Dysregulation of Type I Interferon Signaling in Systemic Sclerosis: a Promising Therapeutic Target?

Purpose of Review There are several lines of evidence at the genetic and gene expression levels linking type I interferon (IFN) activation to systemic sclerosis (SSc) pathogenesis. Herein, we summarize the potential role of type I IFN signaling components as therapeutic targets. Recent Findings All type I IFN cytokines signal through the interferon-alpha/beta receptor (IFNAR). Early phase studies indicate that anifrolumab (a human monoclonal antibody against IFNAR subunit 1) has an acceptable safety profile and can attenuate transforming growth factor beta (TGF-beta)-mediated fibrosis in SSc skin, supporting its further clinical development. Janus kinase (JAK) signaling pathways are downstream from IFNAR. Building on their efficacy in hereditary interferonopathies, JAK inhibitors have the potential to block the deleterious IFN and other profibrotic cytokine activation in SSc and are promising drug targets. Moreover, interferon regulator factor (IRF) 5, 7, and 8 have been linked to the profibrotic response in SSc preclinical studies, underscoring their potential as therapeutic targets. Lastly, depletion of plasmacytoid dendritic cells (pDCs) attenuates the IFN activation and fibrotic response in vitro and murine model experiments and can be studied as a viable drug target in future clinical studies. Summary There is increasing evidence linking the prominent type I IFN activation to the observed exaggerated fibrotic response in SSc. Key components of type I IFN signaling are druggable therapeutic targets that can be pursued in future randomized clinical trials, in order to develop more effective therapeutic options for SSc.