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. doi: 10.1016/j.jaci.2021.11.001. Epub 2021 Nov 10.


Background: Psoriasis, a chronic inflammatory disease dependent on the IL-23/TH17 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/TH17 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/TH17 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.

Trial registration: NCT02931838.

Keywords: Deucravacitinib; Janus kinase; psoriasis; selective; tyrosine kinase 2.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers / metabolism
  • Heterocyclic Compounds* / therapeutic use
  • Humans
  • Interferon Type I
  • Interleukin-12
  • Interleukin-23
  • Psoriasis* / metabolism
  • TYK2 Kinase* / antagonists & inhibitors


  • Biomarkers
  • Heterocyclic Compounds
  • Interferon Type I
  • Interleukin-23
  • Interleukin-12
  • TYK2 Kinase
  • deucravacitinib

Associated data