Development of pulmonary hypertension in a high-risk population with systemic sclerosis in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) cohort study

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Abstract

Objectives

PHAROS registry is a prospective longitudinal cohort study to understand the natural history of pulmonary hypertension (PH) in systemic sclerosis (SSc).

Methods

“At-risk” pulmonary arterial hypertension (PAH) is defined by these entry criteria: echocardiogram (echo) systolic pulmonary arterial pressure (sPAP) >40 mmHg, diffusion lung capacity of carbon monoxide (DLco) <55% predicted, or ratio of percentage forced vital capacity (FVC)/percentage DLco >1.6, as measured by pulmonary function testing (PFT). Patients were followed up annually and right heart catheterization (RHC) performed if PH was suspected. We used descriptive statistics and Kaplan–Meier estimate of time to PH diagnosis.

Results

A total of 251 “at-risk” subjects were enrolled between 2005 and 2012 and followed up for mean of 2.5 ± 1.2 years. The mean age at entry was 56.7 ± 11.0 and disease duration was 9.9 ± 8.7 years.

Overall, 82 patients had RHC, and 35 were confirmed to have new PH. There were no differences in age, gender, SSc subtypes, antibodies, and disease duration between the “at-risk” and new PH groups. Using Kaplan–Meier survival, the time to PH was 10% at 2 years, 13% at 3 years, and 25% at 5 years. Most new PH patients at entry met the PFT criteria (76%), had significantly higher sPAP (p = 0.013), had shorter 6-min walk distance, and had exercise-induced hypoxia (p = 0.003) than “at-risk” PAH group.

Conclusions

A low DLco, high FVC/DLco, exercise-induced hypoxia and entry echo sPAP > 40 were strongly associated with future PH, though RHC was necessary to confirm PH. This ongoing prospective study confirms that these high-risk factors do predict future PH.

Introduction

Systemic sclerosis (SSc) is a rare, often fatal disease with an unknown cause and no known effective therapy. One of the most serious complications of systemic sclerosis is pulmonary arterial hypertension (PAH), which has a prevalence of 8–12%, and is the most frequent cause of death in patients with this disease [1]. New treatments for PAH have significantly improved outcomes of this previously uniformly fatal complication but scleroderma patients have poorer outcomes [2]. Autopsy evidence [3] of arterial involvement prior to PAH onset supports the observation that this complication develops over long periods of time; therefore, early identification of scleroderma-associated PAH is critical. Dyspnea is a common symptom in scleroderma and can be attributed to many contributing causes in addition to cardiopulmonary etiologies in a given patient, including anemia, cardiac dysfunction, or interstitial lung disease. Thus, PAH is challenging to detect in its earliest stages, when it is believed that intervention would have the greatest impact on survival [4].

Classically, PAH develops in patients with limited cutaneous SSc and manifests as isolated pulmonary arterial hypertension (PAH) 10–15 years after onset of Raynaud׳s phenomenon [5]. Although an elevated resting systolic pulmonary arterial pressure (sPAP) >40 mmHg measured by echocardiography has been associated with PAH [5], it has not been shown to be predictive of future PAH. However, an isolated decrease in the diffusing capacity for carbon monoxide (percentage DLco) may occur years prior to the development of increased pulmonary arterial pressure [5] in the absence of significant pulmonary fibrosis. The %FVC/%DLco ratio >1.6 is considered a risk factor from retrospective analyses but has not been demonstrated prospectively [6].

Patients with diffuse cutaneous SSc are at greatest risk of developing interstitial lung disease (ILD) within 5 years of disease onset [6], usually marked by a decline in forced vital capacity (percentage FVC). This group may also develop modest pulmonary hypertension (PH) at any stage in their disease course as a consequence of chronic hypoxia from their extensive ILD. A subgroup of diffuse cutaneous SSc patients may develop rapidly worsening PH in the setting of extensive ILD and the mortality rate has been reported to be 5-fold compared to those with the isolated PAH [6], [7].

The PHAROS registry is a prospective observational longitudinal cohort study that was established to determine the time to PH in a group of patients with pre-determined high-risk factors (the “at-risk” PH cohort) for developing PH and PAH, and the natural history of definite SSc-PAH and SSc-PH. This article will address 2 study objectives in the population enrolled in PHAROS: to determine the risk of progression from “at-risk” PH to diagnosable pulmonary hypertension based on right heart catheterization, and to identify additional risk factors or clinical characteristics that may predict who will develop significant PH.

Section snippets

Methods

The PHAROS study has been previously described [8]. Overall, 18 US medical centers with a special interest in scleroderma participated in PHAROS in compliance with the US Health Insurance Portability and Accountability Act (HIPAA). Each participating center׳s local institutional review board approved the study protocol. Eligible subjects were identified by the principal investigator at their site and each subject was enrolled willingly after signing the informed consent form. Although funded by

Statistical analysis

The Fisher exact test and the chi-square test were used to compare the distribution of categorical characteristics such as sex, race, SSc subtype, antibody of subgroups, and hypoxia during exercise and number of patients who met PFT or echo sPAP criteria. The Student t-test was used to assess for differences in continuous variables, such as FVC/DLco, echo sPAP, and age at SSc onset and SSc duration among subgroups. Univariate logistic regression analyses were performed to detect risk factors

Total “at-risk” population

There were 251 “at-risk” for PAH subjects enrolled in PHAROS between May 2005 and June 2012 and followed up for a mean of 2.5 ± 1.2 years. There were 33 (13%) males; mean age of SSc at enrollment was 56.7 ± 11.0 years and mean years from onset of Raynaud׳s symptoms was 11.5 ± 11.6 years. There were 72.6% Caucasians, 18% African Americans, 5.7% Hispanics, and 4% other ethnic groups. Scleroderma antibodies were known in 217 patients: 26% anti-centromere (ACA), 16% anti-topoisomerase (Scl70), 7.3%

Discussion

This study demonstrates that patients who are at high risk for PH actually do develop definite PH during the 6-year follow-up time period and this risk increased with time. Our pre-determined risk factors, along with other known demographic features did identify patients, particularly those with long-standing limited scleroderma, those with DLco < 55% predicted, an FVC/DLco > 1.6, or resting echo sPAP > 40 mmHg who did develop definite PH. Additionally, a decreasing 6-min walk distance and

Conclusion

We have prospectively confirmed that high-risk systemic sclerosis patients do develop PH. In addition to a low DLco, a high FVC/DLco ratio, and an entry echo sPAP > 40 mmHg, exercise-induced hypoxia was strongly associated with future PH. Frequent false elevations in echo sPAP required a RHC to confirm PH. This ongoing prospective study is an important resource to elucidate outcomes and risk factors for PAH. We remain optimistic that early identification and treatment of SSc–PH will

Acknowledgments

We are indebted to Dr. Qi Cheng for her statistical support in this article.

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    Institution of origin: Georgetown University School of Medicine, Washington, DC.

    Sources of support: Gilead Sciences, Actelion Pharmaceuticals, Scleroderma Foundation, and the Mackley Foundation of Sibley Hospital. The sponsors had no role in the design, collection, analysis, or interpretation of data for this study.

    Competing interests: Dr. Hsu has received honoraria (<$10,000) for consulting services from United Therapeutics and research funding from Gilead, United Therapeutics, and Pfizer. Dr. Chung has received honoraria for consulting services from Gilead and Actelion and research funding from Gilead, United Therapeutics, and Pfizer. Dr. Fischer has received honoraria for consulting services from Actelion and Gilead. Dr. Furst has received honoraria for consulting services from Actelion and Gilead. Dr. Khanna has served on the Speakers׳ Bureau for Actelion and United Therapeutics; has served as a consultant for Actelion, Bayer, BMS, Genentech, Gilead, and United Therapeutics; and has received research funding from Actelion, PHA, Scleroderma Foundation, and United Therapeutics. Dr. Molitor has served on a Data Monitoring Committee for Actelion. Dr. Simms has served on the Speakers׳ Bureau for Gilead and Actelion and has received research funding from Gilead, Actelion, and United Therapeutics. Dr. Mayes received more than $10,000 consulting fees from Actelion. Dr. Steen has served on the Speakers׳ Bureau for Actelion and Gilead; has served as a consultant for Gilead and United Therapeutics; and has received research funding from Actelion, Gilead, Pfizer, and United Therapeutics.

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