1. Wednesday, November 15, 2006 Washington, DC Richard M. Silver, MD, Program Chair VASCULAR COMPLICATIONS OF SYSTEMIC SCLEROSIS

2. AGENDA 1:30 – 1:35 PM Welcome and Introduction Richard M. Silver, MD, Program Chair 1:35 – 1:55 PM Pathogenesis of Vascular Disease in Scleroderma Richard M. Silver, MD 1:55 – 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 Sclerosis Myung H. Park, MD, FACC 2:45 – 3:05 PM Future Directions in Treatment of Systemic Sclerotic Complications Janet Pope, MD 3:05 – 3:25 PM Panel Discussion Richard M. Silver, MD, Program Chair, Moderating 3:25 – 3:30 PM Concluding Remarks Richard M. Silver, MD, Program Chair VASCULAR COMPLICATIONS OF SYSTEMIC SCLEROSIS

3. 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 COMPLICATIONS OF SYSTEMIC SCLEROSIS

4. DISCLOSURE STATEMENT It 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 COMPLICATIONS OF SYSTEMIC SCLEROSIS

5. Welcome and Introduction Richard M. Silver, MD, Program Chair Professor of Medicine and Pediatrics Director, Division of Rheumatology and Immunology Medical University of South Carolina Charleston, South Carolina

6. VASCULAR COMPLICATIONS OF SYSTEMIC SCLEROSIS DISCLOSURE STATEMENT Richard M. Silver, MD Grants/research support, consultant: Actelion Pharmaceuticals US, Inc. Advisory and Speaker Bureau Actelion Pharmaceuticals US, Inc. Encysive Pharmaceuticals Inc. Genentech, Inc. and Biogen Idec Inc.

7. VASCULAR COMPLICATIONS OF SYSTEMIC SCLEROSIS Pathogenesis of Vascular Disease in Scleroderma Richard M. Silver, MD

8. Pathogenesis of Vascular Disease in Scleroderma Richard M. Silver, MD Medical University of South Carolina

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

10. SSc: A Collagen Vascular Disease Semin Arthritis Rheum. 1975;4:351-368. E. Carwile LeRoy 1933-2002

11. Vascular Disease: Skin

12. Vascular Disease: Visceral Scleroderma Renal Crisis Pulmonary Arterial Hypertension

13. Endothelial Cell Injury/Activation Endothelin-1 Soluble ICAM-1 Soluble VCAM-1 Thrombomodulin Von Willebrand factor protein Endoglin

14. ET-1 Plasma Levels Are Increased in SSc and Other Forms of PAH 0 2 4 6 8 10 Idiopathic PAH IrET-1 (pg/mL) 4 6 8 10 Concentration of ET-1 (pg/mL) Non-PAH Scleroderma PAHNon-PAHPAH

15. 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

16. Endothelial Cell Apoptosis Sgonc R et al. J Clin Invest. 1996;98:785-792.

17. Endothelial Cell Activation Carvalho D et al. J Clin Invest. 1996;97:111-119. 0 20 40 60 % adhesion 01002505001000 IgG (  g/mL) IgG, AECA(+) SSc serum IgG, AECA(–) SSc serum IgG, normal serum IgG, AECA(–) SSc serum

18. 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

19. A New Vascular Hypothesis: SSc Is a Disease of Inadequate Vascular Repair

20. 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

21. 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

22. 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 Rheumatoid arthritis Healthy controls Systemic sclerosis p<0.001p=0.4

23. Circulating EPCs in SSc Del Papa N et al. Arthritis Rheum. 2006;54:2605-2615. 0 1000 2000 3000 4000 5000 6000 7000 8000 EPCs (no. of cells/mL) SScEarly SSc Late SSc HC 0 5 10 15 20 PB EPCs (cells/  L blood) Years of disease 5101520253035400 R s = –0.412 p=0.001

24. Del Papa et al. Arthritis Rheum. 2006;54:2605-2615. Plasma VEGF in SSc 0 100 200 300 400 500 600 700 800 900 VEGF concentration (pg/mL) HCEarly p<0.001 Late SSc p<0.05

25. Defective Vasculogenesis in SSc Kuwana M et al. Lancet. 2004;364:603-610. Systemic sclerosis (n=8) 0 20 60 100 80 40 Mature CEP (%) p<0.001 Healthy controls (n=9)

26. Bone Marrow Endothelial Progenitors Are Defective in SSc Del Papa et al. Arthritis Rheum. 2006;54:2605-2615.

27. Vascular Injury Systemic Sclerosis: A Disease of Vascular Injury and Inadequate Repair AECA ? CMV Cytokines Granzyme Endothelial Cell Apoptosis Insufficient Angiogenesis Defective Vasculogenesis

28. Wednesday, November 15, 2006 Washington, DC Richard M. Silver, MD, Program Chair VASCULAR COMPLICATIONS OF SYSTEMIC SCLEROSIS