Achieving sustained control of disease activity in patients with systemic lupus erythematosus has been impeded by the complexity of its immunopathogenesis as well its clinical heterogeneity. In spite of these challenges, gains in understanding disease mechanisms have identified immune targets that are currently under study in trials of candidate therapeutics. Defining the type I interferon (IFN–I) pathway and autoantibodies specific for nucleic acid binding proteins as core pathogenic mediators allows an analysis of approaches that could control production of those mediators and improve patient outcomes. This review describes therapeutic targets and agents that could achieve control of the IFN-I pathway. Toll-like receptor 7, involved in IFN-I production and differentiation of B cells, and long-lived plasma cells, the producers of autoantibodies specific for RNA-binding proteins, components of the immune complex drivers of IFN-I, are particularly attractive therapeutic targets.

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