1. VASCULAR COMPLICATIONS OF SYSTEMIC SCLEROSIS Future Directions in Treatment of Systemic Sclerotic Complications Janet Pope, MD Professor Division of Rheumatology St. Joseph’s Health Centre University of Western Ontario, London London, Ontario, Canada

2. VASCULAR COMPLICATIONS OF 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 StudyNo.Prevalence (%) Japan12516 Britain93013 USA81511 Canada344 5 France6737 Burlington3435 Canada53925 (10% Class III-IV) France599 8 USA90927 (abnormal echos)

4. Canadian SSc-PAH Distribution 25% Had Elevated PAP on Echo Pope J. J Rheumatol. 2005;32:1273-1278. Isolated: 54.8% Secondary to fibrosis: 29.8% Undetermined: 15.3%

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. Ratio of % FVC to % DLCO Influences Survival in Systemic Sclerosis 01234567891011121314151617181920 0.5 0.6 0.7 0.8 0.9 1.0 Duration of disease (yr from onset) Probability of survival % FVC / % DLCO <1.8 (n=337) % FVC / % DLCO ≥1.8 (n=169) p=0.007 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 Current Rx Bosentan N=45 Historical Standard & Flolan N=47 Open Label Extension Bosentan N=44 1 yr survival % 816886 2 yr survival % 714773 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 Rx Time to Clinical Worsening Denton C. Presented at EULAR 2006, ACR 2006. Time (weeks) 100 25 0 50 75 120483624 Patients at risk 535245403525144942 Patients without events (%)

10. TRUST: Survival Analysis Excellent one-year survival with bosentan treatment Time (weeks) 100 25 0 50 75 120483624 Patients at risk 53 52504837225352 Patients without events (%) Denton C. Presented at EULAR 2006, ACR 2006.

11. STRIDE unpublished data. One-Year Survival Percent Survival Weeks N=27 N=25 0481216202428323640444852 0 10 20 30 40 50 60 70 80 90 100 Sitaxsentan Bosentan N=26 N=20 96% 79% HR: 0.17 (95% CI: 0.02, 1.42) 1 vs. 5 deaths

12. Visceral Vascular Disease: Systemic Sclerosis Renal crisis PAH

13. 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0510152025 Years with SSc before death Survival (%) SRC Increases All-Cause Scleroderma Mortality Normal kidneys SRC 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. Vasculopathy in Scleroderma Masson-Trichrome Stain of Digital Artery in SSc 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 Ulcers in 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. 0 10 20 30 40 50 60 70 80 90 100 ≥1≥1≥4≥4≥7≥7≥10 Number of new ulcers (n) Patients with n or more ulcers (%) ≥1≥1≥4≥4≥7≥7≥10 Number of new ulcers (n) ITT ITT with baseline DU PlaceboBosentan Bosentan Reduces No. of Patients With New Digital Ulcers Korn JH et al. Arthritis Rheum. 2004;50:3985-3993.

32. RAPIDS-1 AND RAPIDS-2 RAPIDS-1RAPIDS-2 16 weeks Bos Pbo 24 weeks Bos Pbo Patients (n)79 4390 98 Ulcers at baseline (%)1.9 2.23.7 3.6 New DUs (n) 1.4 2.7 -48% ( p=0.008) 1.9 2.7 -30% (p=0.035) HealingNS Korn JH et al. Arthritis Rheum. 2004;50:3985-3993. Seibold J, EULAR 2006. Pope J. ACR 2006. 79

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