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Original Research: Pulmonary Vascular Disease |

Unique Predictors of Mortality in Patients With Pulmonary Arterial Hypertension Associated With Systemic Sclerosis in the REVEAL RegistryPredictors of Mortality in SSc-APAH OPEN ACCESS

Lorinda Chung, MD; Harrison W. Farber, MD, FCCP; Raymond Benza, MD; Dave P. Miller, MS; Lori Parsons, BS; Paul M. Hassoun, MD, FCCP; Michael McGoon, MD, FCCP; Mark R. Nicolls, MD; Roham T. Zamanian, MD
Author and Funding Information

From the Division of Immunology and Rheumatology (Dr Chung), and the Division of Pulmonary and Critical Care Medicine (Drs Nicolls and Zamanian), Stanford University, Stanford, CA; Vera Moulton Wall Center for Pulmonary Vascular Disease (Drs Nicolls and Zamanian), Stanford, CA; Veteran Affairs Palo Alto Health Care System (Drs Chung and Nicolls), Palo Alto, CA; the Division of Pulmonary and Critical Care Medicine (Dr Farber), Boston University, Boston, MA; the Division of Cardiovascular Medicine (Dr Benza), Allegheny General Hospital, Pittsburgh, PA; ICON Clinical Research (Mr Miller and Ms Parsons), San Francisco, CA; the Division of Pulmonary and Critical Care Medicine (Dr Hassoun), Johns Hopkins University, Baltimore, MD; and the Division of Cardiology (Dr McGoon), Mayo Clinic, Rochester, MN.

CORRESPONDENCE TO: Lorinda Chung, MD, 3801 Miranda Ave, VA Palo Alto Health Care System, Palo Alto, CA 94304; e-mail: shauwei@stanford.edu


FUNDING/SUPPORT: Actelion Pharmaceuticals US Inc is the sponsor of REVEAL Registry and provided funding and support for the analysis presented.

This is an open access article distributed under the terms of the Creative Commons Attribution-Noncommercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted use, distribution, and reproduction to noncommercial entities, provided the original work is properly cited. Information for reuse by commercial entities is available online.


Chest. 2014;146(6):1494-1504. doi:10.1378/chest.13-3014
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BACKGROUND:  Patients with pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc-APAH) experience higher mortality rates than patients with idiopathic disease and those with other connective tissue diseases (CTD-APAH). We sought to identify unique predictors of mortality associated with SSc-APAH in the CTD-APAH population.

METHODS:  The Registry to Evaluate Early and Long-Term PAH Management (REVEAL Registry) is a multicenter, prospective US-based registry of patients with previously and newly diagnosed (enrollment within 90 days of diagnostic right-sided heart catheterization) PAH. Cox regression models evaluated all previously identified candidate predictors of mortality in the overall REVEAL Registry population to identify significant predictors of mortality in the SSc-APAH (n = 500) vs non-SSc-CTD-APAH (n = 304) populations.

RESULTS:  Three-year survival rates in the previously diagnosed and newly diagnosed SSc-APAH group were 61.4% ± 2.7% and 51.2% ± 4.0%, respectively, compared with 80.9% ± 2.7% and 76.4% ± 4.6%, respectively, in the non-SSc-CTD-APAH group (P < .001). In multivariate analyses, men aged > 60 years, systolic BP (SBP) ≤ 110 mm Hg, 6-min walk distance (6MWD) < 165 m, mean right atrial pressure (mRAP) > 20 mm Hg within 1 year, and pulmonary vascular resistance (PVR) > 32 Wood units remained unique predictors of mortality in the SSc-APAH group; 6MWD ≥ 440 m was protective in the non-SSc-CTD-APAH group, but not the SSc-APAH group.

CONCLUSIONS:  Patients with SSc-APAH have higher mortality rates than patients with non-SSc-CTD-APAH. Identifying patients with SSc-APAH who are at a particularly high risk of death, including elderly men and patients with low baseline SBP or 6MWD, or markedly elevated mRAP or PVR, will enable physicians to identify patients who may benefit from closer monitoring and more aggressive treatment.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov

Figures in this Article

Pulmonary arterial hypertension (PAH) is a rare complication in patients with connective tissue diseases (CTDs), and it is associated with high mortality rates, particularly in patients with systemic sclerosis (SSc).1 Studies have shown that patients with CTD-associated PAH (CTD-APAH) experience poorer survival compared with patients with idiopathic PAH (IPAH).24 In addition, despite similar baseline hemodynamics, patients with PAH associated with SSc (SSc-APAH) have the poorest survival rates when compared with other CTD-APAH subgroups, including patients with systemic lupus erythematosus, mixed CTD, and rheumatoid arthritis, in both incident and prevalent populations.3,5

Risk score calculators have been developed for patients with PAH as a whole, incorporating variables predictive of high mortality, including World Health Organization (WHO) group 1 subgroup, age, sex, New York Heart Association (NYHA) functional class (FC), vital signs, 6-min walk distance (6MWD), brain natriuretic peptide (BNP) level, presence of pericardial effusion, diffusion capacity of the lung for carbon monoxide (Dlco), and baseline hemodynamic variables such as mean right atrial pressure (mRAP), pulmonary vascular resistance (PVR), and cardiac output.6,7 A study focusing on the CTD-APAH population found that higher mRAP, lower 6MWD, higher FC, and the presence of a pericardial effusion were predictive of death.8 In contrast, studies including patients with SSc-APAH alone have identified male sex, lower Dlco, older age, and FC IV status as independent predictors of death.9,10 No studies have evaluated a large cohort of patients with CTD-APAH to identify unique predictors of mortality in patients with SSc-APAH. We sought to use the large Registry to Evaluate Early and Long-Term PAH Management (REVEAL Registry) cohort of patients with CTD-APAH to identify unique predictors of mortality in the patients with SSc-APAH compared with patients with CTD other than SSc (non-SSc-CTD)-APAH that may account for the mortality differences between these groups.

REVEAL Registry

The REVEAL Registry is a longitudinal registry involving 54 pulmonary hypertension centers in the United States (e-Appendix 1). Each participating center obtained institutional review board approval prior to patient enrollment. The design and objectives of the REVEAL Registry are described elsewhere.11 All patients provided informed consent prior to enrollment, and “enrollment” was defined as the date consent was given. “Diagnosis” was defined as the date of diagnostic right-sided heart catheterization (RHC) occurring at or before the date of enrollment. Patients with new diagnoses were defined as those whose diagnostic RHC occurred within 90 days of enrollment. All consecutive patients who, in the opinion of the enrolling investigator, had a clinical diagnosis of PAH WHO group 112 and met the following inclusion criteria were eligible for enrollment: (1) mean pulmonary artery pressure of > 25 mm Hg at rest or 30 mm Hg with exercise, (2) mean pulmonary capillary wedge pressure or left ventricular end diastolic pressure of ≤ 18 mm Hg, (3) PVR of ≥ 240 dynes/s/cm5 (divide by 80 for Wood units [WU]), and (4) ≥ 3 months of age.

Data Collection

The data in the REVEAL Registry was collected prospectively, but the analyses for this study were performed retrospectively. Data collection methods have been described previously.3 Patients were enrolled from March 2006 through December 2009. Demographics, clinical characteristics, and outcomes were assessed at enrollment and quarterly thereafter. The database of 3,515 patients was locked on February 4, 2013, for the current analyses. We developed an algorithm (Fig 1) to exclude patients with exercise-induced PAH, in accordance with the Dana Point Classification Criteria,12 and those with pulmonary capillary wedge pressure > 15 mm Hg, who have been shown to differ in many respects from those meeting the traditional hemodynamic definition of PAH,13 and included only patients with CTD-APAH. We also excluded those with evidence of significant interstitial lung disease (ILD), defined as those with evidence of “severe” fibrosis on high-resolution CT scan of the chest or “moderate” fibrosis if pulmonary function testing revealed a total lung capacity of < 60% predicted.14 We divided the patients with CTD-APAH into those with SSc-APAH (SSc group) and those with non-SSc-CTD-APAH (non-SSc group).

Figure Jump LinkFigure 1 –  STROBE diagram of the Registry to Evaluate Early and Long-Term PAH Management (REVEAL) Registry patients used in this analysis. We included only patients with CTD-APAH who met the strict criteria of World Health Organization group 1 pulmonary arterial hypertension. CTD-APAH = pulmonary arterial hypertension associated with connective tissue disease; HRCT = high-resolution CT scan of the chest; ILD = interstitial lung disease; non-SSc-CTD = connective tissue disease other than systemic sclerosis; PCWP = pulmonary capillary wedge pressure; SSc = systemic sclerosis; TLC = total lung capacity.Grahic Jump Location
Statistical Analysis

Baseline characteristics at the time of enrollment were compared between the SSc and non-SSc groups, using the Student t or Wilcoxon test to compare continuous variables and the χ2 or Fisher exact test to compare categorical variables. Because BNP levels were highly skewed, the variables were log transformed for comparison as continuous variables. Cumulative probabilities of survival at 3 years were calculated using the Kaplan-Meier estimator for both the previously and newly diagnosed populations, and differences between the SSc and non-SSc groups were compared using the log-rank test. Follow-up time was calculated from the date of enrollment. Cox regression models identified significant predictors of mortality in the SSc and non-SSc populations. All variables identified previously as candidate predictors of mortality in the overall REVEAL Registry population were evaluated in univariate and multivariate models. Stepwise selection was used to determine the final model, retaining only variables with P < .05. SAS, version 9.1 (SAS Institute Inc) statistical software was used for all analyses.

Baseline Characteristics in Patients With CTD-APAH

Of 3,515 patients enrolled in the REVEAL Registry, 815 were identified as having CTD-APAH (Fig 1). Of these, 804 (500 SSc and 304 non-SSc) who did not have significant ILD were selected for these analyses. The majority of patients in the non-SSc group had systemic lupus erythematosus-APAH or mixed CTD-APAH (Table 1). Patients with SSc were older and had a shorter time between diagnostic RHC and enrollment into the database than did the patients with non-SSc-CTD-APAH (Table 2). Patients with SSc-APAH had more severe disease overall, with a higher NYHA FC, shorter 6MWD, higher Borg dyspnea index, lower Dlco, and higher BNP level. Patients with SSc-APAH were also more likely to have renal insufficiency and pericardial effusions than patients with non-SSc-CTD-APAH. Although there was a strong trend toward higher mRAP in the SSc group, there were no significant differences in hemodynamics or PAH-specific therapies at the time of enrollment in the SSc vs non-SSc groups.

Table Graphic Jump Location
TABLE 1 ]  Types of CTD-APAH

APAH = associated with pulmonary arterial hypertension; CTD = connective tissue disease; non-SSc-CTD = connective tissue disease other than systemic sclerosis; SSc = systemic sclerosis.

Table Graphic Jump Location
TABLE 2 ]  Characteristics, Hemodynamics, and Cardiac and Pulmonary Function at Enrollment

P value calculation uses χ2 test for categorical data or Fisher exact test for categorical data with small cell counts (≤ 5%), and Student t test for continuous data. 6MWD = 6-min walk distance; BNP = brain natriuretic peptide; bpm = beats per min; CCB = calcium channel blocker; Dlco = diffusion capacity of the lung for carbon monoxide; ERA = endothelin receptor agonist; FC = functional class; FCO = Fick cardiac output; mPAP = mean pulmonary arterial pressure; mRAP = mean right atrial pressure; NYHA = New York Heart Association; PAH = pulmonary arterial hypertension; PCWP = pulmonary capillary wedge pressure; PDE-5 = phosphodiesterase type-5; PVR = pulmonary vascular resistance; RHC = right-sided heart catheterization. See Table 1 legend for expansion of other abbreviations.

a 

Age = (date of informed consent − date of birth)/365.25.

b 

Cardiac output = FCO, or, if FCO is missing, then cardiac output = thermodilution cardiac output.

c 

PVR (Wood units) = (mean pulmonary arterial pressure at rest − PCWP at rest)/cardiac output, where cardiac output = FCO, or, if FCO is missing, then cardiac output = thermodilution cardiac output.

d 

Predicted value based on Hankinson et al14 computation.

e 

FEV1/FVC ratio is missing if FVC is zero.

Poorer Survival in SSc-APAH Compared With Non-SSc-CTD-APAH

Three-year survival in the SSc group was worse than in the non-SSc group in both the previously and newly diagnosed populations (61.4% ± 2.7% vs 80.9% ± 2.7% and 51.2% ± 4.0% vs 76.4% ± 4.6%, respectively; P < .001) (Fig 2).

Figure Jump LinkFigure 2 –  Three-year survival curves in patients with SSc and non-SSc-CTD-APAH. A, Three-year survival from enrollment in the newly diagnosed SSc group was 51.2% ± 4.0% compared with 76.4% ± 4.6% in the non-SSc-CTD group (P < .001). B, Three-year survival from enrollment in the previously diagnosed SSc group was 61.4% ± 2.7% compared with 80.9% ± 2.7% in the non-SSc-CTD group (P < .001). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location
Unique Predictors of Mortality in SSc-APAH

Figure 3 shows the univariate analyses of previously identified predictors of mortality from the overall REVEAL Registry cohort in the SSc and non-SSc groups. The following variables were predictive of mortality in both groups: age > 60 years, NYHA FC III or IV status, 6MWD < 165 m, and BNP > 180 pg/mL. 6MWD ≥ 440 m was protective in both groups. Unique predictors of mortality in the SSc group, but not the non-SSc group, included male sex, systolic BP (SBP) ≤ 110 mm Hg, pericardial effusion, Dlco ≤ 32% predicted, mRAP > 20 mm Hg within 1 year, PVR > 32 WU, and newly diagnosed status. BNP levels < 50 pg/mL were protective in patients with SSc (hazard ratio [HR] = 0.34; 95% CI, 0.16-0.72; P = .005) but not in the non-SSc group (HR = 0.68; 95% CI, 0.36-1.29; P = .24). Figure 3 also shows the univariate analyses of additional variables that are relevant to the CTD-APAH population. A higher glomerular filtration rate was protective in both groups. Mild to moderate ILD was the only feature that increased mortality in patients with non-SSc-CTD-APAH but not in patients with SSc-APAH (HR = 2.19; 95% CI, 1.14-4.23; P = .02 vs HR = 0.84; 95% CI, 0.55-1.30; P = .44). When compared with IPAH, mRAP > 20 mm Hg within 1 year, PVR > 32 WU, and newly diagnosed status remained unique predictors of death in the SSc-APAH group.

Figure Jump LinkFigure 3 –  Predictors of mortality for patients with SSc-APAH and non-SSc-CTD-APAH using univariate Cox regression analyses. Unique predictors of mortality in the SSc group, but not the non-SSc group, included male sex, SBP ≤ 110 mm Hg, pericardial effusion, DLCO ≤ 32% predicted, mRAP > 20 mm Hg within 1 y, PVR > 32 WU, and newly diagnosed status. BNP levels < 50 pg/mL were protective in patients with SSc, but not in the non-SSc group. Higher GFR was protective in both groups. Mild to moderate ILD was the only feature that increased mortality in the non-SSc group but not in patients with SSc. 6MWD = 6-min walk distance; BNP = brain natriuretic peptide; DLCO = diffusion capacity of the lung for carbon monoxide; FC = functional class; GFR = glomerular filtration rate; HR = hazard ratio; mRAP = mean right atrial pressure; NYHA = New York Heart Association; PVR = pulmonary vascular resistance; SBP = systolic BP; WHO = World Health Organization; WU = Wood units. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location

In multivariate analyses, the following variables remained predictive of mortality in both the SSc and non-SSc groups: NYHA FC III or IV status and BNP > 180 pg/mL (Table 3). Unique predictors of mortality in the SSc group included men > 60 years, SBP ≤ 110 mm Hg, 6MWD < 165 m, mRAP > 20 mm Hg within 1 year, and PVR > 32 WU. 6MWD ≥ 440 m was protective in the non-SSc group, but not in the SSc group, whereas BNP < 50 pg/mL was protective in the SSc group, but not in the non-SSc group.

Table Graphic Jump Location
TABLE 3 ]  Multivariate Model of Predictors of Mortality

HR = hazard ratio. See Table 1 and 2 legends for expansion of other abbreviations.

Our study provides further evidence that patients with SSc-APAH experience higher mortality rates than do patients with other CTD-APAH in both incident and prevalent populations. Our results validate the usefulness of the risk score calculator in patients with CTD-APAH, including in patients with SSc-APAH. We identified several baseline risk factors that were significantly associated with mortality in the SSc-APAH population in comparison with the non-SSc-CTD-APAH population, including being an elderly man, having a low SBP, having poor exercise capacity, and having severe hemodynamic indices including elevated mRAP and PVR. Identifying patients with SSc-APAH with high mortality risk based on the presence of these unique predictors of mortality will enable physicians to monitor these patients more closely and escalate therapy when indicated.

Three-year survival in the newly diagnosed SSc-APAH population was 51%, which is similar to survival rates found in other cohorts assessed in the modern treatment era.1,5,9,15,16 Other studies have found better survival rates (75%-81%) in patients with SSc-APAH; these rates are similar to the survival rate of 77% that we and others observed in patients with non-SSc-CTD-APAH.3,5,10,17,18 This survival discrepancy could be related to early detection algorithms that have been implemented in these SSc-APAH cohorts, with the goal to initiate PAH-specific therapy when the disease is less severe. Survival in patients with non-SSc-CTD-APAH appears to be more similar to those with IPAH than to those with SSc-APAH, despite similar baseline hemodynamics and PAH-specific therapies.3 Whether initiating aggressive PAH treatment in patients with SSc-APAH with a particular high mortality risk may improve outcomes remains an important question to be answered.

Overall, predictors identified in the multivariate model in SSc-APAH were very similar to the core predictors for PAH as a whole, including all subtypes.6 Our results concur with those of other studies on patients with SSc-APAH in that male sex, older age, and FC III and IV status were significant predictors of death.5,9,10,15 Our results confirmed those of a single-center study that identified high PVR as a strong predictor of mortality.19 Unlike these other studies, we did not find that low Dlco or glomerular filtration rate were predictive of mortality in the SSc-APAH group in multivariate analyses, although they were significant in univariate analyses. Lefèvre et al15 identified additional poor prognostic factors in patients with SSc with pulmonary hypertension in a meta-analysis including patients with WHO groups II and III pulmonary hypertension: pericardial effusion, low 6MWD, high mean pulmonary arterial pressure, poor cardiac index, and elevated mRAP were poor prognostic factors. Although pericardial effusion lost its significance in our multivariate analysis of patients with SSc-APAH, poor exercise capacity and elevated mRAP remained significant predictors of death. Interestingly, 6MWD < 165 m was predictive of death only in the SSc group, whereas 6MWD ≥ 440 m was protective only in the non-SSc-CTD-APAH group in multivariate analyses. A potential explanation for these discrepancies is that patients with SSc can suffer from the presence of contractures and tendon friction rubs that can significantly limit mobility (particularly those with diffuse skin disease) in addition to other factors that limit exercise capacity (such as anemia and joint or muscle inflammation) in patients with other CTDs.20,21 However, including all variables in the multivariate model without stepwise selection, 6MWD < 165 m was a significant predictor of death in the non-SSc group (HR = 2.03; 95% CI, 1.01-4.12; P = .05), and 6MWD ≥ 440 m showed a trend toward a protective effect in the SSc group (HR = 0.62; 95% CI, 0.33-1.15; P = .13). In addition, when we evaluated the effect of 6MWD on mortality risk in the various cutaneous subgroups of SSc, an increase in distance of 100 m was significantly protective in all three groups (P < .001): diffuse HR = 0.53 (95% CI, 0.38-0.75); limited 0.59 (95% CI, 0.51-0.68); unclassified 0.54 (95% CI, 0.40-0.71).

In our study, BNP > 180 pg/mL increased the risk of death in both the SSc and non-SSc-APAH groups by more than twofold, as has also been shown in patients with IPAH.22 We and others have shown that patients with SSc-APAH have markedly elevated BNP and N-terminal-pro-BNP (NT-pro-BNP) levels compared with patients with IPAH and patients with non-SSc-CTD-APAH.3,23 Williams et al24 found in a UK SSc-APAH cohort that for every order of magnitude increase in baseline NT-pro-BNP level there was a fourfold increased risk of death (P = .002). In addition, several studies have found that NT-pro-BNP is useful in the screening and early detection of PAH in patients with SSc, and this biomarker has been integrated into novel screening algorithms.2527 To our knowledge, our study is the first to show that BNP is an independent predictor of mortality in patients with CTD-APAH and SSc-APAH, in particular. Unfortunately NT-pro-BNP levels were not available in 89% of our CTD-APAH cohort, and, therefore, they could not be included in the regression models.

To our knowledge, this is the first study to identify low baseline SBP ≤ 110 mm Hg as an independent predictor of death in patients with SSc-APAH. Other studies have shown that low SBP, both at peak exercise and upon admission to the hospital for right-sided heart failure, is an independent risk factor for death in PAH.28,29 A potential pathophysiologic explanation for this finding is that the presence of high right ventricular pressure results in a more pronounced effect of low SBP on coronary perfusion. Thus, low SBP can lead to greater right ventricular dysfunction caused by ischemia. In addition, low SBP may be a sign of low cardiac output, reduced stroke volume, and neurohormonal activation.29 Unless complicated by renal disease, patients with SSc have relatively low baseline BP,30 and the mean SBP was 119 ± 19 mm Hg in the patients with SSc-APAH in our study. Given that BP can be monitored easily, identification of low baseline SBP as a risk factor in SSc-APAH is an important finding.

We did not find that mild to moderate ILD was predictive of death in patients with SSc-APAH. Although a significant predictor in the non-SSc-APAH group in univariate analysis, it was no longer significant in multivariate analysis. We attempted to exclude patients with substantial ILD as defined previously but did not have precise measurements regarding the degree of fibrosis on imaging.

Our study does have some limitations. The SSc-APAH and non-SSc-CTD-APAH cohorts are smaller than the overall cohort. Thus, differences in significant multivariable predictors may be caused by loss of power as opposed to true differences in predictors for different subtypes. In addition, the model does not include therapies. The majority of REVEAL Registry patients, particularly patients who had previous diagnoses, were receiving phosphodiesterase-5 inhibitors, endothelin receptor antagonists, prostacyclins, or a combination. Therefore, the model does not provide insights into prognosis for untreated patients. Although 86% of the patients with CTD-APAH were enrolled at sites that routinely involve a rheumatologist in the diagnosis and care of these patients, misclassification of some patients may have occurred. Finally, the analysis only assessed variables available in the REVEAL Registry database. There may be additional factors particular to patients with CTD-APAH, such as autoantibody status, that could impact the results.

In conclusion, patients with SSc-APAH have higher mortality rates than patients with non-SSc-CTD-APAH. Our results validate the usefulness of the PAH risk score in patients with SSc-APAH. We have identified unique predictors of mortality in patients with SSc-APAH, including being an older man, having a low baseline SBP, having poor exercise capacity, and having an elevated mRAP and PVR; these can be used to identify high-risk patients who may benefit from closer monitoring and more aggressive treatment.

Author contributions: L. C. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. L. C., H. W. F., R. B., D. P. M., L. P., P. M. H., M. M., M. R. N., and R. T. Z. contributed to data analysis and interpretation, drafting and critical review of the manuscript, and approval of the final version.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Chung has received research support funding from Gilead Sciences, Inc; United Therapeutics Corp; Pfizer, Inc; and Actelion Pharmaceuticals Ltd, and has served on the Advisory Board for Gilead Sciences, Inc. Dr Farber has served as a consultant for Gilead Sciences, Inc, Actelion Pharmaceuticals Ltd, Bayer, United Therapeutics Corp, and Bristol-Myers Squibb; has served on the speakers bureau for Actelion Pharmaceuticals Ltd, Gilead Sciences, Inc, and Bayer; and has received grant support from Gilead Sciences, Inc and United Therapeutics Corp. Dr Benza has grant support from Actelion Pharmaceuticals Ltd and is a member of the Steering Committee for the REVEAL Registry. Mr Miller is an employee of ICON Clinical Research, a company that receives funding from Actelion Pharmaceuticals Ltd and acts as a BioStatistical CRO for the REVEAL Registry, as well as received funding from other pharmaceutical companies. Ms Parsons is an employee of ICON Clinical Research, a company that receives funding from Actelion Pharmaceuticals Ltd and acts as a BioStatistical CRO for the REVEAL Registry, as well as received funding from other pharmaceutical companies. Dr Hassoun has received research funding support from Actelion/CoTherix and is on the Advisory Board for Novartis. Dr McGoon has received research funding from Gilead Sciences, Inc and Medtronic, Inc and has served on steering committees for Gilead Sciences, Inc and Lung Rx, LLC and has participated on clinical end-point committees in studies sponsored by Actelion Pharmaceuticals Ltd. He is on a Data Safety Monitoring Board for a study sponsored by Gilead Sciences, Inc and has received honoraria for his service on the REVEAL Registry Steering Committee, which is supported by Actelion Pharmaceuticals Ltd. Dr Zamanian has received research funding support through the Enteligence-Actelion career development research grant and has served as a consultant to United Therapeutics Corporation and Gilead Sciences, Inc. Dr Nicolls has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsor, Actelion Pharmaceuticals US Inc, provided the study design, statistical analysis plan, and management of study registry and participated in data analysis, interpretation, and preparation of manuscript.

Other contributions: The authors thank Wolters Kluwer for coordinating feedback among the authors.

Additional information: The e-Appendix can be found in the Supplemental Materials section of the online article.

6MWD

6-min walk distance

BNP

brain natriuretic peptide

CTD

connective tissue disease

CTD-APAH

pulmonary arterial hypertension associated with connective tissue disease

Dlco

diffusion capacity of the lung for carbon monoxide

FC

functional class

HR

hazard ratio

ILD

interstitial lung disease

IPAH

idiopathic pulmonary arterial hypertension

mRAP

mean right atrial pressure

non-SSc-CTD

connective tissue disease other than systemic sclerosis

NT-pro-BNP

N-terminal-pro-brain natriuretic peptide

NYHA

New York Heart Association

PAH

pulmonary arterial hypertension

PVR

pulmonary vascular resistance

REVEAL Registry

Registry to Evaluate Early and Long-Term PAH Management

RHC

right-sided heart catheterization

SBP

systolic BP

SSc

systemic sclerosis

SSc-APAH

pulmonary arterial hypertension associated with systemic sclerosis

WHO

World Health Organization

WU

Wood units

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Lefèvre G, Dauchet L, Hachulla E, et al. Survival and prognostic factors in systemic sclerosis-associated pulmonary hypertension: a systematic review and meta-analysis. Arthritis Rheum. 2013;65(9):2412-2423. [CrossRef] [PubMed]
 
Mukerjee D, St George D, Coleiro B, et al. Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis. 2003;62(11):1088-1093. [CrossRef] [PubMed]
 
Hachulla E, Launay D, Yaici A, et al; French PAH-SSc Network. Pulmonary arterial hypertension associated with systemic sclerosis in patients with functional class II dyspnoea: mild symptoms but severe outcome. Rheumatology (Oxford). 2010;49(5):940-944. [CrossRef] [PubMed]
 
Humbert M, Yaici A, de Groote P, et al. Screening for pulmonary arterial hypertension in patients with systemic sclerosis: clinical characteristics at diagnosis and long-term survival. Arthritis Rheum. 2011;63(11):3522-3530. [CrossRef] [PubMed]
 
Campo A, Mathai SC, Le Pavec J, et al. Hemodynamic predictors of survival in scleroderma-related pulmonary arterial hypertension. Am J Respir Crit Care Med. 2010;182(2):252-260. [CrossRef] [PubMed]
 
Khanna PP, Furst DE, Clements PJ, Maranian P, Indulkar L, Khanna D; D-Penicillamine Investigators. Tendon friction rubs in early diffuse systemic sclerosis: prevalence, characteristics and longitudinal changes in a randomized controlled trial. Rheumatology (Oxford). 2010;49(5):955-959. [CrossRef] [PubMed]
 
Avouac J, Walker U, Tyndall A, et al; EUSTAR. Characteristics of joint involvement and relationships with systemic inflammation in systemic sclerosis: results from the EULAR Scleroderma Trial and Research Group (EUSTAR) database. J Rheumatol. 2010;37(7):1488-1501. [CrossRef] [PubMed]
 
Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation. 2000;102(8):865-870. [CrossRef] [PubMed]
 
Mathai SC, Bueso M, Hummers LK, et al. Disproportionate elevation of N-terminal pro-brain natriuretic peptide in scleroderma-related pulmonary hypertension. Eur Respir J. 2010;35(1):95-104. [CrossRef] [PubMed]
 
Williams MH, Handler CE, Akram R, et al. Role of N-terminal brain natriuretic peptide (N-TproBNP) in scleroderma-associated pulmonary arterial hypertension. Eur Heart J. 2006;27(12):1485-1494. [CrossRef] [PubMed]
 
Allanore Y, Borderie D, Avouac J, et al. High N-terminal pro-brain natriuretic peptide levels and low diffusing capacity for carbon monoxide as independent predictors of the occurrence of precapillary pulmonary arterial hypertension in patients with systemic sclerosis. Arthritis Rheum. 2008;58(1):284-291. [CrossRef] [PubMed]
 
Thakkar V, Stevens WM, Prior D, et al. N-terminal pro-brain natriuretic peptide in a novel screening algorithm for pulmonary arterial hypertension in systemic sclerosis: a case-control study. Arthritis Res Ther. 2012;14(3):R143. [CrossRef] [PubMed]
 
Coghlan JG, Denton CP, Grünig E, et al; DETECT study group. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis. 2014;73(7):1340-1349. [CrossRef] [PubMed]
 
Wensel R, Opitz CF, Anker SD, et al. Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise testing. Circulation. 2002;106(3):319-324. [CrossRef] [PubMed]
 
Campo A, Mathai SC, Le Pavec J, et al. Outcomes of hospitalisation for right heart failure in pulmonary arterial hypertension. Eur Respir J. 2011;38(2):359-367. [CrossRef] [PubMed]
 
Weng HH, Ranganath VK, Oh M, et al. Differences in presentation of younger and older systemic sclerosis patients in clinical trials. Clin Exp Rheumatol. 2010;28(5 Suppl 62):S10-S14. [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  STROBE diagram of the Registry to Evaluate Early and Long-Term PAH Management (REVEAL) Registry patients used in this analysis. We included only patients with CTD-APAH who met the strict criteria of World Health Organization group 1 pulmonary arterial hypertension. CTD-APAH = pulmonary arterial hypertension associated with connective tissue disease; HRCT = high-resolution CT scan of the chest; ILD = interstitial lung disease; non-SSc-CTD = connective tissue disease other than systemic sclerosis; PCWP = pulmonary capillary wedge pressure; SSc = systemic sclerosis; TLC = total lung capacity.Grahic Jump Location
Figure Jump LinkFigure 2 –  Three-year survival curves in patients with SSc and non-SSc-CTD-APAH. A, Three-year survival from enrollment in the newly diagnosed SSc group was 51.2% ± 4.0% compared with 76.4% ± 4.6% in the non-SSc-CTD group (P < .001). B, Three-year survival from enrollment in the previously diagnosed SSc group was 61.4% ± 2.7% compared with 80.9% ± 2.7% in the non-SSc-CTD group (P < .001). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 3 –  Predictors of mortality for patients with SSc-APAH and non-SSc-CTD-APAH using univariate Cox regression analyses. Unique predictors of mortality in the SSc group, but not the non-SSc group, included male sex, SBP ≤ 110 mm Hg, pericardial effusion, DLCO ≤ 32% predicted, mRAP > 20 mm Hg within 1 y, PVR > 32 WU, and newly diagnosed status. BNP levels < 50 pg/mL were protective in patients with SSc, but not in the non-SSc group. Higher GFR was protective in both groups. Mild to moderate ILD was the only feature that increased mortality in the non-SSc group but not in patients with SSc. 6MWD = 6-min walk distance; BNP = brain natriuretic peptide; DLCO = diffusion capacity of the lung for carbon monoxide; FC = functional class; GFR = glomerular filtration rate; HR = hazard ratio; mRAP = mean right atrial pressure; NYHA = New York Heart Association; PVR = pulmonary vascular resistance; SBP = systolic BP; WHO = World Health Organization; WU = Wood units. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Types of CTD-APAH

APAH = associated with pulmonary arterial hypertension; CTD = connective tissue disease; non-SSc-CTD = connective tissue disease other than systemic sclerosis; SSc = systemic sclerosis.

Table Graphic Jump Location
TABLE 2 ]  Characteristics, Hemodynamics, and Cardiac and Pulmonary Function at Enrollment

P value calculation uses χ2 test for categorical data or Fisher exact test for categorical data with small cell counts (≤ 5%), and Student t test for continuous data. 6MWD = 6-min walk distance; BNP = brain natriuretic peptide; bpm = beats per min; CCB = calcium channel blocker; Dlco = diffusion capacity of the lung for carbon monoxide; ERA = endothelin receptor agonist; FC = functional class; FCO = Fick cardiac output; mPAP = mean pulmonary arterial pressure; mRAP = mean right atrial pressure; NYHA = New York Heart Association; PAH = pulmonary arterial hypertension; PCWP = pulmonary capillary wedge pressure; PDE-5 = phosphodiesterase type-5; PVR = pulmonary vascular resistance; RHC = right-sided heart catheterization. See Table 1 legend for expansion of other abbreviations.

a 

Age = (date of informed consent − date of birth)/365.25.

b 

Cardiac output = FCO, or, if FCO is missing, then cardiac output = thermodilution cardiac output.

c 

PVR (Wood units) = (mean pulmonary arterial pressure at rest − PCWP at rest)/cardiac output, where cardiac output = FCO, or, if FCO is missing, then cardiac output = thermodilution cardiac output.

d 

Predicted value based on Hankinson et al14 computation.

e 

FEV1/FVC ratio is missing if FVC is zero.

Table Graphic Jump Location
TABLE 3 ]  Multivariate Model of Predictors of Mortality

HR = hazard ratio. See Table 1 and 2 legends for expansion of other abbreviations.

References

Hesselstrand R, Wildt M, Ekmehag B, Wuttge DM, Scheja A. Survival in patients with pulmonary arterial hypertension associated with systemic sclerosis from a Swedish single centre: prognosis still poor and prediction difficult. Scand J Rheumatol. 2011;40(2):127-132. [PubMed]
 
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Chung L, Liu J, Parsons L, et al. Characterization of connective tissue disease-associated pulmonary arterial hypertension from REVEAL: identifying systemic sclerosis as a unique phenotype. Chest. 2010;138(6):1383-1394. [CrossRef] [PubMed]
 
Rubenfire M, Huffman MD, Krishnan S, Seibold JR, Schiopu E, McLaughlin VV. Survival in systemic sclerosis with pulmonary arterial hypertension has not improved in the modern era. Chest. 2013;144(4):1282-1290. [CrossRef] [PubMed]
 
Condliffe R, Kiely DG, Peacock AJ, et al. Connective tissue disease-associated pulmonary arterial hypertension in the modern treatment era. Am J Respir Crit Care Med. 2009;179(2):151-157. [CrossRef] [PubMed]
 
Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010;122(2):164-172. [CrossRef] [PubMed]
 
Humbert M, Sitbon O, Yaïci A, et al; French Pulmonary Arterial Hypertension Network. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J. 2010;36(3):549-555. [CrossRef] [PubMed]
 
Ngian GS, Stevens W, Prior D, et al. Predictors of mortality in connective tissue disease-associated pulmonary arterial hypertension: a cohort study. Arthritis Res Ther. 2012;14(5):R213. [CrossRef] [PubMed]
 
Launay D, Sitbon O, Hachulla E, et al. Survival in systemic sclerosis-associated pulmonary arterial hypertension in the modern management era. Ann Rheum Dis. 2013;72(12):1940-1946. [CrossRef] [PubMed]
 
Chung L, Domsic RT, Lingala B, et al. Survival and predictors of mortality in systemic sclerosis associated pulmonary arterial hypertension: outcomes from the PHAROS registry. Arthritis Care Res (Hoboken). 2014;66(3):489-495. [CrossRef] [PubMed]
 
McGoon MD, Krichman A, Farber HW, et al. Design of the REVEAL registry for US patients with pulmonary arterial hypertension. Mayo Clin Proc. 2008;83(8):923-931. [CrossRef] [PubMed]
 
Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. [CrossRef] [PubMed]
 
Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137(2):376-387. [CrossRef] [PubMed]
 
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general US population. Am J Respir Crit Care Med. 1999;159(1):179-187. [CrossRef] [PubMed]
 
Lefèvre G, Dauchet L, Hachulla E, et al. Survival and prognostic factors in systemic sclerosis-associated pulmonary hypertension: a systematic review and meta-analysis. Arthritis Rheum. 2013;65(9):2412-2423. [CrossRef] [PubMed]
 
Mukerjee D, St George D, Coleiro B, et al. Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis. 2003;62(11):1088-1093. [CrossRef] [PubMed]
 
Hachulla E, Launay D, Yaici A, et al; French PAH-SSc Network. Pulmonary arterial hypertension associated with systemic sclerosis in patients with functional class II dyspnoea: mild symptoms but severe outcome. Rheumatology (Oxford). 2010;49(5):940-944. [CrossRef] [PubMed]
 
Humbert M, Yaici A, de Groote P, et al. Screening for pulmonary arterial hypertension in patients with systemic sclerosis: clinical characteristics at diagnosis and long-term survival. Arthritis Rheum. 2011;63(11):3522-3530. [CrossRef] [PubMed]
 
Campo A, Mathai SC, Le Pavec J, et al. Hemodynamic predictors of survival in scleroderma-related pulmonary arterial hypertension. Am J Respir Crit Care Med. 2010;182(2):252-260. [CrossRef] [PubMed]
 
Khanna PP, Furst DE, Clements PJ, Maranian P, Indulkar L, Khanna D; D-Penicillamine Investigators. Tendon friction rubs in early diffuse systemic sclerosis: prevalence, characteristics and longitudinal changes in a randomized controlled trial. Rheumatology (Oxford). 2010;49(5):955-959. [CrossRef] [PubMed]
 
Avouac J, Walker U, Tyndall A, et al; EUSTAR. Characteristics of joint involvement and relationships with systemic inflammation in systemic sclerosis: results from the EULAR Scleroderma Trial and Research Group (EUSTAR) database. J Rheumatol. 2010;37(7):1488-1501. [CrossRef] [PubMed]
 
Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation. 2000;102(8):865-870. [CrossRef] [PubMed]
 
Mathai SC, Bueso M, Hummers LK, et al. Disproportionate elevation of N-terminal pro-brain natriuretic peptide in scleroderma-related pulmonary hypertension. Eur Respir J. 2010;35(1):95-104. [CrossRef] [PubMed]
 
Williams MH, Handler CE, Akram R, et al. Role of N-terminal brain natriuretic peptide (N-TproBNP) in scleroderma-associated pulmonary arterial hypertension. Eur Heart J. 2006;27(12):1485-1494. [CrossRef] [PubMed]
 
Allanore Y, Borderie D, Avouac J, et al. High N-terminal pro-brain natriuretic peptide levels and low diffusing capacity for carbon monoxide as independent predictors of the occurrence of precapillary pulmonary arterial hypertension in patients with systemic sclerosis. Arthritis Rheum. 2008;58(1):284-291. [CrossRef] [PubMed]
 
Thakkar V, Stevens WM, Prior D, et al. N-terminal pro-brain natriuretic peptide in a novel screening algorithm for pulmonary arterial hypertension in systemic sclerosis: a case-control study. Arthritis Res Ther. 2012;14(3):R143. [CrossRef] [PubMed]
 
Coghlan JG, Denton CP, Grünig E, et al; DETECT study group. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis. 2014;73(7):1340-1349. [CrossRef] [PubMed]
 
Wensel R, Opitz CF, Anker SD, et al. Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise testing. Circulation. 2002;106(3):319-324. [CrossRef] [PubMed]
 
Campo A, Mathai SC, Le Pavec J, et al. Outcomes of hospitalisation for right heart failure in pulmonary arterial hypertension. Eur Respir J. 2011;38(2):359-367. [CrossRef] [PubMed]
 
Weng HH, Ranganath VK, Oh M, et al. Differences in presentation of younger and older systemic sclerosis patients in clinical trials. Clin Exp Rheumatol. 2010;28(5 Suppl 62):S10-S14. [PubMed]
 
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