Type 2 Inflammation in PN

Raj Chovatiya, MD, PhD; Shawn Kwatra, MD; and Sarina B. Elmariah, MD, PhD, discuss the pathophysiology on PN and the role of type 1 inflammation in the disease.

Raj Chovatiya, MD, PhD: I like how you put that, because I try to sometimes think about how best to explain this when I get these questions. I think the more we’ve started to learn about type 2 inflammation as a process, both its physiologic and pathologic manifestations, it allows us to really think about all the different ways something could potentially go wrong and almost all the different flavors you can get in terms of aberrations in that process. Dr Elmariah, walk us through that a little bit, thinking about what we understand about types of inflammation and the role it may play with prurigo nodularis [PN]-associated conditions, and perhaps maybe deravel some of what Dr Kwatra was trying to explain to us.

Sarina B. Elmariah, MD, PhD: You both highlight some important points. The first, I cannot underscore enough, because I think it’s led to some confusion, not only within dermatology but also amongst the experts who treat this. The number of different types of PN there are, with this understanding that there probably are all these various risk factors but then a common pathophysiology once the lesions and the itch-scratch cycle begins, which is where type 2 inflammation starts to make a critical impact on the disorder. So, one thing—just even going back to the clinical manifestations—we think of the hallmarks of the nodule. Everybody knows it’s itchy. That is very central to this disease. But even the nodules, although characteristic, some can be very excoriated. Sometimes I’ll see a patient who has clear ulcerations within their nodules, and it doesn’t negate the nodularis component of it. But then speaking to the pathophysiology again, we’re at the tip of the iceberg of understanding this. Honestly, a lot of the work is being done by our co-panelist, Dr Kwatra.

The idea is that there is some seeding state, where there is an underlying itch, or dysregulation, as we say in the neuroimmune access—whatever that is, or the predisposing factors like medical factors that lead up to that. Once that itch begins, there’s an itch-scratch cycle that starts to lead to other pathophysiologic changes that recruit an amplified Th2 [T Helper 2 cell] dysregulation. That’s where we start to see an increase in numerous cytokines of Th2, IL-4 [Interleukin-4], IL-13, IL-31, and then even non–type 2 cytokines and interleukins that will be increased in terms of IL-17 and IL-22. Dr Kwatra, some of your work talks about this, so you can certainly describe that in more detail.

The other thing that’s important to know is although these cytokines are increased in the lesions themselves, they’ve also been detected in nonlesional skin. There’s something about that particular area of the nodule that’s also making the state of the skin more susceptible. That’s where we believe there is some component of neural sensitization that’s contributing to this. There’s work by Dr Sonia Ständer, MD, professor of dermatology and neurodermatology and head of the Interdisciplinary Competence Center for Chronic Pruritus at the University Hospital Münster in Germany, and Dr Gil Yosipovitch, MD, professor and chair of medical dermatology in the Dr Phillip Frost Department of Dermatology at the University of Miami Miller School of Medicine in Florida, and others, looking at the neural components, as well. I feel like we’re at the cusp of really trying to understand where Th2 cytokines, and other cytokines, are influencing that neural access and vice versa, where the cutaneous nerves are influencing the inflammatory milieu to set up diseases like PN, as well as other kinds of classically inflammatory skin diseases.

Raj Chovatiya, MD, PhD: You make a cool point. With PN, there are these peripheral nervous and central nervous system components, both of which are key to the disease. And this idea of sensitization is not necessarily a topic that is super familiar to most dermatologists, and we’re really beginning to understand this. Could you talk a little more about that neural part, Dr Kwatra, so someone who may not think about PN all day understands what we mean?

Shawn Kwatra, MD: Yeah, absolutely. We know itch is the dominant feature in PN, so we have to zoom in on those nerve fibers. And there are thinly myelinated Aδfibers and unmyelinated C nerve fibers that are in the dermis and some layers of the epidermis. Dr Elmariah has done a lot of great work on the neural aspect of itch, as well, so please correct me if I’m missing anything. But there’s a transmission system through the spinal cord, through the brain, and we know stress can worsen PN and a lot of these peripheral inputs. Before, we thought it may just be limited to the nodule. Now we know in the nodule, you had in the dermis highly coiled. they’re branching a lot with all that stuff in the dermis and nerve fibers going through there. That may explain how patients have an itch, but then they also have burning sensations, stinging sensations, and some patients even have the feeling that bugs are present.

But like Dr Elmariah was alluding to, there’s been work done, looking at lesional and nonlesional skin. The thing that fascinates me about this disorder is that nonlesional skin of a patient with PN has less nerves going through the epidermis overall, and they have more coiling of the nerves in the dermis. So that reorients the disease, and now I view the disease as more of a neuro-inflammatory disorder. If you think about things, such as multiple sclerosis, where you have issues specifically in the nerves, that’s the way we’re viewing this condition now. So, any effective therapy has to modulate the nerves, as well. That’s what we’re learning.

Raj Chovatiya, MD, PhD: It is interesting how far we’ve come in a short period of time, because when you track some of these papers back, with some of the initial findings based on nerve density…people wondered whether this was a small fiber neuropathy of some sort. That died pretty quickly when a lot of this work came about, showing that it’s far bigger and a little more complicated than that. And that ties into why we’re talking about the disease, because the impact on patient lives is huge. All of us can speak to that, being in places where a lot of patients end up coming to find us in one way or another. It’s that burden patients face in day-to-day life, whether it’s the amount of itch, lack of sleep, the huge mental health component, or just the physical changes of the skin, trying to spend all the time covering that up during the day for patients who can’t really go out like that. That often leads to so much more complexity when you unravel how to treat the patient here.

Transcript edited for clarity

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