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

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There are SO many causes to itch. Each person's skin condition is truly unique. My guest today, Dr. Shawn Kwatra, is deep in the trenches with research varying from what causes itchiness to how the gut microbiome could be a major cause for things like eczema and psoriasis.

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 include 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.

Have you tried any outside-the-box therapies to stop your itchiness? Let me know in the comments what worked for you!

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In this episode:

  • Breaking down the itch cycle in your body
  • Tips to STOP the itch + disrupt the itch signal
  • Why histamine is NOT always the cause of itchiness or eczema
  • Sedating vs. non-sedating antihistamines (pros + cons)
  • How your vagus nerve connects gut problems to itch (FASCINATING)
  • Latest research on IL-31 (the “master conductor of itch”)
  • What happens when you don't get relief from itchiness (especially long-term)
  • Why you can't “just stop scratching”


“There was a study showing that even vagal nerve stimulation can actually alter itch sensation, and one of the new frontiers in inflammatory skin diseases is looking at alterations in the gut microbiome as well… I believe some of these bacterial specials, viral species, fungal species, may be signaling through the vagus nerve to help propagate itch sensation.” [16:27]

“The studies that have been done today across many different indications have shown that IL-31 (cytokine) blockade is one of the most potent, if not the most potent anti itch medicines and inhibitory factors that exist. And so monoclonal antibodies targeting this agent are in deep late phase development.” [19:38]


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. 265: Problem with Antihistamines That No One Tells You w/ Dr. Chris Thompson, MD

Healthy Skin Show ep. 253: Eczema Expo 2022 Recap

Healthy Skin Show ep. 257: Itchiness + Histamine Intolerance – Why Am I Itchy?

Healthy Skin Show ep. 070: Stopping The Itch In Children & Babies w/ Dr. Elisa Song


275: Why You're So Itchy (HINT: It's Probably Not Histamine) w/ Dr. Shawn Kwatra FULL TRANSCRIPT

Jennifer Fugo: Thank you so much for being here, Dr. Kwatra. I have been so excited to have you come on the show to talk about itch. This is a big topic for a lot of different people who are struggling with a lot of different skin conditions, and I'm excited that we're going to dig into this today.

Dr. Shawn Kwatra: Thank you so much for having me, Jen. I've been following some of your podcasts. I'm really impressed with everything you've done with the show.

Jennifer: Cool. Well, so let's kick this off and talk about the itch scratch cycle. I think that's a good place to begin. And what really causes us to be itchy? Especially we have psoriasis, which can be itchy, you have eczema, and obviously, we have hives and all different sorts of things. So I guess in general, what causes us to become itchy?

Dr. Kwatra: It's a great question and something I go through every clinic that I have with patients. A great way to think about it is that you can't have itch without nerves. That's the most important thing because the nerves are what transmit that sensation of itch. And these nerve fibers travel all the way from the skin to the spinal cord to the brain. And so the first things first, you can have an alteration or anatomical dysfunction of those nerves. Or you can have activation of those nerves by a variety of different substances, neurotransmitters, and in what is the case of most of the diseases, inflammatory skin diseases like eczema or psoriasis, you have inflammation. So many of these cytokines that are there and they're propagating, and then they set off these nerve fibers, and that starts this transmission pathway.

Once you have the itch transmission pathway started, those nerves become sensitized. And once they're sensitized, even things that may not have normally made you itchy can start to make you itchy. So an example is in eczema, folks who have their nerves very sensitive, there's actually a process called alloknesis, where when they are exposed to painful stimuli, as compared to a person who doesn't have eczema, they're more likely to interpret that as itch. And we all know when folks wear certain wool sweaters or other types of garments and clothing, if you have eczema, and I have eczema too, so I know from personal experience, it's more likely to just set off those nerves. And then you get the itch message going to the spinal cord being amplified, going to the brain, transmitting back, and then once you have that cycle that's set in, that's where it becomes very difficult because the process and the itch scratch cycle continues unabated.

Jennifer: And this obviously, if you were scratching the skin, there can be destruction of the nerves on the skin. Right?

Dr. Kwatra: Absolutely. So those nerves that are in the skin actually go almost all the way out to the outer layer, so they have different names. One of the names for them is C fibers, which are unmyelinated fibers. You also have another set of nerve fibers called A-delta fibers that are thinly myelinated fibers. And when you look at the nerves of a patient with eczema and other itch disorders, what you find is that they are dysregulated. There's a drop out of them. They're cut, they're broken, even from scratching. So scratching can actually cut and break these nerves and these neural circuits. Also, these nerves are transmitting itch, but they're transmitting pain, temperature disturbances, vibrationary inputs. So that's why a lot of these different sensations can also become intermingled with itch as well.

Jennifer: And could they also maybe be helpful in some regards, like in terms of if you're really itchy, could you use something else? I know a lot of people say, “Oh, if I jump in a shower, it's hot. It almost gets the itch to stop.” And then you have other people that'll use ice packs.

Dr. Kwatra: Absolutely. So that's actually one of the secrets of the transmission pathways of these nerves is that if you increase the input of those sensory endpoints with another stimuli, then you can dampen the itch response. So I have several patients who when they have these itch bouts, they have ice packs. And the ice packs go on the itchy areas, then these nerves become occupied with this temperature signal and the itch is processed less through the spinal cord and the brain, so definitely temperature dysregulation can help. Usually we think about colder temperatures helping, but in some folks, even warm temperatures can still take the attention off of those nerves.

Interestingly, other things that could help that are outside the box, there are TENS units, trans-electrical nerve stimulation units. So some folks have itch that has a little bit less inflammation and it's normal appearing skin. And they've actually been able to use some of those units to be able to reorganize some of these neural messages of itch. So it's actually very fascinating being able to kind of distract yourself and have these different sensory inputs.

Jennifer: Actually, so now as you're talking about this, I'm just kind of curious. People will say if they get a skin infection, they can also be really, really itchy. Is this sort of the same problem, or is it a different problem, like a skin infection itself would … How does that translate in terms of the nerves and itch?

Dr. Kwatra: Yeah, it's a great question. So actually, one of the most common skin infections is staphylococcus aureus, so staph aureus and staph infections happen all the time with eczema patients. And there are different byproducts that occur on the skin if you have a staph infection. One of those is proteases. And proteases are enzymatic reactions also that are able to stimulate the nerves. So actually, if you're having an infection directly, you're more likely to make byproducts in the skin that directly stimulate nerves. Also, staph infections have greater release of several of these inflammatory cytokines, the ones that we know can stimulate nerve endings as well. So it's kind of many different ways the byproducts of an infection can actually stimulate the nerves.

Jennifer: Oh, my goodness. There's so many different things that can contribute to this, it sounds like. And the other part to this I want to ask is, my theory has been for a while just having worked with clients, is that a lot of people assume because they're itchy, they have a histamine problem, that there's too much histamine in their system. But when I assess someone, certain things with a lot of people actually doesn't … They don't add up. And I'm like, “I don't think histamine's actually the issue here.” Do you have any thoughts about is all itch associated with histamine? Or is it possible that it could be associated with something else?

Dr. Kwatra: Jen, this is one of my favorite topics, so I'm so glad you asked. There is a humongous misconception also among many dermatologists about the role of histamine and antihistamines. So let me tell you, some of the itch conditions or itch disorders that are definitely associated with histamine, chiefly among them is urticaria or chronic hives. And so this is characterized, as we all know, where you have these welts on your skin. They're red. They get very edematous and inflamed. And those areas go away after a few hours or less than a day. And we know the antihistamines in particular can help prevent those flares from occurring and also once they occur.

But the itch associated with many inflammatory skin diseases, I'm talking about psoriasis, I'm talking about atopic dermatitis and beyond, in these conditions, the itch does not involve histamine. And there've been many studies showing that histamine does not have a role. There've been very nicely conducted studies showing that non sedating antihistamines do not help with the disease process or the itch. Where it becomes a little bit interesting is sedating antihistamines. So non sedating antihistamines are things like Claritin and Allegra and all those things that are thought to be not making you super sleepy.

Sedating antihistamines, things like Benadryl or one of the prescription agents, Hydroxyzine, they make you tired, and I'm sure many folks know that they can help with itch perception. But it is not because it modulates the itch pathway of eczema. It's because it makes you tired, and there's actually a study looking at this showing that sedating antihistamines in your brain activate areas that are associated with scratch relief, and so they're helping with itch. But then my question is: What else are they doing that is not helping? Because there's some studies that are showing that antihistamine use, even non sedating, low level over the course of a few years might be associated with an increased dementia risk.

And for folks who have younger children, we don't know. Could it be associated with ADHD development, other things like that? And so honestly, when I'm treating patients, I am looking for: What is the mechanistic cause of their itch and how can we address it? A sedating antihistamine's a Band-Aid. So it can help intermittently, but it's not curing the problem and it's not the underlying etiology.

Jennifer: Yeah. I appreciate you sharing that. We actually have an episode with an allergist who also shared his concerns about what tends to be long-term use of antihistamines. And he too also, he's concerned. He said, “There's some concerning research that I think we need to rethink how we're approaching this.” And so it's not just you in dermatology that has a concern. I'm hearing this on the allergist side as well. And I appreciate you for sharing that because that's been my concern for a while, that the clinical picture that I see didn't make sense. And oftentimes, I've had some clients that are on three different antihistamine drugs, even sometimes famotidine, which is normally used for when people have heartburn and GERD. But it's used because it's again another one of these, can be helpful when we have too much histamine in us, but they're just not getting any relief. And they think that they're kind of a lost cause. So it's nice to hear you share that. The reason it's not working is because it's not a histamine problem. You know?

Dr. Kwatra: And if you go see a dermatologist, it's not their fault. But because in their training programs, it's long been held in a dogma that if you're itching, you just give an antihistamine. It's actually what we wish the drug was, something that just helped with your itching and help relieve things. But it's actually not the case, and I think that there's been a dramatic misperception of the effect of antihistamine. So many patients are getting these prescriptions and recommendations for over the counter agents, but if we look purely at itch biology and pathophysiology, it's not really doing much.

Jennifer: Yeah. Actually, I want to ask you this because I think listeners may need to know this. You study this. Right? I just want to be very … Could you just share? You are literally in the trenches studying this now. Right? That's why you are … Because I don't want someone to go, “Well, those are theories.” You're in this. Right?

Dr. Kwatra: Absolutely. So at Johns Hopkins, I have a basic science laboratory as well. So we have a lab where we do investigations, we do mouse models. I am a dermatologist, so I treat patients. And we also have a very significant translational research arm, so we collect blood, we sample microbiome. Sometimes we do skin biopsies. And we're trying to put it all together, and we're looking at different causes of itch in the laboratory, from what we see from patients, so trying to put it all together, even involved in trials. Absolutely, we're in the ground. We're living and breathing all of this stuff dynamically.

Jennifer: And so I just want people to know that what they're hearing, this is where we are right now, and so they could also maybe even share this episode with their derm or with their doctor if the doctor is not familiar with this, so that they can also help get educated on some new ideas and concepts around this because I think it's important that we all learn from each other and know that there are new developments coming that could really make patient care a lot better, which is important.

Dr. Kwatra: Absolutely. It's so tough right now for providers I think, who are general dermatologists and other providers because there's such an explosion of new agents in development or recently approved, and in terms of our understanding of phenotypes. So my big thing is we're going towards precision medicine whether we want to or not, but every person is different. Every person's eczema is different too, and I think that is truly the future. And as time goes on, we're going to be peeling the layers back about these different subtypes and forms and all of that.

Jennifer: Yeah. Well, let's talk a little bit about the vagal nerve. So for those who are listening, I remember years ago, my dad, who was a surgeon, he'd mentioned the vagus nerve to me, and I was like, “The what?” And he's like, “The vagal nerve, the vagus nerve travels and it's like a vagabond. It travels through the body. It wanders.” And I was like, “Okay.” Well, when I went for my master's degree, I came to learn that it's in the brain, but then it also innervates all throughout the GI tract as well. So do you want to share a little bit about your thoughts on how itch and scratching and such may be associated with something going on that the vagal nerve is picking up?

Dr. Kwatra: Absolutely. So a little bit about the vagus nerve, which is the longest cranial nerve, running all the way from your brain to your large intestine, so truly the vagus nerve is a modulator of an emerging concept, the brain gut axis. And there have been recent studies about the role of the brain gut axis and a whole host of neurological conditions and inflammatory conditions as well. There was a study showing that even vagal nerve stimulation can actually alter itch sensation. And one of the new frontiers in inflammatory skin diseases is looking at alterations in the gut microbiome as well. And one of the hypothesis I actually have is that there's altered gut microbiome in many of these patients, and especially in eczema patients, it's been known. We know that there's altered skin microbiome and gut microbiome. And I believe some of these bacterial specials, viral species, fungal species, may be signaling through the vagus nerve to help propagate itch sensation.

And we're getting new studies across various disciplines of medicine, and so certainly there's a connection, a role. And also, it's bidirectional. So let me tell you, I have eczema, and I also have stressed induced hives. So if I think about a very stressful thing, I'll break out in hives on my body. But that just shows you that you can have top down processing, so from your brain to your vagus nerve, or from other nerves, then that message gets transmitted. So I think folks should really think about how it's all connected. And the vagus nerve is one of the biggest connectors that we have in our body, namely our brain to the gut.

Jennifer: And so essentially what you're saying is that if we've got some problem kids hanging out in the GI tract, theoretically you're vagus nerve is picking those signals up and kind of trying to communicate it to your brain, but perhaps how it's translated to us could literally be itchiness.

Dr. Kwatra: Absolutely. And so we know that there's an imbalanced microbiome in the gut of many eczema patients. And we know that certainly has role in inflammation, neural inflammation, and definitely nerve activity, so it is all connected.

Jennifer: Now I wanted to ask you because we've talked a little bit about some cytokines and immune activation. And obviously, everyone who listens to this, a lot of the listeners are somewhat familiar with biologic drugs, and I've talked about cytokines on the show before. And there was a cytokine that you had talked about in your presentation called IL-31, which was new to me. I had never heard of it before. I'm definitely not an expert. I'm just really curious. And how is IL-31 associated with itch?

Dr. Kwatra: Yeah. IL-31, everybody's going to be hearing a lot more about it. So IL-31 is thought to be one of the, if not the absolute master conductor of itch sensation. IL-31 is a molecule that we know is expressed in the skin, in the blood, but also on nerve endings, nerve endings in the skin, nerve endings in the spinal cord. And the studies that have been done today across many different indications have shown that IL-31 blockade is one of the most potent, if not the most potent anti itch medicines and inhibitory factors that exist. And so monoclonal antibodies targeting this agent are in deep late phase development. And I think the ability of an antibody to target a cytokine is very important for safety. That makes it leaps and bounds safer than all these nonspecific agents like steroids, et cetera, which we hate giving.

And for itch sensation, picking those agents is very important. So we know that there's some data about IL-4 and IL-13 as well in terms of nerve activation. And IL-31 does that too. It's involved with the nerve signaling and with inflammation, and it's very potent at reducing itch. So we're going to have a new kind of player in terms of itch sensation. And I find it just remarkable that you could be given a drug and it could not only work at the site, but it could also be simultaneously dampening that nerve transmission, and that's what leads to this unbreakable itch scratch cycle. But if you target specific cytokines, then you can just break it flat out.

Jennifer: Any idea what could be triggering that release of, or generation of a high level of IL-31 that could cause this?

Dr. Kwatra: Yeah, no, it's a great question. So I think it's disease specific. It goes by each disease. But what we know is there are T cells, so kinds of immune cells, that become pathogenic. And those T cells then are one of the sources of many of these cytokines that we're seeing, while IL-31 is also secreted by other immune cells and macrophages and all those things. But what actually happens is this inflammation has a memory. And so what I predict as the future of many of these conditions, psoriasis, eczema, you can look at psoriasis. Look how psoriasis has gone. The first agents, Humira, and other agents like that were every two weeks. Then we got IL-17 inhibitors every four weeks. Now we have IL-23 inhibitors every two months or three months.

What folks want is longer term remissions, and so what I think is going to be the solution to this is being able to target more upstream like you were alluding to. And I believe blocking the memory, so these memory T cells that are remembering inflammation can be so helpful. In the case of eczema, if you have a leaky barrier, so folks with eczema like myself have thickened palms, and we have more likely to have dry skin, and that impaired barrier lets different microbes and environmental factors penetrate the skin. And no matter what, if that happens, you'll have inflammation that's triggered. So in the terms of eczema, that's why it's important to really moisturize and seal your barrier and do all of that stuff. But for other conditions, we know that there's a variety of other factors that are also involved in pathogens.

Jennifer: In terms of certain markers and things, you had mentioned something about C-reactive protein. What does the data that you've looked at show you? C-reactive protein's pretty easy to get tested. Could that be a helpful marker to look at? Or does that tell us anything about someone's disease severity or itching?

Dr. Kwatra: It's a great question. So we're kind of stretching the bounds of normal medicine, dermatology, that's what we do. And in our laboratory also, we looked at C-reactive protein levels in particular in itch patients. And definitely found that folks who have severe itch in several instances have increased global inflammation. And one of the rough and dirty markers of global inflammation is C-reactive protein. Another one is something like ferritin, and there's several other markers, erythrocyte sedimentation rate as well. What is posit is if you are super itchy all over, then you're going to have disrupted sleep. If you have disrupted sleep, you're more likely to have a whole host of disease comorbidities. You're more likely to have blood glucose intolerance or diabetes. You're more likely to have cardiac and cardio-metabolic events.

And so C-reactive protein levels tend to be higher is what we found in patients who have chronic itch. In terms of actually measuring it on a clinical basis, the only reason I would hesitate is because I'm not sure if it's necessarily actionable in terms of if it is high, so you'll still want to reduce folks' itch.

Jennifer: Exactly.

Dr. Kwatra: Right? But knowing if you're itchy and you're not sleeping, you are at risk of having a whole host of inflammation associated diseases that emerge. That's a powerful concept because then there's a price not to treat, and that's the one thing I tell folks because I always counsel on drugs and side effects, but now I started counseling on the price of not treatment. And I tell folks, if you're itching all over and you're itching to the point where you're not sleeping, you likely have more inflammation in your blood. One of the rough and dirty markers also of increased inflammation, blood is eosinophils, so those are cells that are in your blood. It's frequently high in atopic dermatitis or eczema. And folks who have very high increased blood eosinophils are at greater risk of cardiac events, other types of events from chronic inflammation. So I tell folks there is also a price and a side effect, is something you could say, of not treating yourself, of letting yourself go unchecked with this type of inflammation.

And honestly, when I'm counseling folks, that's kind of had a paradigm effect, change, kind of total shift thinking about: If I don't get this under control, then what could this do to the rest of my body? And what could develop?

Jennifer: And that is an important question to be asked. I think we sometimes don't fully realize the toll or the price of being … It is chronic illness to some degree. I mean, depending on especially the severity, I'm sure you've seen severe cases. I've certainly worked with severe cases. And when you can't be a mom to your kids, when you can't get out of bed, when you can't go to work because you are in so much pain, your skin barrier's so degraded, or you have difficulty just functioning because you're in so much pain, it's very … You're right. I mean, that's a really valid point is to ask. What is the severity of this? And we don't want it to get to that point where it is so severe that now the, oh goodness, the lifestyle factors that are now being compromised, the facets of your life, like sleep and such, that are really crucial. They're important. They play an important role in overall health.

Dr. Kwatra: And Jen, this is such an important point to bring up because what I've found is there's not as much respect for a person and what they're going through if they're dealing with chronic itch versus something else like chronic pain. So I'll tell you on a personal level, I study itch, this is what I do. I treat patients from all over the world at our itch center at Hopkins, and I really do a lot of outside the box therapies. When I tell my friends, “Oh, I treat patients with itch,” I've had folks laugh at me.

Jennifer: Really?

Dr. Kwatra: Honestly. They say, “Oh, you're a doctor and you're treating itch. Don't you think you should be treating something more meaningful?” True story. This happens. And then my patients, when I have deep conversations with them, it comes out that they're itchy and other folks are like, “Just stop scratching.” No, it's not just stop scratching. This is an impulse that's going on. There've been videos done of folks while they're sleeping. They're not conscious and they're scratching everywhere. It's a reflex to a real thing that's going on, a real pathology. And so when we looked at all of our patients, we published a study in the Journal of Investigative Dermatology, and we looked at the overall impact of health related quality of life of patients with chronic itch in our clinic. And you'll be surprised to hear it was just as severe, actually more severe than patients who had a stroke, patients who had heart failure, and patients who were on hemodialysis, more severe, chronic itch.

So that's what we should be talking about in terms of severity. The mismatch is there. And if you look through history and all of the references to itching, you look at Dante's Inferno, I mean itching, fierce itching that nothing could relieve is the eighth ring of hell. If you look at tribes in India, one of the punishments is to be in a triangular cage that is covered with an itch causing substance, and then to have that sensation, it is hell. And so I think that I'm so glad that we're talking about this because it's something that we deal with every day, and I've made it kind of one of my personal missions, is to increase our awareness of just how severe this is. This inflammation can really wreck your whole life, and it is a form of hell. And pain gets so much more respect. If you have chronic pain, everybody's empathetic. We need that to be the case for itch, so I'm really glad that you brought that up.

Jennifer: Well, I feel like there's so much to talk about with this. And I know, well, we already talked, you're going to come back and we're going to do more episodes.

Dr. Kwatra: I [inaudible 00:29:54].

Jennifer: But you do see patients, as you mentioned. How can everyone … Where are you seeing patients out of? And how can they get in touch? And obviously, we'll put all the details in the show notes as well.

Dr. Kwatra: Sure. So I'm the director of the Johns Hopkins Itch Center. And so I see patients in Baltimore, Maryland. And folks sometimes come from out of town, so happy to see folks as well.

Jennifer: Perfect. Perfect. Well, thank you so much for being here. I really appreciate it. And I love that you have a level of empathy. I mean, I feel for you and I don't wish eczema on you, and hives and such, but I think that everyone listening can hear the level you really empathize with the people that you are working with. And I think there's something about that, that makes your relationship to this special, that perhaps somebody who doesn't know what that's like might not quite understand because you've literally lived it.

Dr. Kwatra: Yeah, thank you so much. I think that's one of the keys. And I tell everyone we're never going to give up and love thinking outside the box. The other thing is, every person is different, so every person may need a different solution, and so it's working together to find that solution.

Jennifer: Yeah. Well, thank you for being here. I appreciate it.

Dr. Kwatra: Thanks so much for having me. I really had a great time.

“There was a study showing that even vagal nerve stimulation can actually alter itch sensation, and one of the new frontiers in inflammatory skin diseases is looking at alterations in the gut microbiome as well... I believe some of these bacterial specials, viral species, fungal species, may be signaling through the vagus nerve to help propagate itch sensation."