Biomarkers for Pulmonary Vascular Remodeling in Systemic Sclerosis: A Pathophysiological Approach

Abstract

Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc) associated with high morbidity and mortality. There are several biomarkers of SSc-PAH, reflecting endothelial physiology, inflammation, immune activation, extracellular matrix, metabolic changes, or cardiac involvement. Biomarkers associated with diagnosis, disease severity and progression have been identified, however, very few have been tested in a prospective setting. Some antinuclear antibodies such as nucleosome antibodies (NUC), anti-centromere antibodies (CENP-A/B) and anti-U3-ribonucleoprotein (anti-U3-RNP) are associated with PAH while anti-U1-ribonucleoprotein (anti-U1-RNP) is associated with a reduced PAH risk. Anti-endothelin receptor and angiotensin-1 receptor antibodies might be good markers of SSc-PAH and progression of pulmonary vasculopathy. Regarding the markers reflecting immune activation and inflammation, there are many inconsistent results. CXCL-4 was associated with SSc progression including PAH and lung fibrosis. Growth differentiation factor (GDF)-15 was associated with PAH and mortality but is not specific for SSc. Among the metabolites, kynurenine was identified as diagnostic marker for PAH, however, its pathologic role in the disease is unclear. Endostatin, an angiostatic factor, was associated with heart failure and poor prognosis. Established heart related markers, such as N-terminal fragment of A-type natriuretic peptide/brain natriuretic peptide (NT-proANP, NT-proBNP) or troponin I/T are elevated in SSc-PAH but are not specific for the right ventricle and may be increased to the same extent in left heart disease. Taken together, there is no universal specific biomarker for SSc-PAH, however, there is a pattern of markers that is strongly associated with a risk of vascular complications in SSc patients. Further comprehensive, multicenter and prospective studies are warranted to develop reliable algorithms for detection and prognosis of SSc-PAH.

The Transcription Factor SCX is a Potential Serum Biomarker of Fibrotic Diseases

“…In contrast, low levels prevailed in healthy controls and HP, an inflammatory lung disease with few fibrotic cases. SCX as a biomarker will probably be more useful if applied together with other noninvasive IPF and SSc markers in a diagnostic-prognostic panel including chemokines (CCL18 and CXCL13), interleukins (Il-6, Il-13, and Il-8), and metalloproteinases (MMP7, MMP8, MMP9, MMP10, and MMP28) [7,[55][56][57], once validated as fibrosis markers.…”

Distinct T cell chromatin landscapes in scleroderma subtypes

“…ACA and RNAIII antibodies are mutually exclusive in > 95% of patients (Domsic and Medsger, 2016) and are associated with different clinical outcomes (e.g., pulmonary arterial hypertension and scleroderma renal crisis most commonly present in ACA and RNAIII-positive SSc patients, respectively) (Nguyen et al, 2010;Odler et al, 2018;Steen et al, 2007). Given these clinical attributes, the lack of a significant number of Scl70 patients, and the consistent presence of ANA in nearly every patient, we focused our autoantibody analyses on differences arising from ACA and RNAIII expression ( Table 1).…”

Role of Growth Differentiation Factor 15 in Lung Disease and Senescence: Potential Role Across the Lifespan

“…Significantly, circulating concentrations of GDF15 are elevated and correlate with severity of disease in IPF patients (41). GDF15 levels were also increased in patients with systemic sclerosis and correlated with clinical symptoms of lung fibrosis and deterioration in lung function (78). Determining the nature of GDF15's role in pulmonary fibrosis will be crucial to elucidating how GDF15 may be used alone or in combination as a diagnostic, prognostic biomarker, or both.…”