Pulmonary disease is the leading cause of death in persons with systemic sclerosis (SSc) (1). SSc causes fibrosis and small vessel vasculopathy of multiple organ systems including the skin, lungs, heart, gastrointestinal tract, and kidneys. Since the widespread use of angiotensin-converting enzyme inhibitors, mortality from scleroderma renal crisis and its sequelae has fallen dramatically. As a result, SSc-related lung disease (SSc-LD), manifesting as either interstitial fibrosis (SSc-interstitial lung disease (SSc-ILD) or pulmonary hypertension, is now the predominant cause of death. For patients with advanced SSc-LD, medical therapies are frequently ineffective and 3-year mortality exceeds 50% (2–5).
The systemic involvement of SSc makes consideration of lung transplantation (LT) controversial. In 2006, the International Society of Heart and Lung Transplantation (ISHLT) endorsed LT as an option for persons with advanced lung disease secondary to connective tissue diseases (6). Many programs, however, consider SSc a contraindication to transplantation based on the concern that extrapulmonary organ involvement may negatively impact posttransplantation allograft function and patient survival. Specifically, there is concern that esophageal dysfunction and gastroparesis may increase the risk of aspiration with resultant allograft injury (7, 8). Additional concerns include corticosteroid precipitation of SSc renal crisis and calcineurin inhibitor acceleration of renal dysfunction (9).
A limited number of studies have demonstrated equivalent survival in carefully selected persons transplanted for SSc-LD compared with persons with idiopathic pulmonary fibrosis (IPF) or pulmonary arterial hypertension (10–14). In two of these studies, there were no differences in acute rejection and risk of bronchiolitis obliterans syndrome (BOS), either (10, 13). Common across these studies was the exclusion of persons with evidence of more than mild proximal gastrointestinal tract pathology (e.g., esophageal stricture, dysmotility, achalasia, delayed gastric emptying, or symptoms not controlled by acid-suppressive medications). Thus, the impact of more severe proximal gastrointestinal involvement on outcomes after LT remains unknown.
The lung transplant program at University of California at San Francisco does not exclude persons with SSc-LD with proximal gastrointestinal tract disease regardless of severity. Therefore, we sought to evaluate the risks of mortality, BOS, and acute cellular rejection in persons undergoing LT for SSc-LD, including those with moderate to severe gastrointestinal involvement.
Between 1998 and 2010, 328 persons underwent LT. Of these, 23 (7%) underwent LT for SSc-LD. All 23 subjects and the 46 nonconnective tissue disease–related ILD (nCTD-ILD) matched controls underwent bilateral LT. The SSc-LD group was 53% female; mean±SD age was 49.3±8.8 years (Table 1). No differences in age, gender, ethnicity, smoking history, serum creatinine, pulmonary function, or lung allocation scores (LAS) were identified between the SSc-LD and the controls (IPF [n=44] and nCTD nonspecific interstitial pneumonitis [n=2]; all P values>0.19; Table 1). Subjects with SSc-LD, however, had lower body mass index (BMI; 22.9 vs. 26.9; P<0.01). Although the SSc-LD group had higher mean pulmonary artery pressure (41.2±16.4 vs. 29.0±12.8; P<0.01) and pulmonary vascular resistance (8.2±7.1 vs. 3.6±2.1; P=0.01) than the control group, pulmonary capillary wedge pressures were similar (8.2±3.7 vs. 8.8±5.8; P=0.93).
Fourteen of 23 (61%) persons with SSc-LD and 25 of 46 (54%) persons with nCTD-ILD underwent esophageal testing before LT. The SSc-LD group trended toward higher DeMeester scores than the nCTD-ILD group (65.2±58.2 vs. 31.0±26.8; P=0.13). Overall esophageal dysfunction was common in both the SSc-LD group (52%) and the nCTD-ILD group (41%; P=0.47).
Persons with SSc-LD were further classified as limited cutaneous SSc (lcSSc; n=17 [74%]), diffuse cutaneous SSc (n=4 [17%]), and SSc sine scleroderma (SSSS; n=2 [9%]; Table 2). Time from diagnosis of SSc to LT was 7.3±6.0 years.
Twelve (52%) subjects underwent both pH testing and esophageal motility evaluation. Normal motility, “mild nonspecific dysmotility”, and aperistalsis were each observed in 3 (25%) persons, “severe nonspecific dysmotility” in 2 (17%), and nutcracker esophagus in 1 (8%). Two additional subjects underwent pH testing without manometry. Only 4 of 14 (27%) persons had normal DeMeester scores (≤14). Six (26%) subjects underwent Nissen fundoplication an average of 4.9 months post-LT for clinical evidence of aspiration (median, 4.9 months; 25% [1.1] and 75% [10.5]). One subject did not have esophageal dysmotility pre-LT. This subject underwent fundoplication 5.7 years post-LT for severe reflux and recurrent aspiration. Five control subjects underwent Nissen fundoplication an average of 4.8 months post-LT (median, 4.8 months; 25% [3.5] and 75% [5.5]). One underwent Nissen fundoplication 2.3 years pre-LT. In all cases, fundoplication occurred before the diagnosis of BOS.
Survival was similar between the SSc-LD and the nCTD-ILD groups (P=0.47; Fig. 1). For the SSc-LD group, estimated survival was 83%, 83%, and 76% at 1, 3, and 5 years post-LT compared with 91%, 77%, and 64% for the nCTD-ILD group.
Analyses restricted to subjects with esophageal evaluation data showed that survival was similar between the two groups (P=0.99). For the SSc-LD group, 1-, 3-, and 5-year estimated survival was 86%, 86%, and 76% compared with 96%, 83%, and 75% for patients transplanted for nCTD-ILD (Fig. 2).
The diagnosis of SSc-LD (odds ratio [OR], 1.5; 95% confidence interval [CI], 0.27–8.65; P=0.64), esophageal dysfunction (OR, 2.0; 95% CI, 0.28–20.66; P=0.55), and Nissen fundoplication were not associated with death (P=0.72).
Freedom From Bronchiolitis Obliterans Syndrome
Freedom from BOS (fBOS) was similar between the SSc-LD and the nCTD-ILD groups (P=0.83; Fig. 3). For the SSc-ILD group, 1-, 3-, and 5-year estimated fBOS was 100%, 74%, and 74%, respectively, compared with 98%, 77%, and 69% in the nCTD-ILD group.
Analyses restricted to only those patients who underwent esophageal evaluation demonstrated that fBOS was similar between the two groups (P=0.87). For the SSc-LD group, 1-, 3-, and 5-year estimated fBOS for was 100%, 79%, and 79%, respectively, compared with 96%, 83%, and 75% for patients transplanted for nCTD-ILD.
The diagnosis of SSc-LD (OR, 1.0; 95% CI, 0.16–6.69; P=0.98), esophageal dysfunction (OR, 1.3; 95% CI, 0.17–9.26; P=0.81), and Nissen fundoplication were not associated with fBOS (P=0.46).
The SSc-LD and nCTD-ILD groups had similar rates of acute rejection (grade ≥A2; Fig. 4). The SSc-LD group experienced 1.4 episodes per 10 patient-years compared with 2.4 episodes per 10 patient-years (P=0.05). In the SSc-LD group, there were 12 episodes of acute rejection among 9 persons; within the nCTD-ILD group, there were 43 episodes among 20 persons. This difference was not attributable to differences in the number of bronchoscopies with transbronchial biopsies performed per group. The SSc-LD group underwent 227 bronchoscopies with transbronchial biopsy (mean per patient, 11.7±5.4) and the nCTD-ILD group underwent 447 bronchoscopies with transbronchial biopsy (12.0±4.9; P=0.4).
We found that patients undergoing LT for SSc-LD who have esophageal dysfunction have similar 5-year survival as patients transplanted for ILD unrelated to connective tissue diseases (nCTD-ILD). Notably, our 5-year survival for persons with SSc-LD was similar to the international 5-year survival for all LT recipients (15). Further, persons with SSc-LD do not appear to be at increased risk for BOS or acute rejection compared with persons with nCTD-ILD.
Our study adds important additional information to the modest published literature evaluating LT for SSc-LD. Our experience with 23 subjects is one of the largest single-center studies of LT for SSc-LD representing 28% of the published experience in transplantation for this condition (10–12, 14). Moreover, our long-term follow-up suggests that the previously reported short- and medium-term outcomes are durable. Notably, the 76% 3-year survival in our cohort appears better than previously reported (10, 13). An analysis of the U.S. national registry identified a 67% 3-year survival after LT for SSc-LD (13). Further, our 74% fBOS at 3 years is similar to or better than a report of 52% (10).
An important finding with clinical implications is that patients with SSc-LD and severe esophageal dysfunction can undergo successful LT. One explanation may be our center’s comprehensive and proactive approach to esophageal dysfunction in persons with SSc-LD. Before and after LT, a multidisciplinary team of pulmonologists, rheumatologists, and gastroenterologists, thoracic and abdominal surgeons, and speech pathologists design individual treatment plans for each patient. Symptoms of gastroesophageal reflux disease or evidence of aspiration are aggressively monitored and treated with a combination of behavior modification, medication, or surgery. It is notable that 7 of the 14 persons with SSc-LD who underwent esophageal evaluation would have likely been declined for transplant in previous studies based solely on their manometry results.
Unlike a previous study, we identified modestly lower rates of acute rejection in those who underwent transplantation for SSc-LD compared with nCTD-ILD. Saggar et al. (10) found that 62% of persons transplanted for SSc-LD developed acute rejection (grade ≥2A) at 1 year compared with 22% transplanted for IPF (P=0.007). Saggar et al. postulated that esophageal dysfunction in the SSc-LD group may have explained this difference. Our findings in a cohort with more severe esophageal reflux and dysmotility than the Saggar et al. (10) cohort suggest that an alternative mechanism may be operational. Alternatively, our proactive approach to esophageal dysfunction in persons with SSc-LD attenuated any potentially attributable risk.
Our study has certain limitations. First, not all subjects underwent complete esophageal evaluation before LT (39% of SSc-LD and 46% of nCTD-ILD subjects did not). Although this could have introduced selection bias, we did not observe worse (or a trend toward worse) outcomes in our sensitivity analysis. This suggests that either esophageal dysfunction in SSc-LD does not impact outcomes beyond that seen in persons without SSc-LD or that an aggressive multidisciplinary approach to screening and treatment can mitigate its effects.
Second, our modest sample size may limit our ability to detect small differences. In our analysis, neither SSc nor esophageal dysfunction were associated with an increased odds of death. The point estimates for these outcomes, however, were substantially greater than 1. Although the stability of these point estimates in larger sample sizes cannot be estimated, it is possible we were underpowered to detect true differences. Further, our modest sample size limited additional analyses investigating the impact of interventions such as Nissen fundoplication on outcomes. Although our sensitivity analysis did not identify an association with fundoplication with either BOS or death, it would be speculative to interpret our results because demonstrating fundoplication is not effective in mitigating the possible risk of gastrointestinal reflux on allograft or patient outcomes. Additionally, the survival and fBOS in our cohort was similar to internationally reported outcomes (15). Although modest from a statistical standpoint, however, our study represents one of the largest cohorts of patients undergoing LT for SSc-LD. Given the rarity of transplant for this condition, a multicenter study would be needed to detect small differences in outcomes.
Third, we reported herein a single-center retrospective experience. Therefore, the subclassification of SSc may have been subject to inaccuracies. We identified a high proportion of lcSSc in our cohort. Although possible, the proportion of lcSSc in our cohort is similar to an earlier study (10). We identified a substantial number of subjects with antinuclear antibodies (which include anti-U3-RNP fibrillarin and anti-Th/To) that can be quite specific for SSc. Importantly, nucleolar antibodies in SSc have been associated with a higher frequency of ILD and pulmonary arterial hypertension, which would be consistent with the need for LT (16). It is also possible that our cohort of SSc-LD may have included subjects with overlap syndromes with SSc (i.e., mixed connective tissue disease or undifferentiated connective tissue disease). Indeed, approximately 20% of SSc patients may have overlap syndromes (17). We cannot speculate on the prevalence of these conditions in our cohort; however, we do not consider mixed connective tissue disease or undifferentiated connective tissue disease to be contraindications to LT. Finally, our findings may not be generalizable to other centers.
In conclusion, we show patients undergoing LT for SSc-LD have similar survival, fBOS, and risk of acute rejection as patients with nCTD-ILD. These outcomes do not appear to be impacted by SSc involvement of the esophagus. At specialized transplant centers, SSc should not be a contraindication to LT.
MATERIALS AND METHODS
We performed a retrospective cohort study of all persons undergoing LT for SSc-LD between January 1, 1998 and December 31, 2010. Follow-up data were abstracted through April 7, 2012. Controls with nCTD-ILD were randomly matched by age (±3 years) and gender in a 2:1 fashion to persons with SSc-LD. Persons with nCTD-ILD had either IPF or nCTD nonspecific interstitial pneumonitis. Diagnoses were identified by the listing diagnosis submitted to the United Network for Organ Sharing and were confirmed by explanted lung pathology. Institutional review board approval was obtained (IRB#11-08211).
LT recipients with SSc-LD were initially identified by United Network for Organ Sharing listing diagnosis. Two rheumatologists (T.R.K. and M.K.C.) with expertise in SSc confirmed the diagnoses by applying the American College of Rheumatology criteria for the diagnosis of SSc (18). Data were obtained from record review at our transplant center and from referring physicians. Based on these data, patients were further classified as diffuse cutaneous SSc, lcSSc, or SSSS according to the classification of LeRoy et al. (19) and Poormoghim et al. (20). Patients were classified as lcSSc by default if skin thickening proximal to the elbows/knees and/or trunk was not mentioned. Classification of SSSS required a clinical diagnosis of SSc without skin thickening and one or more of the following: distal esophageal hypomotility, small bowel hypomotility, pulmonary fibrosis, pulmonary hypertension, cardiac involvement, or SSc renal crisis (20).
The most proximate data to the date of LT were collected from medical records including age, gender, ethnicity, BMI, serum creatinine, antinuclear antibody titer and pattern by immunofluorescense assay, anti–topoisomerase I (Scl-70) antibody titer, mean pulmonary artery pressure, pulmonary vascular resistance, and pulmonary capillary wedge pressure by right heart catheterization, forced expiratory volume at 1 s, percent predicted of forced expiratory volume at 1 s, forced vital capacity, percent predicted of forced vital capacity, LAS, and duration of disease before LT. For persons transplanted before 2005, LAS was calculated from available medical records. If data needed for calculating the LAS were missing, assumptions included a 2LPM oxygen requirement, functional status requiring “some assistance”, no mechanical ventilation, a partial pressure of carbon dioxide of 40 mm Hg, and 6-min walk distance of 500 ft. These assumptions were consistent with clinical LAS scoring, which assume the same values when missing.
As part of the LT evaluation, persons with SSc or nCTD-ILD usually undergo testing of esophageal function by pH testing (Bravo pH Monitoring; Given Imaging, Duluth, GA) and manometry (ManoScan-360; Sierra Scientific Instruments, Los Angeles, CA). Patients referred for pH testing routinely stop proton pump inhibitors 14 days before testing and transition to H2 blockers. H2 blockers are stopped 3 days before testing. If studies were available, DeMeester scores (a composite pH monitoring score [normal ≤14]) and esophageal motility data were collected. Esophageal motility reports included the descriptors: normal, mild nonspecific motility disorder, severe nonspecific motility disorder, nutcracker esophagus, or aperistalsis.
When evaluating patients with SSc-LD for LT, SSc-specific criteria are considered. We consider active digital ischemia and renal insufficiency (glomerular filtration rate <60 mL/min calculated by Cockcroft and Gault or by nuclear medicine study (21)) absolute contraindications to LT. Further, symptoms of gastroesophageal reflux disease or frank aspiration must be controlled by lifestyle modifications and acid suppressive therapy. Persons with SSc-LD are not, however, excluded from LT based solely on abnormal pH monitoring or esophageal manometry studies.
Consideration for LT involves building a unique patient-specific risk profile. For patients with SSc-LD, the SSc-specific evaluation criteria are combined with our standard selection criteria. The same weighting of standard relative and absolute contraindications is applied to patients with SSc-LD. Indeed, from 2007 to 2012, reasons for transplant denial for patients with SSc-LD included multivessel coronary artery disease, illicit drug use, renal insufficiency, and poor medical adherence.
Our immunosuppression regimen includes prednisone, tacrolimus, and mycophenolate mofetil. Prophylaxis against opportunistic infections targets cytomegalovirus, pneumocystis, and fungus. Patients are prescribed proton pump inhibitors, calcium supplements, and bisphosphonates.
Persons with SSc-LD suspected of having oropharyngeal dysfunction undergo swallow evaluations immediately post-LT by clinical speech pathologists. Evaluations include fiber optic study with liquids and solids coated in toluene blue to screen for macroaspiration. Patients are educated in swallow techniques to minimize aspiration. Feeding tubes or limitations on oral intake of food are not routinely instituted. If there is evidence of gross aspiration not attributable to oropharyngeal dysfunction, fundoplication is considered.
After LT, all patients undergo routine surveillance for occult infection or acute rejection that includes spirometry, high-resolution computed tomography, fiber optic–flexible bronchoscopy with bronchoalveolar lavage, and transbronchial biopsies. Surveillance is routinely performed on postoperative day 14 and months 1, 2, 3, 6, 12, 18, and 24. Annual surveillance high-resolution computed tomography and spirometry are continued thereafter (22). Additional testing is performed as clinically indicated. Transbronchial biopsies are performed during clinically indicated bronchoscopy if acute rejection is a diagnostic consideration. They are not routinely performed if there is clear evidence of infection (i.e., imaging consistent with infection and purulent secretions evident during bronchoscopy). Transbronchial biopsy specimens were evaluated by a single expert pulmonary pathologist and scored for acute rejection and bronchiolitis obliterans based on the ISHLT criteria (23).
Our primary outcome was overall survival. Secondary outcomes included fBOS stage ≥1 and the rate of acute cellular rejection. BOS was defined according to the ISHLT criteria (24). Acute cellular rejection was defined as grade ≥A2 according to the ISHLT criteria (23). Some of these data were published earlier in abstract form (25).
Baseline characteristics were compared by chi-square test or Wilcoxon rank-sum test. Because differences in acute rejection might be attributable to indication bias, we collected the number of bronchoscopies with transbronchial biopsies. The number of bronchoscopies performed per patient was normally distributed. Therefore, the number of biopsies performed per patient in each group was tested by t test. Survival and fBOS at 1, 3, and 5 years was estimated using Kaplan–Meier methods. Equality of survivor functions was tested by log-rank test. Acute rejection rates were compared by t test.
Esophageal dysfunction was categorically defined as either an abnormal DeMeester score (>14) or manometry findings more severe than “mild nonspecific disorder”. Multivariate logistic regression was used to test the relative risk of death and fBOS, controlling for gender, BMI, creatinine and esophageal dysfunction. Complete esophageal testing was not available for all subjects, introducing the potential for selection bias. We therefore performed a sensitivity analysis employing the same regression model and estimated survival for only those with complete data available. The associations between Nissen fundoplication and survival and between fundoplication and BOS were tested by Fisher exact test.
Analyses were performed using Stata 11.2 (StataCorp LP, College Station, TX).
The authors thank Kerry Kumar, Jill Obata, Millie Camba, and Karen Breen, the nurse coordinators of the lung transplant program, for their assistance and perspective throughout the preparation of this article and Joan Chen and Monica Dean for their help in acquiring data for this study.
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