Cardiac involvement and treatment-related mortality after non-myeloablative haemopoietic stem-cell transplantation with unselected autologous peripheral blood for patients with systemic sclerosis: A retrospective analysis

Division of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Electronic address: .
The Lancet (Impact Factor: 45.22). 01/2013; 381(9872). DOI: 10.1016/S0140-6736(12)62114-X
Source: PubMed
ABSTRACT
BACKGROUND: Autologous haemopoietic stem-cell transplantation (HSCT) benefits patients with systemic sclerosis but has been associated with significant treatment-related mortality and failure to improve diffusion capacity of carbon monoxide (DLCO). We aimed to assess efficacy of HSCT and use of rigorous cardiac screening in this group. METHODS: We assessed patients with diffuse systemic sclerosis or limited systemic sclerosis and interstitial lung disease who were treated with HSCT as part of a study or on a compassionate basis at Northwestern University (Chicago, IL, USA) or the University of São Paulo (Ribeirão Preto, Brazil). Unselected peripheral blood stem cells were harvested with cyclophosphamide (2 g/m(2)) and filgrastim. The transplant regimen was a non-myeloablative regimen of cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulin (rATG; 4·5-6·5 mg/kg). We followed patients up to 5 years for overall survival, relapse-free survival, modified Rodnan skin score, and pulmonary function tests. FINDINGS: Five (6%) of 90 patients died from treatment-related causes. Despite standard guidelines that recommend echocardiogram for screening before transplantation, four treatment-related deaths occurred because of cardiovascular complications (one constrictive pericarditis, two right heart failures without underlying infection, and one heart failure during mobilisation), and one death was secondary to sepsis without documented underlying heart disease. Kaplan-Meier analysis showed survival was 78% at 5 years (after eight relapse-related deaths) and relapse-free survival was 70% at 5 years. Compared with baseline, we noted improvements after HSCT in modified Rodnan skin scores at 1 year (58 patients; p<0·0001), 2 years (42 patients; p<0·0001), and 3 years (27 patients; p<0·0001) and forced vital capacity at 1 year (58 patients; p=0·009), 2 years (40 patients; p=0·02), and 3 years (28 patients; p=0·004), but total lung capacity and DLCO were not improved significantly after HSCT. Overall mean DLCO was significantly improved in patients with normal baseline echocardiograms (p=0·005) or electrocardiographs (p=0·05). INTERPRETATION: Autologous HSCT with a non-myeloablative regimen of cyclophosphamide and rATG with a non-selected autograft results in sustained improvement in skin thickness and forced vital capacity. DLCO is affected by baseline cardiac function. Guidelines for cardiac screening of patients with systemic sclerosis to assess treatment-related risk from pulmonary artery hypertension, primary cardiac involvement, or pericardial disease should be reconsidered and updated. FUNDING: None.
Articles
www.thelancet.com Published online January 28, 2013 http://dx.doi.org/10.1016/S0140-6736(12)62114-X
1
Cardiac involvement and treatment-related mortality after
non-myeloablative haemopoietic stem-cell transplantation
with unselected autologous peripheral blood for patients
with systemic sclerosis: a retrospective analysis
Richard K Burt, Maria Carolina Oliveira, Sanjiv J Shah, Daniela A Moraes, Belinda Simoes, Mihai Gheorghiade, James Schroeder, Eric Ruderman,
Dominique Farge, Z Jessie Chai, Zora Marjanovic, Sandeep Jain, Amy Morgan, Francesca Milanetti, Xiaoqiang Han, Borko Jovanovic,
Irene B Helenowski, Julio Voltarelli*
Summary
Background Autologous haemopoietic stem-cell transplantation (HSCT) benefi ts patients with systemic sclerosis but
has been associated with signifi cant treatment-related mortality and failure to improve di usion capacity of carbon
monoxide (DLCO).We aimed to assess e cacy of HSCT and use of rigorous cardiac screening in this group.
Methods W
e assessed patients with di use systemic sclerosis or limited systemic sclerosis and interstitial lung disease
who were treated with HSCT as part of a study or on a compassionate basis at Northwestern University (Chicago, IL,
USA) or the University of São P
aulo (Ribeirão Preto, Brazil). Unselected peripheral blood stem cells were harvested
with cyclophosphamide (2 g/m²) and fi lgrastim. The transplant regimen was a non-myeloablative regimen of
cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulin (rATG; 4·5–6·5 mg/kg). We followed patients up
to 5 years for overall survival, relapse-free survival, modifi ed Rodnan skin score, and pulmonary function tests.
Findings F
ive (6%) of 90 patients died from treatment-related causes. Despite standard guidelines that recommend
echocardiogram for screening before transplantation, four treatment-related deaths occurred because of cardiovascular
complications (one constrictive pericarditis, two right heart failures without underlying infection, and one heart
failure during mobilisation), and one death was secondary to sepsis without documented underlying heart disease.
Kaplan-Meier analysis showed survival was 78% at 5 years (after eight relapse-related deaths) and relapse-free survival
was 70% at 5 years. C
ompared with baseline, we noted improvements after HSCT in modifi ed Rodnan skin scores at
1 year (58 patients; p<0·0001), 2 years (42 patients; p<0·0001), and 3 years (27 patients; p<0·0001) and forced vital
capacity at 1 year (58 patients; p=0·009), 2 years (40 patients; p=0·02), and 3 years (28 patients; p=0·004), but total
lung capacity and DLCO were not improved signifi cantly after HSCT. Overall mean DLCO was signifi cantly improved
in patients with normal baseline echocardiograms (p=0·005) or electrocardiographs (p=0·05).
Interpretation Autologous HSCT with a non-myeloablative regimen of cyclophosphamide and rATG with a non-
selected autograf
t results in sustained improvement in skin thickness and forced vital capacity. DLCO is a ected by
baseline cardiac function. G
uidelines for cardiac screening of patients with systemic sclerosis to assess treatment-
related risk from pulmonary artery hypertension, primary cardiac involvement, or pericardial disease should be
reconsidered and updated.
Funding None.
Introduction
Systemic sclerosis generally a ects young women and is a
chronic autoimmune disease of unknown cause com pli-
cated by a combination of di use vasculopathy, immune
activation, and tissue brosis.
1
Standard thera pies are
unable to reverse disease progression, although several
non-randomised trials involving small numbers of
patients suggest that autologous haemo poietic stem-cell
transplantation (HSCT) can improve skin and stabilise or
improve forced vital capacity.
2–11
In the only randomised
trial published to date (the American Scleroderma Stem
Cell versus Immune Suppression Trial [ASSIST]),
2
autologous HSCT improved both skin and forced vital
capacity, whereas disease progression was noted in
patients treated with the standard therapy of monthly
intravenous cyclo phosphamide.
Several transplantation trials for systemic sclerosis have
been complicated by treatment-related mortal ity.
3,4,6,7,10,12
Such mortality was 10% (eight of 79 patients) in the largest
reported trial to date, the European Autologous Stem cell
Tra nsp lanta tion Int ern ation al Scl erode rma ( AST IS) tr ial .
12
For cancer
13
and auto immune diseases including systemic
sclerosis,
14,15
pub lished guidelines recommend an echo-
cardiogram to assess cardiac reserve to establish whether
a patient can safely tolerate a transplant. However, unlike
other diseases for which haemopoietic transplantation is
done, the usual disease-related cause of death for systemic
sclerosis is cardiac complications arising from pulmonary
Published Online
January 28, 2013
http://dx.doi.org/10.1016/
S0140-6736(12)62114-X
See Online/Comment
http://dx.doi.org/10.1016/
S0140-6736(12)62176-
X
*Died March 21, 2012
Division of Immunotherapy
(R K Burt MD, S Jain MD,
A Morgan NP, X Han MD),
Division of Cardiology
(S J Shah MD, Z J Chai BS),
Center for Cardiovascular
Innovation
(M Gheorghiade MD), Division
of Rheumatology
(J Schroeder MD,
E Ruderman MD), Department
of Medicine, Northwestern
University Feinberg School of
Medicine, Chicago, IL, USA;
Department of Clinical
Medicine, School of Medicine
of Ribeirão Preto, University
of São Paulo, Ribeirão Preto,
Brazil (M C Oliveira MD,
D A Moraes MD, B Simoes MD,
J Voltarelli MD); Saint Louis
Hospitaux, Unité de Médecine
Interne et Pathologie
Vasculaire, Assistance
Publique Hopitaux de Paris,
Paris 7 University,
INSERM U 976, France
(D Farge MD); Saint Antoine
Hospitaux, Hematology
Department, Assistance-
Publique Hôpitaux de Paris,
Paris 6 University, Paris,
France (Z Marjanovic MD);
Division of Clinical
Immunology and
Rheumatology, Sant Andrea
Hospital, Sapienza, University
of Rome, Rome, Italy
(F Milanetti MD); and
Department of Preventive
Medicine, Northwestern
University Feinberg School of
Medicine, Chicago, IL, USA
(B Jovanovic PhD,
I B Helenowski PhD)
Page 1
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www.thelancet.com Published online January 28, 2013 http://dx.doi.org/10.1016/S0140-6736(12)62114-X
Correspondence to:
Dr Richard K Burt, Division of
Immunotherapy, Department of
Medicine, Northwestern
University Feinberg School of
Medicine, Chicago, IL 60611, USA
rburt@northwestern.edu
artery hypertension and primary cardiac or pericardial
involvement.
16
Therefore, we analysed results from two centres that
used the same mobilisation and non-myeloablative
HSCT regimen without selection or manipulation of the
graft to assess the causes of treatment-related mortality,
whether impaired cardiac function a ects outcome, and
the appropriate screening method before transplantation
to prevent enrolment of patients with insu cient cardiac
reserve to safely tolerate the procedure.
Methods
Study design and patients
We undertook a retrospective analysis of all patients
treated with HSCT, either as part of a study or on
a compassionate basis, at Northwestern University
(Chicago, IL, USA) and the University of São Paulo
(Ribeirão Preto, Brazil). P
atients were enrolled in
institutional review board (IRB)-approved studies and
retrospective IRB approval was obtained to report o -
study patients. We defi
ned duration of disease as
duration from time of diagnosis of systemic sclerosis.
Patients were followed up for 5 years after HSCT.
Patients who underwent transplantation had di use
systemic sclerosis, defi ned as cutaneous involvement
proximal to the elbow or knee with a modifi ed Rodnan
skin score
17
of 14 or more and internal organ involvement
defi ned as pulmonary brosis or ground glass on chest
CT, abnormal electrocardiograph, or gastrointestinal
track involvement. Patients with little cutaneous in-
volvement (modifi ed Rodnan skin score <14) were
eligible if they had coexistent pulmonary involvement.
Patients were excluded if they had a total lung capacity of
less than 45%, left ventricular ejection fraction of less
than 40% or pulmonary artery systolic pressure (PASP)
of more than 42 mm Hg, or positive serology for HIV or
hepatitis B surface antigen. All patients had an echo-
cardiogram and cardiac assessment. Additional cardiac
testing was done on an individual basis until imple-
mentation of a standard screening in the last 12 patients
enrolled; this screening consisted of echocardiogram
with tricuspid annular plane systolic excursion (TAPSE),
right heart catheterisation measured before and after a
500 mL intravenous normal saline bolus, and cardiac
MRI with gadolinium. Fluid bolus was contraindicated if
resting cardiac catheterisation right atrial pressure was
more than 12 mm Hg or pulmonary capillary wedge
pressure (PCWP) was more than 15 mm Hg. In Chicago,
patients were ineligible for study inclusion if they were
older than 55 years or had a disease duration of more
than 4 years.
Procedures
Peripheral blood stem cells were mobilised with intra-
venous cyclophosphamide (2 g/m²) and 5–10 µL/kg
subcutaneous lgrastim daily started 1 day after
cyclophosphamide at the University of São Paulo or
5 days after cyclophosphamide at Northwestern
University. Peripheral blood stem cell apheresis was
done on day 10 after start of cyclophosphamide and
peripheral blood stem cells were cryopreserved without
manipulation. The conditioning regimen was
200 mg/kg intravenous cyclophosphamide given in
four equal fractions on day –5 to day –2 before stem-cell
infusion. rATG (thymoglobulin) was dosed at
0·5 mg/kg intravenously on day –5 and then either
1·0 mg/kg or 1·5 mg/kg intravenously every day on
day –4 to day –1.
Blood products were irradiated, cytomegalovirus-safe,
and leucocyte depleted. Filgrastim (10 µL/kg per day) was
started 5 days after stem-cell infusion and continued until
engraftment. Dependent on centre guidelines, intra venous
prophylactic cefepime or piperacillin-tazobactam was
started prophylactically or withheld until development of
neutropenic fever. Oral aciclovir or valaciclovir was started
on admission to the transplant centre and continued for
2 months after transplantation at the University of o
Paulo or 12 months after transplantation at Northwestern
University. Patients received oral daily uconazole and
either oral trimethoprim-sulfamethoxazole 2–3 times per
week or aerosolised pentamidine every month for
2–6 months.
Patients started hyperhydration (150–200 mL normal
saline per h) with diuretics or normal hydration at
50–75 mL per h with addition of continuous bladder
irrigation (125–150 mL normal saline per h) and intra-
venous mesna at 100% the dose of cyclophosphamide
with every dose of cyclo phosphamide, continued for 24 h.
Patients received methylprednisolone intravenously
(250–1000 mg) before rATG (at Northwestern University)
or as part of each rATG infusion bag (at University of
São Paulo; 125 mg per bag).
Figure 1: Trial profi le
143 patients with systemic sclerosis
screened
53 excluded
39 too severe disease
10 limited skin and no
pulmonary involvement
3 confounding illness (previous
malignant disease or coronary
artery disease)
1 refused to allow blood
transfusion
90 enrolled
59 on study (10 on phase 1 study,
31 on non-randomised phase 2,
18 on randomised phase 2 study)
21 on a compassionate basis (aged
>55 years or disease duration
>4 years)
10 o study after closing phase 1
but before opening phase 2 study
(met the same study criteria)
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3
On admission, patients were prescribed an oral calcium-
channel blocker to prevent Raynaud’s phe nom ena and an
oral angiotensin-converting enzyme inhibitor or angio-
tensin receptor antagonist to prevent renal crisis. We
monitored viral loads of cytomegalovirus after transplant-
ation for 2–3 months and pre-emptively treated patients
by switching them from aciclovir to oral valganciclovir
(900 mg twice-daily) or intravenous ganciclovir (5 mg/kg
twice-daily) until they were cyto megalovirus negative.
The main outcome was treatment-related mortality
in patients who underwent HSCT. We also assessed skin
thickness by modifi ed Rodnan skin score and pulmonary
function by forced vital capacity, total lung capacity,
and di using capacity of carbon monoxide (DLCO;
percentage predicted and corrected for haemo globin).
We administered quality of life questionnaires (short
form [SF]-36) for the last 30 consecutive patients from
one site (Northwestern University). We defi ned relapse
as any of the following criteria: increase from best
improvement of skin score by 25% or decline in forced
vital capacity by 10%, renal crisis, start of total parenteral
nutrition, or restarting of immune suppressive or
modulating medication.
Statistical analysis
We calculated overall survival and relapse-free survival
with Kaplan-Meier methods. We used two-tailed paired
t tests for comparisons within the transplantation group.
We analysed the e ect of cardiac function and sex on
pulmonary function and skin thickness by least-square
means and standard deviations adjusted by repeated
measures across all visits (averaged over time) via a
mixed e ects model for outcome. We used the r cor-
relation coe cient to determine linear relations between
variables. A correlation coe cient of more than 0·8 was
regarded as strong, whereas less than 0·5 was regarded
Patients (n=90)
Median age, years 42 (16–71)
Sex, female 73 (81%)
Ethnicity
White 70 (78%)
Black 11 (12%)
Hispanic 5 (6%)
Biracial 3 (3%)
Native American 1 (1%)
Median disease duration from diagnosis to HSCT,
months
25 (2–156)
History of Raynauďs phenomena 83 (92%)
Median modifi ed Rodnan skin score 24 (3–47)
Di use systemic sclerosis 72 (80%)
Gastrointestinal track disorders 81 (90%)
Gastro-oesophageal refl ux disease 51 (63%)
Patulous esophagous 52 (64%)
Gastrointestinal antral vascular ectasia 5 (6%)
Small bowel involvement 3 (4%)
Total parenteral nutrition 1 (1%)
Pulmonary function tests
Median forced vital capacity 67% (31–103)
Median DLCO (corrected for haemoglobin) 64% (19–123)
Abnormal lung involvement on imaging 73 (81%)
Interstitial lung disease 73 (100%)
Nodules or micronodules 4 (5%)
Bronchiectasis 7 (10%)
Honeycombing 2 (3%)
Oxygen dependency 2 (3%)
Previous renal crisis 1 (1%)
Abnormal electrocardiography 44 (49%)
Non-specifi c T-wave abnormalities 17 (39%)
Right bundle branch block 8 (18%)
Left bundle branch block 2 (5%)
Left anterior fasicular block 4 (9%)
Pacemaker 1 (2%)
Intraventricular conduction delay 3 (7%)
First degree atrioventricular block 1 (2%)
Prolonged QT interval 5 (11%)
Ventricular premature contractions 3 (7%)
Atrial fi brillation 1 (2%)
Supraventricular tachycardia 1 (2%)
Atrioventricular nodal re-entry tachycardia 1 (2%)
(Continues in next column)
Patients (n=90)
(Continued from previous column)
Echocardiography
LVEF >40%* 89 (99%)
Abnormal 25 (28%)
Mild (grade 1) diastolic dysfunction 13 (52%)
Enlarged chambers 7 (28%)
LVEF (40–50%) 3 (12%)
Interventricular septal fl attening 3 (12%)
Pericardial e usion >1 cm with diastolic atrial
indentation
2 (8%)
Enlarged pulmonary artery 2 (8%)
Septal bounce 1 (4%)
Serology
ANA positive (>1:40) 87 (97%)
Scl-70 positive (>10 IU) 43 (48%)
Previous immunotherapy† 84 (93%)
Data are median (range) or n (%), unless otherwise stated. HSCT=haemopoietic
stem-cell transplantation. DLCO=di usion capacity of carbon monoxide. LVEF=left
ventricular ejection fraction. ANA=anti-nuclear antibody. *One echocardiogram was
not done; trace mitral regurgitation and left ventricular hypertrophy with no other
abnormalities were regarded as normal. †Corticosteroids (60 patients), oral
cyclophosphamide (six patients), intravenous cyclophosphamide (28 patients),
methotrexate (32 patients), mycophenolate mofetil (17 patients), penicillamine
(15 patients), azathioprine (four patients), lidocaine (11 patients),
hydroxychloroquine (fi ve patients), minocycline (fi ve patients), protein
tyrosine-kinase inhibitor (imatinib or dasatinib; four patients), TNF-inhibitor
(infl iximab or adalimumab; three patients), or colchicine (two patients).
Table 1: Patient demographics
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as weak. We did all analyses with Graphpad Prism 5
software (Graphpad, CA, USA).
Role of the funding source
There was no funding source for this study. The
statisticians (BJ, IBH), corresponding author (RKB),
study nurse (AM), and research fellows (XH and SJ) had
full access to all the data in the study and had nal
responsibility for the decision to submit for publication.
Results
Between November, 2002, and July, 2011, we included
59 patients at Northwestern University and 31 patients at
the University of São Paulo (fi gure 1). 59 patients were in
IRB-approved studies (28 from Northwestern University
and 31 from University of São Paulo) and retrospective
IRB approval was obtained for 31 patients. Table 1 shows
demographic characteristics of 90 patients who were
o ered au tologous HSCT.
Median day of engraftment (absolute neutrophil count
>1000 cells per µL) was day 9 (range 8–11). 63 patients
(70%) developed fever of more than 38°C, which was
blood-culture negative in 59 patients (two patients had
Klebsiella pneumoniae infections, one had Pseudomonas
aeruginosa infection, and one had Acinetobacter baumannii
infection). On admission, fi ve patients had positive rectal
or nasal surveillance cultures for colonisation with
vancomycin-resistant enterococcus. Five patients de-
veloped Clostridium di cile toxin-positive diarrhoea
during hospitalisation.
14 patients had a volume overload of more than 5 kg
because of hyperhydration (200 mL per h of normal
saline) during the conditioning regimen. Af
ter the rst
20 patients were treated, hydration during conditioning
was decreased to 50–100 mL/h, supplemented with
intravenous mesna infusion and intravesicle bladder
irrigation (150 mL/h of normal saline) with no further
episodes of volume overload. One patient developed
transient acute tubular necrosis (confi
rmed by renal
biopsy) from the combination of diuretics and angio-
tensin-converting enzyme inhibitor. Another patient
developed transient renal crisis during transplantation
mandating temporary dialysis. One further patient had
paradoxical emboli from a patent foramen ovale and
needed distal amputation of three toes.
No patients developed fungal or cytomegalovirus
infections. Two months after discharge home, one
patient developed West Nile virus encephalomyelitis with
prolonged but continuing recovery. No patients developed
leukaemia, myelodysplasia, or cancer.
One enrolled patient declined treatment and one
patient received treatment but did not return for follow-
up. Five patients (6%) had treatment-related deaths. Four
treatment-related deaths were from cardiac events, with
one sudden cardiac arrest during mobilisation and three
sudden cardiac arrests during transplant ation (one
because of constrictive pericarditis and two secondary to
heart failure). One death was secondary to septic
neutropenia in a patient not on pre-emptive broad-
spectrum antibiotics.
For 88 patients with follow-up, 5 year overall survival
was 78% and relapse-free survival was 70% (fi gure 2).
Eight (62%) of 13 patients who relapsed subsequently
died of their disease despite reinstitution of immuno-
therapy. Deaths related to relapse were related to
cardiopulmonary causes for six patients (three deaths
~2 years after transplantation and three deaths 3–4 years
after transplantation) and were related to renal crisis for
two patients (3 months and 4 months after trans-
plantation). The initial presentation of relapse was renal
crisis in four patients (3, 4, 12, and 18 months after
transplantation).
Modifi ed Rodnan skin scores improved after trans-
plantation (fi gure 3). Compared with the mean score
before transplantation (24·1), mean scores had improved
by 6 months (16·5; p<0·0001), 12 months (12·9;
p<0·0001), 24 months (12·2; p<0·0001), 36 months (11·1;
p<0·0001), 48 months (10·3; p=0·0001), and 60 months
(8·9; p=0·0003).
Forced vital capacity also improved after transplantation
(fi gure 3). Compared with a mean forced vital capacity
before transplantation of 66·2%, patients had improve-
ments at 6 months (70·8%; p=0·0009), 12 months (71·1%;
Figure 2: Overall survival (A) and relapse-free survival (B) after haemopoietic
stem-cell transplantation
0
10
20
30
40
50
60
70
80
90
100
Overall survival (%)
A
01224364860
0
10
20
30
40
50
60
70
80
90
100
Relapse-free survival (%)
Time (months)
B
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p=0·009); 24 months (72·6%; p=0·02), and 36 months
(76·1%; p=0·004), but these improvements were not
signifi cant at 48 months (73·4%; p=0·11) or 60 months
(73·0%; p=0·26). Total lung capacity and percentage
DLCO corrected for haemo
globin did not change for the
entire group (fi
gure 3). Compared with mean DLCO values
before trans plantation (68·2%), values after transplantation
did not di er at 6 months (64·9%; p=0·41), 12 months
(66·5%; p=0·56), 24 months (72·8%; p=0·82), 36 months
(68·3%; p=0·27), 48 months (64·5%; p=0·48), and
60 months (64·5%; p=0·67).
We noted at best a weak correlation (r<0·5) between
DLCO values after transplantation and modifi ed Rodnan
skin score, age, and duration of disease before trans-
plantation (table 2). We identifi ed an intermediate
correlation (r=0·5–0·8) between baseline DLCO values
and DLCO values after transplantation, but baseline
DLCO, forced vital capacity, and modifi ed Rodnan skin
scores had weak correlation with change in DLCO after
transplantation (table 2). The only baseline factors that
correlated signifi cantly with DLCO outcome after trans-
plantation were baseline echocardiogram or electro-
cardiograph abnormalities (table 3, gure 4). DLCO
values after transplantation were improved if the base-
line electrocardiograph or echocardiogram was normal
(p=0·05 for electrocardiograph and p=0·005 for echo-
cardiogram).
Cardiac assessments before transplantation evolved
during the study from echocardiogram and cardiac
assessment (for 90 patients) to include echocardiogram
with TAPSE and right heart catheterisation (for
23 patients and 39 patients, respectively), and nally a
consistent approach of echocardiogram with TAPSE,
right heart catheterisation without and with uid
Figure 3: Modifi ed Rodnan skin score and pulmonary function tests before (0 months) and after haemopoietic stem-cell transplantation
Vertical lines show standard error at each time point. mRSS=modifi ed Rodnan skin score. DLCO=di usion capacity of carbon monoxide.
Number of patients
89 66 58 42 27 17 12
0
5
10
15
20
25
30
24·1
16·5
12·2
11·1
10·3
8·9
12·9
mRSS
A
88 65 58 40 28 14 11
64
66
68
70
72
74
78
76
66·2
70·8
72·6
76·1
73·4
73·0
71·1
Forced vital capacity (%)
B
Number of patients
0 6 12 18 24 30 36 42 48 54 60
82 59 54 41 28 14 11
Time (months)
65
70
75
80
85
90
77·3
80·6
81·8
82·1
78·8
77·4
79·9
Total lung capacity (%)
C
0 6 12 18 24 30 36 42 48 54 60
75 62 53 42 27 15 11
Time (months)
50
55
60
65
70
75
80
68·2
64·9
72·8
68·3
64·5
64·5
66·5
DLCO (%)
D
Before
HSCT
1 year
after HSCT
Duration of disease since diagnosis vs DLCO
–0·34 –0·47
Patients age vs DLCO
–0·25 –0·08
mRSS vs DLCO before transplantation
0·26 0·43
FVC vs DLCO before transplantation
0·58 0·63
DLCO before transplantation vs DLCO after transplantation
NA 0·65
mRSS before transplantation vs change from baseline in DLCO after transplantation
NA –0·003
FVC before transplantation vs change from baseline in DLCO after transplantation
NA –0·04
DLCO before transplantation vs change from baseline in DLCO after transplantation
NA –0·36
Duration of disease vs change from baseline in DLCO after transplantation
NA –0·08
Age vs change from baseline in DLCO after transplantation
NA 0·14
Data are linear correlation coe cients (r>0·8 is strong correlation, r<0·5 is weak correlation). HSCT=haemopoietic
stem-cell transplantation. mRSS=modifi ed Rodnan skin score. DLCO=di using capacity of carbon monoxide
(% predicted, corrected for haemoglobin). FVC=forced vital capacity (% predicted). NA=not applicable.
Table 2: Correlation coe cient (r) between pretransplantation parameters and DLCO before or after
transplantation
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challenge, and cardiac MRI with gadolinium for the last
12 patients assessed (table 3).
Table 4 shows the information for the last 12 patients
enrolled provided by echocardiogram, cardiac
catheterisation without and with fl uid challenge, and
cardiac MRI. Patients without signifi cant pulmonary
artery hyper tension tolerated uids without signifi cant
increase in PASP. By comparison, after infusion of
500 mL normal saline, patients with underlying
pulmonary artery hypertension had a striking increase in
PASP, mean pulmonary pressure, and pulmonary
vascular resistance. In these patients, cardiac MRI
showed signifi cant indentation of the right ventricle into
the left ventricle via the common interventricular
septum—ie, diastolic septal fl attening or D-sign.
In patients without pulmonary artery hypertension, fl uid
challenge with 500 mL normal saline could also provoke
left ventricle compromise, shown by increase of PASP,
mean pulmonary pressure, and PCWP without an increase
in pulmonary vascular resistance (table 4). These patients
also usually show di use gadolinium enhancement on
cardiac MRI and a history of palpi tations, recurrent atrial,
ventricular premature contrac tions, or recurrent, multi-
focal, non-sustained ventricular tachycardia.
Quality of life before transplantation and at last follow-
up
improved signifi
cantly in total score and in all scales
and dimensions apart from emotional role limitation and
mental health score (table 5).
Discussion
HSCT was associated with treatment-related mortality in
ve (6%) of 90 patients in our study, which is about half
the rate (eight [10%] of 79 patients) in the European
multicentre ASTIS trial.
12
Treatment-related mortality in
our study was predominantly related to cardiac events
(four of fi ve deaths). We attribute the reduced mortality in
our study compared with ASTIS to recognition that
echocardiogram and resting right heart catheterisation
might be insu cient to assess cardiac risk in patients
with systemic sclerosis (panel). The ASTIS trial
12
mandated
echocardiogram whereas cardiac catheterisation was only
required for patients with pulmonary artery hyper tension
suggested by an echocardiogram. However, pulmonary
artery hypertension determined by echo cardio graphic
calculation of PASP can signifi cantly overestimate or
underestimate invasive PASP because of image problems,
Doppler alignment, or violation of viscosity assumptions
in the modifi ed Bernoulli equation used to calculate
echocardiographic PASP.
18,19
Normal echocardiogram
or electrocardiograph or
female sex
Abnormal echocardiogram
or electrocardiograph or
male sex
p value*
DLCO
Group: echocardiogram Normal 71·3% (3·1) Abnormal 56·7% (3·8)† 0·0045
Group: electrocardiograph Normal 73·3% (4·6) Abnormal 62·0% (3·0)‡ 0·045
Group: sex Female 66·3% (2·8) Male 64·5% (4·9) 0·75
FVC
Group: echocardiogram Normal 70·8% (3·2) Abnormal 68·4% (2·4) 0·58
Group: electrocardiograph Normal 73·6% (4·6) Abnormal 68·2% (2·1) 0·28
Group: sex Female 66·1% (2·5) Male 66·3% (3·1) 0·95
Total lung capacity
Group: echocardiogram Normal 80·3% (3·4) Abnormal 78·8% (2·3) 0·70
Group: electrocardiogram Normal 81·9% (4·4) Abnormal 78·7% (2·1) 0·51
Group: sex Female 75·8% (2·4) Male 75·2% (3·0) 0·80
mRSS
Group: echocardiogram Normal 16·1 (1·7) Abnormal 18·2 (1·3) 0·33
Group: electrocardiograph Normal 16·1 (2·4) Abnormal 17·8 (1·1) 0·51
Group: sex Female 17·0 (1·4) Male 16·4 (2·1) 0·77
DLCO=di usion capacity for carbon monoxide (% predicted, corrected for haemoglobin). FVC=forced vital capacity
(% predicted). mRSS=modifi ed Rodman skin score. *Least-square means (SDs) adjusted by repeated measurements
across all visits (before and after transplantation) averaged over time via a mixed e ects model. †Abnormal
echocardiogram was diastolic or systolic dysfunction, enlarged chambers, left ventricular ejection fraction <50%,
interventricular diastolic fl attening, pericardial e usion >1 cm with diastolic atrial indentation, enlarged pulmonary
artery, or septal bounce. ‡Abnormal electrocardiogram was non-specifi c T-wave abnormalities, bundle branch or fasicular
block, conduction delay, pacemaker, prolonged QT interval, ventricular premature contractions, or arrhythmias.
Table 3: E ect of cardiac function and sex on lung and skin disease in patients with systemic sclerosis
Figure 4: DLCO corrected for haemoglobin before and after HSCT, by normal
or abnormal echocardiogram or electrocardiograph before transplantation
Abnormal echocardiogram was diastolic or systolic dysfunction, enlarged
chambers, left ventricular ejection fraction <50%, interventricular diastolic
attening, pericardial e usion >1 cm with diastolic atrial indentation, enlarged
pulmonary artery, or septal bounce. Abnormal electrocardiograph was
non-specifi c T-wave abnormalities, bundle branch or fasicular block, conduction
delay, pacemaker, prolonged QT interval, ventricular premature contractions, or
arrhythmias. HSCT=haemopoietic stem-cell transplantation.
45
50
55
60
65
70
75
70
63·9
50·2
73·4
71·8
56·7
75·2
56·4
86·6
59·2
79·3
60·4
60·4
52·1
60·4
61·6
74·6
74·3
79·8
72·2
80
85
Normal echocardiogram before HSCT
Abnormal echocardiogram before HSCT
DLCO (%)
A
0 6 12 18 24 36
50
55
60
65
70
75
80
85
90
DLCO (%)
Time (months)
B
30
Normal electrocardiograph before HSCT
Abnormal electrocardiograph before HSCT
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7
Right heart catheterisation is regarded as the gold
standard to rule out pulmonary artery hypertension
20,21
and
is recommended for early detection of pulmonary artery
hypertension in patients with systemic scler osis.
21–23
Nevertheless, PASP obtained via resting right heart
catheterisation can be falsely reassuring for patients with
systemic sclerosis. As shown in table 4, pulmonary artery
pressure can be volume dependent in patients who have
systemic sclerosis because of ab normal sti ening of
pulmonary arteries or myocardium. At the time of
measurement, patients are relatively volume depleted
because they have had no oral hydration since the previous
night in preparation for the procedure. In our study, uid
challenge unmasked patients with volume dependent
pulmonary artery hypertension manifest by increase in
PASP, mean pulmonary pres sure, and pulmonary
vascular resistance and patients with pulmonary venous
hypertension because of left ventricle compromise in
which pulmonary artery and PCWP increased without an
increase in pulmonary vascular resistance.
Because patients with systemic sclerosis might not
notice cardiopulmonary symptoms at rest but have
symptoms only with exertion or volume loading, volume
confrontational testing might be required to diagnose
Echocardiogram Right heart catheterisation Cardiac MRI/arrhythmias
Summary LVEF PASP PASP
(mPAP)
PASP (mPAP)
after 500 mL
normal saline
PCW PCW after
500 mL
normal saline
PVR PVR after
500 mL
normal saline
Eligible for HSCT
Patient 1 Normal 65% 35 26 (18) 35 (25) 7 13 148 143 Normal
Patient 2 Normal 65% 30 23 (18) 25 (21) 10 15 89 65 Normal
Patient 3 Normal 55% NR 27 (20) 34 (29) 11 18 93 85 Normal
Patient 4 LVH 65% 22 19 (14) 25 (21) 3 5 95 179 Patchy myocardial enhancement, LVH, LADB
Patient 5 Normal 60% 24 16 (11) 22 (18) 5 11 69 86 Normal
Patient 6 Grade 1 diastolic dysfunction 55% 23 27 (19) 36 (30) 10 19 105 NR Normal
Patient 7 Normal 60% 34 30 (22) 46 (38) 12 25 119 198 Patchy left ventricular myocardial enhancement
Denied HSCT because of PAH
Patient 8 Septal fl attening 65% 27 42 (27) 51 (34) 14 7 110 225 D-sign, interventricular septal diastolic
attening, atrial premature beats
Patient 9 Grade 1 diastolic dysfunction 55% NR 38 (28) 51 (39) 14 19 175 240 D-sign, interventricular septal diastolic fl attening,
enlarged right ventricle, inferior infarct
Denied HSCT because of right or left ventricle dysfunction
Patient 10 Grade 1 diastolic dysfunction 46% 40 31 (23) 42 (31) 9 16 174 158 LVEF 40%; systolic hypokinesis and diastolic
dysfunction
Patient 11 Septal fl attening 55% 26 31 (24) NP NP NP 119 NR LVEF 39%; D-sign, notably enlarged right
ventricle; di use left and right ventricular
enhancement; frequent PVCs, low QRS voltage
Patient 12 Normal* 55% 23 13 (8) 21 (14) 3 7 61 81 LVEF 45%; right ventricular ejection fraction
30%; di use left and right ventricular myocardial
enhancement; right ventricular dilatation,
non-sustained multifocal ventricular tachycardia
LVEF=left ventricular ejection fraction. PASP=pulmonary artery systolic pressure (mm Hg). mPAP=mean pulmonary artery pressure (mm Hg). PCW=pulmonary capillary wedge (mm Hg). PVR=pulmonary vascular
resistance (dynes·s·cm
). HSCT=haemopoietic stem-cell transplantation. NR=not reported. LVH=left ventricular hypertrophy. LADB=left anterior divisional block. PAH=pulmonary artery hypertension. NP=not
performed. PVCs=premature ventricular contractions. *Echocardiogram reported as normal but after obtaining results of cardiac MRI, reassessment of echocardiogram reported as inferior hypokinesis.
Table 4: Echocardiogram, right heart cardiac catheter parameters before and after fl uid challenge, and cardiac MRI in 12 consecutive patients with systemic sclerosis referred for HSCT
Scale Dimension Total SF-36
score
Physical
function
Physical role
limitation
Body pain General health
perception
Vital energy
fatigue
Social
functioning
Emotional
role limitation
Mental
health
Physical
health
Mental
health
Before HSCT 28 23 45 38 39 47 58 74 35 51 44
Last follow-up after HSCT 58 53 62 52 52 69 71 76 55 64 62
Di erence (SD) 30 (31·47) 30 (47·20) 17 (26·47) 14 (46·98) 13 (27·84) 22 (35·12) 13 (46·84) 2 (11·70) 20 (27·69) 13 (23·36) 18 (20·25)
p value <0·0001 0·001 0·001 0·105 0·024 0·002 0·129 0·308 <0·0001 0·005 <0·0001
SF-36=short form 36. HSCT=haemopoietic stem-cell transplantation.
Table 5: Quality of life by SF-36 before and after HSCT
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8
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and assess the severity of pulmonary artery hyper tension
23
as has been reported in assessment of portopulmonary
hypertension in recipients of liver transplants.
24
Our data
for cardiac catheterisation with and without uid con-
frontation argue for reconsideration of the presently
published cardiac guidelines about assessment of cardiac
risk in patients with systemic sclerosis.
14,15
However, a
confrontational uid challenge might, itself, be dangerous
in patients with little cardiac reserve.
25
Thus, we excluded
uid challenge in patients with resting cardiac catheter-
isation right atrial pressure of more than 12 mm Hg or
PCWP of more than 15 mm Hg.
Cardiac MRI is helpful for assessment of ventricular
volumes, function, wall motion, and myocardial brosis
or infl ammation in patients with systemic sclerosis.
26,27
Pulmonary artery hypertension-induced displacement
of the common interventricular wall into the left ventricle
(diastolic septal attening or D-sign) decreases left
ventricular compliance and impairs left ventricular
lling, thereby potentially increasing left atrial pressure
and causing pulmonary oedema in the setting of
hyperhydration. Myocardium scar detected by late
gadolinium enhancement of myocardium on cardiac
MRI is an indication of poor myocardial reserve,
increased risk of arrhythmias,
28
and left ventricle dys-
function as uncovered by uid challenge during cardiac
catheterisation. Patients with systemic sclerosis compli-
cated by either pulmonary artery hyper tension or
myocardial brosis are volume sensitive and uids might
precipitate cardiac failure. One death in our study was
due to constrictive pericarditis, which is another
complication that is exacerbated by uids and that, in
retrospect, might have been identifi ed by pericardial
enhancement or septal bounce on cardiac MRI or cardiac
catheterisation with rapid fl uid challenge.
29
In three patients, the rst manifestation of relapse
was renal crisis after the transplantation. None of the
patients who developed renal crisis had been maintained
on angiotensin blockade. We currently recommend
that patients start an angiotensin-converting enzyme
inhibitor or angiotensin receptor blocker on admission
and indefi nite continuation after discharge from the
transplant centre.
30
Factors that reduce DLCO include: anaemia, lung
disease that impairs alveolar gas exchange or results in
uneven distribution of air, intrapulmonary or intracardiac
shunts, and cardiac insu ciency.
31
Because heart failure
can diminish DLCO
32–34
and systemic sclerosis involves
the heart, in retrospect, our ndings that abnormal
baseline echocardiograms correlate with a decline in
DLCO after transplantation that does not return to
baseline for at least 2 years is not surprising (fi gure 3). By
comparison, normal baseline echocardiograms cor relate
with improved DLCO after transplantation.
Because our study was non-randomised, our patients
might have been at a later stage of disease where skin
thickness and quality of life can improve without
intervention. However, our results are consistent with
those from our previous randomised trial in a smaller
subset of patients in which skin score, forced vital capacity,
and quality of life improved equally in the transplantation
group but declined in the control group.
2
Moreover, no
other type of therapy or natural history study has reported
improvement in pulmonary func tion—ie, in forced vital
capacity or DLCO. Furthermore, we noted no correlation
between duration of disease before transplantation and
improvement in DLCO after transplantation. Conversely,
DLCO values after transplantation correlated with cardiac
structure and function before HSCT.
In conclusion, previous reports of high treatment-
related mortality might suggest to physicians that HSCT
should be reserved as salvage therapy. However, this
bias would result in a self-fulfi lling prophecy of high
transplant-related mortality, especially without appro-
priate cardiac assessment before HSCT. Our fi ndings
suggest that cardiac screening guidelines for systemic
sclerosis should incorporate not only echocardiogram
but also confrontational right heart catheterisation,
including a uid challenge test and cardiac MRI to
appropriately assess procedure risk. We also showed that
DLCO can improve after transplantation if baseline
cardiac function and electrocardiograph ndings are
normal. Systemic sclerosis-related cardiac involvement
before an HSCT is an important variable in determining
both treatment-related mortality and DLCO after
transplantation. HSCT can be considered as upfront
therapy if baseline cardiac assessment is favourable.
Panel: Research in context
Systemic review
We searched PubMed without language restriction for original research articles published
between June 25, 1997
, and May 1, 2012, with the terms “stem cell transplantation” and
“systemic sclerosis”. We identifi ed no distinct large phase 2 non-randomised studies or
phase 3 trials with long-term follow-up that used the same regimen as our study. The only
completed randomised trial reported to date
2
was strongly in favour of transplantation
and was stopped early after 19 patients. We identifi ed no distinct phase 2 or phase 3
studies that identifi ed risk factors for transplantation, focused on extensive cardiac
assessment before transplantation, or documented improvement in di using capacity of
carbon monoxide (DLCO) after transplantation. Two randomised trials have yet to be
concluded, the European Autologous Stem cell Transplantation International Scleroderma
(ASTIS) trial
12
and Scleroderma Cyclophosphamide versus Transplant (SCOT) trial; ASTIS
has reported a treatment-related mortality of 10% (eight of 79 patients).
Interpretation
Previous studies showed improvement in patients’ skin scores and forced vital capacity
after haemopoietic stem-cell transplantation (HSCT) but transplantation based on
published guidelines for baseline cardiac screening have shown no improvement in DLCO
and a number of deaths. To our knowledge, our study is the fi rst to show a benefi t of
extensive cardiac screening at baseline and that pretransplantation cardiac structure,
function, and electrophysiology a ect DLCO after transplantation. These ndings argue for
early referral of patients for transplantation before onset of cardiac or pericardial-related
compromise in heart function and for reassessment of present cardiac screening
guidelines for systemic sclerosis.
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9
Contributors
All authors contributed to review and proof of this report. RKB designed
the protocol, wrote the report, and was responsible for the conduct of the
trial in Chicago, IL, USA. RKB, SJ, and AM were responsible for
treatment and care of patients in Chicago. SJS and MG were responsible
for baseline cardiac consultation. JS and ER were responsible for
baseline rheumatology consultation. JV, MCO, DAM, and BS were
responsible for conduct of the trial and care of patients in São Paulo,
Brazil. SJS and ZJC assessed all echocardiograms. XH and SJ collected
data and reviewed records. IBH and BJ did statistical analysis.
Confl icts of interest
We declare that we have no confl icts of interest.
Acknowledgments
We dedicate this manuscript to the memory of our colleague and friend,
Professor Julio Voltarelli MD, PhD (Dec 17, 1948–March 21, 2012).
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