LB1142 Characterization of the response to secukinumab in psoriasis using novel immunologic and genetic profiling

Psoriasis is an immune-mediated disease thought to be driven by heightened Th17 and Th1 responses. Secukinumab is an IL17A inhibitor used for the treatment of psoriasis. We aimed to understand the impact of secukinumab on psoriatic whole skin tissue as well as specific skin immune cell populations. We treated 15 psoriasis patients with secukinumab and characterized the response of whole skin lesional tissue and cutaneous T cell subsets (CD4+ T regulatory cells (Tregs), CD4+ T and CD8+ T effector cells) to treatment. We characterized the native biology of untreated psoriasis at the cellular and molecular levels with baseline skin biopsies. At baseline we observed that IL17A overexpression predominates in psoriatic CD8+ T cells rather than CD4+ T cells, thus highlighting the importance of Tc17 compared to Th17 cells in the pathogenesis of psoriasis. The most globally dysregulated T cell subset at baseline in psoriasis compared to healthy controls was Tregs, with an increase in Treg percentage at baseline (p<0.001) but with this subset showing downregulation of >1700 genes in psoriatic patients compared to healthy controls, suggesting diminished functional capacity. Secukinumab treatment was clinically effective, as 100% of patients achieved PASI75. Although secukinumab targets IL17A, we observed reduction of IL17A, IL17F, IL23A, IL23R and IFNγ in lesional skin by week 2 and normalization of these cytokine and cytokine receptor levels by week 12. Secukinumab treatment normalized Treg percentage (p<0.05) and reduced IL17A and IL17F expression in CD8+ T cells. T cell subset cytokine stimulation assays demonstrated that secukinumab does not impair the ability of cutaneous T cells to produce IL17A, TNFα or IFNγ. Overall, secukinumab appears to reverse many of the cellular and molecular hallmarks of psoriasis, while not adversely affecting cutaneous cellular immunity.