A Conversation About JAK Inhibitors in Atopic Dermatitis - Episode 2

The JAK-STAT Pathway and the Mechanisms of JAK Inhibitors


Thought leaders discuss why JAK inhibitors are well suited for the management of itch and inflammation in the treatment of moderate to severe atopic dermatitis.

Raj Chovatiya, MD, PhD: We’re talking a little about JAK inhibitors, which is one of the most exciting advancements, not only just for atopic dermatitis and dermatology. Maybe I can go into a little detail about what makes JAK inhibition a very attractive target for therapy and how this works for atopic dermatitis. I know you love it when I cover this section instead of you, so I’ll give it my special stamp.

Lisa Swanson, MD, FAAD: It’s all yours.

Raj Chovatiya, MD, PhD: When we think about atopic dermatitis, there are big buckets at play. Barrier dysfunction is important—the external environment, different allergens, toxins, irritants, microbiome, and microbes in general. So is immune activation and immune dysregulation, and a lot of this skews toward type 2 inflammatory signaling. When you think about some of the classic cytokine signals that are important to atopic dermatitis—like IL-4, IL-13, IL-31, TSLP, IL-33; you just add some letters and numbers added to that list—these are all proteins that are floating around communicating with cells in the skin and immune cells, locally and throughout the whole body, signaling a lot of the things that happen in atopic dermatitis. You can’t get a protein to float its way into the cells. Think about the JAK-STAT signaling pathway, Janus kinase, signal transducer, and activator transcription as a relay race intermediary system that translates something from the outside the cell into something the nucleus can act on, with transcription and translation and further pro-inflammatory signals down the line. The JAK family is 1 that consists of 4 separate proteins: JAK1, JAK2, JAK3 and TYK2.

As the name suggests, Janus kinase is like the Roman god of duality, occurring in pairs on the intracellular portion of cytokine receptors. Once a protein binds to a receptor, it activates the JAK protein, which then activates the STAT proteins. They make their way into the nucleus and cause those downstream pro-inflammatory changes. Imagine if you had multiple signals that were important for inflammation—for barrier issues, for itch, for other early phase reactions—and you could hit many of them at once. That would be very attractive at an upstream level for treating atopic dermatitis. In a nutshell, that’s what JAK inhibition does by virtue of signaling and stopping. A lot of times JAK1 is an important 1, but you can also see mixed inhibition in the case of JAK1 and JAK2 and in ruxolitinib as well. You cut off a lot of the important signaling that causes the downstream effects that we see in atopic dermatitis. That’s different from a biologic, which isn’t a small molecule working inside the cell. It’s an antibody that’s binding to receptors or proteins outside the cell and stopping the signal in a different way. By comparison, with a JAK inhibitor, in many ways you can hit more targets at once than you might be able to hit with a biologic therapy. Any thoughts on that, Lisa?

Lisa Swanson, MD, FAAD: Yes, I’d like to give my dumbed-down version for everyone in the audience. I think about the inflammatory cascade in atopic dermatitis like a relay race. Each runner is a cytokine. Typically, 1 cytokine passes the baton and creates another cytokine, which takes the race and runs with it. If you’re inhibiting a cytokine like IL-4 or IL-13, you’re knocking out those individual runners. If you take the baton away by inhibiting JAK, you’re affecting all the relay races, and nobody can run.

Raj Chovatiya, MD, PhD: I like that. I’m not giving my version anymore. What Lisa is saying is that the core of the way signal transduction works. You can think about all those different runners in the race and all those cytokines; they all have different roles.IL-4 and IL-13 have importance in itch but also in barrier dysfunction. IL-31 has a lot of important roles as it relates to itch. TSLP and IL-33 are important early phase cytokines or alarmins that set things off from an epidermal level. IL-22 is important for a lot of the reactive thickening we see. There are other more broader signals, like interferon gamma, that can be upregulated as well. But the cool thing is that even though they do different things, they all require much of the same machinery to get the message across.

Transcript edited for clarity