JAK inhibitors in the treatment of atopic dermatitis

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disorder associated with heterogenous presentation and often immense patient burden. Safe, targeted treatment options are currently limited. This focused review of the published literature, including clinical trial results, case reports, and abstracts, as well as presentations from scientific meetings and data from industry press releases, describes the use of topical and systemic Janus kinase (JAK) inhibitors in the treatment of AD. New topical JAK inhibitors include ruxolitinib (JAK1/2) and delgocitinib (pan-JAK). Ruxolitinib cream met all primary and secondary endpoints in phase 3 clinical trials for mild-to-moderate AD with minimal treatment-emergent adverse events. Delgocitinib ointment was recently approved in Japan for pediatric and adult AD. Oral JAK inhibitors include baricitinib (JAK1/2), abrocitinib (JAK1-selective), and upadacitinib (JAK1-selective). All 3 met primary and secondary endpoints across numerous trials for moderate-to-severe AD. Treatment-emergent adverse events were mainly mild to moderate and included acne, nausea, headache, upper respiratory tract infection, and to a lesser degree, herpes infection and selected laboratory abnormalities. JAK inhibitors hold great promise as the next generation of targeted AD therapy. While their outstanding efficacy is balanced by a favorable safety profile in clinical trials, real-world data are needed to better understand long-term safety, durability, and treatment success.

Keywords: Atopic dermatitis; JAK inhibitor; eczema; itch; therapy.

Figure 1.. JAK-STAT signaling and advanced therapeutics in atopic dermatitis.

(A) Cytokine binding induces receptor subunit dimerization which leads to intracellular phosphorylation by janus kinase (JAK) proteins. Signal transducer and activator of transcription (STAT) proteins are then recruited to the phosphorylated receptor and phosphorylated by JAK proteins. Phosphorylated STAT proteins dimerize and translocate to the nucleus to regulate gene transcription. (B) Cytokines bind to JAK-STAT dependent receptors to propagate inflammation and itch in atopic dermatitis (AD). IL-4 binds to a heterodimer consisting of the IL-4Rα and common gamma chain (γc) subunits and is dependent on JAK1/3. IL-13 binds to a heterodimer consisting of IL-4Rα and IL-13Rα1 (JAK1/2, TYK2), while IL-31, IL-22, and TSLP bind to IL-31Rα / OSM, IL-22Rα1 / IL-10Rβ2, and CRLF2 / IL-7Rα heterodimers, respectively (JAK1/2). IL-5, which has less clear functional significance in AD, binds to the IL-5Rα and cytokine receptor common subunit beta (βc) heterodimer (JAK1/2). Topical and oral JAK inhibitors reversibly inhibit JAK proteins with varying specificity: abrocitinib and upadacitinib (JAK1); ruxolitinib and baricitinib (JAK1/2); tofacitinib (JAK1/3); and delgocitinib (JAK1/2/3,TYK2). Biologic monoclonal antibody therapies inhibit upstream cytokine signaling. Dupilumab binds to the IL-4Rα receptor subunit shared by IL-4 and IL-13. Emerging biologic therapies for AD include lebrikizumab and tralokinumab (IL-13) and nemolizumab (IL-31Rα).

Figure 1.. JAK-STAT signaling and advanced therapeutics in atopic dermatitis.

(A) Cytokine binding induces receptor subunit dimerization which leads to intracellular phosphorylation by janus kinase (JAK) proteins. Signal transducer and activator of transcription (STAT) proteins are then recruited to the phosphorylated receptor and phosphorylated by JAK proteins. Phosphorylated STAT proteins dimerize and translocate to the nucleus to regulate gene transcription. (B) Cytokines bind to JAK-STAT dependent receptors to propagate inflammation and itch in atopic dermatitis (AD). IL-4 binds to a heterodimer consisting of the IL-4Rα and common gamma chain (γc) subunits and is dependent on JAK1/3. IL-13 binds to a heterodimer consisting of IL-4Rα and IL-13Rα1 (JAK1/2, TYK2), while IL-31, IL-22, and TSLP bind to IL-31Rα / OSM, IL-22Rα1 / IL-10Rβ2, and CRLF2 / IL-7Rα heterodimers, respectively (JAK1/2). IL-5, which has less clear functional significance in AD, binds to the IL-5Rα and cytokine receptor common subunit beta (βc) heterodimer (JAK1/2). Topical and oral JAK inhibitors reversibly inhibit JAK proteins with varying specificity: abrocitinib and upadacitinib (JAK1); ruxolitinib and baricitinib (JAK1/2); tofacitinib (JAK1/3); and delgocitinib (JAK1/2/3,TYK2). Biologic monoclonal antibody therapies inhibit upstream cytokine signaling. Dupilumab binds to the IL-4Rα receptor subunit shared by IL-4 and IL-13. Emerging biologic therapies for AD include lebrikizumab and tralokinumab (IL-13) and nemolizumab (IL-31Rα).