There is a need to optimise biologic therapy for psoriasis. The aim of this study was to identify gene expression signatures that predict response to two commonly prescribed biologics. Bulk RNAseq analysis was performed on skin biopsies of lesional and non-lesional skin of 82 psoriasis patients initiating treatment with adalimumab (Humira; TNF inhibitor) or ustekinumab (Stelara; IL-12/23 inhibitor) at baseline, 1 week and 12 weeks. Clinical response was defined by percentage reduction in psoriasis severity area index (PASI) at week 12 compared to baseline (ΔPASI). A Limma-Voom pipeline was used to identify differentially expressed genes (DEGs) at all three time points that associate with absolute PASI (aPASI); and ΔPASI in both drug cohorts. Principal component analysis of sample features driving transcriptome differential expression showed that tissue, time, and PASI (in that order) were the main drivers of transcriptome variation. Ingenuity pathway analysis of DEGs in both analyses showed common regulatory signals in both drug cohorts. Nevertheless, downregulation of the NFkB and p38 pathways showed stronger associations with aPASI in the adalimumab compared to the ustekinumab cohort. Downregulation of interferon (IFN) signalling at baseline strongly associated with ΔPASI in the ustekinumab but not the adalimumab cohort; downregulation of IFN signalling at weeks 1 and 12 associated with ΔPASI in both drug cohorts. This suggests that dampening of IFN signalling is a common mechanism involved in clearing psoriasis, but the activation state of this pathway at baseline has greater power in predicting response to ustekinumab compared to adalimumab. However, downregulation of inflammasome signalling at baseline and week 1 associated with ΔPASI in the adalimumab cohort but not the ustekinumab cohort. This work highlights the potential for stratification of biologic therapy for psoriasis based on gene expression at baseline and during the early phases of treatment.

Distinct gene expression signatures differentiate clinical response to ustekinumab compared to adalimumab in psoriasis