Anifrolumab—A Potential New Systemic Sclerosis Treatment

<b>Background/Objectives:</b> Systemic sclerosis (SSc) is a rare autoimmune disease characterized by chronic inflammation, microvascular injury, and fibrosis of the skin and internal organs. Although there are therapies, there is a need for treatments targeting early pathogenic mechanisms. Type I interferons (IFN-I) are key mediators linking immune dysregulation to vascular and fibrotic damage in SSc. This review summarizes the current evidence supporting IFN-I blockade with anifrolumab as a novel therapeutic strategy. <b>Methods:</b> A narrative review of preclinical, translational, and emerging clinical studies was conducted to evaluate the role of IFN-I signaling in SSc and the therapeutic potential of anifrolumab. Particular focus was placed on the IFN signature, upregulation of interferon-stimulated genes (ISGs), and the association with disease activity and organ involvement. <b>Results:</b> Anifrolumab, a fully human monoclonal antibody targeting the IFN-I receptor subunit 1 (IFNAR1), inhibits the signaling of all IFN-I isoforms, suppressing downstream JAK-STAT activation and ISG expression. Mechanistic data suggest that IFNAR blockade modulates vascular injury, immune activation, and fibrosis. Early findings and ongoing trials indicate potential benefits, particularly in patients with a high IFN signature or rapidly progressive cutaneous and cardiac disease. <b>Conclusions:</b> The current evidence supports IFN-I pathway inhibition as a promising approach in SSc. Ongoing trials will help to determine the clinical efficacy, safety, and optimal patient selection for anifrolumab in this rare but severe disease.