- Liu, Jared;
- Chang, Hsin-Wen;
- Grewal, Robby;
- Cummins, Daniel D;
- Bui, Audrey;
- Beck, Kristen M;
- Sekhon, Sahil;
- Yan, Di;
- Huang, Zhi-Ming;
- Schmidt, Timothy H;
- Yang, Eric J;
- Sanchez, Isabelle M;
- Nakamura, Mio;
- Bhattarai, Shrishti;
- Thibodeaux, Quinn;
- Ahn, Richard;
- Pauli, Mariela;
- Bhutani, Tina;
- Rosenblum, Michael D;
- Liao, Wilson
The IL-17A inhibitor secukinumab is efficacious for the treatment of psoriasis. To better understand its mechanism of action, we investigated its impact on psoriatic lesions from 15 patients with moderate-to-severe plaque psoriasis undergoing secukinumab treatment. We characterized the longitudinal transcriptomic changes of whole lesional skin tissue as well as cutaneous CD4+ and CD8+ T effector cells and CD4+ T regulatory cells across 12 weeks of treatment. Secukinumab was clinically effective and reduced disease-associated overexpression of IL17A , IL17F, IL23A, IL23R, and IFNG in whole tissue as soon as 2 weeks after initiation of treatment. IL17A overexpression in T-cell subsets, primarily CD8+ T cells, was also reduced. Although secukinumab treatment resolved 89‒97% of psoriasis-associated expression differences in bulk tissue and T-cell subsets by week 12 of treatment, we observed expression differences involved in IFN signaling and metallothionein synthesis that remained unresolved at this time point as well as potential treatment-associated expression differences involved in IL-15 signaling. These changes were accompanied by shifts in broader immune cell composition on the basis of deconvolution of RNA-sequencing data. In conclusion, our study reveals several phenotypic and cellular changes within the lesion that underlie clinical improvement from secukinumab.