Serum IGFBP-2 in Systemic Sclerosis as a Protective Factor of Lung Dysfunction

Abstract

Background Systemic sclerosis (SSc) is a rare connective tissue disease associated with rapid evolving interstitial lung disease (SSc-ILD), driving its mortality. Specific biomarkers associated with the progression of this lung disease are highly needed. We aimed to identify specific biomarkers of SSc-ILD to predict the evolution of the disease.Methods We compared prospectively serum levels of several biomarkers associated with lung fibrosis in SSc patients (n = 102) compared to healthy subjects (HS) (n = 39). We also performed a longitudinal study in a subgroup of 28 patients analyzing biomarkers variations and pulmonary function tests over a period of 2 years. Furthermore, we performed in vitro analysis to study the impact of Insulin like Growth Factor Binding Protein (IGFBP)-2 on fibrotic activity of human lung fibroblasts.Results Serum levels of IGFBP-1, IGFBP-2, interleukin-8 and matrix metallopeptidase-9 were significantly increased in SSc patients compared to HS while IGF-1 and IGFBP-3 were reduced. The variation of IGFBP-2 between baseline and 2-year follow-up was positively correlated with pulmonary function (assessed by carbon monoxide transfer coefficient (KCO)) at 2-year follow-up (r = 0.6, p < 0.001). Receiver operating characteristic curve analysis enabled us to identify that baseline IGFBP-2 < 105 ng/ml was associated with a better outcome (low risk to display KCO < 70% predicted) at 2-year follow-up (area under the curve = 0.75 at 75% sensibility and 68% specificity, p < 0.05). In vitro functional study showed that IGFBP-2 significantly reduced fibroblast proliferation and pro-fibrotic activity.Conclusions We showed for the first time that serum levels of IGFBP-2 might predict the evolution of SSc-ILD. Baseline IGFBP-2 above 105 ng/ml might be a prognostic factor of alveolo-capillary dysfunction.