Wednesday, November 15, 2006 • Washington, DC • Richard M. Silver, MD, Program Chair
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Transcript of Wednesday, November 15, 2006 • Washington, DC • Richard M. Silver, MD, Program Chair
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Wednesday, November 15, 2006 • Washington, DC • Richard M. Silver, MD, Program Chair
VASCULAR COMPLICATIONS OF SYSTEMIC SCLEROSIS
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AGENDA1:30 – 1:35 PM Welcome and Introduction
Richard M. Silver, MD, Program Chair1:35 – 1:55 PM Pathogenesis of Vascular Disease in Scleroderma
Richard M. Silver, MD1:55 – 2:15 PM Early Diagnosis of PAH in Systemic Sclerosis:
How Do We Recognize the Warning Signs? Joseph C. Shanahan, MD
2:15 – 2:45 PM Treatment Targets for PAH in Systemic SclerosisMyung H. Park, MD, FACC
2:45 – 3:05 PM Future Directions in Treatment of SystemicSclerotic ComplicationsJanet Pope, MD
3:05 – 3:25 PM Panel DiscussionRichard M. Silver, MD, Program Chair, Moderating
3:25 – 3:30 PM Concluding RemarksRichard M. Silver, MD, Program Chair
VASCULAR COMPLICATIONSOF SYSTEMIC SCLEROSIS
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OBJECTIVES
• Describe pathogenic processes and mediators of vascular injury in systemic sclerosis, and identify potential treatment targets
• Outline current approaches to effective screening and diagnosis of pulmonary arterial hypertension, and recognize key decision points for early recognition in patients with systemic sclerosis
• Define appropriate targets and optimal long-term treatment plans for patients with systemic sclerosis based on current guidelines and emerging clinical data
• Identify new directions in managing systemic sclerotic complications
VASCULAR COMPLICATIONSOF SYSTEMIC SCLEROSIS
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DISCLOSURE STATEMENTIt is the policy of Medical Education Resources (MER) to ensure balance, independence, objectivity, and scientific rigor in all its educational activities. All faculty participating in our programs are expected to disclose any relationships they may have with commercial companies whose products or services may be mentioned so that participants may evaluate the objectivity of the presentations.
VASCULAR COMPLICATIONSOF SYSTEMIC SCLEROSIS
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VASCULAR COMPLICATIONSOF SYSTEMIC SCLEROSIS
Welcome and Introduction
Richard M. Silver, MD, Program ChairProfessor of Medicine and Pediatrics
Director, Division of Rheumatology and ImmunologyMedical University of South Carolina
Charleston, South Carolina
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VASCULAR COMPLICATIONSOF SYSTEMIC SCLEROSIS
DISCLOSURE STATEMENTRichard M. Silver, MD
Grants/research support, consultant:Actelion Pharmaceuticals US, Inc.
Advisory and Speaker BureauActelion Pharmaceuticals US, Inc.Encysive Pharmaceuticals Inc.Genentech, Inc. and Biogen Idec Inc.
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VASCULAR COMPLICATIONSOF SYSTEMIC SCLEROSIS
Pathogenesis of Vascular Disease in Scleroderma
Richard M. Silver, MD
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Pathogenesis of Vascular Disease in Scleroderma
Richard M. Silver, MDMedical University of
South Carolina
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Raynaud M. De l'asphyxie locale et de la gangrène symétrique des extrémités. Doctoral thesis, published February 25, 1862.
Raynaud’s Phenomenon
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SSc: A Collagen Vascular Disease
Semin Arthritis Rheum. 1975;4:351-368.
E. Carwile LeRoy1933-2002
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Vascular Disease: Skin
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Vascular Disease: Visceral
Scleroderma Renal Crisis
Pulmonary Arterial Hypertension
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Endothelial Cell Injury/Activation
• Endothelin-1
• Soluble ICAM-1
• Soluble VCAM-1
• Thrombomodulin
• Von Willebrand factor protein
• Endoglin
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ET-1 Plasma Levels Are Increased in SSc and Other Forms of PAH
0
2
4
6
8
10Idiopathic PAHIdiopathic PAH
IrET-
1(p
g/m
L)4
6
8
10
Con
cent
ratio
n of
ET-
1(p
g/m
L)
Non-PAH
SclerodermaScleroderma
PAH Non-PAH PAH
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Endothelial Cell Injury/Activation
• EC apoptosis is an early event • AECA’s in SSc sera induce leukocyte adhesion to
HVEC in vitro• SSc sera containing scleroderma-specific auto-
antibodies down-regulate genes for angiogenesis and up-regulate genes for apoptosis
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Endothelial Cell Apoptosis
Sgonc R et al. J Clin Invest. 1996;98:785-792.
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Endothelial Cell Activation
Carvalho D et al. J Clin Invest. 1996;97:111-119.
0
20
40
60
% adhesion
0 100 250 500 1000IgG (g/mL)
IgG, AECA(+) SSc serumIgG, AECA(–) SSc serumIgG, normal serumIgG, AECA(–) SSc serum
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Endothelial Cell Injury/Activation
• Evidence for EC injury/activation• EC apoptosis is an early event • AECA’s in SSc sera induce leukocyte adhesion to
HVEC in vitro• SSc sera containing scleroderma-specific auto-
antibodies down-regulate genes for angiogenesis and up-regulate genes for apoptosis
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A New Vascular Hypothesis:
SSc Is a Disease of Inadequate Vascular Repair
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Endothelial Progenitor Cells (EPCs)
• Derived from bone marrow
• Detectable in peripheral blood
• Home to sites of active neovascularization
• Differentiate to mature ECs in situ, thus contributing to endothelial cell replacement
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• Circulating EPCs in SSc– fewer in number than in healthy controls– increased number in early disease, but not in
late disease• Bone marrow EPCs in SSc
– reduced numbers of EPCs and stromal cells– impaired function
Endothelial Progenitor Cells in SSc
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Defective Vasculogenesis in SSc
Kuwana M et al. Lancet. 2004;364:603-610.
EPCs(no. per 20 mL
peripheral blood)
p<0.001
0
1000
2000
3500
3000
1500
500
2500
Rheumatoidarthritis
Healthycontrols
Systemicsclerosis
p<0.001 p=0.4
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Circulating EPCs in SSc
Del Papa N et al. Arthritis Rheum. 2006;54:2605-2615.
0
1000
2000
3000
4000
5000
6000
7000
8000
EPC
s (n
o. o
f cel
ls/m
L)
SSc EarlySSc
LateSSc
HC0
5
10
15
20
PB E
PCs
(cel
ls/
L bl
ood)
Years of disease5 10 15 20 25 30 35 400
Rs= –0.412p=0.001
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Del Papa et al. Arthritis Rheum. 2006;54:2605-2615.
Plasma VEGF in SSc
0100200300400500600700800900
VEGF concentration
(pg/mL)
HC Early
p<0.001
Late SSc
p<0.05
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Defective Vasculogenesis in SSc
Kuwana M et al. Lancet. 2004;364:603-610.
Systemicsclerosis
(n=8)
0
20
60
100
80
40
Mature CEP (%)
p<0.001
Healthycontrols
(n=9)
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Bone Marrow Endothelial ProgenitorsAre Defective in SSc
Del Papa et al. Arthritis Rheum. 2006;54:2605-2615.
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Vascular Injury
Systemic Sclerosis: A Disease of Vascular Injury and Inadequate Repair
AECA? CMVCytokinesGranzyme
Endothelial Cell ApoptosisInsufficient AngiogenesisDefective Vasculogenesis
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Wednesday, November 15, 2006 • Washington, DC • Richard M. Silver, MD, Program Chair
VASCULAR COMPLICATIONS OF SYSTEMIC SCLEROSIS