- Email: [email protected]
Lung transplantation for scleroderma: Strength in numbers
Accepted Manuscript Title: Lung transplantation for scleroderma: strength in numbers Author: Allan C. Gelber PII: DOI: Reference:
S1297-319X(17)30161-6 http://dx.doi.org/doi:10.1016/j.jbspin.2017.09.002 BONSOI 4630
To appear in: Received date: Accepted date:
7-8-2017 6-9-2017
Please cite this article as: Gelber AC, Lung transplantation for scleroderma: strength in numbers, Joint Bone Spine (2017), http://dx.doi.org/10.1016/j.jbspin.2017.09.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Lung transplantation for scleroderma: strength in numbers
ip t
Allan C. Gelber Johns Hopkins University School of Medicine, 5200 Eastern Avenue, Mason F. Lord Bldg, Center Tower,
us
Corresponding Author:
cr
Suite 4100, Baltimore MD 21224, United-States
Allan C. Gelber
5200 Eastern Avenue
an
Johns Hopkins University School of Medicine
M
Mason F. Lord Bldg, Center Tower, Suite 4100 Baltimore MD 21224
(410) 550-2072
Ac ce pt e
Fax
d
Phone (410) 550-2018
e-mail: [email protected]
Keywords:
Scleroderma, Systemic Sclerosis, Lung Transplantation, Outcomes, Survival
Page 1 of 10
Across the spectrum of the autoimmune rheumatic disorders, a new diagnosis of systemic sclerosis (scleroderma) too often portends a particularly poor prognosis [1,2]. Whereas in the first half of the
ip t
twentieth century, several rheumatic disorders, including scleroderma, systemic lupus erythematosus and granulomatosis with polyangiitis, were too often life-threatening and life-shortening, particularly in
cr
the presence of severe acute kidney injury with resultant renal failure, the advances in therapy achieved
us
in the second half of the century for scleroderma lagged too far behind the other disorders [3-5]. Notably, the advent of corticosteroid therapy, and thereafter of other immunosuppressive approaches,
an
critical to treating glomerulonephritis, and the later dissemination of renal replacement therapy, fundamentally altered the course and prognosis of these three disorders, but less so for scleroderma.
M
Moreover, whereas the arrival of angiotensin-converting enzyme inhibitors ameliorated the outcome of patients with scleroderma renal crisis, the lung supplanted the kidney as the leading organ-specific
d
cause of mortality among those afflicted with scleroderma [6-7].
Ac ce pt e
Given the relatively limited efficacy of conventional medical therapy to alter (and to arrest and reverse) the fibrotic process, vascular perturbations and end-organ dysfunction characteristic of sclerodermarelated damage to the lungs, kidneys, heart and gastrointestinal tract, above and beyond compromised cutaneous and musculoskeletal structure and function, novel approaches, including consideration of transplantation, have been pursued. For several decades, renal transplantation has been employed by some to erase end-stage renal disease status, thereby eliminating dialytic dependence [8-9]. Yet, notwithstanding meaningful renal recovery, other key organs may evolve and spiral downward, resulting, for example, in progressive cardiac and gastrointestinal dysfunction [10]. Moreover, in a recent French renal transplant series, pulmonary dysfunction stood out as an independent risk factor for mortality [10].
2
Page 2 of 10
An entirely different transplant approach has been broader in scope. Rather than being focused on a single solid organ transplant for advanced, or end-stage, dysfunction of that vital organ, stem cell transplantation has sought to tilt the hematologic balance from the dysfunctional scleroderma state to a
ip t
more favorable, ‘re-booted’ or reset immune system [11]. Meaningful improvement in skin and pulmonary outcome measures, and in quality-of-life measures, have been observed with this approach.
cr
At the same time, stem cell transplantation is associated with a heightened risk of early mortality from
us
treatment-related toxicity [12]. Cytotoxic therapy with high-dose cyclophosphamide alone, without
an
stem cell rescue, has also been associated with high up-front fatality [13].
In this context, there has been sustained interest in lung transplantation, given the ongoing focus on the
M
lung as the leading cause of death among those afflicted with scleroderma [7]. Initially, published
d
reports on outcomes following lung transplantation for scleroderma were often small in number, single
Ac ce pt e
center-based, and lacking a control group. Such a comparator group is essential in the effort to tease apart the risk associated with scleroderma from that associated with the surgical procedure itself. Then, in 2005, the aggregated experience at 23 transplant centers within the United States was reported, consisting of 47 patients with scleroderma [14]. Women constituted just over half the studied patients; their mean age was 46 years. These lung transplants were performed between 1990 and 2004. Importantly, the number of lung transplants performed at these participating centers varied tremendously, from 1 to 11, indicative of considerable variability in surgical transplant volume, and variability in surgical experience with scleroderma as the underlying indication. In this series, sixteen centers performed one transplant only for scleroderma. As such, even though the aggregate count was large, the individual center counts too often were quite small. Notably, during the first postoperative month, seven (15%) patients died, including two each from graft failure and an untoward cardiac event.
3
Page 3 of 10
Seventeen other patients died beyond the one year anniversary of their transplant, primarily from infectious complications. Overall, 23 patients (49%) remained alive at a mean follow-up period of 2 years following transplantation.
ip t
As related to the priority matter of an appropriate comparison group, a decade ago, the experience at two American transplant centers was combined to examine survival following lung transplantation
cr
among patients with scleroderma compared to those with idiopathic pulmonary fibrosis (IPF) and
us
idiopathic pulmonary arterial hypertension (iPAH) [15]. The histologic and radiographic features of these primary pulmonary disorders demonstrate parenchymal fibrosis and pulmonary arterial hypertension,
an
respectively, the predominant causes of pulmonary dysfunction in scleroderma. These patients underwent lung transplantation between 1989 and 2002, at Johns Hopkins and at the University of
M
Pittsburgh. During this interval, 29 transplants were performed for patients with scleroderma, 70 for IPF, and 38 for iPAH. An average of 17 months was spent on the waiting list prior to transplantation, overall
d
and at both centers. Median disease duration, from first symptom attributable to scleroderma until
Ac ce pt e
transplantation, was a dozen years. At two years post-transplantation, 11 (38%) patients with scleroderma, 14 (37%) with iPAH and 23 (33%) with IPF had died. When focusing the analytic lens on the early postoperative period, cumulative survival at six months following surgery was 69% for scleroderma compared with 79% for iPAH and 80% for IPF; these differences in survival rates between groups were not statistically significant. Still, within the first postoperative month, mortality was particularly high among those with scleroderma compared with the two primary pulmonary disorders. Seven lung transplant recipients with underlying scleroderma died during this period; four of these early deaths resulted from primary graft failure; three from bacterial pneumonia. Primary graft failure and infectious complications were the leading causes of death among the patients with iPAH and IPF as well.
4
Page 4 of 10
A key development was the publication in 2015 of the Nationwide Cohort Study examining one year survival outcomes following lung transplantation for patients with systemic sclerosis using data aggregated from throughout the United States [16]. These data were amassed by the United Network
ip t
for Organ Sharing which tracks all solid organ transplants performed across the country. From 2005 through 2012, a total of 3763 adults underwent lung transplantation, consisting of 229 with scleroderma
cr
(roughly evenly split between those with PH versus those with ILD), in comparison to 201 with idiopathic
us
PAH and 3333 with idiopathic ILD. Notably, the report demonstrated that mortality at one year posttransplant was comparable among those with scleroderma in relation to idiopathic PAH. In contrast, the
an
risk of mortality was approximately 50% greater in those with scleroderma versus those with idiopathic ILD. These associations persisted even following adjustment for potential confounding by patient
M
characteristics, donor characteristics and following adjustment for procedure-related characteristics. That the surgical period was more current that earlier reports is an important advantage, diminishing
d
any untoward effect from being ‘early’ on the learning curve. Further, the number of patients with
reports.
Ac ce pt e
scleroderma aggregated across the country was an order of magnitude greater than any of the earlier
In the current issue of the Journal, we read with interest the findings from a single center cohort which evaluated survival as well as post-lung transplant pulmonary function [17]. The cohort was assembled in Barcelona, Spain, at the Hospital Universitari Vall D’Hebron and was conducted from 2005 through 2015, again culled from the most recent time interval. During this period a total of 15 patients with scleroderma underwent transplantation. Their outcomes were compared to 500 others with nonscleroderma indications, particularly ILD and COPD, but also including pulmonary hypertension and cystic fibrosis. The postoperative immunosuppressive regimen largely consisted of tacrolimus, mycophenolate mofetil and methylprednisolone; alternate agents were everolimus and rapamycin. The patients with scleroderma were evenly divided between the limited (n=7) and diffuse (n=8) cutaneous 5
Page 5 of 10
subsets of disease. Two-thirds, or ten, were women; all but one required oxygen therapy at home preoperatively. Eight of these patients underwent transplantation due to advanced ILD; 4 had ILD together with PAH and 3 had PAH alone. Overall, 5 (33%) of these patients with scleroderma died
ip t
following transplantation, none during the first postoperative month. Two died during the first postoperative year. The cause of death was sepsis in 4 cases; a pre-existing lung cancer in the fifth case.
cr
Sepsis was the leading cause of death in those without scleroderma as well. Thus, at 1 year of follow-up
us
following transplantation, survival was 80% in those with scleroderma and 78% in those without scleroderma, quite comparable. At 3 years postoperatively, these rates were 65% and 63%, respectively,
an
again essentially the same. Thus, overall, survival was quite similar in both groups. In terms of lung function, median forced vital capacity rose from 38% preoperatively to 59% at six months
M
postoperatively. At the one year mark, the improvement in FVC was sustained and all surviving patients with scleroderma were free of home oxygen supplementation. This report underscores the growth in
Ac ce pt e
across continents [17-20].
d
surgical centers and in countries at which lung transplantation for scleroderma is performed, including
One of the important inferences to draw from the increasing number of reports examining outcomes following lung transplantation in scleroderma is of strength in numbers. The message that can be gleaned is made clearer by analysis of cohorts of increasingly large size. Large numbers at a single center, and particularly upon merging volume across an entire health care system, or throughout a single payer insurance system, or across a whole country, enables meaningful enhancement in power. Statistical power, the ability to detect a difference when the biologic truth indicates that such a difference actually exists, is enhanced by aggregation into large cohorts. Strength in numbers also enlightens the flip side of the coin. As such, if the relative risk estimate of mortality, when comparing scleroderma to pathologically similarly primary pulmonary disorders, is essentially null, then one may conclude with confidence that no difference exists between the groups being compared. Importantly, 6
Page 6 of 10
when both the numerator and denominator of the relative risk estimate calculation are large, thereby translating into narrower, or tighter, confidence intervals surrounding the estimate, the yield and message of the investigative effort is enriched. Clearer quantitative assessments arising from strength in
cr
ip t
numbers optimizes our learning regarding outcomes following lung transplantation for scleroderma.
Ac ce pt e
d
M
an
us
Disclosure of Interest: The author declares that he has no competing interest.
7
Page 7 of 10
References 1.
Steen VD, Medsger TA Jr. Epidemiology and natural history of systemic sclerosis. Rheum Dis Clin
Gelber AC, Manno RL, Shah AA, et al. Race and association with disease manifestations and
cr
2.
ip t
North Am. 1990;16:1-10.
mortality in scleroderma: a 20-year experience at the Johns Hopkins Scleroderma Center and review of
Chung L, Domsic RT, Lingala B, et al. Survival and predictors of mortality in systemic sclerosis-
an
3.
us
the literature. Medicine (Baltimore). 2013;92:191-205
associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension assessment
4.
M
and recognition of outcomes in scleroderma registry. Arthritis Care Res (Hoboken). 2014;66:489-95. Austin HA 3rd, Klippel JH, Balow JE, et a. Therapy of lupus nephritis. Controlled trial of
5.
Ac ce pt e
d
prednisone and cytotoxic drugs. N Engl J Med. 1986;314:614-9. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Ann
Intern Med. 1992;116:488-98. 6.
Lopez-Ovejero JA, Saal SD, D'Angelo WA, Cheigh JS, Stenzel KH, Laragh JH. Reversal of vascular
and renal crises of scleroderma by oral angiotensin-converting-enzyme blockade. N Engl J Med. 1979; 300:1417-9. 7.
Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum
Dis. 2007;66:940-4. 8.
Richardson JA. Hemodialysis and kidney transplantation for renal failure from scleroderma.
Arthritis Rheum. 1973;16:265-71.
8
Page 8 of 10
9.
Keane WF, Danielson B, Raij L. Successful renal transplantation in progressive systemic sclerosis.
Ann Intern Med. 1976;85:199-202. 10.
Bertrand D, Dehay J, Ott J, et al. Kidney transplantation in patients with systemic sclerosis: a
Sullivan KM, Shah A, Sarantopoulos S, Furst DE. Review: Hematopoietic Stem Cell
cr
11.
ip t
nationwide multicentre study. Transpl Int. 2017;30:256-265.
Transplantation for Scleroderma: Effective Immunomodulatory Therapy for Patients With Pulmonary
van Laar JM, Farge D, Sont JK, et al. Autologous hematopoietic stem cell transplantation vs
an
12.
us
Involvement. Arthritis Rheumatol. 2016;68:2361-71.
intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial.
13.
M
JAMA. 2014;311:2490-8.
Tehlirian CV, Hummers LK, White B, Brodsky RA, Wigley FM. High-dose cyclophosphamide
14.
Ac ce pt e
d
without stem cell rescue in scleroderma. Ann Rheum Dis. 2008;67:775-81. Massad MG, Powell CR, Kpondonu J et al. Outcomes of lung transplantation in patients with
scleroderma. World Journal of Surgery. 2005. 29:1510-5. 15.
Schachna L, Medsger TA Jr, Dauber JH, et al. Lung transplantation in scleroderma compared with
idiopathic pulmonary fibrosis and ideiopathic pulmonary arterial hypertension. Arthritis Rheum. 2006;54:3954-71. 16.
Bernstein EJ, Peterson ER, Sell JL, et al. Survival of adults with systemic sclerosis following lung
transplantation: A nationwide cohort study. Arthritis Rheumatol. 2015;67:1314-22. 17.
Fernández-Codina A, Berastegui C, Pinal-Fernández I, et al. Lung transplantation in systemic
sclerosis: A single center cohort study. Joint Bone Spine. 2017. Apr 11. [Epub ahead of print]
9
Page 9 of 10
18.
Shitrit D, Amital A, Peled N, et al. Lung transplantation in patients with scleroderma: case series,
review of the literature, and criteria for transplantation. Clin Transplant. 2009;23:178-83. 19.
Khan IY, Singer LG, de Perrot M, et al. Survival after lung transplantation in systemic sclerosis. A
Crespo MM, Bermudez CA, Dew MA, et al. Lung Transplant in Patients with Scleroderma
cr
20.
ip t
systematic review. Respir Med. 2013;107:2081-7. .
Compared with Pulmonary Fibrosis. Short- and Long-Term Outcomes. Ann Am Thorac Soc. 2016;13:784-
Ac ce pt e
d
M
an
us
92.
10
Page 10 of 10
S1297-319X(17)30161-6 http://dx.doi.org/doi:10.1016/j.jbspin.2017.09.002 BONSOI 4630
To appear in: Received date: Accepted date:
7-8-2017 6-9-2017
Please cite this article as: Gelber AC, Lung transplantation for scleroderma: strength in numbers, Joint Bone Spine (2017), http://dx.doi.org/10.1016/j.jbspin.2017.09.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Lung transplantation for scleroderma: strength in numbers
ip t
Allan C. Gelber Johns Hopkins University School of Medicine, 5200 Eastern Avenue, Mason F. Lord Bldg, Center Tower,
us
Corresponding Author:
cr
Suite 4100, Baltimore MD 21224, United-States
Allan C. Gelber
5200 Eastern Avenue
an
Johns Hopkins University School of Medicine
M
Mason F. Lord Bldg, Center Tower, Suite 4100 Baltimore MD 21224
(410) 550-2072
Ac ce pt e
Fax
d
Phone (410) 550-2018
e-mail: [email protected]
Keywords:
Scleroderma, Systemic Sclerosis, Lung Transplantation, Outcomes, Survival
Page 1 of 10
Across the spectrum of the autoimmune rheumatic disorders, a new diagnosis of systemic sclerosis (scleroderma) too often portends a particularly poor prognosis [1,2]. Whereas in the first half of the
ip t
twentieth century, several rheumatic disorders, including scleroderma, systemic lupus erythematosus and granulomatosis with polyangiitis, were too often life-threatening and life-shortening, particularly in
cr
the presence of severe acute kidney injury with resultant renal failure, the advances in therapy achieved
us
in the second half of the century for scleroderma lagged too far behind the other disorders [3-5]. Notably, the advent of corticosteroid therapy, and thereafter of other immunosuppressive approaches,
an
critical to treating glomerulonephritis, and the later dissemination of renal replacement therapy, fundamentally altered the course and prognosis of these three disorders, but less so for scleroderma.
M
Moreover, whereas the arrival of angiotensin-converting enzyme inhibitors ameliorated the outcome of patients with scleroderma renal crisis, the lung supplanted the kidney as the leading organ-specific
d
cause of mortality among those afflicted with scleroderma [6-7].
Ac ce pt e
Given the relatively limited efficacy of conventional medical therapy to alter (and to arrest and reverse) the fibrotic process, vascular perturbations and end-organ dysfunction characteristic of sclerodermarelated damage to the lungs, kidneys, heart and gastrointestinal tract, above and beyond compromised cutaneous and musculoskeletal structure and function, novel approaches, including consideration of transplantation, have been pursued. For several decades, renal transplantation has been employed by some to erase end-stage renal disease status, thereby eliminating dialytic dependence [8-9]. Yet, notwithstanding meaningful renal recovery, other key organs may evolve and spiral downward, resulting, for example, in progressive cardiac and gastrointestinal dysfunction [10]. Moreover, in a recent French renal transplant series, pulmonary dysfunction stood out as an independent risk factor for mortality [10].
2
Page 2 of 10
An entirely different transplant approach has been broader in scope. Rather than being focused on a single solid organ transplant for advanced, or end-stage, dysfunction of that vital organ, stem cell transplantation has sought to tilt the hematologic balance from the dysfunctional scleroderma state to a
ip t
more favorable, ‘re-booted’ or reset immune system [11]. Meaningful improvement in skin and pulmonary outcome measures, and in quality-of-life measures, have been observed with this approach.
cr
At the same time, stem cell transplantation is associated with a heightened risk of early mortality from
us
treatment-related toxicity [12]. Cytotoxic therapy with high-dose cyclophosphamide alone, without
an
stem cell rescue, has also been associated with high up-front fatality [13].
In this context, there has been sustained interest in lung transplantation, given the ongoing focus on the
M
lung as the leading cause of death among those afflicted with scleroderma [7]. Initially, published
d
reports on outcomes following lung transplantation for scleroderma were often small in number, single
Ac ce pt e
center-based, and lacking a control group. Such a comparator group is essential in the effort to tease apart the risk associated with scleroderma from that associated with the surgical procedure itself. Then, in 2005, the aggregated experience at 23 transplant centers within the United States was reported, consisting of 47 patients with scleroderma [14]. Women constituted just over half the studied patients; their mean age was 46 years. These lung transplants were performed between 1990 and 2004. Importantly, the number of lung transplants performed at these participating centers varied tremendously, from 1 to 11, indicative of considerable variability in surgical transplant volume, and variability in surgical experience with scleroderma as the underlying indication. In this series, sixteen centers performed one transplant only for scleroderma. As such, even though the aggregate count was large, the individual center counts too often were quite small. Notably, during the first postoperative month, seven (15%) patients died, including two each from graft failure and an untoward cardiac event.
3
Page 3 of 10
Seventeen other patients died beyond the one year anniversary of their transplant, primarily from infectious complications. Overall, 23 patients (49%) remained alive at a mean follow-up period of 2 years following transplantation.
ip t
As related to the priority matter of an appropriate comparison group, a decade ago, the experience at two American transplant centers was combined to examine survival following lung transplantation
cr
among patients with scleroderma compared to those with idiopathic pulmonary fibrosis (IPF) and
us
idiopathic pulmonary arterial hypertension (iPAH) [15]. The histologic and radiographic features of these primary pulmonary disorders demonstrate parenchymal fibrosis and pulmonary arterial hypertension,
an
respectively, the predominant causes of pulmonary dysfunction in scleroderma. These patients underwent lung transplantation between 1989 and 2002, at Johns Hopkins and at the University of
M
Pittsburgh. During this interval, 29 transplants were performed for patients with scleroderma, 70 for IPF, and 38 for iPAH. An average of 17 months was spent on the waiting list prior to transplantation, overall
d
and at both centers. Median disease duration, from first symptom attributable to scleroderma until
Ac ce pt e
transplantation, was a dozen years. At two years post-transplantation, 11 (38%) patients with scleroderma, 14 (37%) with iPAH and 23 (33%) with IPF had died. When focusing the analytic lens on the early postoperative period, cumulative survival at six months following surgery was 69% for scleroderma compared with 79% for iPAH and 80% for IPF; these differences in survival rates between groups were not statistically significant. Still, within the first postoperative month, mortality was particularly high among those with scleroderma compared with the two primary pulmonary disorders. Seven lung transplant recipients with underlying scleroderma died during this period; four of these early deaths resulted from primary graft failure; three from bacterial pneumonia. Primary graft failure and infectious complications were the leading causes of death among the patients with iPAH and IPF as well.
4
Page 4 of 10
A key development was the publication in 2015 of the Nationwide Cohort Study examining one year survival outcomes following lung transplantation for patients with systemic sclerosis using data aggregated from throughout the United States [16]. These data were amassed by the United Network
ip t
for Organ Sharing which tracks all solid organ transplants performed across the country. From 2005 through 2012, a total of 3763 adults underwent lung transplantation, consisting of 229 with scleroderma
cr
(roughly evenly split between those with PH versus those with ILD), in comparison to 201 with idiopathic
us
PAH and 3333 with idiopathic ILD. Notably, the report demonstrated that mortality at one year posttransplant was comparable among those with scleroderma in relation to idiopathic PAH. In contrast, the
an
risk of mortality was approximately 50% greater in those with scleroderma versus those with idiopathic ILD. These associations persisted even following adjustment for potential confounding by patient
M
characteristics, donor characteristics and following adjustment for procedure-related characteristics. That the surgical period was more current that earlier reports is an important advantage, diminishing
d
any untoward effect from being ‘early’ on the learning curve. Further, the number of patients with
reports.
Ac ce pt e
scleroderma aggregated across the country was an order of magnitude greater than any of the earlier
In the current issue of the Journal, we read with interest the findings from a single center cohort which evaluated survival as well as post-lung transplant pulmonary function [17]. The cohort was assembled in Barcelona, Spain, at the Hospital Universitari Vall D’Hebron and was conducted from 2005 through 2015, again culled from the most recent time interval. During this period a total of 15 patients with scleroderma underwent transplantation. Their outcomes were compared to 500 others with nonscleroderma indications, particularly ILD and COPD, but also including pulmonary hypertension and cystic fibrosis. The postoperative immunosuppressive regimen largely consisted of tacrolimus, mycophenolate mofetil and methylprednisolone; alternate agents were everolimus and rapamycin. The patients with scleroderma were evenly divided between the limited (n=7) and diffuse (n=8) cutaneous 5
Page 5 of 10
subsets of disease. Two-thirds, or ten, were women; all but one required oxygen therapy at home preoperatively. Eight of these patients underwent transplantation due to advanced ILD; 4 had ILD together with PAH and 3 had PAH alone. Overall, 5 (33%) of these patients with scleroderma died
ip t
following transplantation, none during the first postoperative month. Two died during the first postoperative year. The cause of death was sepsis in 4 cases; a pre-existing lung cancer in the fifth case.
cr
Sepsis was the leading cause of death in those without scleroderma as well. Thus, at 1 year of follow-up
us
following transplantation, survival was 80% in those with scleroderma and 78% in those without scleroderma, quite comparable. At 3 years postoperatively, these rates were 65% and 63%, respectively,
an
again essentially the same. Thus, overall, survival was quite similar in both groups. In terms of lung function, median forced vital capacity rose from 38% preoperatively to 59% at six months
M
postoperatively. At the one year mark, the improvement in FVC was sustained and all surviving patients with scleroderma were free of home oxygen supplementation. This report underscores the growth in
Ac ce pt e
across continents [17-20].
d
surgical centers and in countries at which lung transplantation for scleroderma is performed, including
One of the important inferences to draw from the increasing number of reports examining outcomes following lung transplantation in scleroderma is of strength in numbers. The message that can be gleaned is made clearer by analysis of cohorts of increasingly large size. Large numbers at a single center, and particularly upon merging volume across an entire health care system, or throughout a single payer insurance system, or across a whole country, enables meaningful enhancement in power. Statistical power, the ability to detect a difference when the biologic truth indicates that such a difference actually exists, is enhanced by aggregation into large cohorts. Strength in numbers also enlightens the flip side of the coin. As such, if the relative risk estimate of mortality, when comparing scleroderma to pathologically similarly primary pulmonary disorders, is essentially null, then one may conclude with confidence that no difference exists between the groups being compared. Importantly, 6
Page 6 of 10
when both the numerator and denominator of the relative risk estimate calculation are large, thereby translating into narrower, or tighter, confidence intervals surrounding the estimate, the yield and message of the investigative effort is enriched. Clearer quantitative assessments arising from strength in
cr
ip t
numbers optimizes our learning regarding outcomes following lung transplantation for scleroderma.
Ac ce pt e
d
M
an
us
Disclosure of Interest: The author declares that he has no competing interest.
7
Page 7 of 10
References 1.
Steen VD, Medsger TA Jr. Epidemiology and natural history of systemic sclerosis. Rheum Dis Clin
Gelber AC, Manno RL, Shah AA, et al. Race and association with disease manifestations and
cr
2.
ip t
North Am. 1990;16:1-10.
mortality in scleroderma: a 20-year experience at the Johns Hopkins Scleroderma Center and review of
Chung L, Domsic RT, Lingala B, et al. Survival and predictors of mortality in systemic sclerosis-
an
3.
us
the literature. Medicine (Baltimore). 2013;92:191-205
associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension assessment
4.
M
and recognition of outcomes in scleroderma registry. Arthritis Care Res (Hoboken). 2014;66:489-95. Austin HA 3rd, Klippel JH, Balow JE, et a. Therapy of lupus nephritis. Controlled trial of
5.
Ac ce pt e
d
prednisone and cytotoxic drugs. N Engl J Med. 1986;314:614-9. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Ann
Intern Med. 1992;116:488-98. 6.
Lopez-Ovejero JA, Saal SD, D'Angelo WA, Cheigh JS, Stenzel KH, Laragh JH. Reversal of vascular
and renal crises of scleroderma by oral angiotensin-converting-enzyme blockade. N Engl J Med. 1979; 300:1417-9. 7.
Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum
Dis. 2007;66:940-4. 8.
Richardson JA. Hemodialysis and kidney transplantation for renal failure from scleroderma.
Arthritis Rheum. 1973;16:265-71.
8
Page 8 of 10
9.
Keane WF, Danielson B, Raij L. Successful renal transplantation in progressive systemic sclerosis.
Ann Intern Med. 1976;85:199-202. 10.
Bertrand D, Dehay J, Ott J, et al. Kidney transplantation in patients with systemic sclerosis: a
Sullivan KM, Shah A, Sarantopoulos S, Furst DE. Review: Hematopoietic Stem Cell
cr
11.
ip t
nationwide multicentre study. Transpl Int. 2017;30:256-265.
Transplantation for Scleroderma: Effective Immunomodulatory Therapy for Patients With Pulmonary
van Laar JM, Farge D, Sont JK, et al. Autologous hematopoietic stem cell transplantation vs
an
12.
us
Involvement. Arthritis Rheumatol. 2016;68:2361-71.
intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial.
13.
M
JAMA. 2014;311:2490-8.
Tehlirian CV, Hummers LK, White B, Brodsky RA, Wigley FM. High-dose cyclophosphamide
14.
Ac ce pt e
d
without stem cell rescue in scleroderma. Ann Rheum Dis. 2008;67:775-81. Massad MG, Powell CR, Kpondonu J et al. Outcomes of lung transplantation in patients with
scleroderma. World Journal of Surgery. 2005. 29:1510-5. 15.
Schachna L, Medsger TA Jr, Dauber JH, et al. Lung transplantation in scleroderma compared with
idiopathic pulmonary fibrosis and ideiopathic pulmonary arterial hypertension. Arthritis Rheum. 2006;54:3954-71. 16.
Bernstein EJ, Peterson ER, Sell JL, et al. Survival of adults with systemic sclerosis following lung
transplantation: A nationwide cohort study. Arthritis Rheumatol. 2015;67:1314-22. 17.
Fernández-Codina A, Berastegui C, Pinal-Fernández I, et al. Lung transplantation in systemic
sclerosis: A single center cohort study. Joint Bone Spine. 2017. Apr 11. [Epub ahead of print]
9
Page 9 of 10
18.
Shitrit D, Amital A, Peled N, et al. Lung transplantation in patients with scleroderma: case series,
review of the literature, and criteria for transplantation. Clin Transplant. 2009;23:178-83. 19.
Khan IY, Singer LG, de Perrot M, et al. Survival after lung transplantation in systemic sclerosis. A
Crespo MM, Bermudez CA, Dew MA, et al. Lung Transplant in Patients with Scleroderma
cr
20.
ip t
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