PuSH - Publication Server of Helmholtz Zentrum München: TYK2 inhibition improves clinical and molecular hallmarks in various subtypes of cutaneous lupus.

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Wasserer, S.* ; Seiringer, P.* ; Kurzen, N.* ; Jargosch, M. ; Eigemann, J. ; Aydin, G.* ; Raunegger, T.* ; Schmidt-Weber, C.B. ; Eyerich, S. ; Biedermann, T.* ; Eyerich, K.* ; Lauffer, F.*

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

Br. J. Dermatol. 193, 1192-1203 (2025)

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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.

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