From Cytokines to Clinic: Translating Type 2 Biology Into PN Treatment

Dr Brian Kim explores how IL-4 and IL-13 drive itch, fibrosis, and nodule formation in prurigo nodularis through neuroimmune and type 2 inflammatory pathways. Learn why treatment responses vary, how periostin links inflammation to tissue remodeling, and how emerging therapies—including dual cytokine inhibitors and novel biomarkers like IL-31—may shape personalized care in PN.

Brian S. Kim, MD, MTR, FAAD, is vice chair of research and site chair of Morningside and Mount Sinai West, in the Kimberly and Eric J. Waldman department of dermatology. He is also director of the Mark Lebwohl Center for Neuroinflammation and Sensation and lead of the Allen Discovery Center for Neuroimmune Interactions at the Icahn School of Medicine at Mount Sinai.

Transcript

How does IL-4/IL-13 signaling contribute to both pruritus and nodule formation in PN?

Dr Kim: We know for a fact that IL-4 and IL-13 as we described, hits the nerve, causes hypersensitivity of the nerve. So we can surmise from that kind of neuro hypersensitivity causes itch to result in scratching, which begets more itch and more itch as a consequence of both the scratching as well as the inflammation. But we also know that these cytokines, a lot of people perhaps don't realize that type 2 inflammation is actually not just designed to cause itch, but it's actually evolutionarily designed to actually wall off, and cause actually is a way to cause extravasation and wall off in some element of fibrosis to protect against certain kinds of parasitic infections. As I said recently in my clinic to a resident, everything, every disease is just evolution gone wrong and itch is exactly that. And prurigo nodules is exactly that. It's that every response and prurigo nodularis evolutionarily was probably designed to prevent parasitic invasion of your skin, but by going wrong, your body thinks there's a parasite when there isn't. And that's why you get these nodules that are inflammatory, itchy and attempting to wall off something that's not there. So that's again the many tentacles of type 2 inflammation by way of IL-4 and -13, type 2 inflammation begets type 2 inflammation, type 2 inflammation begets itch, which begets itch and itch and scratching and type 2 inflammation, all beget fibrosis as well. And then this is a vicious feedforward cycle.

Why does targeting type 2 inflammation improve symptoms in some PN patients but not others?

Dr Kim: So this gets into the heterogeneity of prurigo nodularis. So not a hundred percent of patients are going to respond to type 2 inflammatory blockade. So we know that if you block IL-4 and -13, some patients will not respond. But also if you block IL-31 alone, some patients may not necessarily respond, the key being some, is that because these pathways say IL-4 and -13 can compensate for IL-31 and vice versa perhaps. But also it's very possible that there are other pathways that we don't know about that are much more peripheral. So in the old days we talked about type 2 inflammation as simply IL-4, -5, and -13. Now we describe it as IL-4, -5, -13 and -31. And then some people would also include TSLP, IL-33, IL-25. You could go even further out depending on how many cytokines you want to incorporate or even non cytokines in the type 2 immune response. So I think there's still a lot that we have to learn with regard to the heterogeneity of all that is type 2 inflammation. It's not just a couple cytokines and it's definitely not just a couple cells, it's a repertoire. And the way I always describe type 2 inflammation, sure there might be a finite number of keys on the piano, but there are many, many songs you could play on the piano.

How does periostin fit into the link between type 2 inflammation, fibrosis, and chronic itch?

Dr Kim: So this is a follow-up to the idea that there's type 2 inflammation in terms of the cytokines that define it. And then there's type 2 inflammation that goes beyond what other pathways and molecules does it actually trigger. So periostin is another molecule that's obviously not a cytokine, but that is actually produced by oftentimes epithelial cells like keratinocytes as well as fibroblasts. So this actually links to this whole idea of tissue remodeling that is activated in the setting of type 2 inflammation and that's where periostin comes in and it activates these kind of integrin receptors and that's where periostin comes in as a different kind of module of tissue remodeling.

How should dermatologists think about sequencing biologics that target different type 2 pathways in PN?

Dr Kim: Well, I think the way dermatologists would think of how biologics fit in, it's really straightforward right now because essentially the only drugs that are approved to treat PN are either, you either block IL-4, -13 at the receptor level by way of IL-4 receptor alpha, or IL-31 at the receptor of level by way of IL-31RA. So it's really those 2. And I think the idea is that really you can actually treat PN with either of drugs. One thing is that, as I mentioned earlier, because IL-31 is so linked with itching, it's often easy to think of blocking IL-31 as the go-to, but also there's a lot of inflammation in PN, there's a lot of fibrosis and because of that you could lean more towards blocking IL-4 receptor alpha as a modality. But the reality of it is both of these treatments work quite well for both inflammation and itch.

And so if you think about as a Venn diagram, how much do they overlap? Quite a bit probably in terms of therapeutic outcomes, but there's also elements of non-overlap as well. So I think there's room for personalized medicine, but it's really at this point it's almost a coin flip in terms of what you would want to do initially. Now that could change over time as new drugs come to market for PN, there are companies that are actually developing treatments like bispecific antibodies, if not antibodies, to target both type 2 classical type 2 cytokines as well as IL-31 to target both inflammation and itch. And I think I'm very, very excited about those possibilities in the near term.

Is there evidence that early suppression of type 2 inflammation could prevent chronic nodular remodeling?

Dr Kim: Frankly, a PN probably takes a long time to occur. It probably does not happen overnight. So the idea is that if you could intervene early, could you avert it? Sure, absolutely. Is this something that's done routinely? Probably not. Oftentimes, PN's not well recognized until it's gone pretty far in my opinion. It's usually not even months, but often years in the making by the time you see these patients. But yes, I think that if you could intervene early, it could be very, very effective, and you could change the trajectory of the disease. But I believe that also is true in atopic dermatitis as well. I think that if you were to treat earlier in life, you could probably change the long-term severity of the disease as well. I don't think that's particularly provocative. I think that's a very intuitive idea in terms of any disease.

What biomarkers hold the most promise for identifying type 2–driven PN in clinical practice?

Dr Kim: Yeah, there are not any solid biomarkers for PN, but personally I think whether it's classical type 2 cytokine blockade by way of IL-4 receptor alpha or IL-31 receptor, what we're finding in general, and this is not limited to PN, is that IL-31 itself is a great biomarker for itch. How it's a great biomarker is not entirely clear yet. So it's not just simple as do you have high or low IL-31. It's not as quite simple as that. It might be kind of where your IL-31 levels are at the beginning and whether they go down over time with treatment, but that seems to be a very promising biomarker if we're able to develop a diagnostic tool for that. And so you could also perhaps argue other things like IL-13 could also be a good biomarker, but there are more to come maybe periostin, but it depends on whether it is you're able to assay for it and how you'd assay and the ease with which you can assay for these things.

Looking forward, what are some of the new things on the horizon for type 2 inflammation and prurigo nodularis?

Dr Kim: Yeah, I mean I think I mentioned some of it that you have these kind of dual type 2 cytokine IL-31 blockers. You have kind of IL-13 IL-31 double blockers that are coming. There have been a number of trials in that area. Full disclosure, I advise for a company that's developing an antibody in this regard called Attovia Therapeutics. There's also another company that I'm advising for called Triveni Bio, actually has an IL-13, KLK7, Kallikrein 7, which we've published on exquisitely elevated in the setting of itchy atopic dermatitis. It's not a cytokine, it's a protease. And they have a dual blocker for KLK 5 and 7 as well as blocking IL-13. And that's a very, very exciting strategy as well. Additionally, if you want to think of mast cells as part of the type 2 repertoire, which in my view they very much are, there's a number of companies that have MRGPRX2 antagonists that are in development. I'd advise for a number of them as well as full disclosure companies like Avammune and Septerna are very interesting companies that have antagonists for those as well. So there's a number of new ways in which both type 2 and type 2 adjacent or associated molecules are being targeted. And I think that's very, very exciting. Something to look out for.