Transcript Document

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)
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Types of Scleroderma
Scleroderma
Localized
Scleroderma
Morphea
Linear
Scleroderma
Systemic
Scleroderma
(Systemic Sclerosis)
Limited
Scleroderma
Diffuse
Scleroderma
Sine
Scleroderma
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Limited and Diffuse SSc—
Skin Involvement
Limited
Diffuse
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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
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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
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Diffuse Cutaneous

Associated with substantial morbidity
and mortality resulting from—
 Vascular dysfunction
 Organ fibrosis and inflammation


Gastrointestinal dysmotility
Myocardial involvement
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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.
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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.
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Clinical Features

Raynaud’s phenomenon

Skin

Gastrointestinal

Cardiovascular

Pulmonary

Renal

Systemic

Musculoskeletal
(myositis, arthritis)
Dr. Jonathon Goldin, UCLA Radiology Core.
Used with permission.
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Clinical Features
Copyright ©2005. Duke University Medical Center.
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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.
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Current Treatment Approaches

Raynaud’s
phenomenon

Gastrointestinal

Cardiovascular

Pulmonary

Renal

Systemic

Musculoskeletal
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SCOT—Study Arms
Monthly IV pulse
cyclophosphamide
for 12 months
High-dose
immunosuppressive
therapy (HDIT) with
autologous stem cell
transplantation
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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)
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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
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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
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SCOT—Key Eligibility Criteria

SSc with poor prognosis

Extensive skin involvement (mRSS  16)

Early internal organ involvement
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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.
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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
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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
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HDIT, Conditioning Regimen

TBI 800 cGy

ATGAM 90 mg/kg

Cyclophosphamide
120 mg/kg
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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
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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.
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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
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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
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SCOT—More Information

PIs: Pease add your site
contact info here

SCOT phone: 1-866-909-SCOT

SCOT website:
www.sclerodermatrial.org
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