Plasma CXCL4–DNA/RNA Complexes and Anti-CXCL4 Antibodies Modulation in an SSc Cohort under Iloprost Treatment

Background: Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular and immunity alterations and skin/internal organ fibrosis. Aberrant levels of plasma CXCL4, CXCL4-RNA/DNA complexes, type I IFN (IFN-I) and anti-CXCL4 antibodies characterize SSc. These parameters influence each other: CXCL4-self-DNA/RNA complexes are triggers of IFN-I in plasmacytoid dendritic cells (pDCs), and anti-CXCL4 autoantibodies amplify this effect. Here, we assess the modulation over time of plasma CXCL4 and the related parameters of CXCL4-DNA/RNA complexes, anti-CXCL4 antibodies, IFN-alpha and TNF-alpha in an SSc cohort under the synthetic analogue of prostacyclin PGI2 (iloprost) treatment to address contribution of these parameters to pathogenesis and their role as biomarkers. Methods: We analyzed immunological parameters at baseline (T0) and after 3 (T3) and 6 (T6) months in 30 SSc patients. Responders were the patients that lowered their disease activity parameters after six months of treatment. Results: Anti-CXCL4 autoantibodies correlated with both IFN-alpha and TNF-alpha levels in SSc plasma. Responders significantly down-regulated serum IFN-alpha. In seven patients with a shorter disease duration, improvement coincides with a decrease in plasma IFN-alpha, CXCL4 and TNF-alpha. Iloprost efficiently blocks pDCs IFN-alpha production induced by CXCL4-DNA/RNA complexes in vitro. Conclusions: The data suggest a possible role of iloprost as a disease-modifying drug, mainly accompanied by down-regulation of plasma IFN-I levels. Since CXCL4, IFN-I and TNF-alpha down-modulation was evident and significant in improving SSc patients with a shorter disease duration, these results warrant future investigations on the early use of iloprost to slow SSc progression.