The IL-23/IL-17 axis in Behçet's syndrome pathogenesis: from immunological perspectives to therapeutic implications

Behçet's Syndrome (BS) is a systemic vasculitis characterized by variable vessel involvement and an elusive etiology, though immunogenetic studies strongly implicate the IL-23/IL-17 axis which bridges innate and adaptive immunity, orchestrating type 17 T-cell responses thus modulating neutrophil function- with this cell a central player in both BS clinical features and immunopathology. Additionally, the contribution of Th1 cytokines-such as interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα)-reflects the broader immune plasticity observed in BS pathophysiology. Despite the immunogenetics incriminating the IL-23/IL-17 axis, clinical evidence confirming the role of IL-23/IL-17/inhibition in BS therapy is still limited including disappointing results with secukinumab in trials for Behçet's uveitis. However, emerging evidence from small-scale retrospective studies, prospective trials, and case reports indicates that IL-23/IL-17 axis inhibition may benefit mucocutaneous and articular manifestations, as well as neuro-Behçet's disease and the licensed PDE4 inhibitor apremilast regulates multiple aspects of IL-23/17 axis and neutrophil biology. Interestingly, anti-IL-17 therapy has been linked to BS induction. Herein, we discuss IL-23/IL-17 axis inhibition in BS and why it should be used cautiously and be limited to mucocutaneous and/or articular manifestations at this juncture. Further randomized controlled trials are imperative to dissect the IL-23/IL-17 axis in BS including high-dose anti-IL-23 therapy antagonism given that neutrophils are an abundant source of IL-23 and consider novel strategies including IL-23R antagonism.