IGFBP-2: a new pathway in systemic sclerosis associated interstitial lung disease

Background: Systemic sclerosis (SSc) is a rare connective tissue disease associated with potential rapid evolving interstitial lung disease (SSc-ILD), driving the mortality of these patients. Therefore, a specific biomarker associated with the evolution of that disease is highly needed to identify patients with an increased risk of death. Aim of the Study: Identify specific biomarkers of SSc-ILD to predict the evolution of the disease. Methods: In this prospective longitudinal study, we compared serum levels of biomarkers assumed to be associated with lung fibrosis (TGF-β, IGF-1, IGFBP-1, IGFBP-2, IGFBP-3, IL-8, MMP-7, MMP-9, YKL-40 and TNF-α) among three groups: SSc-ILD (n=39), SSc without ILD (n=63) and healthy subjects (HS)(n=39). We also prospectively analyzed variations of biomarkers and correlated them to pulmonary function tests (n=28). Then, we realized an in vitro analysis to study the potential anti-fibrotic effect of IGFBP-2 (n=3). Results: IGFBP-2, IL-8 and MMP-9 are increased in SSc patients compared to HS (p<0.05, p<0.0001, p<0.05 respectively). IGFBP-1 is reduced in SSc-ILD compared to those without ILD (p<0.05). An increase of 25% of the initial IGFBP-2 serum level is associated with an improvement of DLCO/VA (R=0.6;p<0.0001). Finally, the in vitro study showed that anti-IGFBP-2 significantly increased pro-Col-I production (p<0.5) and fibroblast proliferation (p<0.05). Conclusion: IGFBP-1 has a potential interest to identify early SSc-ILD whereas IGFBP-2 would rather predict the risk of a rapid evolution of lung fibrosis. Moreover, in vitro studies confirmed the anti-fibrotic effect of IGFBP-2 underlying its potential interest in further mechanical studies and therapeutic aspects.