Prurigo Nodularis: When Type 2 Inflammation Meets Neuronal Sensitization

In this interview, Dr Raj Chovatiya highlights the role of type 2 inflammation, IL-31–mediated itch signaling, and cytokines like IL-4 and IL-13 in the fibrosis and neuronal sensitization of prurigo nodularis (PN) and describes how periostin and neuroinflammatory loops sustain disease.

The Dermatologist: How does type 2 inflammation interact with sensory neurons to drive extreme itch in PN?
Dr Chovatiya: PN is a quintessential neuroinflammatory disease. We know that there is involvement of not only the immune system and its dysregulated inflammatory process, but also neuronal sensitization and neuronal activation. And it is the crosstalk of these 2 features that drives both the itch and the lesional differences we see in individuals with PN. Type 2 inflammation is the process that underlies this communication. Many of the different canonical cytokines we think about in type 2 inflammatory diseases are important for this discussion that is happening between immune cells and nerves, and fibroblasts as well.

The Dermatologist: Why is IL-31 particularly central to pruritus in PN?
Dr Chovatiya: IL-31 is a prototypical pruritogen in inflammatory disease. As a soluble cytokine, it is a direct on-off signal of itch. IL-31 can bind to neurons, and in addition to contributing to the sensitization process, it can also directly activate itch on neurons, 
resulting in the production of a variety of local soluble inflammatory factors that act back on immune cells. That is the reason why IL-31 is so important to this disease state. The other critical part of IL-31’s biology is the role it plays in fibrosis. We know that in PN nodules, there is a heavy degree of fibrotic pathophysiology taking place.

The Dermatologist: 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 type 2 inflammatory cytokines that play a few different roles in the PN immune process. IL-4 and IL-13 are important peripherally, particularly IL-13, in terms of driving 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, allowing for differentiation of type 2 T-helper cells, which are a big source of inflammatory cytokines. And then we also know that these 2 cytokines can help drive the production of other cytokines like IL-31, which are important for itch itself.Beyond those roles, IL-4 and IL-13 can directly bind to neurons themselves and they are an important sensitizer of cutaneous neurons, lowering the threshold for activity. While they are not direct pruritogens, you can think of them as a volume knob on a stereo amplifying itch signaling to a large degree as opposed to an on-off switch.

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

The Dermatologist: What role does periostin play in linking inflammation, itch, and tissue remodeling?
Dr Chovatiya: Periostin is a good example of a soluble factor produced by fibroblasts that can then act directly back on immune cells and neurons. It is a way that we connect the fibrotic process of PN, fibrosis being critical to the formation of these thickened nodules. And it connects the immune dysregulation, along with neuronal sensitization and neuronal activation. So, it is yet another loop that exists in this disease state where there are several localized neuroinflammatory loops taking place.

The Dermatologist: Why does PN often persist even when underlying triggers are controlled?
Dr Chovatiya: In addition to involving local neurons and the local elements of the immune system, PN probably also has a 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 is difficult to break an itch-scratch loop. And one of the reasons why is probably because of what is happening centrally in addition to peripherally. It is only a hypothesis right now, but it is believed that trying to modify and change this behavioral loop is an important element of the disease state. But we also know that with many of our neuroimmune or even immune diseases, simply treating the disease may not be sufficient to remit it. This 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 enact longer-lasting changes.

The Dermatologist: What does PN teach us about disease endotypes within type 2 inflammation?
Dr Chovatiya: We now think about type 2 inflammation as a process that once it becomes apparent can touch many different disease states. It seems to be shared by numerous cutaneous diseases; across different disease states in different body surfaces, there is something about barrier disruption, dysregulation and/or immune activity that seems to be important.

PN is a good example of a disease state that is not necessarily directly related to the barrier surface; rather, it is happening at a deeper place but still being driven by a lot of the same processes we think about in diseases like atopic dermatitis or asthma. When we think about endotypes of type 2 inflammatory disease, we are looking at the different clinical and symptomatic manifestations that we can see through some type of alteration between the signals related to type 2 inflammation. The good news is despite the different endotypes of type 2 inflammatory disease, there are shared signals that allow for shared therapeutic strategies across these disease states.

The Dermatologist: Are there any tips or insights you would like to share regarding type 2 inflammation and PN?
Dr Chovatiya: At the end of the day, if you can diagnose PN, you can treat it. I think the argument about mild, moderate, or severe is a little overblown. We sometimes get trapped in thinking about severity but also nailing down the diagnosis. If your patient has itch that has been going on for longer than 6 weeks with evidence of rubbing, scratching, or picking and nodule formation, they have PN. This allows me to jump them up to a targeted systemic therapy that will help break the cycle they are stuck in.