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Limited Cutaneous and Diffuse Cutaneous Scleroderma: Circulating Biomarkers Differentiate Lung Involvement

Kevin J Keen, Stephan F van Eeden and James V Dunne

Study background: Insufficient or absent angiogenesis are hallmarks of scleroderma (SSc). Microvascular change is an early manifestation of SSc followed by intimal proliferation and fibrosis of arterioles resulting in reduced blood flow and tissue ischemia. This ongoing vasculopathy in the lungs presents clinically as pulmonary hypertension and characteristically precedes lung fibrosis in patients.

The purpose of this preliminary study is to elucidate possible interrelationships amongst circulating microparticles, angiogenic and angiostatic factors in SSc patients that are predictive of interstitial lung disease and high values of right ventricular systolic pressure (RVSP) by trans-thoracic Doppler-echocardiography (TTE).

Methods: Nineteen cases with limited cutaneous SSc (lcSSc) and 11 cases with diffuse cutaneous SSc (dcSSc) were compared to 30 age- and sex-matched healthy controls. High resolution computed tomography was used to establish the diagnosis of interstitial lung disease and TTE was used to estimate RVSP and to diagnose putative pulmonary arterial hypertension (PAH). Plasma concentrations of circulating factors were assessed in patients and controls.

Results: Angiopoetin-2, endostatin, E-selectin and platelet microparticles were higher in lcSSc cases compared to healthy controls (p<0.0001, p=0.0008, p=0.0003, p=0.0020, respectively). Only endostatin was higher in dcSSc cases (p=0.0020). In a classification tree analysis, concentrations of soluble E-selectin of at least 44.7 ng/ml and 37.2 ng/ml were predictive of ILD and PAH, respectively, in lcSSc cases, whereas, endothelial microparticle levels higher than 96 per μl were predictive of ILD in dcSSc cases.

Conclusion: Scleroderma cases can be differentiated from healthy controls based on higher concentrations of the angiostatic factor endostatin. E-selectin was associated with lung involvement in lcSSc, whereas, high levels of endothelial microparticles were associated with ILD in dcSSc.