Potential Role of JAK Inhibitors in Atopic Dermatitis Treatment - Episode 1

Overview of Atopic Dermatitis

Jamie L. McConaha, PharmD, NCTTP, BCACP, CDE, provides an overview of atopic dermatitis.

Peter Lio, MD: Hello and welcome to this Pharmacy Times® Peer Exchange, “Potential Role of JAK Inhibitors in Atopic Dermatitis Treatment.” My name is Dr Peter Lio. I’m a clinical assistant professor of dermatology and pediatrics at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

Joining me today in this virtual discussion are: Dr Kristen Demundo, supervising pharmacist at Long Island Apothecary in Commack, New York; Dr Jamie McConaha, associate professor of pharmacy practice at Duquesne University School of Pharmacy in Pittsburgh, Pennsylvania; and Dr Shannon Rotolo, clinical pharmacy specialist at University of Chicago Medicine in Chicago, Illinois. Today we are going to talk about several topics pertaining to atopic dermatitis [AD], including an overview of atopic dermatitis, unmet needs regarding treatment, the potential use of JAK inhibitors in atopic dermatitis management, and the critical role of pharmacists.

We’re going to begin with an overview of atopic dermatitis. Let’s start with a few basic questions. What is the pathophysiology of atopic dermatitis, and what is the typical age of onset? Can we start with Jamie?

Jamie L. McConaha, PharmD, NCTTP, BCACP, CDE: The pathophysiology of atopic dermatitis is somewhat complex. Historically, there were 2 competing pathophysiologic principles. The first was the epidermal-based model or the outside-in model, and this suggested that atopic dermatitis was all about genetic epidermal barrier defects that triggered abnormal keratinocyte hyperplasia. Then the immune activation was considered secondary in this model. This hypothesis really received a revival in 2006 when the filaggrin mutation was found. The other model is the immune-based model, or the inside-out model, and this model suggests that abnormal epidermal phenotype in lesional atopic dermatitis skin was infiltrated or initiated by the increased expression of cytokines that induce the epidermal abnormalities.

We know now that these 2 different models are not mutually exclusive, and we have components of both. Going a little bit more in depth with each of those, as I mentioned with the first model, the outside-in, the epidermal, we do have barrier defects in atopic dermatitic skin. This is due to changes in ceramide composition, so lipids, and decreases in levels of total ceramides. We also have the filaggrin mutations that I mentioned earlier. That’s a structural protein that is responsible for the stratum corneum homeostasis, and when we have these abnormalities or mutations in filaggrin, we see increases in transepidermal water loss and reductions in skin hydration. We also see in the skin barrier in the stratum corneum abnormalities in the junctions in the skin.

We also have the immune component that we know now plays a huge role in atopic dermatitis. We have activation of immune molecules, particularly type 2 cytokine activation. These are going to be your interleukin-4, interleukin-13, and interleukin-31, which is the itch cytokine, as well as well as the type 22 pathway. Studies have shown that interleukin-4 and 13 are the leading type 2 cytokines that are able to downregulate filaggrin and other barrier molecules. They also downregulate antimicrobial peptides. Why is that important? Patients with atopic dermatitis have a higher risk of infection with staphylococcus aureus.

That also leads into the theory or the model discussing the microbiome in the skin of these patients with atopic dermatitis. We know that the microbiome is abnormal, and as I mentioned, it’s highly colonized by staph aureus. Patients are more prone to infection, especially with the repeated scratching that is characteristic of this disease state. All of the components that I discussed are really important. There’s an interplay between those type 2 inflammation cytokines and staphylococcus aureus. We’re not sure which induces which, but the main point is that the entire process results in increased skin inflammation and barrier alterations.

We also see that we have increase in these Th2 [T helper cell type 2] and Th22 cytokines in acute skin disease, but even more so in chronic diseases. As you mentioned, Peter, the JAK/STAT pathway is really important in our pathophysiology of atopic dermatitis. JAK/STAT, if you’re not familiar, stands for Janus kinase, which is JAK, and then signal transducer and activator transcription, which is STAT. What happens in this pathway is that we have a binding of ligands to the receptors that causes this JAK activation. This then phosphorylates and it activates the STATs. This in its active form then translocates to the cell nucleus to target certain genes. A lot of our newer therapies that we’ll be discussing today target this JAK/STAT pathway and work to disrupt the signaling pathway and reduce inflammatory mediators.

Peter Lio, MD: Thank you for that fantastic overview. That’s a very information-packed overview and it gives us a sense of what’s going on under the hood. I wanted to ask one little follow-up question, which is, we know the majority of patients really present with atopic dermatitis in the first 5 years of life. It’s probably even more than 80% of them, and we know that it can look kind of differently even on an individual, more acute lesions, more subacute, and then of course even chronic lichenified areas. What are some of the differences we might see between pediatric AD [atopic dermatitis] and adult AD even beyond this?

Jamie L. McConaha, PharmD, NCTTP, BCACP, CDE: Yes. As you mentioned, it’s definitely more common in children. Most of the cases develop by age 5. We see the highest incidence between ages 3 and 6 months, and about 75% of patients will have a spontaneous remission before adolescence. As you were saying, there are 3 clinical phases to atopic dermatitis: acute, subacute, and chronic. The acute phase presents almost as a wet look, it’s weeping, there are papules and vesicles, and they’re really on this background of erythematous skin. In the subacute, this is more of a dry presentation. The patient may develop scales and lichenification, which is thickening of the skin, usually due to repeated scratching.

Then chronic is where we really see that lichenification start to play a major role there.

The second part of your question I believe was asking about the presentation difference between children and adults. There are different body parts that are affected in children vs adults. And this plays a role in the diagnosis of atopic dermatitis because it has to meet what the guidelines say, “atypical” morphology in presentation. In young children and infants, we see this more commonly on the scalp, the face, meaning the cheeks and the chin, and the extensor surfaces of the extremities, things like the elbows or the knees. In adults, however, it’s more common in flexor surfaces, so it would be like the inside of the elbows or behind the knees, and the neck, wrists, and ankles.

This transcript has been edited for clarity.