Wednesday, November 15, 2006 • Washington, DC • Richard M. Silver, MD, Program Chair

VASCULAR COMPLICATIONS OF SYSTEMIC SCLEROSIS

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

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

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

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

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.

VASCULAR COMPLICATIONSOF SYSTEMIC SCLEROSIS

Pathogenesis of Vascular Disease in Scleroderma

Richard M. Silver, MD

Pathogenesis of Vascular Disease in Scleroderma

Richard M. Silver, MDMedical University of

South Carolina

Raynaud M. De l'asphyxie locale et de la gangrène symétrique des extrémités. Doctoral thesis, published February 25, 1862.

Raynaud’s Phenomenon

SSc: A Collagen Vascular Disease

Semin Arthritis Rheum. 1975;4:351-368.

E. Carwile LeRoy1933-2002

Vascular Disease: Skin

Vascular Disease: Visceral

Scleroderma Renal Crisis

Pulmonary Arterial Hypertension

Endothelial Cell Injury/Activation

• Endothelin-1

• Soluble ICAM-1

• Soluble VCAM-1

• Thrombomodulin

• Von Willebrand factor protein

• Endoglin

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

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

Endothelial Cell Apoptosis

Sgonc R et al. J Clin Invest. 1996;98:785-792.

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

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

A New Vascular Hypothesis:

SSc Is a Disease of Inadequate Vascular Repair

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

• 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

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

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

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

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)

Bone Marrow Endothelial ProgenitorsAre Defective in SSc

Del Papa et al. Arthritis Rheum. 2006;54:2605-2615.

Vascular Injury

Systemic Sclerosis: A Disease of Vascular Injury and Inadequate Repair

AECA? CMVCytokinesGranzyme

Endothelial Cell ApoptosisInsufficient AngiogenesisDefective Vasculogenesis

Wednesday, November 15, 2006 • Washington, DC • Richard M. Silver, MD, Program Chair

VASCULAR COMPLICATIONS OF SYSTEMIC SCLEROSIS