Faculty Collaboration Database

Molecular and clinical effects of selective tyrosine kinase 2 inhibition with deucravacitinib in psoriasis. J Allergy Clin Immunol 2022 Jun;149(6):2010-2020.e8

Date

11/13/2021

Pubmed ID

34767869

DOI

10.1016/j.jaci.2021.11.001

Scopus ID

2-s2.0-85121371307 (requires institutional sign-in at Scopus site)   59 Citations

Abstract

BACKGROUND: Psoriasis, a chronic inflammatory disease dependent on the IL-23/T_H17 pathway, is initiated through plasmacytoid dendritic cell activation and type I IFN induction in the skin. Deucravacitinib, a selective tyrosine kinase 2 (TYK2) inhibitor, blocks IL-23, IL-12, and type I IFN signaling in cellular assays.

OBJECTIVE: We investigated changes in IL-23/T_H17 and type I IFN pathway biomarkers and gene responses as well as measures of selectivity for TYK2 over Janus kinases (JAKs) 1-3 in patients with moderate to severe psoriasis receiving deucravacitinib.

METHODS: Deucravacitinib was evaluated in a randomized, placebo-controlled, dose-ranging trial. Biopsy samples from nonlesional (day 1) and lesional skin (days 1, 15, and 85) were assessed for changes in IL-23/IL-12 and type I IFN pathway biomarkers by quantitative reverse-transcription polymerase chain reaction, RNA sequencing, and immunohistochemistry. Laboratory markers were measured in blood. Percentage change from baseline in Psoriasis Area and Severity Index (PASI) score was assessed.

RESULTS: IL-23 pathway biomarkers in lesional skin returned toward nonlesional levels dose-dependently with deucravacitinib. IFN and IL-12 pathway genes were normalized. Markers of keratinocyte dysregulation, keratin-16, and β-defensin genes approached nonlesional levels with effective doses. Select laboratory parameters affected by JAK1-3 inhibition were not affected by deucravacitinib. Greater improvements in PASI scores, correlated with biomarker changes, were seen with the highest doses of deucravacitinib versus lower doses or placebo.

CONCLUSION: Robust clinical efficacy with deucravacitinib treatment was associated with decreases in IL-23/T_H17 and IFN pathway biomarkers. The lack of effect seen on biomarkers specific to JAK1-3 inhibition supports selectivity of deucravacitinib for TYK2; larger confirmatory studies are needed.

Author List

Catlett IM, Hu Y, Gao L, Banerjee S, Gordon K, Krueger JG

Author

Kenneth Brian Gordon MD Professor in the Dermatology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Biomarkers
Heterocyclic Compounds
Humans
Interferon Type I
Interleukin-12
Interleukin-23
Psoriasis
TYK2 Kinase