SSc is a complexe multi-organ disorder with heterogeneous clinical features. As the diagnosis of SSc-ILD is complex, there is a need to develop novel biomarkers to identify early patients in order to deliver more appropriate treatment. Here, we quantified serum level of several SSc- or IPF-associated growth factors in SSc patients compared to HS. SSc patients featured a marked increase in serum levels of IGFBP-1, IGFBP-2, IL-8, MMP-9 and CRP whereas IGF-1 and IGFBP-3 were significantly reduced compared to HS. Of interest, IGFBP-2 was negatively correlated to KCO at baseline. Two-year longitudinal analysis determined that IGFBP-2 variation was positively correlated with the KCO measurement. Of great interest, initial levels of IGFBP-2 above 105 ng/ml were associated with a poor patient’s outcome 2 years later (KCO < 70% predicted), suggesting that serum levels of IGFBP-2 might predict the evolution of SSc-ILD.
In previous studies, we have identified that IGFBP-2 was positively associated with lung fibrosis in serum and induced sputum of IPF patients [32, 34]. Moreover, IGFBP-2 was reduced in IPF patients receiving anti-fibrotic therapy, although serum levels remained higher in IPF patients than in HS . Other studies on lung fibrosis identified a significant increase of IGFBP-2 in bronchoalveolar lavage (BAL) fluid and in lung tissue of ILDs without focusing on systemic sclerosis . In this study, we showed that patients suffering from SSc exhibited higher levels of IGFBP-2 than HS, but to a lesser extent than patients suffering from IPF (as previously shown in one of our study ). Of interest, we demonstrated that level variation of IGFBP-2 was associated with the severity of lung dysfunction. Indeed, baseline serum level of IGFBP-2 above 105 ng/ml allows identifying patients with a poor prognosis at 2-year follow-up (KCO < 70% predicted). This interesting observation suggests the potential prognostic value of baseline IGFBP-2 to identify SSc patients with risk of rapid evolution. Integrating new biomarkers in the follow up of SSc-ILD is challenging taking into account the variability of other clinical markers like symptoms, CRP, DLCO or FVC. Moreover, it is suitable to avoid repeated chest imaging in the follow-up of the patients to limit as much as possible irradiation. The use of serum biomarker IGFBP-2 could be a good candidate to predict the progression of SSc-ILD and need to be explored.
In our study, serum levels of TGF-β were similar for all groups even though TGF-β is widely known to be associated with the pathophysiology of fibrosing lung disease . Similarly, our previous study focusing on IPF did not find any difference in TGF-β levels between HS and patients suffering from IPF leading to the conclusion that serum TGF-β is not a good biomarker of lung fibrosis .
YKL-40 was negatively correlated with pulmonary function tests in our study (FEV1, FVC, DLCO). Confirming previous studies, we identified that YKL-40 is associated with the lung function impairment of patients suffering from SSc [37–39]. Therefore, these observations need further explorations to see whether YKL-40 could act as a predictor of lung degradation for patients with SSc.
IL-8 was also increased in our study in SSc patients. IL-8 is known to be a strong chemotactic agent for neutrophils and can impact the pathophysiological process of SSc by recruiting neutrophils in lungs [40, 41]. Of interest, it should be noted that blood neutrophils were increased in SSc patients compared to HS. Furthermore, several studies have shown that patients with SSc-ILD patients have elevated levels of pro-inflammatory cytokines such as interleukin IL-8, IL-6, TNF-α in BAL fluid and serum [6, 42, 43]. In the same line, MMP-9 was also increased in SSc context. MMP-9 is known to be actively secreted by neutrophils [44, 45], which are increased in SSc patients.