Role of JAK inhibitors for the treatment of atopic dermatitis
Linda Stein Gold, MD: At this point, I want to talk a little more specifically about JAK inhibitors and how they have revolutionized our therapeutic approach to atopic dermatitis. Raj, let’s start with you. Can you give us a bit of context? What are they? Talk a bit about what makes them suitable for the treatment of atopic dermatitis.
Raj Chovatiya, MD, PhD: Sure. For several decades we have been living in this revolution of biological therapies through psoriasis and atopic dermatitis, so the thought of oral small molecule therapy requires a bit of a mental reset. Let’s talk a bit about the high-level concepts of inflammation and immune signaling. You can largely think of it as one big relay race. The fancy word we use is signal transduction, but let’s talk about it like a relay race. You have signals hanging outside the cell. They’re trying to tell the cell to do something inside, like cause changes in signal transcription, translation, and inflammation, barrier changes, and all that good stuff. You can think of biologics or antibodies acting outside the cell. They block a receptor. They prevent something from binding to the receiver or stopping the signal at that point. It would be something that drives the specific cytokine like IL-4 [interleukin 4], IL-13, or something like that. Now, J.A.K. [Jansen kinase] the inhibitors actually act on the intracellular part of the cell, which means that there is a family of proteins, the JAKs. There are 4: JAK 1, 2, 3 and TYK2 [trosine kinase 2]. They bind in various combinations to different cytokine receptors on cells. When you get something binding outside the cell that causes changes inside the cell, JAKs activate a class of proteins called STATs. [signal transducer and activator of transcriptions], and these go into the kernel and do their thing. You can imagine that a small molecule JAK inhibitor will not be an antibody, but rather a small molecule that gets inside the cell and can act on some of these JAK proteins. One of the reasons they are exciting for atopic dermatitis, as my colleagues keep saying, is this heterogeneity of the disease. We know that there are very different combinations of signs and symptoms and burden in different individuals. It has a lot to do with the intricacies of how all that signaling works. The cool thing about JAK inhibitors is that a single molecule can work on several different signaling pathways, binding to one of these JAK proteins and thus stopping inflammation at a very early source. Whereas a biological therapy can be an injectable, you’re going to pass it through the bloodstream, absorb it that way, and an oral that you take once a day. It’s a molecule that goes through the cell and works in a very different way.
Linda Stein Gold, MD: It was a great overview. We learn so much. One of the issues is that when I think back to medical school and residency, I didn’t learn the JAK-STAT pathway, so we have to start learning our immunology a little better over and over and over. It was a good overview of what we can expect and why they might work especially in atopic dermatitis, as well as other inflammatory skin conditions.
Transcript edited for clarity