JAK inhibitors for Atopic Dermatitis – STAT!

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The future is promising for those with atopic dermatitis (AD). Over the past decade, our understanding of AD pathomechanism has evolved, giving way to numerous potential therapeutic targets. During this time, Janus kinase (JAK) inhibitors—a new class of medications—has also emerged. While the JAK-signal transducer and activator of transcription (JAK-STAT) pathway  did not seem to be an obvious target early on,1 JAK inhibitors are likely to be the next generation of agents FDA approved for the treatment of moderate to severe AD. Indeed, JAK inhibitors are demonstrating benefit across multiple dermatologic diseases and constitute a promising frontier for dermatologic therapy overall. 

JAK-STAT Pathway

The therapeutic role of JAK inhibitors in AD and other diseases can be explained simply. Cytokine signaling, in which extracellular messages are transmitted to the nucleus, utilizes the JAK-STAT pathway. As in a relay race, cytokines, including interleukins, interferons, and other molecules, dock at the cell surface and pass the baton to JAK enzymes, which in turn pass the baton to STAT proteins, which translocate to the nucleus where they regulate gene transcription (Figure 1). In analogy to the relay race, where hobbling any single runner would interrupt the passing of the baton, cytokine signaling may be interrupted by blocking the cytokines, the JAK enzymes, or the STAT proteins. Therefore, when cytokines are prominent mediators of disease, either an antibody that binds to a specific cytokine (or its receptor) or a JAK inhibitor may effectively disrupt disease pathogenesis, leading to clinical improvement.

Jak pathway chart

Figure 1. The JAK-STAT pathway in cytokine signaling. A cytokine binds to its cell surface receptor (A). JAKs phosphorylate STATs (B). Phosphorylated STATs dimerize and translocate to the nucleus (C). Activation of target gene expression (D). 

There are 4 members of the JAK family of enzymes: JAK1, JAK2, JAK3, and tyrosine kinase 2 (Tyk2). JAK inhibitors are small molecules that target the JAK family of enzymes, with variable selectivity for the different members. Therefore, some JAK inhibitors are more selective, (eg, JAK1 inhibitor or JAK3 inhibitor), and others have broader activity, (eg, JAK1/3 inhibitor). Although many JAK inhibitors are in development for dermatologic and other diseases, 3 JAK inhibitors are currently FDA approved: ruxolitinib (Jakafi), tofacitinib (Xeljanz), and baricitinib (Olumiant). Ruxolitinib is a JAK1/2 inhibitor approved for myelofibrosis and polycythemia vera.2 Tofacitinib is a JAK1/3 inhibitor approved for rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis.3 Baricitinib is a JAK1/2 inhibitor recently approved for rheumatoid arthritis.4 

Many of the cytokines that are implicated in the pathogenesis of AD signal directly through the JAK-STAT pathway: IL-4, IL-5, IL-6, IL-12, IL-13, IL-23, and IL-31.5-7 Dupilumab (Dupixent), FDA approved for moderate to severe AD in 2017,8 modulates IL-4 and IL-13 signaling by binding the alpha subunit of the IL-4 receptor (IL-4Rα), thus preventing IL-4 and IL-13 binding (and signaling). Interestingly, IL-4 signals through JAK1/3 and IL-13 through JAK1/Tyk2.9,10

There may be a role for the JAK-STAT pathway not only in mediating inflammation but also AD-associated pruritus, independent of inflammation. Pruritus is the hallmark symptom of AD and causes significant impairment of quality of life. IL-31, implicated in pruritus associated with AD,11,12 signals through 3 different pathways, including JAK-STAT (via JAK1/2).13 It was recently shown that neuronal IL-4Rα signaling is important for chronic itch; IL-4Rα signals through JAK1.14 

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