JAK inhibitors for the Management of Atopic Dermatitis (AD) - Episode 6
Raj J. Chovatiya, MD, PhD, provides an overview of JAK inhibitors and their use in atopic dermatitis treatment.
Linda Stein Gold, MD: At this point, I want to move a little bit more towards talking specifically about JAK inhibitors and how these have revolutionized our treatment approach to atopic dermatitis. Raj, let's start with you. Can you give us some background? What are they? Talk a little bit about what makes them suitable for the treatment of atopic dermatitis.
Raj Chovatiya, MD, PhD: Sure. For a number of decades, we've been living in this revolution of biological therapies right across psoriasis and atopic dermatitis, so the thought of an oral small-molecule therapy requires a little bit of mental resetting. Let's just talk a little bit about high-level concepts of inflammation and immune signaling. You can largely think of it as 1 big relay race. The fancy word that we use is signal transduction, but let's talk about it like a relay race. You have signals hanging out on the outside of the cell. They're trying to tell the cell to do something on the inside, such as cause changes in transcription, translation, and signal inflammation, barrier changes, and all of that good stuff. You can think about biologics or antibodies acting on the outside of the cell. They're blocking a receptor. They're preventing something from binding to the receptor or stopping the signal at that point. This would be something that drags the specific cytokine like IL-4 [interleukin 4], IL-13, or something like that. Now, JAK [Jansen kinase] inhibitors actually act on the intracellular portion of the cell meaning that there's a family of proteins, JAKs. There are 4 of them: JAK 1, 2, 3, and TYK2 [trosine kinase 2]. They bind in varying combinations to different cytokine receptors on cells. When you get something binding on the outside of the cell that causes changes on the inside of the cell, JAKs activate a class of proteins called STATs [signal transducer and activator of transcriptions], and those go into the nucleus and do their thing. You could imagine that a small-molecule JAK inhibitor is not going to be an antibody, but rather, a small molecule that gets inside of the cell and that can work on some of these JAK proteins. One of the reasons why these are exciting for atopic dermatitis, as my colleagues keep talking about, is this heterogeneity of disease. We know that there are very different combinations of signs and symptoms and burden across individuals. A lot of that has to do with subtleties in how all of this signaling works. The cool thing about JAK inhibitors is a single molecule can work across multiple different signaling pathways, binding to 1 of these JAK proteins and thereby stopping inflammation at a very early source. Whereas a biologic therapy might be an injectable, you're going to take it through the bloodstream, absorb it that way, and an oral you take once a day. It's a molecule that makes its way through the cell, and it functions in a very different way.
Linda Stein Gold, MD: That was a great overview. We're learning so much. One of the issues is when I think back to medical school and residence, I didn't learn about the JAK-STAT pathway, so we're having to start to learn our immunology a little bit better and over again. That was a nice overview of what we can expect and why they might work particularly in atopic dermatitis, as well as other inflammatory skin diseases.
Transcript Edited for Clarity