1. 1 Sponsored by: National Institutes of Health (NIH) through its Division of Allergy, Immunology and Transplantation (DAIT) in the National Institute of Allergy and Infectious Diseases (NIAID) National Institutes of Health (NIH) through its Division of Allergy, Immunology and Transplantation (DAIT) in the National Institute of Allergy and Infectious Diseases (NIAID)

2. 2 Types of Scleroderma SclerodermaScleroderma Localized Scleroderma Systemic Scleroderma (Systemic Sclerosis) MorpheaMorphea Linear Scleroderma Limited Scleroderma Diffuse Scleroderma Sine Scleroderma

3. 3 Limited and Diffuse SSc— Skin Involvement LimitedDiffuse

4. 4 Limited Cutaneous Formally called CREST Formally called CREST Involvement of acral skin Involvement of acral skin Raynaud’s phenomenon for years prior to skin thickening Raynaud’s phenomenon for years prior to skin thickening Occasionally pulmonary HTN with or without interstitial lung disease Occasionally pulmonary HTN with or without interstitial lung disease Majority anti-centromere antibody positive (80–90%) Majority anti-centromere antibody positive (80–90%) Nailfold capillaroscopy—dilated capillary loops Nailfold capillaroscopy—dilated capillary loops

5. 5 Diffuse Cutaneous Widespread with early involvement of internal organs Widespread with early involvement of internal organs Raynaud’s phenomenon Raynaud’s phenomenon Truncal and acral skin involvement Truncal and acral skin involvement Absent for anti-centromere antibody Absent for anti-centromere antibody Nailfold capilaroscopy—capillary dilatation and destruction Nailfold capilaroscopy—capillary dilatation and destruction Focus of the SCOT study Focus of the SCOT study

6. 6 Diffuse Cutaneous Associated with substantial morbidity and mortality resulting from— Associated with substantial morbidity and mortality resulting from— Vascular dysfunction Vascular dysfunction Organ fibrosis and inflammation Organ fibrosis and inflammation Gastrointestinal dysmotility Gastrointestinal dysmotility Myocardial involvement Myocardial involvement

7. 7 Epidemiology Approximately 75,000–100,000 cases in US 1 Approximately 75,000–100,000 cases in US 1 20 new adult cases per million diagnosed annually 2 20 new adult cases per million diagnosed annually 2 Peak incidence Peak incidence 30- to 50-year-old females 30- to 50-year-old females More females than males (4:1) 2 More females than males (4:1) 2 Severe phenotype in young black women, with no other racial or ethnic differences 3 Severe phenotype in young black women, with no other racial or ethnic differences 3 1.Mayes. Rheum Dis Clin North Am 2003; 29(2):239-254. 2.Mayes et al. In: Clements PJ, Furst D, editors. Systemic Sclerosis. 2005: 1-15. 3.Laing et al. Arthritis Rheum 1997; 40(4):734-742.

8. Pathophysiology Copyright © 2004. Annals of Internal Medicine. All rights reserved.

9. 9 Clinical Features Raynaud’s phenomenon Raynaud’s phenomenon Skin Skin Gastrointestinal Gastrointestinal Cardiovascular Cardiovascular Pulmonary Pulmonary Renal Renal Systemic Systemic Musculoskeletal (myositis, arthritis) Musculoskeletal (myositis, arthritis) Copyright © 2002. Massachusetts Medical Society. All rights reserved.

10. 10 Clinical Features Raynaud’s phenomenon Raynaud’s phenomenon Skin Skin Gastrointestinal Gastrointestinal Cardiovascular Cardiovascular Pulmonary Pulmonary Renal Renal Systemic Systemic Musculoskeletal (myositis, arthritis) Musculoskeletal (myositis, arthritis) Dr. Jonathon Goldin, UCLA Radiology Core. Used with permission.

11. 11 Copyright ©2005. Duke University Medical Center. Clinical Features

12. 12 Prognosis Extent of internal organ involvement influences survival in limited and diffuse forms of SSc Extent of internal organ involvement influences survival in limited and diffuse forms of SSc In diffuse SSc, mortality rate 5 to 8 times higher than general population 4 In diffuse SSc, mortality rate 5 to 8 times higher than general population 4 For those with limited skin involvement, mortality rate 2 times higher than general population 4 For those with limited skin involvement, mortality rate 2 times higher than general population 4 Lung disease most common scleroderma-related cause of death Lung disease most common scleroderma-related cause of death 4.Denton C. UpToDate, 2004.

13. 13 Current Treatment Approaches Raynaud’s phenomenon Raynaud’s phenomenon Gastrointestinal Gastrointestinal Cardiovascular Cardiovascular Pulmonary Pulmonary Renal Renal Systemic Systemic Musculoskeletal Musculoskeletal

14. 14 Monthly IV pulse cyclophosphamide for 12 months Monthly IV pulse cyclophosphamide for 12 months SCOT—Study Arms High-dose immunosuppressive therapy (HDIT) with autologous stem cell transplantation

15. 15 SCOT—Rationale Current treatments are inadequate Current treatments are inadequate Evidence that SSc is an autoimmune- mediated disease Evidence that SSc is an autoimmune- mediated disease Patients with expected poor survival may benefit from aggressive approach (supported by the data) Patients with expected poor survival may benefit from aggressive approach (supported by the data)

16. 16 Previous Clinical Studies Autologous stem cell transplantation Pilot study (FHCRC Protocol 1019) Pilot study (FHCRC Protocol 1019) Preliminary ASTIS trial data Preliminary ASTIS trial data Autologous stem cell transplantation Pilot study (FHCRC Protocol 1019) Pilot study (FHCRC Protocol 1019) Preliminary ASTIS trial data Preliminary ASTIS trial data Monthly IV pulse cyclophosphamide Significant weight of evidence from uncontrolled or open-label studies Significant weight of evidence from uncontrolled or open-label studies Monthly IV pulse cyclophosphamide Significant weight of evidence from uncontrolled or open-label studies Significant weight of evidence from uncontrolled or open-label studies

17. 17 SCOT—Primary Endpoint Event-free survival at 44 months after randomization Death Death Respiratory failure Respiratory failure Chronic renal dialysis Chronic renal dialysis Cardiomyopathy Cardiomyopathy NYHA heart failure class III or IV, or NYHA heart failure class III or IV, or LVEF < 30% for 3 months LVEF < 30% for 3 months

18. 18 SCOT—Key Eligibility Criteria SSc with poor prognosis SSc with poor prognosis Extensive skin involvement (mRSS  16) Extensive skin involvement (mRSS  16) Early internal organ involvement Early internal organ involvement

19. 19 SCOT—High-Dose Cyclophosphamide Arm High-dose pulse cyclophosphamide IV at 28–32 day intervals for a total of 12 infusions. Initial dose is 500 mg/m 2 followed by 750 mg/m 2 for subsequent doses.

20. 20 SCOT—High-Dose Cyclophosphamide Arm Total lung capacity (TLC), carbon monoxide diffusion capacity (DLCO), and arterial oxygen tension (PO 2 ) before and after intravenous pulse cyclophosphamide treatment in patients with interstitial lung disease due to collagen vascular diseases. 100 – 90 – 80 – 70 – 60 – 50 – 40 – 30 – 0 – DLCO (% of predicted) PREPOST 100 – 90 – 80 – 70 – 60 – 50 – 40 – 30 – 0 – TLC (% of predicted) PREPOST 110 – 100 – 90 – 80 – 70 – 60 – 50 – 40 – 0 – PO 2 (mmHg) PREPOST Schnabel A, Reuter M, Gross WL. Arthritis Rheum 1998; 41(7):1215-1220.

21. 21 Autologous Stem Cell Transplant Arm Stem cell mobilization Stem cell mobilization G-CSF G-CSF Leukapheresis Will have graphics improve images

22. 22 CD34+ Selection Successful CD34 selection technology results in efficient T cell removal from PBSC grafts Successful CD34 selection technology results in efficient T cell removal from PBSC grafts Frequently used method to prevent GVHD in allogenic transpantation Frequently used method to prevent GVHD in allogenic transpantation Minimize likelihood of reintroducing disease causing cells after HDIT Minimize likelihood of reintroducing disease causing cells after HDIT

23. 23 HDIT, Conditioning Regimen TBI 800 cGy TBI 800 cGy ATGAM 90 mg/kg ATGAM 90 mg/kg Cyclophosphamide 120 mg/kg Cyclophosphamide 120 mg/kg

24. 24 Rationale for HDIT Maximal tolerable immunosuppression with acceptable toxicity Maximal tolerable immunosuppression with acceptable toxicity Dose of 800 cGY is less than dose used in treatment of malignancy (> 1200 cGY) Dose of 800 cGY is less than dose used in treatment of malignancy (> 1200 cGY) Lung and renal radiation dose limited to 200 cGY Lung and renal radiation dose limited to 200 cGY

25. 25 Stem Cell Transplantation Autologous CD34-selected cells infused after HDIT Autologous CD34-selected cells infused after HDIT Goal: Reset the immune system 5,6 Goal: Reset the immune system 5,6 5.Murano PA, et al. JEM 2005; 201:805-816. 6.Hakim FT, et al. JCI 2005; 115:930-939.

26. 26 SCOT—Risk Reduction Plan Patients with significant pulmonary HTN or cardiac disease excluded Patients with significant pulmonary HTN or cardiac disease excluded Shielding from radiation of lung and kidneys Shielding from radiation of lung and kidneys ATGAM use for additional anti-T cell activity ATGAM use for additional anti-T cell activity Antihistamines and corticosteroids to reduce side effects of ATGAM Antihistamines and corticosteroids to reduce side effects of ATGAM Selection of CD34+ cells to decrease likelihood of reintroducing disease-causing immune cells after HDIT Selection of CD34+ cells to decrease likelihood of reintroducing disease-causing immune cells after HDIT Prophylactic measures to reduce risk of opportunistic infection Prophylactic measures to reduce risk of opportunistic infection

27. 27 SCOT—Study Centers NORTHWEST NORTHEAST SOUTHEAST SOUTH CENTRAL SOUTHWEST NORTH CENTRAL California Pacific MC U. of Colorado Mayo Clinic Scottsdale U. of Texas Southwestern U. of Tenn. Memphis U. of Florida Gainesville Med. U. of South Carolina Ctr for Rheum. Georgetown U. Duke U. UCLA & City of Hope U. of TX – Houston & MD Anderson CC Boston U. & Mass. Gen. Hosp. Mercy Arthritis North Shore Long Island UMDNJ Hosp. for Special Surgery U. Chicago U. of WI U. of Michigan MC of Ohio WUSTL U. of Alabama FHCRC & Virginia Mason & U. of WA U. of Kentucky Confirmed Rheumatology Center Potential Rheumatology Center Confirmed Transplant Center U. of Cincinnati MC of Wisconsin

28. 28 SCOT—More Information PIs: Pease add your site contact info here PIs: Pease add your site contact info here SCOT phone: 1-866-909-SCOT SCOT phone: 1-866-909-SCOT SCOT website: www.sclerodermatrial.org SCOT website: www.sclerodermatrial.org