INVOLVED IN ACCELERATED
ATHEROSCLEROSIS IN AUTOIMMUNITY- aPL
CAN WE IMMUNOMODULATE ATHEROSCLEROSIS?
Yaniv Sherer, MD
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NON-INVASIVE METHODS FOR DETECTION OF
ATHEROSCLEROSIS
Endothelial dysfunction assessed by brachial
flowmediated vasodilatation
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NON-INVASIVE METHODS FOR DETECTION OF
ATHEROSCLEROSIS
Ultrasound measurement of carotid intimal-medial
thickness (IMT)
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NON-INVASIVE METHODS FOR DETECTION OF
ATHEROSCLEROSIS
Coronary artery calcifications detected by
electron beam / spiral CT
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ACCELERATED ATHEROSCLEROSIS IN AUTOIMMUNE DISEASES
SYSTEMIC LUPUS ERYTHEMATOSUS ANTIPHOSPHOLIPID
SYNDROME RHEUMATOID ARTHRITIS SYSTEMIC
VASCULITIS SJOGRENS SYNDROME SYSTEMIC SCLEROSIS
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ATHEROSCLEROSIS IN SLE
Coronary artery disease prevalence in SLE-
6-10 the risk of developing CAD is 4 to 8 times
higher in SLE than normal
Bimodal distribution of the causes of death in
SLE An early peak caused by SLE
severity/activity or infections A late peak
caused by CVD
Coronary artery calcifications detected by
electron beam CT in 31 of SLE patients
Asanuma et al. N Engl J Med 200334920472015
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ATHEROSCLEROSIS IN SLE
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ATHEROSCLEROSIS IN ANTIPHOSPHOLIPID SYNDROME
The antiphospholipid syndrome is a prothrombotic
state characterized by recurrent arterial and
venous thrombosis, recurrent pregnancy loss
Accelerated atherosclerosis was suggested as an
additional clinical feature of APS
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ATHEROSCLEROSIS IN ANTIPHOSPHOLIPID SYNDROME
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Atherosclerosis in Rheumatoid Arthritis
Patients with rheumatoid arthritis have a reduced
life expectancy Standardized mortality ratios
ranging from 0.87 to 3.0 CVDs represent the main
cause of death in both clinical and
community-based cohorts of RA populations
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Atherosclerosis in Rheumatoid Arthritis
Functional abnormalities of the endothelium in
distinct cohorts of RA patients independently of
patients age, duration of the disease, degree of
disease activity, or seropositivity
Many investigations provided evidence
of increased carotid IMT in RA
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Early Atherosclerosis in Rheumatoid
Arthritis Effects of Smoking on Thickness of
the Carotid Artery Intima Media
ROBERTO GERLI, YANIV SHERER, GAETANO
VAUDO, GIUSEPPE SCHILLACI, BORIS GILBURD, ANDREA
GIORDANO, ELENA BARTOLONI BOCCI, ROSITA
ALLEGRUCCI, SIMONA MARCHESI, ELMO MANNARINO,
YEHUDA SHOENFELD
Ann N Y Acad Sci 20051051281-90
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Atherosclerosis in Systemic Vasculitis
Common carotid artery IMT was significantly
increased among 29 patients having inactive
Wegeners granulomatosis compared with 26 control
subjects
de Leeuw et al. Accelerated atherosclerosis in
patients with Wegeners granulomatosis. Ann Rheum
Dis. 200564753759.
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Atherosclerosis in Systemic Vasculitis
Carotid Artery Intima-Media Thickness, Heat-Shock
Proteins and Oxidized LDL Autoantibodies in
Systemic Necrotizing Vasculitis Yaniv Sherer,
Christian Pagnoux, Gilles Chironi, Alain Simon,
Loïc Guillevin, Luc Mouthon, Boris Gilburd,
Yehuda Shoenfeld
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Atherosclerosis in Sjogrens syndrome
Sjogrens syndrome patients had Higher IMT than
controls at both the carotid and the femoral
arteries Higher prevalence of carotid
intima-media thickening (49 versus 11 of
controls)
Vaudo G et al. Precocious intima-media thickening
in patients with primary Sjogren's syndrome.
Arthritis Rheum 2005523890-7.
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Atherosclerosis in Systemic Sclerosis
Abnormal IMT levels were significantly more
common in SSc patients compared with control
subjects. Age was found as the sole most
significant clinical parameter associated with
carotid artery IMT in SSc. Disease duration,
type of SSc, lung function tests and
cardiovascular risk factors were not associated
with IMT in these patients.
Early Atherosclerosis and Autoantibodies to
Heat-Shock Proteins and Oxidized LDL in Systemic
Sclerosis. Y Sherer, MM Cerinic, F Bartoli, J
Blagojevic ,ML Conforti, B Gilburd, M Ehrenfeld,
Y Shoenfeld. Ann N Y Acad Sci 2007 (in press).
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Drugs used for treatment
High prevalence of classical risk factors for
atherosclerosis
Methotrexate Steroids TNF blockers?
Smoking Hypertension Dyslipidemia Diabetes
mellitus
MECHANISMS INVOLVED IN ACCELERATED
ATHEROSCLEROSIS IN AUTOIMMUNITY
Long disease duration- enhanced inflammation
Autoantibodies, autoimmunity
Antiphospholipid Anti-oxLDL Anti-HSPs
CRP
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Anti-Cardiolipin Clinical Association with
Thrombosis
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Passive immunization with murine and human
anticardiolipinBlank et al, PNAS 88 3069, 1991

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Animal models of atherosclerosis induced by
anti-cardiolipin
Immunization of mice with aCL antibodies
resulted in development of high titers of mouse
aCL and increased atherosclerosis George et al.
Lupus 19976723
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Passive transfer of atherosclerosis via T cells
reactive to ?2GPI
Circulation 2000
?2GPI Immunization
Atherosclerosis
LDL-RD
Spleen and LN cells depleted of T cells
Spleen cells
Lymph node cells
Atherosclerosis
Atherosclerosis
Atherosclerosis
? 2GPI deposition
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Immune Dysregulation Accelerates Atherosclerosis
and Modulates Plaque Composition in Systemic
Lupus Erythematosus Stanic et al. PNAS
20061037018-23
Lupus susceptibility transferred to LDL-receptor
deficient mice Enhanced Atherosclerosis More
inflammatory plaques, more CD3 T cells Higher
autoantibody levels to oxLDL and anti-cardiolipin
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Anti-cardiolipin correlates with the extent of
atherosclerosis in another autoimmune disease
Ann. N.Y. Acad. Sci. 1051 299303 (2005)
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Thickened Carotid Artery Intima-Media in
Rheumatoid Arthritis is Associated with Elevated
Anti-Cardiolipin Antibodies Yaniv Sherer, Roberto
Gerli, Boris Gilburd, Elena Bartoloni Bocci,
Gaetano Vaudo, Elmo Mannarino, Yehuda Shoenfeld
Lupus 2007 (in press)
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Association between atherosclerosis and
anti-cardiolipin antibody in the general
population
The presence of high levels of aCL was
found as an independent risk factor for
myocardial infarction or cardiac death in
middle-aged men Vaarala et al. Circulation
19959123
aCL was higher in patients with significant
coronary artery stenosis as demonstrated by
coronary angiography compared with patients
without significant coronary artery stenosis
Sherer et al. Cardiology 20019520
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Higher levels of both coronary calcium and
aCL in patients having typical chest pain for
angina pectoris compared with patients with
atypical or no chest pain Sherer et al.
Am J Cardiol 2000861306
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Coronary artery disease, antiphospholipid
antibodies and endothelial dysfunction
Endothelial dysfunction assessed by brachial
flowmediated vasodilatation
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Conclusions- Anti-Cardiolipin and Atherosclerosis
1. Anti-Cardiolipin can induce atherosclerosis in
animals
2. The antiphospholipid syndrome is characterized
by enhanced atherosclerosis
3. Anti-cardiolipin is associated with early
atherosclerosis in rheumatoid arthritis
4. Anti-cardiolipin is associated with
atherosclerosis in various stages measured by
different methods in the general population
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Immunomodulation of Atherosclerosis Sherer Y
Shoenfeld Y Autoimmune Rev 2002121-7
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ROLE OF IVIG IN ATHEROSCLEROSIS
Immunomodulation of atherosclerosis (Sherer Y
Shoenfeld Y- Autoimmunity Reviews 2002121-7)
Y
Y
Y
Y
Y
Y
Y
Y
Y
Anti-idiotypes to oxLDL Abs within IVIG
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IgM anti-oxLDL inhibition of oxLDL binding to
macrophages
MMP-9 production inhibition in macrophages
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Accelerated Atherosclerosis in Autoimmune
Diseases- CONCLUSIONS
Autoimmune diseases are characterized by
ACCELERATED ATHEROSCLEROSIS (various mechanisms
involved- importance of aCL?)
Non-invasive methods (endothelial dysfunction,
IMT, coronary calcification) can detect
atherosclerosis in early stages and large
proportion of patients with autoimmune diseases
Immunomodulation might also have an
anti-atherogenic effect
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What shall we do with patients?

• Aggressively treat modifiable classical risk
  factors for CVD
• HTN, dyslipidemia, diabetes mellitus, smoking,
  obesity.

2. Consider Evaluate non-invasievly presence
of occult CVD Prescribe aspirin? Evaluate
presence of aCL?