302: Prurigo Nodularis 101: Triggers, Body Connections + Crazy Itch w/ Dr. Shawn Kwatra

Brought to you by Quell

This episode is bought to you by Quell — to help support rebuilding healthy skin from the outside-in + inside-out!

Take 10% off your next order! Use promo code QUELL10 at check out — Get started HERE!

– – –

If you've wondered what is prurigo nodularis, you're in for a treat!

Many people have NOT heard about it, but I feel like we will hear about it more and more in the coming years because Dupixent is now cleared for use for prurigo nodularis.

It's an incredibly ITCHY condition, and so many people have suffered from it without having had a skin condition for most of their life (it starts later in life)! That's why I brought Dr. Shawn Kwatra (the Super Man of “itch”) back on the show so he can dive into the condition as well as current prurigo nodularis treatment options.

My guest today is Shawn Kwatra, MD is a Director of the Johns Hopkins Itch Center and an Associate Professor of Dermatology at the Johns Hopkins University School of Medicine in Baltimore, MD, USA. He specializes in medical dermatology areas of clinical expertise, including atopic dermatitis, psoriasis, chronic itch of unknown origin and dermatology for ethnic skin. Dr. Kwatra also runs a basic science laboratory and clinical trials unit and is funded by the National Institutes of Health and multiple foundations. Dr. Kwatra has been an author or co-author on over 200 publications and author of the book Living with Itch.

If you've dealt with prurigo nodularis, what helped quell the extreme itch? I'd love to hear your tips and tricks in the comments!

Or, listen on your favorite app: iTunes (Apple Podcasts) | Spotify | Stitcher | TuneIn | Subscribe on Android

In this episode:

  • What is prurigo nodularis + what are the telltale symptoms?
  • Some possible immune system triggers to watch out for
  • Thoughts on current treatment options (+ what's coming down the pipeline)
  • Comorbidities strongly associated with prurigo nodularis (watch out for these!)
  • Is prurigo nodularis itch histamine-driven? (issues with using antihistamines)
  • How prurigo nodularis impacts mental health (WOW)


“Prurigo nodularis is arguably the itchiest of itch disorders. And so that leads to this impaired sleep. Then that can just wreck your whole life.” [14:00]

“In prurigo nodularis, you don't necessarily have that impaired barrier, but you have this stimulus of intense itch and skin thickening that then leads to secondary colonization (of bacterial infections).” [7:39]


Find Dr. Shawn Kwatra online here and here

Follow Dr. Kwatra on Twitter

Get Dr. Kwatra's book Living with Itch: A Patient's Guide

Healthy Skin Show ep. 275: Why You're So Itchy (HINT: It's Probably Not Histamine) w/ Dr. Shawn Kwatra


302: What Is Prurigo Nodularis: Triggers, Body Connections + Crazy Itch w/ Dr. Shawn Kwatra FULL TRANSCRIPT

Jennifer Fugo (00:15.178)
Dr. Kwatra, thank you so much for joining us back on the Healthy Skin Show. I'm glad you're here.

Shawn Kwatra (00:20.554)
Thanks so much for having me back.

Jennifer Fugo (00:22.73)
So we are gonna talk today about… What I have come to learn is basically like your kind of special expertise. I feel like you're like Superman in regards to Prurigo Nodularis. It's this condition that a lot of people have not heard of. I admittedly did not know about it, probably more so until you and I had a conversation about it. It was not something that was really on my radar, but I feel like we're going to hear about it more in the coming months and years. So, I thought we could kick this off by talking about what are the symptoms that are very common that people experience with this condition and also who seems to end up with this type of skin condition?

Shawn Kwatra (01:05.822)
Yeah, no, thanks so much for having me on and for asking about prurigo nodularis or PN. It's a disease that's been really under recognized for quite a bit of time and a lot of patients have suffered because of that. But broadly, Prurigo Nodularis can be thought of as a unique skin disease, just like you think about atopic dermatitis or psoriasis. Prurigo Nodularis would be just another one of those diseases. And the dominant skin manifestation here is really just a bump on the skin. It can be just a few millimeters. It can be even a few centimeters in terms of size. And it's intensely itchy. So the signs are intense itch, so chronic itch that's lasted for greater than six weeks or longer, signs of repetitive scratching. So when you look at these nodules, oftentimes they're excoriated. There's blood that's coming out. There's even a hemorrhagic crust on top. And those are pretty much all you need to have a diagnosis of prurigo nodularis. It tends to affect the extremities, so areas that can be scratched, so the upper arms, lower arms, the chest, and the back. And what's interesting is that the itch these patients experience is in these nodules, but oftentimes it's also in the normal appearing skin next door.

Jennifer Fugo (02:27.186)
So does the itchiness just impact the lesions themselves or is it also like all over?

Shawn Kwatra (02:34.226)
Yes, so in two-thirds of patients, the itch that they're experiencing is in the nodules, and it's honestly a lot of the time heightened in the nodules. It's very intense in the nodules, but it's also most of the time in that normal appearing skin. And what's really unique about prurigo nodularis is that unlike eczema or psoriasis, which starts earlier in life, prurigo nodularis tends to start a little bit later, so around middle age. The average age is around age 50.

And so you have a lot of folks that haven't had anything their whole life. And then one day out of the blue, they get these intensely itchy nodules. They can't sleep. You know, they have psycho social distress because the appearance of these nodules and it absolutely ravages many aspects of their life.

Jennifer Fugo (03:22.358)
And so this is a mostly adult issue. Do you ever see it in children?

Shawn Kwatra (03:27.234)
It's very rare in children. It is really uncommon in children. In adults, it's a few hundred thousand folks in the U.S., and it's probably even higher than that because it actually only got its own diagnostic code to even be coded in 2015. And so what we're seeing is every year the incidence or prevalence is going up, which means we're probably under-counting the number of folks that have it.

Jennifer Fugo (03:52.526)
Is there a skin condition that maybe, because you're saying, okay, it might be under reported, maybe under diagnosed because there could be a lack of awareness about it. And maybe someone might only see, for example, their primary care doctor and their primary care doctor might confuse. Is it possible it could be getting confused with something else?

Shawn Kwatra (04:14.93)
Absolutely. So a lot of the other docs may just call it rash or eczema or just lump them all together. That's oftentimes what ends up happening that the disease gets confused with other diseases.

Jennifer Fugo (04:26.43)
Is there something similar, like another type of skin condition, like that this would be similar to, you know? Because I think sometimes, you know, there's different rashes where like, okay, maybe seborrheic dermatitis might sort of have some, like might look similar in some respects to like atopic dermatitis. And sometimes people are even, even some derms are like, I'm not sure it could be psoriasis, could be eczema, let's do a biopsy. Sometimes things can kind of look alike. Is there something that this could be similar to?

Shawn Kwatra (05:00.126)
Yeah, so what's really interesting is that atopic dermatitis, especially in African-Americans, sometimes can have these prurigo like nodules also. So there's definitely some similarity with atopic dermatitis. They're both very itchy. Sometimes they can be bumpy. So that's definitely another similarity. Another analogy is think about having bug bites that then become chronic over time all over your body. So that's also another analogy that can be used here.

Jennifer Fugo (05:29.038)
Okay, and do they, does it usually all appear at once or is it something where you get one or two bumps and then they start to spread with time?

Shawn Kwatra (05:38.302)
Yeah, normally there's some type of trigger. It's hard to identify what it is, but we've had some folks, even after they've gotten certain vaccines or they've had an illness or other things they may have had raging uncontrolled type 2 diabetes, something that may stimulate the neural or the immune system to react to get sensitized towards having itch.

And so we know that there tends to sometimes be these triggers that really set the disease off and it can start as just a few on say one extremity but then rapidly they disseminate and you can get on both sides of the body, the trunk, really diffuse.

Jennifer Fugo (06:23.314)
Okay, so I read a paper and I wanted to know if this was true because I know with like psoriasis, occasionally you'll see skin infections in the plaques, occasionally. Then like with eczema, we have issues with staph aureus and sometimes there can be other infections. Is it possible for there to be any type of bacterial infections associated with the lesions themselves?

Shawn Kwatra (06:50.134)
Absolutely. So just like eczema and psoriasis, the lesions here in prurigo nodularis can be secondarily infected with staph. So that's definitely something that can be happening. We don't necessarily think that's the primary driver of the disease because the question is, why are folks developing these nodules that sometimes can be so thick and so fibrotic and there's so much itch, the connection really between the nerves and the immune system is what has gone haywire. And then that chronic itch enables the scratching and then the pathogen. So it's a little bit different from atopic dermatitis. In atopic dermatitis, you actually have a genetically encoded barrier disruption where you're more likely to have an impaired barrier. I have atopic dermatitis, and so if you have that impaired barrier, you're more likely to get colonization with these microbes. In prurigo nodularis, you don't necessarily have that impaired barrier, but you have this stimulus of intense itch and skin thickening that then leads to secondary colonization.

Jennifer Fugo (07:50.618)
This is just, again, so different. And I will also share, I think it's worthwhile to share that your research, and I'm so glad you're here, but your research is funded by the NIH, correct? So you're doing some really revolutionary things right now.

Shawn Kwatra (08:06.098)
Absolutely. We got interested in this topic many years ago because I see all these patients and nobody knows what to do. And so I was applying for NIH funding and someone told me, they said, you'll never get funded only studying this disease. Because they thought there's so little awareness, nobody knows about it. But… lo and behold, we're very happy. We're actually studying both atopic dermatitis and prurigo nodularis from the bench to the bedside. So we see patients in clinic. We draw their blood. Sometimes we do skin biopsies or bacterial swabs. And then we go back to the lab and we try to figure out what's going on. So it's been very gratifying for us because we're able to see patients and then we're doing research, clinical research, and also bench research to figure out what's going on. And we've actually, I think, made some very significant advances in our understanding the last few years.

Jennifer Fugo (09:03.562)
That is awesome. Well, so let's actually talk about the immunology side of this because this is very clearly more than just a skin problem. There is something going on under the surface. And my audience is fairly familiar, I think, with the more superficial idea that cytokines are like chemical messengers in the body. And so they've heard things like IL-4 and IL-13 because that is associated with Dupilimab and atopic dermatitis and then they've probably heard maybe the JAK-STAT pathway as there's been JAK inhibitors that have come up. So are there certain cytokines or even like the JAK-STAT pathway? What is associated from an immunologic standpoint with this condition?

Shawn Kwatra (09:51.014)
It's a great question. And I think all of those things that you mentioned are totally relevant. There's a lot of similarities between a lot of these different skin diseases. So one of the things I believe is that, you know, we have different names for these diseases, psoriasis, atopic dermatitis, chronic spontaneous urticaria, we call something itch of unknown origin, you know, it goes on and on. But actually, the, you know, molecular basis for a lot of these diseases, there may be some similarities across diseases. So that's one of the things that we've been able to learn. Once Dupilimab was FDA approved in 2017 for atopic dermatitis, then you know some reports started coming out that it may be effective in prurigo nodularis, and they actually did a phase three trial showing efficacy on the itch in the nodules for Dupilimab. So that's approved now for prurigo nodularis.

What's also really close and actually I presented the global release of the phase 3 study of nemolizumab in prurigo nodularis also. And that's a drug that targets IL-31, so thought to be one of the master H cytokines, IL-31 receptor alpha. And so I actually also presented that data and we found that just after one injection of this anti IL-31 medicine, there was pretty rapid itch relief also. So now we know we're learning, you know, there's a role for IL-13 and for IL-31. We also know that some of these JAK-STAT mediators that also interact with those cytokines are definitely involved. So there are studies going on with the JAK-STAT pathway.

And then, but beyond that, our group actually did the first bulk RNA, whole RNA sequencing study in these patients and we found multiple immune axes, type two inflammation, but also 17 and 22. And then our group also did the first single cell sequencing study. So we took biopsies from these patients. We isolated all of the individual cells. And basically what we found is that there are, you know, distinct differences between patients. This is like kind of something I've been thinking about is where our field is going with eczema, with psoriasis, with prurigo nodularis, that every patient is different. And so what we were able to see is that some folks, you know, had a phenotype very similar to atopic dermatitis. Some folks were a little bit more indeterminate between atopic dermatitis and psoriasis. And we looked overall with the genes in prurigo nodularis, the disease actually links up great with our epidemiology data, which suggests it's a distinct disease. So prurigo nodularis is distinct molecularly from atopic dermatitis and psoriasis as well. So that's kind of been the big thing. What's unique about prurigo nodularis on a molecular level is there's fibroblasts that leads to the skin thickening that are very unique, very novel in this disease. And actually some of these fibroblasts are associated with development of malignancies as well. So what we found is there's more cutaneous squamous cell carcinomas in these patients. They may be more likely to even get colorectal cancer later on. So the disease emerges in middle age and by looking through the molecules, we're able to find that actually these patients may be at risk for other diseases that are consequences of chronic unchecked systemic inflammation. So type 2 diabetes, chronic kidney disease… We know that these patients are more likely to also have liver disease as well, atherosclerosis and heart disease- just like psoriasis, except prurigo nodularis patients have MORE comorbidities in psoriasis, more comorbidities than atopic dermatitis. Yeah. So it actually has more. When we compare to all three, we had a recent publication, prurigo nodularis patients, even when you control for age and all these other cofactors, had the MOST amount of comorbidities. So type 2 diabetes in particular, some reports over even 20 percent, almost 30 percent of patients are having type 2 diabetes, other things like that. And one of the things I say is prurigo nodularis is arguably the itchiest of itch disorders. And so that leads to this impaired sleep. And then that can just wreck your whole life. So now when I counsel patients, I say, hey, there's a price not to treat here, too.

Jennifer Fugo (14:15.69)
So first of all, I just have to say that's a big, what you just said is a really big deal. That is a really big deal. So I guess I'm wondering, is there a chicken and an egg scenario here? Like does PN show up first and then these other issues show up later? Or is it something where maybe you do have diabetes or one of these other conditions and then PN shows up?

Shawn Kwatra (14:41.866)
Yeah, it's a great, great question. So we looked at data sets and it goes both ways. So folks who have some of these conditions, like type two diabetes, are more likely to develop prurigo nodularis. But patients who have prurigo nodularis are also more likely to develop type two diabetes. So one way to think about it is, folks who have type two diabetes oftentimes get neuropathies, right? So they can get peripheral neuropathies of all type. Actually, itch is a type of peripheral neuropathy because there's damage to the nerves in the skin. There are these nerves that go through the outer layer of the skin. They're called unmyelinated C fibers and A delta thinly myelinated fibers. They go all the way out to their skin. And some of the studies in these patients, we've done them too, finding that even in normal appearing skin, in addition to the lesional skin, you have more branching of these nerves in the dermis and you have almost a neuropathy in the epidermis, a drop out of them. So actually, just like type two diabetes can cause peripheral neuropathies, you can actually cause a peripheral neuropathy that can probably trigger this disease also. So that's one of the fascinating things that we've been able to uncover. Kidney disease, chronic kidney disease also can be a trigger. We basically think that the triggers of this disease can be anywhere along the neuroimmune axis. So some studies have shown folks when they have a stroke, their disease has either been triggered or cleared. Some folks have had a spinal disc disease that trigger their prurigo nodularis. Some folks, like I said, had a vaccine that triggered it. They had an immune illness. They had other types of immune triggers to the disease. And so that's kind of changed the way that we think about the disease. And actually in real time, I have one patient who, she developed the disease when she was going through the most stressful time of her life. That's when it came out. We got her controlled. We got her controlled. She got off therapy for two years. Then she lost her job and it came back.

And folks were telling her, it's all in your head. Before she saw me, it's all in your head. So this poor lady thought, oh, this is all in my head. I should just not scratch and felt the guilt associated with it. And what I told her, no, you have a disease. This is its name. This is why it happens. She started crying just with the diagnosis.

And then when I, you know, when we look at these patients, we see there's neuroimmune triggers. So your mind is just as much a part of your nervous system as any other part of your body. These nerves in your skin go to the dorsal ganglion in your spinal cord and to your brain and they come back and forth. So actually, you know, if you're having the worst, you know, time of your life, you're going through a lot that can be one of these neuroimmune triggers also.

But most patients don't even have any type of psychiatric relationship, but they're just labeled as being crazy, unfortunately. So it's really been damaging for a lot of people that even get the correct diagnosis, because until recently, we didn't have this research about this immune disruption, the neural disruption. That's why I feel a lot of gratitude and also importance that, you know, the work we're also doing can help folks realize that, you know, they don't need to blame themselves. There's something wrong going on. So that to me has been like the one of the most powerful, you know, parts of doing this type of research is helping to explain that. And so, you know, back to your question.

Why do some folks get these nodules? Well, last year at the Society for Investigative Dermatology meeting, we presented data that's now being published on genetic predisposition. So some folks are genetically predisposed to get this nodule. Other folks are just itchy, but they don't get the nodules. So actually it elevates the conversation that you may have a genetic susceptibility to developing these nodules, but it's not just one thing. You need environmental hits too. You may not be eating the right diet, you know. You may not, and we know it's incredibly important that is, because even that vagus nerve in the gut is basically a neural signaling organ. If you're not eating the right type of diet, the high fiber, all that stuff, that can be a source of where the itch can even be disseminated and triggered. Maybe it's other elements of your environment, like we talked about the type two diabetes. HIV, folks who can develop HIV are more likely to develop this condition also because it triggers the immune response. So other kind of different elements like that. So I think we're learning a little bit more of that it's both genetic and environmental inputs.

Jennifer Fugo (19:34.218)
And actually to bounce kind of back, maybe echo back to our previous conversation about itch. So when we spoke the last time you said that, and this was my suspicion, was that all this itch that everyone has may not likely be a histamine itch. Is this a histamine itch or is this as you're kind of you've alluded to that it could be other things in the system that are driving the itch? Because I think that's where most people think it's, oh, just take an antihistamine. And when the antihistamine doesn't work, they take another one, take more. But it's not helping. So is this at all associated with histamine or no?

Shawn Kwatra (20:16.694)
So that's a great question. And I think that's been the perception from dermatologists, providers, patients. Everyone has thought histamine and itch over so many decades, that's just been the thing that everybody thought. In hives or urticaria, absolutely it plays a role. We're finding less and less of a role, though, because there's other things involved. In atopic dermatitis, in this condition, prurigo nodularis, histamine is not what's causing the itch.

If you take a sedating antihistamine like Benadryl, then of course you'll be super sleepy and that can help with the itch, but it's not the underlying pathogenesis and there are risks of taking antihistamines. I don't recommend a lot of my patients take antihistamines. There's some studies suggesting you can get dementia even from a low dose of a non-sedating antihistamine over the course of several years. So I really am very cautious with it. I've moved away from it. And what we're finding is a lot of these cytokines, IL-31 you know, IL-13, IL-4, like many of these cytokines, these are key cytokines driving itch. When you think of itch, you should be thinking of a lot of these cytokines, not histamines. So that's one of the big things we're trying to break.

Jennifer Fugo (21:24.502)
That is awesome because also I, as a clinical nutritionist, do not love the low histamine diet. I realize it may be helpful for some, but I think it's something that when it doesn't work, the idea is let me take out more and more food and we blame something that may, like you have said, may have nothing to do with what's driving the itch under the surface and you're just not seeing any results. And in my world, you're thus limiting nutrition, diet diversity, and even harming your mental health. So let's talk a little bit as we get closer to the end of this conversation, which has been utterly fascinating. What are some of the treatment options? Obviously, there's new things that are coming down the pipeline. I've read some different small studies online that I'm sure if somebody is dealing with this, they might have looked up different treatment options and research. And they might find that there's small studies like on oral ketotifen or topical capsaicin. What works and what doesn't and what should we look forward to in the coming years?

Shawn Kwatra (22:31.326)
Yeah, you know, there's a lot of things that may be listed as potential treatments, but I think it's really important to evaluate the strength of the evidence behind a particular agent. So basically, before this past year, we have had, you know, really not any approved agents, and the evidence was terrible. So like, open label minimal studies like a few patients, not really controlled in any way. And so we really don't actually know from a controlled way the best way to treat this disease. What I can tell you from treating these patients is that we like to think on both the neural and the immune spectrum. So oftentimes these patients are started on say topical steroids first. The problem with topical steroids in this condition even versus eczema and psoriasis is that they're less effective here because that thickened layer of skin of the nodule. So you can't get through that outer dead layer of the skin. So it's a little bit harder for the steroids to penetrate. So what we found is actually intra-lesional steroids can work well because we use a needle to inject the steroids where the inflammation is in the dermis. So that's actually something that's utilized that can give more relief to these itchy spots in these patients, but they have side effects, so atrophy, all of that stuff. There's also traditionally there were some nonspecific immune suppressants that we really don't like prescribing things like methotrexate, cyclosporine, azathioprine. I really don't like these drugs because they're so nonspecific they have side effects. So you know, methotrexate like the liver, the kidneys, same thing with cyclosporine. Again, these patients are more likely to have problems than in comorbidities anyways.

So that's why targeting agents are so important in this disease. And so now, dupilumab's FDA approved injection for prurigo nodularis, like I mentioned, Nemolizumab's very close behind the IL-31 receptor, monoclonal antibody targeting its receptor. And I presented the phase three data, the other trials should be reading out soon. So, you know, that will be another option. And then beyond that, there'll be several other agents.

Jennifer Fugo (24:44.382)
And can I ask, like with the biologic options, if it stops the itch, because I guess that is the initial, I would assume, I'm just imagining because I don't have this condition, but I would think that if my main goal, my first goal, primary goal would be just stop the itch and then maybe worry about the lesions that you might not like and might feel unsightly or embarrassed about. Do the biologic drugs also help with the reduction of the lesions or is it more focused on the itch itself?

Shawn Kwatra (25:16.434)
Yeah, you're absolutely correct here. So this is really the goal of therapy is break the itch scratch cycle. So stop the itch and then the nodules will flatten over time. So that's exactly what we try to do with therapy. And the first readout is usually the itch reduction.

And usually sleep mirrors, sleep should mirror the itch. As the itch improves, the sleep improves as well. And the nodules get better, but it takes time. So some of the primary endpoints have been even as long as six months in the dupilumab study. It was four months, the primary endpoint in the Nemolizumab study for the IL-31. But they also have 24-week data coming out. So the itch relief can happen very quick and then the nodules take a little bit more time because they're thickened and they need to flatten and all of that. But there's also, so Jack inhibitors are also now being developed for prurigo nodularis and that's happening as well. What we found is that some folks have a lot of disease heterogeneity, especially African-Americans. So in inner city Baltimore, I probably see more African-American patients with prurigo nodularis than anybody. And we see that sometimes the lesions are very fibrotic, like very, very thickened. And actually another cytokine, IL-22, my lab found, was being secreted from these patients, mostly African-American in their bloodstream, which is associated with skin thickening. So the JAK inhibitor can also target that. So there's, you know, that's another agent that's coming through. So that it'll be great for patients because these patients have really suffered for a long time and finally that focus is coming to this group of patients.

Jennifer Fugo (26:58.794)
Well, I will say that I feel very honored to have you here because you're like the person to talk about this.

Shawn Kwatra (27:06.426)
Oh my gosh, thank you so much for having me. You know, these types of forums, you have such an incredible following and presence and these types of forums are so important so we can just make people more aware of the disease and for all the patients out there just to, you know, feel reassured that, you know, but all about what your disease is, therapeutics that are coming to feel that, there should be excitement, palpable excitement in this space.

Jennifer Fugo (27:30.13)
Yeah, and you also said that you see patients, they fly in. So you have a whole clinic at Johns Hopkins.

Shawn Kwatra (27:38.246)
Yeah, we actually have folks from all around the world who come in to see us. We're treating patients and trying to make discoveries in our laboratory, my laboratory also.

Jennifer Fugo (27:50.602)
That is awesome. Well, thank you so much for joining us today, Dr. Kwatra, the first ever prurigo nodularis episode. So the first of many, we will discuss this again. But thank you so much. And I look forward to having you on again.

Shawn Kwatra (27:58.634)
The first of many, the first of many. Awesome. Yeah, no thanks so much for having me.

"Prurigo nodularis is arguably the itchiest of itch disorders. And so that leads to this impaired sleep. Then that can just wreck your whole life."