1 sponsored by: national institutes of health (nih) through its division of allergy, immunology and...
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Sponsored by: Sponsored by:
National Institutes of Health (NIH) through its Division of Allergy, National Institutes of Health (NIH) through its Division of Allergy, Immunology and Transplantation (DAIT) in the National Institute of Immunology and Transplantation (DAIT) in the National Institute of
Allergy and Infectious Diseases (NIAID)Allergy and Infectious Diseases (NIAID)
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Types of SclerodermaTypes of Scleroderma
SclerodermaSclerodermaSclerodermaScleroderma
LocalizedLocalizedSclerodermaScleroderma
LocalizedLocalizedSclerodermaScleroderma
SystemicSystemicSclerodermaScleroderma
(Systemic Sclerosis)(Systemic Sclerosis)
SystemicSystemicSclerodermaScleroderma
(Systemic Sclerosis)(Systemic Sclerosis)
MorpheaMorpheaMorpheaMorphea LinearLinearSclerodermaScleroderma
LinearLinearSclerodermaScleroderma
LimitedLimitedSclerodermaScleroderma
LimitedLimitedSclerodermaScleroderma
DiffuseDiffuseSclerodermaScleroderma
DiffuseDiffuseSclerodermaScleroderma
SineSineSclerodermaScleroderma
SineSineSclerodermaScleroderma
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Limited and Diffuse SScLimited and Diffuse SSc——Skin InvolvementSkin Involvement
LimitedLimited DiffuseDiffuse
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Limited CutaneousLimited Cutaneous
Formally called CREST Formally called CREST
Involvement of acral skinInvolvement of acral skin
Raynaud’s phenomenon for years prior to skin Raynaud’s phenomenon for years prior to skin thickeningthickening
Occasionally pulmonary HTN with or without Occasionally pulmonary HTN with or without interstitial lung diseaseinterstitial lung disease
Majority anti-centromere antibody positive Majority anti-centromere antibody positive (80–90%)(80–90%)
Nailfold capillaroscopy—dilated capillary loopsNailfold capillaroscopy—dilated capillary loops
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Diffuse CutaneousDiffuse Cutaneous
Widespread with early involvement Widespread with early involvement of internal organsof internal organs
Raynaud’s phenomenonRaynaud’s phenomenon
Truncal and acral skin involvementTruncal and acral skin involvement
Absent for anti-centromere antibodyAbsent for anti-centromere antibody
Nailfold capilaroscopy—capillary Nailfold capilaroscopy—capillary dilatation and destructiondilatation and destruction
Focus of the SCOT studyFocus of the SCOT study
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Diffuse CutaneousDiffuse Cutaneous
Associated with substantial morbidity Associated with substantial morbidity and mortality resulting from— and mortality resulting from— Vascular dysfunctionVascular dysfunction Organ fibrosis and inflammationOrgan fibrosis and inflammation Gastrointestinal dysmotilityGastrointestinal dysmotility Myocardial involvement Myocardial involvement
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EpidemiologyEpidemiology
Approximately 75,000–100,000 cases in USApproximately 75,000–100,000 cases in US11
20 new adult cases per million diagnosed 20 new adult cases per million diagnosed annuallyannually22
Peak incidencePeak incidence 30- to 50-year-old females30- to 50-year-old females More females than males (4:1)More females than males (4:1)22
Severe phenotype in young black women, Severe phenotype in young black women, with no other racial or ethnic differenceswith no other racial or ethnic differences33
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.
PathophysiologyPathophysiology
Copyright © 2004. Annals of Internal Medicine. All rights reserved.
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Clinical FeaturesClinical Features
Raynaud’s phenomenonRaynaud’s phenomenon
SkinSkin
GastrointestinalGastrointestinal
CardiovascularCardiovascular
PulmonaryPulmonary
RenalRenal
SystemicSystemic
Musculoskeletal Musculoskeletal (myositis, arthritis)(myositis, arthritis)
Copyright © 2002. Massachusetts Medical Society. All rights reserved.
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Clinical FeaturesClinical Features
Raynaud’s phenomenonRaynaud’s phenomenon
SkinSkin
GastrointestinalGastrointestinal
CardiovascularCardiovascular
PulmonaryPulmonary
RenalRenal
SystemicSystemic
Musculoskeletal Musculoskeletal (myositis, arthritis)(myositis, arthritis)
Dr. Jonathon Goldin, UCLA Radiology Core. Used with permission.
11Copyright ©2005. Duke University Medical Center.
Clinical FeaturesClinical Features
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PrognosisPrognosis
Extent of internal organ involvement influences Extent of internal organ involvement influences survival in limited and diffuse forms of SSc survival in limited and diffuse forms of SSc In diffuse SSc, mortality rate 5 to 8 times higher In diffuse SSc, mortality rate 5 to 8 times higher
than general populationthan general population44
For those with limited skin involvement, mortality For those with limited skin involvement, mortality rate 2 times higher than general populationrate 2 times higher than general population44
Lung disease most common scleroderma-related Lung disease most common scleroderma-related cause of deathcause of death
4. Denton C. UpToDate, 2004.
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Current Treatment ApproachesCurrent Treatment Approaches
Raynaud’s Raynaud’s phenomenonphenomenon
GastrointestinalGastrointestinal
CardiovascularCardiovascular
PulmonaryPulmonary
RenalRenal
SystemicSystemic
MusculoskeletalMusculoskeletal
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Monthly IV pulse Monthly IV pulse cyclophosphamide cyclophosphamide
for 12 months for 12 months
Monthly IV pulse Monthly IV pulse cyclophosphamide cyclophosphamide
for 12 months for 12 months
SCOTSCOT—Study Arms—Study Arms
High-dose High-dose immunosuppressive immunosuppressive therapy (HDIT) with therapy (HDIT) with
autologous stem cell autologous stem cell transplantationtransplantation
High-dose High-dose immunosuppressive immunosuppressive therapy (HDIT) with therapy (HDIT) with
autologous stem cell autologous stem cell transplantationtransplantation
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SCOT—RationaleSCOT—Rationale
Current treatments are inadequateCurrent treatments are inadequate
Evidence that SSc is an autoimmune-Evidence that SSc is an autoimmune-mediated disease mediated disease
Patients with expected poor survival may Patients with expected poor survival may benefit from aggressive approach benefit from aggressive approach (supported by the data)(supported by the data)
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Previous Clinical StudiesPrevious Clinical Studies
Autologous stem cellAutologous stem celltransplantationtransplantation Pilot study (FHCRC Pilot study (FHCRC
Protocol 1019)Protocol 1019) Preliminary ASTIS trial Preliminary ASTIS trial
datadata
Autologous stem cellAutologous stem celltransplantationtransplantation Pilot study (FHCRC Pilot study (FHCRC
Protocol 1019)Protocol 1019) Preliminary ASTIS trial Preliminary ASTIS trial
datadata
Monthly IV pulseMonthly IV pulsecyclophosphamidecyclophosphamide Significant weight of Significant weight of
evidence from evidence from uncontrolled or uncontrolled or open-label studiesopen-label studies
Monthly IV pulseMonthly IV pulsecyclophosphamidecyclophosphamide Significant weight of Significant weight of
evidence from evidence from uncontrolled or uncontrolled or open-label studiesopen-label studies
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SCOT—Primary EndpointSCOT—Primary Endpoint
Event-free survival at 44 months after randomizationEvent-free survival at 44 months after randomization
DeathDeath
Respiratory failureRespiratory failure
Chronic renal dialysisChronic renal dialysis
Cardiomyopathy Cardiomyopathy NYHA heart failure class III or IV, orNYHA heart failure class III or IV, or LVEF < 30% for 3 monthsLVEF < 30% for 3 months
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SCOT—Key Eligibility CriteriaSCOT—Key Eligibility Criteria
SSc with poor prognosis SSc with poor prognosis
Extensive skin involvement (mRSS Extensive skin involvement (mRSS 16) 16)
Early internal organ involvementEarly internal organ involvement
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SCOT—High-Dose Cyclophosphamide SCOT—High-Dose Cyclophosphamide ArmArm
High-dose pulse High-dose pulse cyclophosphamide IV cyclophosphamide IV at 28–32 day intervals at 28–32 day intervals for a total of 12 for a total of 12 infusions.infusions.
Initial dose is 500 mg/m2 followed by 750 mg/m2 for subsequent doses.
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SCOTSCOT—High-Dose Cyclophosphamide —High-Dose Cyclophosphamide ArmArm
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.
100 –100 –
90 –90 –
80 –80 –
70 –70 –
60 –60 –
50 –50 –
40 –40 –
30 –30 –
0 –0 –
DL
CO
(%
of
pre
dic
ted
)D
LC
O (
% o
f p
red
icte
d)
PREPRE POSTPOST
100 –100 –
90 –90 –
80 –80 –
70 –70 –
60 –60 –
50 –50 –
40 –40 –
30 –30 –
0 –0 –
TL
C (
% o
f p
red
icte
d)
TL
C (
% o
f p
red
icte
d)
PREPRE POSTPOST
110 –110 –
100 –100 –
90 –90 –
80 –80 –
70 –70 –
60 –60 –
50 –50 –
40 –40 –
0 –0 –
PO
PO
22 (m
mH
g)
(m
mH
g)
PREPRE POSTPOST
Schnabel A, Reuter M, Gross WL. Arthritis Rheum 1998; 41(7):1215-1220.
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Autologous Stem Cell Transplant ArmAutologous Stem Cell Transplant Arm
Stem cell mobilizationStem cell mobilization G-CSFG-CSF
LeukapheresisLeukapheresis
Will have graphics improve images
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CD34+ SelectionCD34+ Selection
Successful CD34 selection Successful CD34 selection technology results in technology results in efficient T cell removal efficient T cell removal from PBSC graftsfrom PBSC grafts
Frequently used method Frequently used method to prevent GVHD in to prevent GVHD in allogenic transpantationallogenic transpantation
Minimize likelihood of Minimize likelihood of reintroducing disease reintroducing disease causing cells after HDITcausing cells after HDIT
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HDIT, Conditioning RegimenHDIT, Conditioning Regimen
TBI 800 cGyTBI 800 cGy
ATGAM 90 mg/kgATGAM 90 mg/kg
Cyclophosphamide Cyclophosphamide 120 mg/kg120 mg/kg
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Rationale for HDITRationale for HDIT
Maximal tolerable immunosuppression with Maximal tolerable immunosuppression with acceptable toxicityacceptable toxicity
Dose of 800 cGY is less than dose used in Dose of 800 cGY is less than dose used in treatment of malignancy (> 1200 cGY)treatment of malignancy (> 1200 cGY)
Lung and renal radiation dose limited to 200 cGYLung and renal radiation dose limited to 200 cGY
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Stem Cell TransplantationStem Cell Transplantation
Autologous CD34-selected Autologous CD34-selected cells infused after HDITcells infused after HDIT
Goal:Goal: Reset the immune Reset the immune systemsystem5,65,6
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 PlanSCOT—Risk Reduction Plan
Patients with significant pulmonary HTN or Patients with significant pulmonary HTN or cardiac disease excludedcardiac disease excluded
Shielding from radiation of lung and kidneysShielding from radiation of lung and kidneys
ATGAM use for additional anti-T cell activityATGAM use for additional anti-T cell activity
Antihistamines and corticosteroids to reduce side Antihistamines and corticosteroids to reduce side effects of ATGAMeffects of ATGAM
Selection of CD34+ cells to decrease likelihood of Selection of CD34+ cells to decrease likelihood of reintroducing disease-causing immune cells after HDITreintroducing disease-causing immune cells after HDIT
Prophylactic measures to reduce risk of Prophylactic measures to reduce risk of opportunistic infectionopportunistic infection
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SCOT—Study CentersSCOT—Study CentersNORTHWESTNORTHWEST NORTHEASTNORTHEAST
SOUTHEASTSOUTHEAST
SOUTH CENTRALSOUTH CENTRAL
SOUTHWESTSOUTHWEST
NORTH CENTRALNORTH CENTRAL
California Pacific MCCalifornia Pacific MC
U. of ColoradoU. of Colorado
Mayo Clinic ScottsdaleMayo Clinic Scottsdale
U. of Texas SouthwesternU. of Texas Southwestern
U. of Tenn. MemphisU. of Tenn. Memphis
U. of Florida GainesvilleU. of Florida Gainesville
Med. U. of South CarolinaMed. U. of South Carolina
Ctr for Rheum.Ctr for Rheum.
Georgetown U.Georgetown U.
Duke U.Duke U.
UCLA &UCLA &City of HopeCity of Hope
U. of TX – Houston &U. of TX – Houston &MD Anderson CCMD Anderson CC
Boston U. &Boston U. &Mass. Gen. Hosp.Mass. Gen. Hosp.
Mercy ArthritisMercy Arthritis North Shore Long IslandNorth Shore Long IslandUMDNJUMDNJ
Hosp. for Special SurgeryHosp. for Special Surgery
U. ChicagoU. Chicago
U. of WIU. of WI
U. of MichiganU. of Michigan
MC of OhioMC of Ohio
WUSTLWUSTL
U. of AlabamaU. of Alabama
FHCRC &FHCRC &Virginia Mason &Virginia Mason &U. of WAU. of WA
U. of KentuckyU. of Kentucky
Confirmed Rheumatology CenterConfirmed Rheumatology Center
Potential Rheumatology CenterPotential Rheumatology Center
Confirmed Transplant CenterConfirmed Transplant Center
U. of CincinnatiU. of Cincinnati
MC of WisconsinMC of Wisconsin
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SCOT—More InformationSCOT—More Information
PIs: Pease add your site PIs: Pease add your site contact info herecontact info here
SCOT phone: 1-866-909-SCOTSCOT phone: 1-866-909-SCOT
SCOT website: SCOT website: www.sclerodermatrial.org www.sclerodermatrial.org