The Janus kinase (JAK) inhibitor tofacitinib as well as apremilast, an inhibitor of the enzyme phosphodiesterase 4 (PDE4) are approved for the treatment of psoriatic arthritis. Both oral therapies have been associated with nasopharyngitis, and upper respiratory tract infections. In addition, increased incidences of herpes zoster have been observed under treatment with tofacitinib but not with apremilast. JAKs are found downstream of the type II cytokine receptor family used by a number of TH17 cell-associated cytokines for signal transduction. Inhibition of PDE4 leads to the accumulation of intracellular cAMP, and subsequent activation of the protein kinase A which is followed by a reduction of a variety of innate and adaptive immune responses including a lower expression of TH17 cell-associated cytokines. These cytokines induce the secretion of antiviral and antimicrobial peptides by keratinocytes. To investigate antiviral effects, primary human keratinocytes were treated with tofacitinib or apremilast and various cytokines and/or bacterial surface proteins and analysed by RT-qPCR. CD69 expression on tofacitinib or apremilast-treated PBMCs was investigated via flow cytometry. We found that in contrast to apremilast, tofacitinib markedly reduced the gene expression of antiviral peptides such as MX1 or ISG15 in keratinocytes in vitro. Additionally, JAK inhibition but not PDE4 inhibition reduced the activation of T cells stimulated with viral VZV gE. Using both substances we did not observed significant effects on antimicrobial responses. To conclude, we report that tofacitinib reduced the expression of antiviral peptides as well as the activation of T cells by viral antigens in vitro while apremilast did not significantly influence the antiviral immunity. These results are in line with the clinical observation of increased numbers for zoster in patients treated with tofacitinib.

ESDR221 - Comparison of Janus kinase and phosphodiesterase 4 inhibition in terms of antiviral responses in vitro

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING