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

Abstract

Objective. 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. Methods. PBMCs were collected from healthy controls (n=10), SSc (SSc) patients without pulmonary hypertension [SSc-noPAH, n=39], and SSc-PAH patients (n=21; mPAP≥25, 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. Results. 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. Conclusion. 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.

Expert Perspectives On Clinical Challenges: Expert Perspectives: Challenges in Scleroderma

“…Approximately 10% of patients with SSc-ILD have a progressively worsening trajectory. Identification of these patients with genomic signatures was reported recently but has not been evaluated prospectively (47,48). Clinical predictors of SSc-ILD progression have been identified-notably more severe physiologic impairment, which is, not surprisingly, associated with higher mortality (45,49,50).…”

“…Recently described genomic predictors of SSc-ILD outcomes (47,48) require further refinement and confirmation before they can potentially become useful in clinical disease management.…”

The Role of Type 2 Inflammation in Schistosoma-Induced Pulmonary Hypertension

“…In these samples, we found the concentration of TSP-1 increased significantly after the patients developed PAH (28). TSP-1 gene expression in peripheral blood mononuclear cells in patients with scleroderma has also been reported to predict the diagnosis of PAH (30). These results are corroborated by another recent report that higher TSP-1 levels in patients with varied forms of PAH correlate with worse prognosis (31).…”

Increased expression of GAB1 promotes inflammation and fibrosis in systemic sclerosis

“…The prognosis of dcSSc is worse than lcSSc because of the higher frequency of internal organ involvement. [2,3] Additionally, SSc is characterized by various autoantibodies in peripheral blood, including anti-DNA topoisomerase I antibodies (ATA), anti-centromere antibodies (ACA), antinuclear antibody (ANA) and anti-U1 RNP antibodies (U1RNP). Autoantibodies in SSc are not only helpful for making an early diagnosis, but also for predicting the disease subset and pattern of organ involvement.…”