Developing new treatments for systemic lupus erythematosus (SLE) has been extremely difficult, because of its clinical and biological heterogeneity, as well as issues with study and endpoints design; as a result only one therapy has been approved for general SLE in the last 60 years. Preclinical validation of multiple therapeutic targets in mouse studies has not been followed by clinical trial success. Therefore, validation first in human SLE has arisen as a new paradigm. The first such target to be translated all the way to approval via clinical trials is type I interferon (IFN).
Innate immune mechanisms which evolved to support responses to viral infection, mediated by IFN, are activated by stimuli hypothesized to include nucleic acid immune complexes. Evidence of IFN activation in SLE includes highly reproducible IFN signature gene (ISG) expression in blood and affected tissues, albeit weakly associated with markers of disease activity. IFN is not primarily pathogenic in classic murine lupus models, but it exacerbates murine models of SLE and IFN treatment of other human diseases can induce SLE-like phenotypes. Together, these data supported trialling IFN-targeting treatments in SLE.
Studies of antibodies to IFNalpha, and of a vaccine inducing neutralizing IFN antibodies, yielded mixed but overall supportive results. Importantly, three randomized trials of an antibody to the type I IFN receptor, which may cause greater suppression of ISG than other agents, showed reproducible efficacy across composite outcome measures, skin disease, and glucocorticoid tapering, although the primary outcome was not met in one of these trials. Safety issues identified include increased rates of herpes zoster, in line with expectations based on the mechanism of action.
These findings confirm the role of IFN in the pathogenesis of SLE, and suggest the potential of treatments targeting this pathway to be transformative for patients. Regulatory approval is currently awaited.