AB0042 PRECLINICAL EVALUATION OF JAK1 SELECTIVE INHIBITORS INCB039110 AND INCB054707 AS TARGETED THERAPY OF CUTANEOUS LUPUS ERYTHEMATOSUS

Background:

Cutaneous lupus erythematosus (CLE) is an autoimmune disease with heterogenous subtypes presenting with inflammatory skin lesions, a histological pattern called “Interface-dermatitis” and enhanced type-1-interferon (IFN)-regulated JAK/STAT (Janus kinase/signal transducers and activators of transcription) pathway signaling. Despite deeper understanding of the pathogenesis still no specifically approved drugs for CLE exist.

Objectives:

The aim of our study was to investigate the effect of JAK1 selective inhibition as potential therapeutic approach for CLE in established preclinical models of cutaneous autoimmunity.

Methods:

The expression of IFN-regulated proteins and genes after JAK1 inhibitor treatment was analysed in cultured, stimulated immortalized and primary human epidermal keratinocytes. In addition the impact of JAK1 inhibition on CLE-like skin lesions in lupus prone MRL/lpr- and TREX1-knockout-mice was determined.

Results:

In vitro investigation revealed a significantly decreased gene- and protein expression of proinflammatory cytokines, in particular CXCL10 as key driver chemokine of lesional inflammation, and other pathophysiologic important IFN-regulated mediators in inflamed keratinocytes after treatment with JAK1 inhibitors. Moreover JAK1 inhibition generated an amelioration of skin lesions in lupus prone mice.

Conclusion:

Our findings indicate that inhibition of JAK1 results in a decreased chemokine expression, subsequent less cytotoxic T cell induced keratinocytic cell death leading to an improvement of lesional skin. By breaking the vicious inflammatory cycle JAK1 inhibitors appear to be promising agents as targeted therapy of CLE. Further investigation has to be performed in clinical trials.

References

[1] Wenzel, J.; Tüting, T. (2008): An IFN-associated cytotoxic cellular immune response against viral, self-, or tumor antigens is a common pathogenetic feature in “interface dermatitis”. In: The Journal of investigative dermatology 128 (10), S. 2392–2402. [2] Kuhn, A.; Landmann, A.; Wenzel, J. (2016): Advances in the treatment of cutaneous lupus erythematosus. In:Lupus 25 (8), S. 830–837. [3] Hornung, T.; Janzen, V.; Heidgen, F.-J.; Wolf, D.; Bieber, T.; Wenzel, J. (2014): Remission of recalcitrant dermatomyositis treated with ruxolitinib. In: The New England journal of medicine 371 (26), S. 2537–2538. [4] Klaeschen, AS.; Wolf, D.; Brossart, Peter; Bieber, T.; Wenzel, J. (2017): JAK inhibitor ruxolitinib inhibits the expression of cytokines characteristic of cutaneous lupus erythematosus. In:Experimental dermatology 26 (8), S. 728–730.

Acknowledgement:

The authors thank Nadine van Holt (University Hospital Bonn) for her most valuable support in preparation of the manuscript and Sandra Ferring-Schmitt and Sonja Sternberg for their great helpfulness in the laboratories.

Disclosure of Interests:

Tanja Fetter: None declared, Paul Smith Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Tugce Gül: None declared, Thomas Bieber: None declared, Jörg Wenzel Grant/research support from: GSK, Incyte, Consultant for: Biogen, Leo, Paid instructor for: Novartis