Tyrosine kinase 2 inhibition improves clinical and molecular hallmarks in subtypes of cutaneous lupus

Abstract Background Cutaneous lupus erythematosus (CLE) is a chronic inflammatory skin disease with various clinical subtypes. Although its pathogenesis is not yet fully understood, T-cell-mediated autoimmunity and elevated levels of type I interferons (IFNs) are two major factors that contribute to the development of cutaneous lesions. Type I IFNs transduce their signal via tyrosine kinase 2 (TYK2). Objectives To investigate the impact of TYK2 signalling in preclinical models of CLE. Methods CLE skin biopsies were investigated by RNA sequencing (RNAseq) and immunohistochemistry. T cells isolated from CLE skin biopsies (lesional T cells) were restimulated with anti-CD3/anti-CD28 and cytokine release was quantified by enzyme-linked immunosorbent assay and Luminex®. Primary human keratinocytes and three-dimensional skin models were stimulated with IFN-α or lesional T-cell supernatant in the presence or absence of the TYK2 inhibitor deucravacitinib, followed by RNAseq. Skin biopsies from patients with different CLE subtypes were treated ex vivo with deucravacitinib followed by real-time quantitative polymerase chain reaction. Results Bulk RNAseq revealed a strong correlation between TYK2 and interface dermatitis, a histological hallmark of CLE. Immunohistochemistry confirmed a high abundance of TYK2 in different CLE subtypes. Inhibiting TYK2 reduced inflammation and normalized epidermal impairments in primary human keratinocytes, reconstructed human epidermis and CLE T cells. Ex vivo TYK2 inhibition in CLE skin biopsies reduced IFN response and necroptosis-related gene expression. Finally, four patients with different therapy-refractory subtypes of CLE (acute, subacute, chronic discoid, chilblain CLE) were successfully treated with deucravacitinib. Conclusions IFN-α and T-cell-derived cytokines both contribute to skin inflammation in CLE. TYK2 inhibition is a promising approach for different subtypes of CLE as it controls inflammation in various preclinical models and patients with CLE who are refractory to treatment.