Article Text
PDF
Abstract
Background Tyrosine kinase 2 (TYK2) mediates signaling of key cytokines (eg, Type 1 IFNs, IL-23, and IL-12) involved in lupus pathogenesis. Deucravacitinib is a first-in-class, oral, selective, allosteric TYK2 inhibitor approved in multiple countries for the treatment of adults with plaque psoriasis.1 2 Deucravacitinib was efficacious in a phase 2 trial in patients with active SLE (PAISLEY; NCT03252587).3 This analysis evaluated the effect of deucravacitinib on biomarkers of TYK2-mediated pathways, B cell pathways, and serological biomarkers in patients in the phase 2 PAISLEY SLE trial.
Methods The 48-week PAISLEY trial randomized 363 patients with SLE 1:1:1:1 to placebo or deucravacitinib 3 mg twice daily (BID), 6 mg BID, or 12 mg once daily (QD). Whole blood transcripts, serum proteins, blood cell subsets, and antibody profiles were measured by immunoassays and flow cytometry.
Results With deucravacitinib treatment, significant reductions were observed in IFNα (at week 48) and IFNλ (week 2 through week 48), and IFNγ was numerically lower after week 12. Deucravacitinib, but not placebo, reduced IFN-regulated gene (IRG) expression as well as expression of cytokines and chemokines downstream of IFN activity, including BAFF, CXCL10, and MCP2 (figure 1). IFNλ, CXCL10, CCL19, and MCP2 were significantly reduced in the BID-dosed arms as early as 2 to 3 days after dose initiation. With deucravacitinib treatment, lymphocyte and neutrophil counts and complement levels increased, while markers associated with B cell activation and differentiation including BLC (CXCL13), CD38 (gene expression), and autoantibodies were reduced.
Conclusions Deucravacitinib suppressed IFN production, IRG expression, IFN-inducible proteins, B cell pathway markers, and serological biomarkers, consistent with clinical symptom improvements in SLE patients treated with deucravacitinib. Suppression of both IFN and B cell pathways suggests a broad reduction in lupus pathophysiology. These results provide a molecular framework for understanding how deucravacitinib modifies molecular networks in SLE.
Deucravacitinib, but not placebo, reduced biomarkers of IFN activity and lupus pathophysiology
References
Armstrong A, et al. J Am Acad Dermatol. 2023;88(1):29–39.
Strober B, et al. J Am Acad Dermatol. 2023;88(1):40–51.
Morand E, et al. Arthritis Rheumatol. 2022 Nov 11 (Epub ahead of print).
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.