A recent study published in the Annals of the Rheumatic Diseases has provided new insights into the mechanism of action of deucravacitinib, an oral, selective tyrosine kinase 2 (TYK2) inhibitor, in patients with systemic lupus erythematosus (SLE). Findings from a post hoc transcriptomic analysis of the phase 2 PAISLEY SLE trial showed that deucravacitinib modulated a broad spectrum of gene expression signatures involved in SLE pathogenesis, supporting its potential as a targeted therapy for this complex autoimmune disease.
SLE is a chronic multisystem autoimmune disorder characterized by dysregulated immune responses, excessive type I interferon signalling, abnormal B-cell activation, and persistent inflammation that can lead to irreversible organ damage. TYK2 is a key intracellular signalling molecule involved in cytokine pathways such as type I interferons, interleukin (IL)-12, and IL-23, all of which contribute to immune dysregulation in SLE. By selectively inhibiting TYK2, deucravacitinib is designed to suppress pathogenic immune signalling while minimizing effects on other Janus kinase (JAK) pathways.
To better understand the biological effects of deucravacitinib, investigators performed whole blood RNA sequencing (RNA-seq) on samples collected from 363 patients with SLE enrolled in the PAISLEY SLE trial and 56 healthy volunteers. Samples obtained at baseline and through week 32 were analysed using differential gene expression analysis with linear mixed-effects models through the DREAM statistical package. Additional analyses included single-sample gene set enrichment analysis (ssGSEA) using MSigDB Hallmark and BloodGen3 gene modules, while the xCell R package was employed to characterize immune cell populations.
At baseline, researchers identified 527 differentially expressed genes (DEGs) in patients with SLE compared with healthy volunteers (logâ‚‚ fold change >1; adjusted P <0.05), highlighting the profound molecular abnormalities associated with the disease. Treatment with deucravacitinib resulted in modulation of up to 2,529 genes, including numerous interferon-regulated genes, which are considered central drivers of SLE pathogenesis.
Gene set enrichment analyses demonstrated that deucravacitinib reduced plasma cell-associated gene signatures while restoring myeloid cell gene expression towards levels observed in healthy individuals. Cellular deconvolution analysis further revealed significant enrichment of dendritic cell populations compared with placebo. In addition, regulatory T-cell gene signatures, which were already elevated in patients with SLE at baseline, increased further following deucravacitinib treatment. Dose-dependent increases in both naĂŻve and memory B lymphocyte populations were also observed.
The study showed that deucravacitinib normalized several immune pathways implicated in lupus by reducing interferon-driven inflammation and shifting immune cell gene signatures towards a resting, non-inflammatory state. These included normalization of the ratios of B cells to plasma cells, activated to immature dendritic cells, and macrophages to monocytes, suggesting broad immunomodulatory effects across both innate and adaptive immune responses.
According to the investigators, whole blood transcriptome profiling confirmed both expected and previously unrecognized molecular effects of deucravacitinib, indicating successful engagement of multiple pathogenic pathways underlying SLE. These findings provide additional mechanistic evidence supporting the therapeutic potential of selective TYK2 inhibition in lupus.
Although the analysis was exploratory and post hoc, the authors noted that the results complement the encouraging clinical efficacy and safety findings previously reported in the PAISLEY SLE trial. They emphasized that the transcriptomic observations require confirmation in larger studies and support the continued evaluation of deucravacitinib in the ongoing phase 3 POETYK SLE clinical trials, which are expected to further define its role in the treatment of systemic lupus erythematosus.
Reference
Vital E, Wu C, Kahlenberg JM, Arriens C, Crow MK, Saxena A, Catlett IM, Hobar C, Hu Y. Whole blood transcriptome profiling in patients treated with deucravacitinib and novel mechanistic insights into TYK2 inhibition in lupus: results from a post hoc analysis of the PAISLEY SLE phase 2 trial. Ann Rheum Dis. 2026 Jul;85(7):1300-1312.