Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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) 1 Types of Scleroderma Scleroderma Localized Scleroderma Morphea Linear Scleroderma Systemic Scleroderma (Systemic Sclerosis) Limited Scleroderma Diffuse Scleroderma Sine Scleroderma 2 Limited and Diffuse SSc— Skin Involvement Limited Diffuse 3 Limited Cutaneous Formally called CREST Involvement of acral skin Raynaud’s phenomenon for years prior to skin thickening Occasionally pulmonary HTN with or without interstitial lung disease Majority anti-centromere antibody positive (80–90%) Nailfold capillaroscopy—dilated capillary loops 4 Diffuse Cutaneous Widespread with early involvement of internal organs Raynaud’s phenomenon Truncal and acral skin involvement Absent for anti-centromere antibody Nailfold capilaroscopy—capillary dilatation and destruction Focus of the SCOT study 5 Diffuse Cutaneous Associated with substantial morbidity and mortality resulting from— Vascular dysfunction Organ fibrosis and inflammation Gastrointestinal dysmotility Myocardial involvement 6 Epidemiology Approximately 75,000–100,000 cases in US1 Peak incidence 30- to 50-year-old females 20 new adult cases per million diagnosed annually2 More females than males (4:1)2 Severe phenotype in young black women, with no other racial or ethnic differences3 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. 7 Pathophysiology Copyright © 2004. Annals of Internal Medicine. All rights reserved. Clinical Features Raynaud’s phenomenon Skin Gastrointestinal Cardiovascular Pulmonary Renal Systemic Musculoskeletal (myositis, arthritis) Copyright © 2002. Massachusetts Medical Society. All rights reserved. 9 Clinical Features Raynaud’s phenomenon Skin Gastrointestinal Cardiovascular Pulmonary Renal Systemic Musculoskeletal (myositis, arthritis) Dr. Jonathon Goldin, UCLA Radiology Core. Used with permission. 10 Clinical Features Copyright ©2005. Duke University Medical Center. 11 Prognosis 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 population4 For those with limited skin involvement, mortality rate 2 times higher than general population4 Lung disease most common scleroderma-related cause of death 4. Denton C. UpToDate, 2004. 12 Current Treatment Approaches Raynaud’s phenomenon Gastrointestinal Cardiovascular Pulmonary Renal Systemic Musculoskeletal 13 SCOT—Study Arms Monthly IV pulse cyclophosphamide for 12 months High-dose immunosuppressive therapy (HDIT) with autologous stem cell transplantation 14 SCOT—Rationale Current treatments are inadequate Evidence that SSc is an autoimmunemediated disease Patients with expected poor survival may benefit from aggressive approach (supported by the data) 15 Previous Clinical Studies Monthly IV pulse cyclophosphamide Significant weight of evidence from uncontrolled or open-label studies Autologous stem cell transplantation Pilot study (FHCRC Protocol 1019) Preliminary ASTIS trial data 16 SCOT—Primary Endpoint Event-free survival at 44 months after randomization Death Respiratory failure Chronic renal dialysis Cardiomyopathy NYHA heart failure class III or IV, or LVEF < 30% for 3 months 17 SCOT—Key Eligibility Criteria SSc with poor prognosis Extensive skin involvement (mRSS 16) Early internal organ involvement 18 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/m2 followed by 750 mg/m2 for subsequent doses. 19 100 – 110 – 90 – 90 – 100 – 80 – 80 – 90 – 70 – 80 – 70 – 60 – 50 – 40 – PO2 (mmHg) 100 – DLCO (% of predicted) TLC (% of predicted) SCOT—High-Dose Cyclophosphamide Arm 60 – 50 – 70 – 60 – 40 – 50 – 30 – 30 – 40 – 0– 0– 0– PRE POST PRE POST Total lung capacity (TLC), carbon monoxide diffusion capacity (DLCO), and arterial oxygen tension (PO2) before and after intravenous pulse cyclophosphamide treatment in patients with interstitial lung disease due to collagen vascular diseases. PRE POST Schnabel A, Reuter M, Gross WL. Arthritis Rheum 20 1998; 41(7):1215-1220. Autologous Stem Cell Transplant Arm Stem cell mobilization G-CSF Leukapheresis Will have graphics improve images 21 CD34+ Selection Successful CD34 selection technology results in efficient T cell removal from PBSC grafts Frequently used method to prevent GVHD in allogenic transpantation Minimize likelihood of reintroducing disease causing cells after HDIT 22 HDIT, Conditioning Regimen TBI 800 cGy ATGAM 90 mg/kg Cyclophosphamide 120 mg/kg 23 Rationale for HDIT Maximal tolerable immunosuppression with acceptable toxicity Dose of 800 cGY is less than dose used in treatment of malignancy (> 1200 cGY) Lung and renal radiation dose limited to 200 cGY 24 Stem Cell Transplantation Autologous CD34-selected cells infused after HDIT Goal: Reset the immune system5,6 5. Murano PA, et al. JEM 2005; 201:805-816. 6. Hakim FT, et al. JCI 2005; 115:930-939. 25 SCOT—Risk Reduction Plan Patients with significant pulmonary HTN or cardiac disease excluded Shielding from radiation of lung and kidneys ATGAM use for additional anti-T cell activity Antihistamines and corticosteroids to reduce side effects of ATGAM Selection of CD34+ cells to decrease likelihood of reintroducing disease-causing immune cells after HDIT Prophylactic measures to reduce risk of opportunistic infection 26 SCOT—Study Centers NORTHWEST NORTHEAST NORTH CENTRAL FHCRC & Virginia Mason & U. of WA Boston U. & Mass. Gen. Hosp. U. of Michigan MC of Wisconsin Ctr for Rheum. U. of WI Mercy Arthritis Hosp. for Special Surgery UMDNJ U. Chicago California Pacific MC Georgetown U. U. of Cincinnati U. of Colorado WUSTL U. of Kentucky SOUTHWEST Confirmed Transplant Center Confirmed Rheumatology Center Potential Rheumatology Center SOUTHEAST Duke U. Mayo Clinic Scottsdale UCLA & City of Hope North Shore Long Island MC of Ohio U. of Tenn. Memphis U. of Texas Southwestern Med. U. of South Carolina U. of Alabama U. of Florida Gainesville U. of TX – Houston & MD Anderson CC SOUTH CENTRAL 27 SCOT—More Information PIs: Pease add your site contact info here SCOT phone: 1-866-909-SCOT SCOT website: www.sclerodermatrial.org 28