Mechanism of Action for Agents Used to Treat Pediatric Atopic Dermatitis
Joshua Zeichner, MD, and Raj Chovatiya, MD, PhD, dive deep into the pathogenesis of atopic dermatitis and discuss how agents treating atopic dermatitis work.
Joshua Zeichner, MD: As we’ve developed a better understanding of the pathophysiology of atopic dermatitis, we’ve also had a flood of new medications that are more specifically targeted to treat atopic dermatitis. Raj, talk to us a little about this.
Raj Chovatiya, MD, PhD: Sure. Vikash Oza laid down the important aspects we think about when it comes to immunologic dysregulation with atopic dermatitis. But very broadly, I like to think about the pathophysiology of the disease in 2 major buckets. We think about barrier dysfunction and immune dysregulation. Most of our therapeutic armamentarium and stepwise therapy that we follow, no matter what guidelines you’re using, are addressing some aspect of that disease. That way, you can think about atopic dermatitis having both outside-in and inside-out mechanisms. What do we mean by that? There are different types of genetic mutations and polymorphisms related to the immune system and the barrier that can cause various cycles of inflammation to start up, leading to atopic dermatitis. We also know there are external perturbations in the environment when it comes to toxic substances, allergens, and irritants that can interact with the barrier, causing further perturbation and inflammation. It’s a chicken-or-egg question, and both probably apply here. People oftentimes like to choose 1 camp or the other, but both are happening at any given time.
When you think about our stepwise approach to therapy, at the base, we’re always trying to optimize barriers. That’s dealing with the 1 big pillar we talked about: barriers. That’s any time you’re using an emollient or trying to avoid a specific irritant that you have on the skin. You could optimize bathing. That’s exactly what you’re doing. The next step up when you’re thinking about anti-inflammatory therapy, typically in a topical form, is where you’re starting to address the immune dysregulation that I talked about. For many years, topical corticosteroids, which are broadly acting across a number of different cells—T cells in particular, but others as well—is largely turning down immune activity in a broader fashion. There’s been evolution in topical therapy slowly over years. Topical calcineurin inhibitors was 1 step forward. These are going to be working mainly on T cells in a slightly more targeted but still pretty broad fashion.
Several years ago, we had the approval of the first phosphodiesterase-4 inhibitor. This is a bit more targeted in terms of therapy. This is going to change cytokine signaling and reduce inflammation through a different route. Most recently, we had a topical JAK inhibitor approved for mild to moderate atopic dermatitis. This is going to specifically target an intracellular signaling pathway that’s important for a lot of different cytokines.
Moving into more of a systemic therapy route, in terms of an injectable and an oral therapy route, we have biologic therapies that Vikash eloquently told us about in the case of dupilumab. Tralokinumab is another one out there. We have a bunch of others coming. These variably target other important cytokines when we think about the type 2 inflammatory cascade, so IL-4 and IL-13. There’s development for other aspects of disease, including IL-31. You’re going to hear more about OX40 ligand and other various signals on that route.
Finally, in terms of the JAK inhibitors, the most recently approved class, these are very different from biologic therapies. Biologic therapies are antibody-based proteins that are going to bind to signals outside the cell, whereas JAK inhibitors are small molecules that are going to be working inside the cell on the JAK/STAT signaling pathway. They’re working broadly across a number of cytokine pathways. Very broadly, we understood that the barrier and immune system were important. But as we’ve come to understand how important immune system activity is, we’ve had a huge boom in a lot of our targeted and safer therapies for atopic dermatitis.
Joshua Zeichner, MD: It’s so interesting. I tend to look at these therapies as upstream or downstream. The more traditional or older therapies were more upstream. They addressed inflammation early on and more broadly. As a result, they had a lot more potential adverse effects. As we understand the pathophysiology and we have more targeted therapies, we have medications that address things more downstream. They’re a bit more focused and perhaps a bit safer, with fewer generalized adverse effects.
Raj Chovatiya, MD, PhD: That’s a good way to think about it. Both therapies have some merit. If we’re going to use psoriasis as an example, think about the third and fourth generation of biologic therapies. You have IL-17, the most downstream in the psoriasis pathway, and IL-23 extremely upstream in terms of Th17 differentiation. Both are extremely effective and work really well on disease. To your point, as we develop more targeted therapies, I bet we’re going to find different ways to inhibit things both early on and later on, arriving at perhaps the same point.
Transcript Edited for Clarity
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