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J Scleroderma Relat Disord. 2018 Oct;3(3):242-248. doi: 10.1177/2397198318764780. Epub 2018 Mar 22.

Patients with systemic sclerosis-associated pulmonary arterial hypertension express a genomic signature distinct from patients with interstitial lung disease.

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Pulmonary and Critical Care Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
Division of Rheumatology, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Clinical Epidemiology Research and Training Unit, Boston University School of Medicine, Boston, Massachusetts, USA.
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, 7400 Remsen, Hanover, NH, 03755, USA.
Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15261, USA.
Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA.



Pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) are major causes of mortality in systemic sclerosis (SSc). We used a previously identified microarray biomarker to determine if SSc-PAH and SSc-ILD patients demonstrate distinct gene expression profiles.


PBMCs were collected from healthy controls (n=10), SSc (SSc) patients without pulmonary hypertension [SSc-noPAH, n=39], and SSc-PAH patients (n=21; mPAP25, PCWP≤15, PVR≥3WU) diagnosed by right heart catheterization (RHC). SSc-ILD patients were defined as those with evidence of fibrosis on chest CT and significant restriction (FVC<70% predicted, n = 11). SSc-PAH biomarker included 69 genes selected by unbiased statistical screening of 3 publicly available microarray studies. RNA levels were measured by Nanostring. Gene expression levels that were significantly correlated with PAH (multiple statistical measures) were chosen as inputs into a forward selection logistic regression model.


When ILD patients were included (n=64), 4 genes (S100P, CD8B1, CCL2, TIMP1) and male sex predicted PAH with a high level of accuracy (AUC = 0.83). Without ILD patients (n=53), 2 genes (THBS1, CD8B1) and male sex predicted PAH with a high level of accuracy (AUC = 0.80). When examining SSc patients with borderline elevated pulmonary pressures (mPAP = 21-24 mmHg), gene expression changes closely resembled the SSc-PAH group, except for THBS1.


SSc-PAH and SSc-ILD have similar, but distinct, gene expression profiles. Many gene expression changes occur early in the disease course, potentially allowing for early detection. THBS1 appears to be an important mediator in the development of PAH-predominant phenotype. Further prospective investigation is warranted.

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