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)