TYK2 inhibition improves clinical and molecular hallmarks in various subtypes of cutaneous lupus.

Background: Cutaneous lupus erythematosus (CLE) is a chronic inflammatory skin disease (ISD) with various clinical subtypes. Though the pathogenesis is not yet fully understood T cell mediated autoimmunity and elevated levels of type 1 interferons are two major factors contributing to the development of cutaneous lesions. Type 1 interferons transduce their signal via TYK2.

Objective: To investigate the impact of TYK2 signaling in pre-clinical models of CLE.

Methods: CLE skin biopsies were investigated by RNA-seq and immunohistochemistry. T cells isolated from CLE skin biopsies (lesional T cells) were re-stimulated with anti-CD2/anti-CD28 and cytokine release was quantified by ELISA and Luminex. Primary human keratinocytes and three-dimensional skin models were stimulated with IFN-α or lesional T-cell supernatant in presence or absence of the TYK2 inhibitor deucravacitinib followed by RNA-seq. Skin biopsies from different CLE subtypes were treated ex vivo with deucravacitinib followed by qRT-PCR.

Results: Bulk RNA sequencing revealed a strong correlation between TYK2 and interface dermatitis (ID), a histological hallmark of CLE. Immunohistochemistry confirmed a high abundance of TYK2 amongst 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 CLE (acute, subacute, chronic discoid, chilblain CLE) were successfully treated with deucravacitinib.

Conclusion: 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 pre-clinical models and therapy refractory CLE patients.