Prurigo Nodularis: When Type 2 Inflammation Meets Neural Sensitization

Dr Raj Chovatiya explores the neuroimmune mechanisms driving prurigo nodularis, highlighting the role of type 2 inflammation, IL-31–mediated itch signaling, and cytokines like IL-4 and IL-13 in fibrosis and neuronal sensitization. Learn how periostin and neuroinflammatory loops sustain disease and what PN reveals about type 2 inflammatory endotypes.

Transcript

Hi there. My name is Dr Raj Chovatiya. I'm an associate professor at the Roslyn Franken University of Medicine and Science, Chicago Medical School and founder and director of the Center for Medical Dermatology and Immunology Research in Chicago, Illinois.

How does type 2 inflammation interact with sensory neurons to drive extreme itch in PN?

Dr Chovatiya: Prurigo Nodularis is a quintessential neuroinflammatory disease, meaning that we know that there's an important involvement of not only the immune system and its dysregulated inflammatory process, but also neuronal sensitization and neuronal activation. And it's really the crosstalk of these 2 features that drive a lot of both the itch and the lesional differences that we see in individuals with PN and type 2 inflammation is kind of the process that underlies a lot of this communication as many of the different canonical cytokines that signaling pathways we think about in type 2 inflammatory diseases are quite important for this discussion that's happening between immune cells and nerves and actually also fibroblasts as well.

Why is IL-31 particularly central to pruritus in PN?

Dr Chovatiya: IL-31 is a typical and honestly prototypical pruritogen in inflammatory disease, meaning that as a soluble cytokine, it's a direct on-off signal of itch. So IL-31 can bind to neurons. And in addition to contributing to the sensitization process, it also can directly activate itch on neurons. And given the fact that we know in prurigo nodularis you have hyperactive neurons that are very easily to excite IL-31 levels that are higher than normal, that seem to bind to the neurons and activate that itch signal and then that itch signal results in the production of a variety of local soluble inflammatory factors that act back on immune cells. It's the reason why IL-31 is so important to this disease state. The other part of IL-31's biology that's so critical is the role that it plays in fibrosis. And we know that in the nodules of prurigo nodularis, there's a heavy degree of fibrotic pathophysiology taking place.

How do IL-4 and IL-13 contribute to nodule formation and dermal fibrosis?

Dr Chovatiya: IL-4 and IL-13 are 2 of our important central type 2 inflammatory cytokines that play a few different roles in the immune process that we think about in prurigo nodularis. So IL-4 and -13 of course, are very, very important peripherally, particularly IL-13, in terms of driving a lot of the immune cell activities and the further production of type 2 inflammatory cytokines that are then going to act on neurons and other surrounding cells like fibroblasts. IL-4 is probably much more important centrally that allows for differentiation of type 2 T-helper cells. They're going to end up being a big source of these inflammatory cytokines. And then we also know that these 2 cytokines can help to drive the production of cytokines like IL-31, which are important for itch itself.

Now beyond those roles, IL-4 and -13 can directly bind to neurons themselves and they're a really important sensitizer of cutaneous neurons, meaning that they lowered the threshold for activity and while they're not direct pruritogens, you could think of them as almost a volume knob on a stereo as opposed to an on and off switch where they're really going to actually amplify itch signaling to a large degree.

Finally, IL-4 and -13 can also act on surrounding cells. In the case of PN, probably fibroblasts are much more important than keratinocytes and it's another way in which it sort of completes this process of being involved in all the steps along the way.

What role does periostin play in linking inflammation, itch, and tissue remodeling?

Dr Chovatiya: Periostin is a really good example of a soluble factor that's produced by fibroblasts that actually can then act directly back on immune cells and neurons. And thus it's a way that we connect the fibrotic process of prurigo nodularis, the fibrosis of course being critical to the formation of these thickened nodules. And it connects the immune dysregulation, immune activity along with the actual neuronal sensitization and neuronal activation as well. So it's yet another loop that exists in this disease state where there's a number of localized neuroinflammatory loops taking place.

Why does PN often persist even when underlying triggers are controlled?

Dr Chovatiya: Prurigo nodularis in addition to involving local neurons, and the local elements of the immune system probably also has a very strong neuronal loop with the central nervous system and the control that the central nervous system plays on the peripheral nervous system and vice versa. It's very, very difficult to break an itch scratch loop. And one of the reasons why that is is probably because of what's happening centrally in addition to what's happening peripherally. And so it's really only a hypothesis at this point in time, but it's believed that really sort of trying to modify and change that behavioral loop is one important element of the disease state. But also we know that with many of our neuroimmune or even immune diseases, simply treating that disease may not be sufficient to remit that disease. And it really is a big question in a lot of our newer treatments where perhaps if we act on multiple nodes of the pathway, we might be able to result in sort of longer lasting changes as well.

What does PN teach us about disease endotypes within type 2 inflammation?

Dr Chovatiya: With type 2 inflammation, we now think about it as a process that once it becomes apparent, it can touch a lot of different disease states. In terms of the cutaneous diseases, it is something that seems to be shared by a lot of them, but across different disease states in different body surfaces, there is something about barrier disruption, dysregulation and/or immune activity that seems to be important.

Prurigo nodularis is a really good example of a disease state that maybe is not necessarily directly related to the barrier surface that is interfacing with the outside world directly with the skin itself, but rather one that's happening at a deeper place but is still being driven by a lot of the same processes we think about in diseases like atopic dermatitis or asthma. And when you think about endotypes of type 2 inflammatory disease, what you're really asking are what are some of the different clinical manifestations and symptomatic manifestations that one can see through some type of alteration between the signals that we think about related to type 2 inflammation. The good news is despite the different endotypes of type 2 inflammatory disease, PN perhaps being one of them, there are shared signals that allow for shared therapeutic strategies across these disease states.

Are there any tips or insights you would like to share regarding type 2 inflammation and prurigo nodularis?

Dr Chovatiya: At the end of the day, if you can diagnose prurigo nodularis, you can treat prurigo nodularis. And truly thinking about mild, moderate, severe, single nodule, a couple nodules. I think that that argument is a little overblown if my patients have itch and scratch in nodules, number 1, they have prurigo nodularis, and number 2, it allows me to really jump them up to a targeted systemic therapy that's going to help to break this cycle that they're stuck in. So I think at the end of the day, we sometimes get trapped in thinking about severity, but also nailing down that diagnosis. But if you can have itch that's been going on for longer than 6 weeks and you have evidence of rubbing, scratching, or picking, and nodule formation, you have PN, and you can definitely treat it.