Revisiting the Interferon Axis in Systemic and Cutaneous Lupus Erythematosus: From Targeted Therapy to Real-World Clinical Practice

For many years, systemic lupus erythematosus (SLE) pathogenesis was interpreted primarily through the lens of adaptive immunity, with emphasis on disruption of T- and B-cell tolerance, autoantibody production, immune-complex deposition, and complement activation. However, a major shift in the understanding of SLE immunopathogenesis has been the recognition that innate immune activation, and particularly the type I interferon (IFN-I) axis, provides a mechanistic link between acid sensing, antiviral-like immune activation, and tissue inflammation. While several approaches have demonstrated biological activity and provided proof-of-concept for therapeutic modulation of the IFN-I pathway, anifrolumab, a monoclonal antibody targeting IFNAR1, currently represents the most clinically validated strategy and the only approved IFN-I-targeted therapy for SLE, based on its efficacy in phase III trials. In this review article, we revisit the IFN-I axis in SLE and cutaneous lupus erythematosus, with special emphasis on its targeted therapies.