O9 Reduction of interferon-γ and elevated baseline cytotoxic gene expression in the blood associate with ustekinumab response in SLE

Background/Purpose Ustekinumab (anti-IL-12/23) improved SLE-disease activity vs. placebo in patients with active SLE despite standard therapy.1 We investigated whether biomarkers collected in this trial could distinguish responders (UST-R) from non-responders (UST-NR) (response defined by SLE Responder Index-4 at week 24) and if these features could help elucidate the mechanism of action of ustekinumab in SLE. Methods We examined whole blood RNA and serum at baseline and longitudinally from this trial of 102 seropositive SLE patients, plus age- and sex-matched healthy controls. Targeted proteomic analysis used ELISA, and gene expression analysis used microarray. RNA-Seq was performed on whole blood stimulated in vitro. Results Changes in serum IL-17A, IL-17F and IL-22 were subtle and did not consistently associate with UST response, while no modulation of type I interferon levels was observed. In contrast, durable reduction in IFN-γ protein occurred only in UST-R. These biomarker effects were sustained through Week 48. A non-biased machine-learning algorithm identified a novel 9-gene (PRF1, KLRD1, GZMH, NKG7, GNLY, FGFBP2, TRGC2, TARP, TRGV2) cytotoxic gene-signature (CGS) enriched in baseline blood samples of UST-R vs UST-NR, which was corroborated using a published NK-cell CGS (figure 1). No significant differences in these gene-signatures were observed between placebo responders vs non-responders. In contrast, decreased expression levels were observed over the course of 24 weeks for both signatures only in the UST-R population. After whole-blood stimulation with recombinant IL-12, but not IL-23, expression of representative members of the CGS increased. Conclusion We identified a novel cytotoxic signature in baseline blood samples that associated with UST response in SLE. Targeted biomarker analysis suggests an important role of IL-12 blockade in the mechanism of action of UST in SLE. Acknowledgement This work was supported by Janssen Research \u0026 Development, LLC. Reference Van Vollenhoven R.F., Hahn, B.H., Tsokos, G.C., et al. Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study. Lancet. 2018;392:1330–1339.