Background/Purpose: Pulmonary arterial hypertension (PAH) is one of the leading causes of death in patients with systemic sclerosis (SSc).  Non-invasive biomarkers are needed to identify patients with early PAH who may benefit from early intervention.  We sought to identify novel cytokines that differentiate patients with incident right heart catheterization (RHC)-confirmed SSc-PAH from SSc patients who are at high risk for PAH.

Methods: The Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) Registry is a registry of SSc patients at high risk for or with incident RHC-confirmed PAH that includes 23 centers throughout the US.  Pre-PAH patients fulfill at least one of the following criteria: pulmonary artery systolic pressure (PASP) ≥ 40 mmHg on transthoracic echocardiogram (TTE), diffusing capacity of carbon monoxide (DLCO) < 55% predicted, or forced vital capacity (FVC)/DLCO ratio > 1.6.   Patients with definite incident PAH have a mean pulmonary artery pressure ≥ 25 mmHg and a pulmonary capillary wedge pressure ≤ 15 mmHg (without significant interstitial lung disease) on RHC performed ≤ 6 months from enrollment.  Cytokine and chemokine profiling of 17 cytokines/chemokines measured by Bio-Plex^TM bead arrays was performed comparing serum samples from 10 pre-PAH patients to 9 definite PAH patients.  Significance Analysis of Microarrays (SAM) was used to identify statistical differences in cytokines/chemokines between the groups with a false discovery rate (q) <0.1%.  We also evaluated for longitudinal changes in cytokine profiles from 3 pre-PAH patients who subsequently developed definite PAH during follow-up.

Results: All patients were female with a mean age of 52±12 years and disease duration from first Raynaud’s symptom of 13±10 years.  Two-thirds of patients had limited cutaneous disease, 37% were anti-centromere antibody positive, 32% had a nucleolar ANA, and 16% were anti-U1RNP antibody positive.  Mean FVC and DLCO were 82±20% and 45±13% predicted, respectively.  Clinical features in the pre- vs. definite PAH groups were not significantly different except with respect to PASP on TTE (34±7 vs. 45±8 mmHg, p=0.006) and 6 minute walk distance (508±115 vs. 393±70 m, p=0.02).  Profiling of the pre-PAH vs. definite PAH group identified only one cytokine whose expression levels significantly differed between the groups—hepatocyte growth factor (HGF) levels were significantly higher in the definite PAH group (q<0.1%).  Evaluation of cytokine profiling from longitudinal samples of pre- to definite-PAH patients did not identify any cytokines with significant changes in expression levels over time.

Conclusion: We found that patients with definite incident PAH from the PHAROS registry expressed higher levels of HGF than patients at high risk for PAH.  HGF is a potent pro-angiogenic and anti-fibrotic factor, and has been shown to correlate significantly with right ventricular systolic pressure on echocardiogram as well as a diagnosis of PAH based on RHC.  Our findings suggest that HGF expression levels may provide predictive information regarding the risk for PAH in patients with SSc in addition to clinical parameters such as DLCO and PASP on TTE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/differential-expression-of-hepatocyte-growth-factor-hgf-in-patients-with-systemic-sclerosis-associated-pulmonary-arterial-hypertension/