Lung transplantation in scleroderma compared with idiopathic pulmonary fibrosis and idiopathic pulmonary arterial hypertension.код для вставкиСкачать
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: firstname.lastname@example.org. 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. 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