Emerging Topical and Systemic JAK Inhibitors in Dermatology

Abstract

Accumulating data on cellular and molecular pathways help to develop novel therapeutic strategies in skin inflammation and autoimmunity. Examples are psoriasis and atopic dermatitis, two clinically and immunologically well-defined disorders. Here, the elucidation of key pathogenic factors such as IL-17A/IL-23 on the one hand and IL-4/IL-13 on the other hand profoundly changed our therapeutic practice. The knowledge on intracellular pathways and governing factors is shifting our attention to new druggable molecules. Multiple cytokine receptors signal through Janus kinases (JAKs) and associated signal transducer and activators of transcription (STATs). Inhibition of JAKs can simultaneously block the function of multiple cytokines. Therefore, JAK inhibitors (JAKi) are emerging as a new class of drugs, which in dermatology can either be used systemically as oral drugs or locally in topical formulations. Inhibition of JAKs has been shown to be effective in various skin disorders. The first oral JAKi have been recently approved for the treatment of rheumatoid arthritis and psoriatic arthritis. Currently, multiple inhibitors of the JAK/STAT pathway are being investigated for skin diseases like alopecia areata, atopic dermatitis, dermatomyositis, graft-versus-host-disease, hidradenitis suppurativa, lichen planus, lupus erythematosus, psoriasis, and vitiligo. Here, we aim to discuss the immunological basis and current stage of development of JAKi in dermatology.

Decoding IL-23 Signaling Cascade for New Therapeutic Opportunities

“…Brepocitinib (PF-06700841) is a Tyk2/Jak1 inhibitor that is being tested in psoriasis [81] (Table 1). Interestingly, the efficacy of topical treatments with Jakinibs is being examined in clinical trials for treatment of dermatological disorders [82]. Topical treatments can potentially reduce the risk of side effects avoiding the systemic action of the drugs, and thus, these therapies are of particular interest for skin conditions, and they can have a great impact on patient quality of life.…”

Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a systematic literature research

“…While JAK inhibition via baricitinib (BARI; JAK-1/2), upadacitinib (UPA; JAK-1/2) and filgotinib (FILGO; JAK-1) also showed good efficacy in different indications, questions on how JAK selectivity influences clinical efficacy as well as the safety profile of all these agents arose and are still insufficiently answered, continue to be issues for debate and future research. 15 To guide the practicing clinician on how (not when) to use JAKi in clinical practice, the consensus meeting on 'Points to consider for the treatment of immunemediated inflammatory diseases with Janus kinase inhibitors' was conducted in 2019. Participants of the consensus task force were informed by this systematic literature research (SLR) on the efficacy and safety of all trials on JAKi conducted in IMIDs.…”

New Treatment Addressing the Pathogenesis of Psoriasis

“…PF-06700841 improves clinical symptoms of chronic plaque psoriasis by inhibiting proinflammatory cytokines that require TYK2 and JAK1 for signal transduction [ 92 ]. Topical PF-06700841 is now under investigation in a phase 2 trial [ 93 ].…”