Hematopoietic Stem Cell

Transplantation for

Systemic Sclerosis

Maria Carolina de Oliveira

Ribeirão Preto Medical School

University of São Paulo

2018

LOCALIZED SCLERODERMA

SYSTEMIC SCLEROSIS

Restricted to the skinBenign

Aesthetic implications

Physical LimitationsPoor quality of life

Mortality

Vasculopathy Fibrosis Inflammation

Allanore et al. Nature Disease Primers 2015

• Skin MethotrexateCyclophosphamideMycophenolate mofetil

• Interstitial lung CyclophosphamideMMF

• GI tract Omeprazol…

• Kidneys ACE inhibitors

• PAH SidenafilBosentan

RituximabTocilizumab

RiociguatNintendanib

Fresolimumab

Conventional Treatment

Under investigation

Despite advances in disease management, mortality of severe systemic sclerosis patients has not changed in the last 40 years.

Elhai et al. Rheumatology 2012

• Mobilization

Cyclophosphamide 2-4g/m2G-CSF

Graft selection?

• Transplantation

Cyclophosphamide 200mg/kgrabbit ATGG-CSF

Autologous Hematopoietic Stem Cell Transplantation

• Diffuse skin involvement with worsening of the Rodnan’s skin score in the past 6 months

or

• Interstitial lung involvement with FVC or DLCO worsening >10% in 6 m

Autologous Hematopoietic Stem Cell Transplantation

INDICATIONS

Sullivan et al, BBMT 2010

Rodnan’s score X time (years after AHSCT)

0 1 2 3 4 5

Burt and Oliveira et al, Lancet 2013

SKIN INVOLVEMENT

Autologous Hematopoietic Stem Cell Transplantation

Forearm biopsies

Baseline 6 months 1 year-100

-75

-50

-25

0

25

50

A B

CD

1 0 0 ! m1 0 0 ! m1 0 0 ! m

1 0 0 ! m1 0 0 ! m1 0 0 ! m

2 0 ! m 2 0 ! m 2 0 ! m

PRE-TRANSPLANT 6 MONTHS 12 MONTHS

Baseline 6 months 1 year-100

-75

-50

-25

0

25

50

* *

Co

lla

ge

n c

ha

ng

e

(% o

f P

icro

siriu

s R

ed

sta

inin

g)

A B

CD

1 0 0 ! m1 0 0 ! m1 0 0 ! m

1 0 0 ! m1 0 0 ! m1 0 0 ! m

2 0 ! m 2 0 ! m 2 0 ! m

Arruda LCM, Tese de Doutorado FMRP-USP, 2017

Autologous Hematopoietic Stem Cell Transplantation

SKIN INVOLVEMENT

Burt and Oliveira et al, Lancet 2013

Pulmonary functiontests

FVC

DLCO

LUNG INVOLVEMENT

Autologous Hematopoietic Stem Cell Transplantation

Burt et al. Lancet 2011

ASSIST:Autologous systemic sclerosis immune suppression trial

AHSCT: randomized studies

Burt et al. Lancet 2011

ASSIST:Autologous systemic sclerosis immune suppression trial

AHSCT: randomized studies

Burt et al. Lancet 2011

ASSIST:Autologous systemic sclerosis immune suppression trial

AHSCT: randomized studies

Rodnan’s score Forced Vital Capacity

van Laar et al. JAMA 2014

ASTIS:Autologous stem cell transplantation vs immunosuppression

AHSCT: randomized studies

van Laar et al. JAMA 2014

ASTIS:Autologous stem cell transplantation vs immunosuppression

AHSCT: randomized studies

Sullivan et al. NEJM 2018

SCOT:Scleroderma cyclophosphamide or transplantation

AHSCT: randomized studies

Sullivan et al. NEJM 2018

SCOT:Scleroderma cyclophosphamide or transplantation

AHSCT: randomized studies

Kowal-Bielecka et al. Ann Rheum Dis 2017

What have we learned over the past 20 years??

RHEUMATOID ARTHRITISMULTIPLE SCLEROSIS

IDIOPATHIC JUVENILE ARTHRITIS

SYSTEMIC SCLEROSISSLE

Global survival per disease, after AHSCT

Farge et al. Haematologica 2010

HEMATOLOGIC CYTOPENIAS

SYSTEMIC SCLEROSIS

What have we learned over the past 20 years??

• Patient selection - do not include advanced disease patients

What have we learned over the past 20 years??

• Patient selection - do not include advanced disease patients

• Cardiac screening

Burt, Oliveira et al. Lancet 2013

90 transplanted patients

Mortality of 6% (5 patients) 4 cardiac-related deaths

• Constrictive pericarditis (1)• Right ventricle dysfunction (2)• Left ventricle dysfunction (1)

• Echocardiography• Holter (24h EKG)• Heart MRI• Right sided heart catheterization

Pre-AHSCT Cardiac Screening

Farge et al. Bone Marrow Transplant 2017

What have we learned over the past 20 years??

• Patient selection - do not include advanced disease patients

• Cardiac screening

• Graft manipulation?

Oliveira, Labopin et al. Bone Marrow Transplant 2016

CD34+ graft selection

p=0.04p=0.05p=0.41

What have we learned over the past 20 years??

• Patient selection - do not include advanced disease patients

• Cardiac screening

• Graft manipulation?

• Effects on vasculopathy?

• Effects on gastrointestinal tract

Daniela Moraes

Juliana Elias

Ana Beatriz Stracieri

Fabiano Pieroni

Renato Cunha

Thalita Costa

Belinda Simões

Maria Carolina de Oliveira

Karla Costa Pereira

Vanessa Leopoldo

Andreia Zombrilli

Marília Cirioli

Ana Luísa Guimarães

Equipe Clínica Hemocentro e Centro de Terapia Celular

Dimas Tadeu Covas,

Maristela Delgado Orellana

Simone Kashima,

Patrícia Palma

Marco Antônio Zago,

Gil de Santis

Benedito Prado

Kelen Malmegrim

Júlia Teixeira de Azevedo,

Gislane Vilela,

João Rodrigues Lima Jr

Marianna Vasconcelos

Maynara Santana

Júlio César Voltarelli (in memoriam)