1

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)

2

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

3

Limited and Diffuse SScLimited and Diffuse SSc——Skin InvolvementSkin Involvement

LimitedLimited DiffuseDiffuse

4

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

5

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

6

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

7

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.

9

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.

10

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

12

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.

13

Current Treatment ApproachesCurrent Treatment Approaches

Raynaud’s Raynaud’s phenomenonphenomenon

GastrointestinalGastrointestinal

CardiovascularCardiovascular

PulmonaryPulmonary

RenalRenal

SystemicSystemic

MusculoskeletalMusculoskeletal

14

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

15

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)

16

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

17

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

18

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

19

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.

20

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.

21

Autologous Stem Cell Transplant ArmAutologous Stem Cell Transplant Arm

Stem cell mobilizationStem cell mobilization G-CSFG-CSF

LeukapheresisLeukapheresis

Will have graphics improve images

22

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

23

HDIT, Conditioning RegimenHDIT, Conditioning Regimen

TBI 800 cGyTBI 800 cGy

ATGAM 90 mg/kgATGAM 90 mg/kg

Cyclophosphamide Cyclophosphamide 120 mg/kg120 mg/kg

24

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

25

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.

26

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

27

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

28

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