LAUSR

Plaque psoriasis is a common, chronic, systemic, immune-mediated inflammatory disease. The Janus kinase‒signal transducer and activator of transcription (JAK-STAT) pathway plays a major role in intracellular cytokine signaling in inflammatory processes involved in psoriasis. Although JAK1-3 inhibitors have demonstrated efficacy in patients with moderate-to-severe psoriasis, safety concerns persist and no JAK inhibitor has received regulatory approval to treat psoriasis. Thus, an opportunity exists for novel oral therapies that are safe and efficacious in psoriasis. Tyrosine kinase 2 (TYK2) is a member of the JAK family of kinases and regulates signaling and functional responses downstream of the interleukin (IL)-12, IL-23, and Type I interferon receptors. Deucravacitinib, an oral, selective inhibitor that binds to the regulatory domain of TYK2, and brepocitinib (PF-06700841) and PF-06826647, topical and oral TYK2 inhibitors, respectively, that bind to the active (adenosine triphosphate-binding) site in the catalytic domain, are in development for psoriasis. Selective, allosteric inhibition of TYK2 signaling may reduce the potential for toxicities associated with pan-JAK inhibitors. This article reviews JAK-STAT and TYK2 signaling, and the efficacy and safety of JAK inhibitors in psoriasis to date, focusing specifically on TYK2 inhibitors.