Selective Janus Kinase 1 Inhibition Is a Promising Therapeutic Approach for Lupus Erythematosus Skin Lesions

Abstract

Background: Cutaneous lupus erythematosus (CLE) is an interferon (IFN)-driven autoimmune skin disease characterized by an extensive cytotoxic lesional inflammation with activation of different innate immune pathways. Aim of our study was to investigate the specific role of Janus kinase 1 (JAK1) activation in this disease and the potential benefit of selective JAK1 inhibitors as targeted therapy in a preclinical CLE model. Methods: Lesional skin of patients with different CLE subtypes and healthy controls (N = 31) were investigated on JAK1 activation and expression of IFN-associated mediators via immunohistochemistry and gene expression analyses. The functional role of JAK1 and efficacy of inhibition was evaluated in vitro using cultured keratinocytes stimulated with endogenous nucleic acids. Results were confirmed in vivo using an established lupus-prone mouse model. Results: Proinflammatory immune pathways, including JAK/STAT signaling, are significantly upregulated within inflamed CLE skin. Here, lesional keratinocytes and dermal immune cells strongly express activated phospho-JAK1. Selective pharmacological JAK1 inhibition significantly reduces the expression of typical proinflammatory mediators such as CXCL chemokines, BLyS, TRAIL, and AIM2 in CLE in vitro models and also improves skin lesions in lupus-prone TREX1 −/−-mice markedly. Conclusion: IFN-associated JAK/STAT activation plays a crucial role in the pathophysiology of CLE. Selective inhibition of JAK1 leads to a decrease of cytokine expression, reduced immune activation, and decline of keratinocyte cell death. Topical treatment with a JAK1-specific inhibitor significantly improves CLE-like skin lesions in a lupus-prone TREX1 −/−-mouse model and appears to be a promising therapeutic approach for CLE patients.

Unexpected Hair Regrowth in a Patient with Longstanding Alopecia Universalis During Treatment of Recalcitrant Dermatomyositis with the Janus Kinase Inhibitor Ruxolitinib

“…This suggestion is supported by recent findings of our group in a lupusprone mouse model (TREX1 -/-), in which treatment of hairless skin lesions with a topical JAK inhibitor resulted in hair growth and a strong upregulation of hair cell cycle associated genes (Fig. 1C) (6).…”

Immunostimulatory Endogenous Nucleic Acids Perpetuate Interface Dermatitis—Translation of Pathogenic Fundamentals Into an In Vitro Model

“…Although it has been detected in keratinocytes of the whole epidermis in LP skin ( 118 ), pDCs are considered to be the main producers of IFNa in vivo ( 17 , 36 , 120 ). Via autocrine loops, all type-I IFNs bind to IFNAR ( 23 , 24 , 121 ) and type-III IFNs signal via their receptor IFNLR ( 24 ). Activation of both receptors causes phosphorylation of JAK1 and TYK2 ( 25 ).…”

“…We are convinced that preclinical studies and clinical trials evaluating innovative future therapeutic approaches should not focus on one particular condition but rather on clusters of diseases featuring common immune response patterns. Our working group has recently successfully employed the here described model to elucidate the influence of JAK inhibition on keratinocytes in an interface-dermatitis-like context ( 121 ). In the herein described refined version of the model IFNy mimics the presence of a T-helper cell mediated cytokine milieu and together with eNA synergistically intensifies the resulting pro-inflammatory signature.…”

RNA tape sampling in cutaneous lupus erythematosus discriminates affected from unaffected and healthy volunteer skin

“…Our finding that IFN pathway genes recovered by tape harvesting distinguish between CLE-A and CLE-U or HV skin is supported in the CLE transcriptomics literature. [44][45][46][47][48][49][50] Many of the IFN response genes with highest ranking fold changes in previous studies are also differentially regulated in this tape-derived RNA study. These include IFI27, IFI44L, IFI44, OAS1 (blood from participants with CLE), 44 CCL5, CXCL9, Mx1, OAS2 and AIM2 (affected skin biopsies from participants with CLE) 45 46 50 and Mx1, IFI6, OAS2, XAF1, CXCL10 and IFI27 (follicular epithelium from participants with CLE).…”