Future Directions in Treatment of Systemic Sclerotic Complications

1. VASCULAR COMPLICATIONSOF SYSTEMIC SCLEROSIS Future Directions in Treatment of Systemic Sclerotic Complications Janet Pope, MD ProfessorDivision of RheumatologySt. Joseph’s Health CentreUniversity of Western Ontario, LondonLondon, Ontario, Canada

2. VASCULAR COMPLICATIONSOF SYSTEMIC SCLEROSIS DISCLOSURE STATEMENT Janet Pope, MD Grants/Research/Advisory Boards Actelion Pharmaceuticals Encysive Pharmaceuticals Inc. Pfizer Off-label uses for products may be discussed.

3. Prevalence of SSc-PAH

4. Canadian SSc-PAH Distribution25% Had Elevated PAP on Echo Undetermined: 15.3% Isolated: 54.8% Secondary to fibrosis: 29.8% Pope J. JRheumatol. 2005;32:1273-1278.

5. Predictors of SSc-PAH • Some elevated PAPs on echo are stable over years • 65% with PASP >35 mm Hg did not deteriorate over 3 yr • Dropping DLCO % predicted and rising FVC/ DLCO ratio may be better predictors of PAH progression in the early stages Steen V. Arthritis Rheum. 2005;52:3698-3700.

6. PAH in Scleroderma • Think about it in long-standing limited systemic scleroderma patients • It can occur in diffuse scleroderma at any stage of the disease with or without associated pulmonary fibrosis • Even patients with fibrosis may benefit from treatment of secondary PAH • No obvious autoantibodies associated with SSc-PAH • ? BNP

7. 1.0 0.9 0.8 0.7 0.6 0.5 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Ratio of % FVC to % DLCO Influences Survival in Systemic Sclerosis % FVC / % DLCO <1.8 (n=337) Probability of survival p=0.007 % FVC / % DLCO ≥1.8 (n=169) Duration of disease (yr from onset) Disproportionate and/or isolated reduction in gas exchange (diffusing capacity) is dominant determinant of survival in all forms of SSc lung. Seibold JR. Personal communication.

8. Survival in SSc-PAH with Bosentan is Improving Williams MH et al. Heart. 2006;92:926-932. Denton C et al. Ann Rheum Dis. 2006;65:1336-1340.

9. TRUST: CTD-PAH Class III Bosentan RxTime to Clinical Worsening 100 75 Patients without events (%) 50 25 0 0 12 24 36 48 Time (weeks) Patientsat risk 53 52 49 45 42 40 35 25 14 Denton C. Presented at EULAR 2006, ACR 2006.

10. 100 75 50 25 0 0 12 24 36 48 TRUST: Survival Analysis Patients without events (%) Time (weeks) Patientsat risk 53 53 53 52 52 50 48 37 22 Excellent one-year survival with bosentan treatment Denton C. Presented at EULAR 2006, ACR 2006.

11. 100 90 80 70 60 50 40 Sitaxsentan 30 Bosentan 20 10 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 N=27 N=25 Weeks One-Year Survival 96% 1 vs. 5 deaths 79% Percent Survival HR: 0.17 (95% CI: 0.02, 1.42) N=26 N=20 STRIDE unpublished data.

12. Visceral Vascular Disease: Systemic Sclerosis PAH Renal crisis

13. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 5 10 15 20 25 SRC Increases All-Cause Scleroderma Mortality Survival (%) Normal kidneys SRC Years with SSc before death Firas, submitted 2006.

14. SRC Risk Factors • Diffuse scleroderma • Rapidly progressive skin involvement • First 4 yr of diagnosis • Male gender • Anti-RNA polymerase III • Prednisone use • Cyclosporin

15. Other Possible Risk Factors • New-onset anemia • Cardiac involvement including pericardial effusions or CHF • Contractures of large joints • High skin score

16. SRC – Pathogenesis • Marked elevations of renin • Endothelial wall injury with • intimal proliferation • vasospasm • decreased renal perfusion

17. Pathogenesis • Hyper-reninemia alone does not suffice • Baseline measures do not predict SRC • Frequently elevated plasma renins • Cold-induced renin elevations • Decreased renal blood flow

18. Prevention of SRC • High index of suspicion • Home BP monitoring in early diffuse or rapidly progressive scleroderma patients • Avoid steroids in these patients if possible • Treat rises of BP aggressively, immediately (treat like pregnancy-induced hypertension)

19. SRC – Other Treatment • ACE inhibitors (not angio II) • decrease renin • increase bradykinin • Add any treatment to control the hypertension • Prostacyclins • ? Statins • ? ET-1 blockers

20. Prostacyclins in SRC • Potent vasodilator • Can be of benefit in severe RP, digital ulcers, and PAH in scleroderma • It can reduce the resistance of the interlobar and cortical vessel arteries • There are a few case reports showing improvement in SRC to control BP added to an ACE

21. Statins in SRC: Theoretical Benefits Coenzyme A reductase inhibitors can: • Decrease cellular proliferation by decreasing the prenylation of proteins • Induce apoptosis of smooth muscle cells and fibroblasts • Reduce ACE activity • Inhibit endothelin production • Inhibit type-I collagen production

22. ET-1 in Scleroderma Kidney • Present in the small renal arteries in SRC • ET-1 is important in scleroderma vasculopathy • ET-1 can increase fibrosis • But there are no studies reported of its use in SRC

23. SRC Is Under-Recognized • Avoid triggers: steroids in early diffuse patients if possible • Think about it • Frequent BP monitoring • Do not stop the ACE inhibitor • The outcome is still not ideal

24. Masson-Trichrome Stain of Digital Artery in SSc Vasculopathy in Scleroderma • Striking fibrotic intimal hyperplasia • Adventitial fibrosis • Arterial lumen severely compromised

25. Digital Vascular Injury in SSc

26. Digital Ulcers • It is unknown if digital ulcers are a marker for poor prognosis • They occur in diffuse and limited disease and are especially severe in limited scleroderma • They can be correlated with the presence of PH • Endothelin level is increased in the digital arteries

27. Prevalence of Digital Ulcers • Raynaud’s occurs in at least 90% of subjects with scleroderma • Old digital ulcers (presence of pits/scars) are part of the minor criteria for the diagnosis of scleroderma • 33% to 75% of scleroderma can have digital ulcers

28. What Is the Burden of Digital Ulcersin Scleroderma?Canadian Scleroderma Research Group • Skin ulcers on fingers: 34/200 (17%) • Pits: 75/200 (38%) • Active volar distal ulcers: 16/197 (8%) • No. of active ulcers: 1.75 (SD 1.3) range 1-6

29. Digital Ulcers: Impact on Quality of Life • Painful • Interfere with activities of daily life as they affect hand function • Some heal spontaneously • Generally slow to heal (3-15 mo) • Can be complicated by secondary infections • Can require amputation or can autoamputate

30. Ulcers and Amputations

31. Bosentan Reduces No. of PatientsWith New Digital Ulcers ITT with baseline DU ITT 100 90 80 70 Patients with n or more ulcers (%) 60 50 40 30 20 10 0 ≥1 ≥4 ≥7 ≥10 ≥1 ≥4 ≥7 ≥10 Number of new ulcers (n) Number of new ulcers (n) Placebo Bosentan Korn JH et al. Arthritis Rheum. 2004;50:3985-3993.

32. RAPIDS-1 AND RAPIDS-2 79 Korn JH et al. Arthritis Rheum. 2004;50:3985-3993. Seibold J, EULAR 2006. Pope J. ACR 2006.

33. Conclusions • Vasculopathy in scleroderma is widespread and may involve many organs • Early recognition may improve prognosis • Different vascular beds may respond to different treatment • Treatment may include multiple drugs to treat the vascular abnormalities and complications