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Lung transplantation in scleroderma compared with idiopathic pulmonary fibrosis and idiopathic pulmonary arterial hypertension.

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ARTHRITIS & RHEUMATISM
Vol. 54, No. 12, December 2006, pp 3954–3961
DOI 10.1002/art.22264
© 2006, American College of Rheumatology
Lung Transplantation in Scleroderma Compared With
Idiopathic Pulmonary Fibrosis and
Idiopathic Pulmonary Arterial Hypertension
Lionel Schachna,1 Thomas A. Medsger, Jr.,2 James H. Dauber,2 Fredrick M. Wigley,1
Neil A. Braunstein,2 Barbara White,3 Virginia D. Steen,2 John V. Conte,1
Stephen C. Yang,1 Kenneth R. McCurry,2 Marvin C. Borja,1 David E. Plaskon,2
Jonathan B. Orens,1 and Allan C. Gelber1
with scleroderma (38%), 23 with IPF (33%), and 14 with
IPAH (37%) died. Cumulative survival at 6 months
posttransplantation was 69% in the scleroderma group
compared with 80% in the IPF group (log-rank P ⴝ
0.21) and 79% in the IPAH group (P ⴝ 0.38). The
estimated risk of mortality at 6 months was increased in
patients with scleroderma compared with those with
IPF (relative risk [RR] 1.70, 95% confidence interval
[95% CI] 0.74–3.93) and those with IPAH (RR 1.52, 95%
CI 0.59–3.96), but the differences were not statistically
significant. Over the following 18 months, there was
convergence in the survival rates such that cumulative
survival at 2 years was comparable, at ⬃64%, among all
3 groups.
Conclusion. Patients with scleroderma who are
recipients of lung transplantation experience similar
rates of survival 2 years after the procedure compared
with those with IPF or IPAH. Lung transplantation may
represent a viable therapeutic option to consider for
patients with end-stage lung disease due to scleroderma.
Objective. Lung transplantation is a viable, lifesaving intervention for several primary pulmonary disorders complicated by severe lung dysfunction. This
study was undertaken to evaluate whether patients with
systemic sclerosis (scleroderma), a systemic autoimmune rheumatic disorder, would receive similar benefit from this intervention.
Methods. Survival following lung transplantation
was examined at 2 university medical centers among 29
patients with scleroderma as compared with 70 patients
with idiopathic pulmonary fibrosis (IPF) and 38 with
idiopathic pulmonary arterial hypertension (IPAH), the
latter groups representing pathologically related primary pulmonary disorders. The end point was death
from any cause. Risk of mortality in patients with
scleroderma was compared with that in patients with
IPF or IPAH, with adjustment for demographic and
clinical parameters.
Results. During 2 years of followup, 11 patients
Dr. Schachna’s work was supported by a Postdoctoral Fellowship Award from the Arthritis Foundation. Dr. Gelber’s work was
supported by a Chapter Grant from the Arthritis Foundation, Maryland Chapter.
1
Lionel Schachna, MBBS, FRACP, PhD, Fredrick M. Wigley,
MD, John V. Conte, MD, Stephen C. Yang, MD, Marvin C. Borja, BS,
Jonathan B. Orens, MD, Allan C. Gelber, MD, MPH, PhD: Johns
Hopkins University, Baltimore, Maryland; 2Thomas A. Medsger, Jr.,
MD, James H. Dauber, MD, Neil A. Braunstein, MD, Virginia D.
Steen, MD, Kenneth R. McCurry, MD, David E. Plaskon, BS:
University of Pittsburgh, Pittsburgh, Pennsylvania; 3Barbara White,
MD: University of Maryland, Baltimore (current address: MedImmune, Gaithersburg, Maryland).
Address correspondence and reprint requests to Allan C.
Gelber, MD, MPH, PhD, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, Mason F. Lord Building, Center Tower,
Suite 4100, Baltimore, MD 21224. E-mail: agelber@jhmi.edu.
Submitted for publication January 30, 2006; accepted in
revised form September 5, 2006.
Systemic sclerosis (SSc; scleroderma) is a chronic
disfiguring autoimmune disorder that often leads to
life-threatening visceral involvement (1). In the 1960s,
scleroderma resulted in a 50% mortality rate at 5 years
(2). Over the last 40 years, the landscape of scleroderma
management has changed considerably. The institution
of angiotensin-converting enzyme inhibitors has substantially improved the outcome following renal crisis
(3). Consequently, the lung has superseded the kidney as
the major organ-specific cause of death in scleroderma
(4). There remains, however, no known cure for scleroderma at the host level, nor is there a cure for its
pulmonary manifestations.
3954
LUNG TRANSPLANTATION IN SCLERODERMA
Interstitial lung disease and pulmonary arterial
hypertension are the principal causes of lung dysfunction
in scleroderma (5). Although immunosuppressive agents
may improve symptoms and vasodilator therapies can
increase functional capacity (6–8), their impact on survival remains uncertain. Lung transplantation, therefore,
represents an important and potentially life-saving approach for the management of scleroderma complicated
by end-stage pulmonary disease. To date, however, there
is a paucity of data regarding lung transplantation in
scleroderma. In fact, according to the 2003 report of the
Registry of the International Society for Heart and Lung
Transplantation (ISHLT), a connective tissue disorder,
including scleroderma, was the indication in only 43
(0.5%) of 9,488 adult patients undergoing lung transplantation procedures performed worldwide between
1995 and 2001 (9). This small surgical volume may be
attributable to the perception that scleroderma, in and
of itself, represents a contraindication to successful
transplantation. Presumed heightened risk in the postoperative period, arising from scleroderma-related gastroesophageal reflux, renal impairment, or skin fibrosis,
likely contributes to this perception. The risk of toxic
effects in the renal system from transplant immunosuppressive agents may augment these concerns.
Of the first 2 reported patients with scleroderma
who underwent lung transplantation, 1 died from multiple organ failure and the other remained alive at 21
months of followup (10). Another patient with scleroderma, who died on the sixteenth postoperative day, has
also been reported (11). To our knowledge, the only
additional published literature addressing the outcome
of lung transplantation in patients with scleroderma
originates from our 2 transplant centers.
We have independently examined post–lung
transplantation survival among patients with scleroderma in previous reports (12–14). Those reports described the outcome in small numbers of patients,
comprising 6 patients with scleroderma at Pittsburgh
(12) and 9 at Johns Hopkins (13), and lacked direct
comparison with other distinct primary pulmonary disorders that are recognized indications for lung transplantation. Adjustment for potential confounding variables was not performed. Moreover, the aggregate data
presented by ISHLT (9) do not provide estimates of
survival following lung transplantation for all connective tissue disorders combined or scleroderma alone. We
sought to address these limitations by combining the
experience at our 2 US transplant centers, including
the initial 15 patients with scleroderma previously described (12,13), to examine survival following lung trans-
3955
plantation among patients with scleroderma in comparison with 2 pathologically related primary pulmonary
disorders.
PATIENTS AND METHODS
Ascertainment of patients. We reviewed the records of
all patients who underwent lung transplantation between December 1, 1989 and June 30, 2002 at the Johns Hopkins
Hospital and the University of Pittsburgh Medical Center. To
ensure confidentiality, personal identifiers were removed from
the research database. Within this computerized database, we
identified all patients with a diagnosis of scleroderma. All of
these patients satisfied the American College of Rheumatology (formerly, the American Rheumatism Association) classification criteria for SSc (scleroderma) (15) and were categorized as having either the limited cutaneous form or the diffuse
cutaneous form of the disease (16).
We also identified all patients with an underlying
diagnosis of idiopathic pulmonary fibrosis (IPF) or idiopathic
pulmonary arterial hypertension (IPAH). These 2 disorders
have well-established indications for lung transplantation and
are characterized by parenchymal fibrosis in IPF and pulmonary arterial hypertension in IPAH, representing the predominant causes of pulmonary dysfunction in scleroderma. The
diagnosis of IPF was established by the following criteria:
abnormal results on pulmonary function tests, including evidence of a restrictive ventilatory defect and/or decreased
diffusion capacity for carbon monoxide, findings on chest
radiography or high-resolution computed tomography suggestive of usual interstitial pneumonitis, and, in patients who
underwent surgical lung biopsy, histologic changes of usual
interstitial pneumonitis. IPAH was defined according to the
diagnostic criteria of the American College of Chest Physicians, including the presence of a resting mean pulmonary
artery pressure higher than 25 mm Hg (17).
Pretransplantation demographic, clinical, and laboratory data were recorded for each patient in a uniform manner,
regardless of underlying disease. These parameters included
age, sex, and race, time on the transplant waiting list, body
mass index (in kg/m2), smoking status (current versus former
versus never smoker), renal function, and donor and recipient
cytomegalovirus (CMV) serologic status. The rate of creatinine clearance prior to transplantation was estimated using a
24-hour urine sample; if a sample was unavailable, creatinine
clearance was calculated from the serum creatinine level using
the modified Cockcroft and Gault formula (18).
Patients with scleroderma who were referred for transplantation were evaluated in accordance with the general
principles established by international guidelines for the selection of candidates for lung transplantation (19). Specifically,
severe renal impairment, as defined by a creatinine clearance
of ⬍50 ml/minute, was an exclusion criterion. Similarly, patients with nonhealing, unresolved, or open skin wounds or
those with severe sclerosis of the chest wall were excluded.
Assessment of esophageal dysfunction was uniformly performed using a cine esophagram. Those with severe gastroesophageal reflux, to the upper third of the esophagus by cine
esophagram, that could not be controlled by medical therapy
3956
SCHACHNA ET AL
were excluded, due to concern that the risk of posttransplantation aspiration would be heightened.
Among the patients with scleroderma undergoing
lung transplantation, we recorded the disease subtype (limited
cutaneous versus diffuse cutaneous) and disease duration, in
addition to anticentromere and anti–topoisomerase I autoantibody status. Interstitial lung disease was defined in this
group as the major indication for transplantation when the
forced vital capacity was ⬍55% of predicted. In contrast,
pulmonary arterial hypertension was defined as the major
indication when the mean pulmonary artery pressure was
⬎35 mm Hg, as measured by right heart catheterization. For
the single patient with scleroderma who did not undergo
catheterization, pulmonary arterial hypertension was judged to
be the major indication for transplantation by the presence of
an echocardiography-estimated systolic pulmonary artery pressure of ⬎50 mm Hg.
Statistical analysis. Demographic and clinical characteristics of the patients are expressed as the mean ⫾ SD or
proportions. We examined the pretransplantation characteristics of the patients with scleroderma compared with those with
IPF and those with IPAH using the Student’s t-test and
chi-square test for continuous and categorical variables, respectively. Survival, in months, was calculated from the time of
transplantation until date of death or end of the followup
period (December 31, 2002). Cumulative survival following
lung transplantation was determined using the Kaplan-Meier
method (20), and the 3 disease groups were compared using
the log-rank test (21).
We estimated the risk of mortality at 6 and 24 months
posttransplantation in transplant recipients with scleroderma
compared with those with IPF and those with IPAH using Cox
proportional hazards analysis (22). In multivariate analysis, the
independent contribution of scleroderma to survival was examined with adjustment for baseline demographic and clinical
parameters, including age, sex, race, waiting time prior to
transplantation, body mass index, smoking status, renal function, CMV serologic status, allograft type, and year and center
of transplantation. Hazard ratios are expressed as the relative
risk (RR) with 95% confidence interval (95% CI). The analyses were repeated after stratification of the transplantation
population by transplant center and by time period of transplantation (before versus after September 1, 1999). Statistical
analyses were performed using Stata statistical software (release 7.0; Stata, College Station, TX). P values are 2-sided and
were considered significant at ␣ ⫽ 0.05.
RESULTS
A total of 689 lung transplantations were performed at the 2 centers during the study period, of which
564 were at the University of Pittsburgh (82%) and 125
at Johns Hopkins Hospital (18%). Twenty-nine transplantations were performed in patients with scleroderma
(4%), 70 in those with IPF (10%), and 38 in those with
IPAH (6%). Among the patients with scleroderma, the
indication for transplantation was pulmonary fibrosis in
15 patients (52%), pulmonary arterial hypertension in 11
Table 1. Frequency of allograft type among patients with systemic
sclerosis (SSc; scleroderma), those with idiopathic pulmonary fibrosis
(IPF), and those with idiopathic pulmonary arterial hypertension
(IPAH)*
Allograft type
Underlying
disease
SLT
BLT
HLT
Total
SSc (scleroderma)
IPF
IPAH
18 (62)
66 (94)†
29 (76)‡
9 (31)
4 (6)
5 (13)
2 (7)
0
4 (11)
29
70
38
* Values are the number (%) of patients undergoing single-lung
(SLT), bilateral-lung (BLT), or combined heart-lung (HLT) transplantation.
† P ⫽ 0.001 versus SSc.
‡ P ⫽ 0.021 versus SSc.
patients (38%), and both of these pulmonary sequelae in
3 patients (10%). Eighteen patients with scleroderma
underwent single-lung transplantation (62%), 9 underwent bilateral-lung transplantation (31%), and 2 underwent combined heart-lung transplantation (7%). Compared with patients with scleroderma, a higher
proportion of patients with IPF (difference 32%; P ⫽
0.001) and those with IPAH (difference 14%; P ⫽ 0.21)
underwent single-lung transplantation (Table 1). All
Table 2. Comparison of demographic and clinical features among
lung transplant recipients with SSc, those with IPF, and those with
IPAH*
Feature
SSc
(n ⫽ 29)
IPF
(n ⫽ 70)
IPAH
(n ⫽ 38)
Age at transplantation, 46.6 ⫾ 9.6
55.7 ⫾ 8.6†
41.5 ⫾ 9.3‡
mean ⫾ SD years
Female
16 (55)
28 (40)
32 (84)§
White
24 (83)
62 (88)
33 (87)
Transplantation pre–
9 (31)
33 (47)
26 (68)§
September 1999
Transplantation at
18 (62)
51 (72)
32 (84)‡
University of
Pittsburgh
Time on waiting list,
521.4 ⫾ 289.3 485.3 ⫾ 336.3 596.9 ⫾ 358.6
mean ⫾ SD days
Former smoker
14 (48)
40 (57)
9 (24)‡
Body mass index,
25.2 ⫾ 2.9
27.5 ⫾ 3.8§
23.2 ⫾ 6.5
mean ⫾ SD kg/m2
Creatinine clearance,
91.6 ⫾ 32.6
98.6 ⫾ 32.8
79.5 ⫾ 29.5
mean ⫾ SD ml/
minute¶
Donor CMV⫹/
7 (24)
12 (17)
10 (27)
recipient CMV⫺#
* Except where indicated otherwise, values are the number (%) of
patients. CMV ⫽ cytomegalovirus (see Table 1 for other definitions).
† P ⬍ 0.001 versus SSc.
‡ P ⬍ 0.05 versus SSc.
§ P ⬍ 0.01 versus SSc.
¶ Results unavailable for 1 patient with SSc, 1 with IPF, and 3 with
IPAH.
# Results unavailable for 3 patients with IPF and 1 with IPAH.
LUNG TRANSPLANTATION IN SCLERODERMA
3957
Table 3. Pretransplantation characteristics of the 29 patients with SSc and their outcome following lung transplantation, by duration of survival*
Clinical or laboratory test
Disease CrCl,
Date of
SSc Transplant Graft duration, ml/
FVC, % MPAP,
Patient transplantation Center subtype indication type
years minute ACA ATA predicted mm Hg Outcome
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
2000
1999
1999
2000
2001
1996
1997
1999
2002
2002
2000
2002
2001
2001
1997
2000
2000
2000
2000
1996
1999
1999
1999
1999
1993
1997
1991
1995
1992
UPMC
UPMC
UPMC
UPMC
JHH
UPMC
JHH
JHH
JHH
JHH
UPMC
UPMC
UPMC
UPMC
UPMC
JHH
UPMC
JHH
JHH
UPMC
UPMC
JHH
JHH
JHH
UPMC
UPMC
UPMC
UPMC
UPMC
lc
dc
dc
lc
lc
lc
dc
lc
dc
dc
lc
dc
lc
dc
lc
lc
lc
dc
dc
lc
lc
lc
dc
lc
lc
dc
lc
dc
lc
PAH
ILD
ILD
ILD
Both
Both
PAH
ILD
ILD
ILD
PAH
Both
PAH
ILD
PAH
PAH
PAH
ILD
PAH
ILD
PAH
ILD
ILD
ILD
ILD
ILD
PAH
ILD
PAH
SLT
SLT
BLT
SLT
SLT
SLT
SLT
HLT
BLT
BLT
HLT
BLT
BLT
SLT
SLT
BLT
BLT
BLT
SLT
SLT
BLT
SLT
SLT
SLT
SLT
SLT
SLT
SLT
SLT
12.8
21.4
19.6
14.7
27.8
36.4
9.3
10.2
12.1
12.9
16.5
14.1
8.9
18.5
13.8
14.3
2.2
11.6
12.6
7.9
9.3
6.7
3.0
7.7
27.5
15.8
3.5
2.2
3.2
69
60
130†
86
64
93
101†
47
49
111
45
54†
115
83
65
65
137
115†
135†
82
83
53
159†
131†
105
83
NA
141
103
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫺
⫺
⫹
⫺
⫺
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫺
⫹
⫺
⫺
⫺
⫺
⫹
⫺
⫹
⫺
⫺
⫺
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫺
64
24
33
28
47
43
76
40
39
35
61
36
77
30
74
65
89
23
90
40
73
39
55
34
26
38
135
55
65
42
22
30
13
66
35
‡
17
24
32
38
50
43
23
51
42
48
10
50
18
47
31
29
12
22
25
42
15
61
Dead
Dead
Dead
Dead
Dead
Dead
Dead
Dead
Dead
Alive
Dead
Alive
Alive
Alive
Dead
Alive
Alive
Alive
Alive
Dead
Alive
Alive
Alive
Alive
Dead
Alive
Dead
Alive
Alive
Cause of
death
PGF
Pneumonia
Pneumonia
Pneumonia
PGF
PGF
PGF
SDH
GBM
Pneumonia
PE
Unknown
Pneumonia
CholangioCA
Survival,
days
9
14
17
18
21
22
31
118
125
205
264
279
373
608
634
815
946
1,014
1,045
1,086
1,163
1,393
1,393
1,400
1,666
1,884
2,752
2,806
3,906
* CrCl ⫽ creatinine clearance; ACA ⫽ anticentromere antibody; ATA ⫽ anti–topoisomerase I antibody; FVC ⫽ forced vital capacity; MPAP ⫽
mean pulmonary artery pressure; UPMC ⫽ University of Pittsburgh Medical Center; lc ⫽ limited cutaneous; PGF ⫽ primary graft failure; dc ⫽
diffuse cutaneous; ILD ⫽ interstitial lung disease; JHH ⫽ Johns Hopkins Hospital; SDH ⫽ subdural hematoma; GBM ⫽ glioblastoma multiforme;
PE ⫽ pulmonary embolism; NA ⫽ not available; cholangioCA ⫽ cholangiocarcinoma (see Table 1 for other definitions).
† Calculated from serum creatinine using modified Cockcroft and Gault formula (18).
‡ Systolic PAP 53 mm Hg by echocardiography.
patients were treated with a triple immunosuppressive
regimen that included a calcineurin inhibitor (tacrolimus
or cyclosporine), an antimetabolite (azathioprine or
mycophenolate mofetil), and corticosteroids.
The majority of the patients were white. Several
demographic and clinical parameters known to be predictors of posttransplantation survival (9,23,24) differed
between the 3 groups (Table 2). Compared with patients
with IPF, those with scleroderma were younger by a
mean of 9.1 years (95% CI 5.2–13.0) and had a lower
body mass index by, on average, 2.3 kg/m2 (95% CI
0.7–3.9). Compared with patients with IPAH, patients
with scleroderma were older by a mean of 5.1 years
(95% CI 0.5–9.7) and had a higher body mass index by,
on average, 2.0 kg/m2 (95% CI 0.4–4.4). The IPAH
group included more women (difference 29%; P ⫽
0.009) and fewer former smokers (difference 24%; P ⫽
0.04) compared with the scleroderma group. A higher
proportion of patients with IPAH than those with scleroderma underwent transplantation prior to September
1999 (difference 37%; P ⫽ 0.002) and had the procedure
at the University of Pittsburgh (difference 22%; P ⫽
0.04). The time on the waiting list prior to transplantation was a mean 17.2 months overall and was similar at
both centers.
Table 3 summarizes the preoperative clinical
features and outcomes following lung transplantation
for the 29 patients with scleroderma, from shortest to
longest duration of survival. Eighteen transplantations
were performed at the University of Pittsburgh (62%)
and 11 at Johns Hopkins (38%). The median time
period of transplantation was September 1999 (range
3958
SCHACHNA ET AL
Figure 1. Kaplan-Meier survival curves indicating the survival rates up to 2 years following lung transplantation in
patients with systemic sclerosis (SSc; scleroderma), those with idiopathic pulmonary fibrosis (IPF), and those with
idiopathic pulmonary arterial hypertension (IPAH). Values in the lower box indicate the numbers of surviving patients
at each time point.
June 1991 to June 2002). The subtype of scleroderma
was the limited cutaneous form in 17 patients (59%) and
diffuse cutaneous in 12 (41%). The median disease
duration (from first symptom attributable to scleroderma) at the time of transplantation was 12.6 years
(range 2.2–36.4 years). The pretransplantation creatinine clearance was within normal limits (mean ⫾ SD
91.6 ⫾ 32.6 ml/minute), although 5 patients had a value
below 60 ml/minute. Four patients with limited scleroderma (24%) had serum anticentromere antibodies,
whereas 5 with diffuse disease (42%) were seropositive
for anti–topoisomerase I antibodies.
Vital status as of December 31, 2002 was determined from the transplant database maintained at both
centers. During the first 2 years of followup, 11 patients
with scleroderma (38%), 23 with IPF (33%), and 14 with
IPAH (37%) died. Cumulative survival at 6 months
posttransplantation was 69% for patients with scleroderma compared with 80% for patients with IPF (logrank P ⫽ 0.21) and 79% for patients with IPAH (P ⫽
0.38) (Figure 1). Of note, within the first postoperative
month, there was a precipitous fall in survival among
patients with scleroderma compared with those in the 2
primary pulmonary disorder groups; during this early
period, 7 lung transplant recipients with scleroderma
died (Table 3). Four of these early deaths were the result
of primary graft failure. These 4 patients each underwent single-lung transplantation for scleroderma-related
pulmonary hypertension. Three additional early deaths
among the patients with scleroderma were the result of
bacterial pneumonia. Primary graft failure and infection
were also the leading causes of death among the patients
with IPF and those with IPAH.
During the first 6 postoperative months, patients
with scleroderma who underwent lung transplantation
experienced a 70% increased risk of mortality (RR 1.70,
95% CI 0.74–3.93) compared with those with IPF, and a
52% increased risk (RR 1.52, 95% CI 0.59–3.96) compared with patients with IPAH (Table 4). These differences, however, were not statistically significant. Multivariate analysis, with adjustment for variables that
significantly differed between the groups, did not meaningfully alter these comparative mortality risks.
Over the subsequent 18 months, there was a
convergence in cumulative survival among the groups of
patients with scleroderma, IPF, and IPAH (Figure 1).
LUNG TRANSPLANTATION IN SCLERODERMA
Table 4.
IPAH*
3959
Relative risk of mortality in patients with SSc compared with those with IPF and those with
Model
At 6 months posttransplantation
Unadjusted
Adjusted for age
Adjusted for sex
Adjusted for body mass index
Adjusted for smoking
Adjusted for creatinine clearance
Adjusted for allograft type
Full multivariate model†
At 24 months posttransplantation
Unadjusted
Adjusted for age
Adjusted for sex
Adjusted for body mass index
Adjusted for smoking
Adjusted for creatinine clearance
Adjusted for allograft type
Full multivariate model†
Compared with IPF
Compared with IPAH
1.70 (0.74–3.93)
1.54 (0.60–3.95)
1.71 (0.74–3.98)
1.87 (0.77–4.56)
1.82 (0.78–4.22)
1.73 (0.75–4.01)
2.03 (0.83–4.98)
2.00 (0.74–5.46)
1.52 (0.59–3.96)
1.40 (0.52–3.76)
1.64 (0.60–4.49)
1.46 (0.56–3.81)
1.36 (0.51–3.63)
1.99 (0.73–5.43)
1.57 (0.60–4.14)
2.00 (0.61–6.63)
1.22 (0.60–2.51)
1.25 (0.56–2.78)
1.21 (0.59–2.50)
1.28 (0.60–2.71)
1.31 (0.64–2.71)
1.24 (0.60–2.54)
1.28 (0.59–2.78)
1.31 (0.55–3.12)
1.11 (0.50–2.45)
1.03 (0.45–2.35)
1.23 (0.54–2.83)
1.07 (0.48–2.38)
1.08 (0.48–2.42)
1.36 (0.60–3.11)
1.13 (0.51–2.50)
1.44 (0.55–3.77)
* Values are the relative risk (95% confidence interval). See Table 1 for definitions.
† Covariates included in full multivariate model were age, sex, body mass index, smoking, creatinine
clearance, and allograft type.
There were only 2 additional deaths among the 20
remaining patients with scleroderma, compared with 9
deaths among the 56 patients with IPF and 6 deaths
among the 30 patients with IPAH. As a result of this
change in mortality over time, cumulative survival at 2
years posttransplantation was similar in all 3 groups
(61% in those with scleroderma, 64% in those with IPF,
and 63% in those with IPAH).
We explored the possibility that a learning curve
might be the explanation for the high rate of early
posttransplantation mortality among the patients with
scleroderma. The above analyses were repeated after
stratification by date of operation. Among transplantations performed prior to the median time period of
transplantation of September 1999, the mortality in
those with scleroderma, at 6 months, was comparable
with that observed in patients with IPF (RR 0.91, 95%
CI 0.19–4.31) and in those with IPAH (RR 1.14, 95% CI
0.22–5.93). For those patients who underwent transplantation after the median time period, however, the mortality risk estimate in the scleroderma group was increased compared with that in the IPF group (RR 2.57,
95% CI 0.86–7.66) and that in the IPAH group (RR
1.46, 95% CI 0.38–5.64). These differences did not
achieve statistical significance.
An analysis of patient survival was similarly conducted with stratification according to the center of
transplantation. No statistically significant differences in
the survival rates at 6 or 24 months posttransplantation
were observed among the 3 underlying disease groups of
patients at the Johns Hopkins Hospital or at the University of Pittsburgh Medical Center (results not shown).
DISCUSSION
In this report, we describe the experience of 29
patients with scleroderma who underwent lung transplantation. Their survival rates were compared in a
direct, head-to-head manner with those in concurrent
cohorts of transplant recipients with IPF or IPAH at the
same medical centers. These 2 primary pulmonary disorders are characterized by well-accepted indications for
transplantation and are representative of the pathologic
processes that result in end-organ lung dysfunction in
scleroderma. At 6 months posttransplantation, cumulative survival was reduced among patients with scleroderma, with a survival rate of 69% compared with
survival rates of 80% and 79% for those with IPF and
those with IPAH, respectively. These differences, however, were not statistically significant, which may reflect
the small number of patients studied. Nevertheless, over
the subsequent 18-month period, cumulative survival
among these 3 disease groups converged, such that
survival at 2 years posttransplantation was similar (61–
64%) among all 3 groups according to indications for
lung transplantation.
Analysis of survival following lung transplantation in these patients revealed a sharp decline during the
3960
first postoperative month (9). Examination of the early
deaths among the patients with scleroderma undergoing
transplantation is instructive. Determination of cause of
death was made by the transplant pulmonologists on the
basis of clinical events prior to death; autopsy reports
were unavailable. Four of the early deaths in the scleroderma group were attributed to primary graft failure,
and 3 were the result of bacterial pneumonia. Primary
graft failure is a clinical syndrome of progressive hypoxemia, decreased lung compliance, and diffuse interstitial
and alveolar infiltrates that develop soon after transplantation (25). In our study, deaths from primary graft
failure among the patients with scleroderma were confined to those with severe pulmonary hypertension who
underwent single-lung transplantation.
Organ transplantation in individuals with scleroderma is not without precedent. Thirty years ago, the
first successful kidney transplantation for renal failure in
a patient with scleroderma was reported (26). Several
additional case reports followed (27–30), and some
investigators expressed concerns about recurrent scleroderma in the transplanted kidney (31,32). In 2 recent
reports in which the United Network for Organ Sharing
registry was examined, 86 patients with scleroderma who
underwent renal transplantation prior to 1996 were
identified (29,30). An overall mortality rate of 24% in
these patients was reported. Furthermore, a 2-fold
heightened risk of mortality following renal transplantation was demonstrated in those with scleroderma compared with those with IgA nephropathy, a disorder with
few extrarenal manifestations.
To date, the published experience regarding lung
transplantation in scleroderma has been rather limited.
A decade ago, Levine et al reported 2 patients with
scleroderma who underwent lung transplantation (10).
Since this initial case series, a total of 43 patients with
connective tissue disorders, only a fraction of whom have
scleroderma, have been reported in the Registry of the
ISHLT (9). However, the outcome in patients with
scleroderma compared with those with the primary
pulmonary disorders, who are widely considered appropriate candidates for lung transplantation, has heretofore not been addressed in the medical literature in
general nor in the transplant registry in particular.
Notwithstanding the overall expansion in lung
transplant programs, patients with underlying systemic
disorders are often deemed inappropriate candidates for
transplantation because of concern about the increased
risk of postoperative complications or progression of
their underlying disorder. In fact, early in the lung
transplantation era, multisystem disorders, including
SCHACHNA ET AL
scleroderma, were considered absolute contraindications to transplantation (33,34). As a result of increased
experience and improved technical proficiency, in addition to newer immunosuppressive regimens, lung transplantation for patients with autoimmune rheumatic disorders is now considered feasible in some instances.
Transplant experts now suggest that each candidate for
transplantation be evaluated on an individual basis (19).
Our study meaningfully contributes to the debate about
whether to widen eligibility criteria for transplantation
to include patients with scleroderma.
Given that pulmonary dysfunction is the leading
organ-specific cause of death in scleroderma, advancing
our understanding of the role of lung transplantation in
this disease is important. We have described the survival
experience of 29 patients with scleroderma, assembled
from 2 academic medical centers, who received lung
transplants over a 12.5-year period. The patients were
carefully selected to maximize the likelihood of a successful outcome.
Our analyses did not consider the effect of variation in the immunosuppressive medical regimen. Thus,
it is possible that the patients with scleroderma were
exposed to less cyclosporine, and thus experienced fewer
nephrotoxic effects, although this was not the practice at
either center. The impression at both transplant centers
was that the immunosuppressive regimens administered
after transplantation did not differ by underlying disease. Finally, we did not examine functional outcomes in
this report.
Despite these limitations, this study demonstrates
that cumulative survival at 2 years following lung transplantation was quite similar, with a survival rate of more
than 60% among patients with scleroderma, those with
IPF, and those with IPAH. Lung transplantation may be
considered a viable therapeutic option in patients with
end-stage lung dysfunction resulting from SSc.
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