Jerry Bagel, MD, MS, and Brett King, MD, PhD, provide an overview of JAK inhibitors and their mechanisms of action in dermatology care.
Jerry Bagel, MD, MS: Welcome to this HCPLive® Peers & Perspectives® presentation titled “Expert Perspectives on JAK Inhibitors in Dermatology Care.” I’m Dr Jerry Bagel from the Psoriasis and Eczema Treatment Center of New Jersey in East Windsor, New Jersey. I’m joined by Dr Brett King, an associate professor of dermatology at the Yale School of Medicine in New Haven, Connecticut, to discuss the role of JAK inhibitors in dermatologic conditions. Let’s begin.
Dr King, thank you for being here. It’s a pleasure to see you and work with you. I have a few questions about JAKs, which is the new course of action in dermatology. Could you briefly introduce Janus kinases, their mechanism of action, and how they block the JAK-STAT signaling pathway?
Brett King, MD, PhD: This class of medicines is profoundly important. We’re seeing it gain a lot of momentum in dermatology. In fact, in a short period of time, we have medicines for atopic dermatitis, alopecia areata, and vitiligo. It’s important for all of us to know a little about this class of medicines. JAK inhibitors are small molecules. They’re not antibodies, and they’re not proteins; they’re small molecules. Because they’re small molecules, they can be administered orally or topically. They modulate the activity of a host of cytokines. They don’t block the activity of cytokines, but they modulate the activity of cytokines. By doing so, if those cytokines are important drivers of skin diseases such as atopic dermatitis, alopecia areata, and vitiligo, then we have an opportunity with a single class of medicines to make myriad diseases in dermatology better.
Jerry Bagel, MD, MS: The blocking of JAK-STAT—could you get into that a little? I know there are about 4 types of JAKs, and there’s TYK2, and there are STATs. Can you get into how the blocking of the JAK-STAT process transpires?
Brett King, MD, PhD: I like to think of signaling as a bit of a relay race. A cytokine is nothing more than a chemical messenger in the body, the way any 2 cells communicate. A cytokine finds its target cell, and it wants to communicate with the nucleus. When it communicates with the nucleus, when the message makes it to the nucleus, biology happens. In the case of the JAK-STAT pathway, a cytokine binds its receptor, the receptor activates intracellular proteins called JAK proteins, of which there are 4: JAK1, JAK2, JAK3, and tyrosine kinase, or TYK2. JAK activate STAT proteins, and STAT proteins migrate to the nucleus, where gene transcription happens. Biology happens or, in the case of what we’re talking about, disease follows. We want to interrupt that messaging from outside the cells to the new nucleus. We can do that with this class of medicines called JAK inhibitors. We can modulate the activity of myriad cytokines by blocking 1 or several of these 4 JAK proteins in the intracellular space of the cell.
Jerry Bagel, MD, MS: We’re ultimately inhibiting specific transcription from occurring in the DNA level. I have a question. We know that IL-12 can induce JAK-STAT pathway. If IL-12 induces that pathway, is it inducing the production of more IL-12? Or is it inducing the production of lots of different proteins?
Brett King, MD, PhD: After gene transcription in the nucleus, there’s a whole host of things that happen. It’s going to depend on what cell we’re talking about. Are we talking about a T cell? Are we talking about a keratinocyte? We should reduce it to a very simple picture: a cytokine outside the cell. If that message makes it to the nucleus of whatever cell we’re talking about, disease is going to follow, whether that’s a psoriasis plaque, itch in AD [atopic dermatitis], dermatitis in AD, or loss of pigment in vitiligo. The idea is we want to halt or interrupt the cytokine outside the cell messaging the nucleus. After that message gets there, disease is going to follow in a bunch of complicated ways that are beyond this conversation. We want to halt or interrupt that process, and we can do that with this class of medicines.
Transcript edited for clarity