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

VASCULAR COMPLICATIONS OF SYSTEMIC SCLEROSIS. Wednesday, November 15, 2006 • Washington, DC • Richard M. Silver, MD, Program Chair. VASCULAR COMPLICATIONS OF SYSTEMIC SCLEROSIS. AGENDA 1:30 – 1:35 PM Welcome and Introduction Richard M. Silver, MD, Program Chair

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

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

  2. VASCULAR COMPLICATIONSOF SYSTEMIC SCLEROSIS AGENDA 1:30 – 1:35 PM Welcome and IntroductionRichard M. Silver, MD, Program Chair 1:35 – 1:55 PM Pathogenesis of Vascular Disease in SclerodermaRichard 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 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

  3. 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

  4. VASCULAR COMPLICATIONSOF SYSTEMIC SCLEROSIS 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.

  5. VASCULAR COMPLICATIONSOF SYSTEMIC SCLEROSIS Welcome and Introduction Richard M. Silver, MD, Program Chair Professor of Medicine and PediatricsDirector, Division of Rheumatology and ImmunologyMedical University of South CarolinaCharleston, South Carolina

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

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

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

  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. 60 40 20 0 Endothelial Cell Activation IgG, AECA(+) SSc serum IgG, AECA(–) SSc serum IgG, normal serum IgG, AECA(–) SSc serum % adhesion 0 100 250 500 1000 IgG (mg/mL) Carvalho D et al. J Clin Invest. 1996;97:111-119.

  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. Endothelial Progenitor Cells in SSc • 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

  22. 3500 3000 2500 2000 1500 1000 500 0 Defective Vasculogenesis in SSc p<0.001 p<0.001 p=0.4 EPCs (no. per 20 mL peripheral blood) Systemicsclerosis Rheumatoidarthritis Healthycontrols Kuwana M et al. Lancet. 2004;364:603-610.

  23. 8000 20 7000 6000 15 5000 4000 10 3000 2000 5 1000 0 0 0 5 10 15 20 25 30 35 40 Circulating EPCs in SSc Rs= –0.412 p=0.001 PB EPCs (cells/L blood) EPCs (no. of cells/mL) SSc EarlySSc LateSSc HC Years of disease Del Papa N et al. Arthritis Rheum. 2006;54:2605-2615.

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

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

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

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

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

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