To Scratch or Not to Scratch, That Is the Question

[Music] Welcome to Derms on Drugs and Video Podcast brought to you by Scholars and Medicine. Derms on Drugs is where cutting edge dirt meets so so comedy. I'm Mad Zires in each week. I'm George by my residency buddies Laura Ferris in Tim Patton. We use our 60 years of combined Derm experience to discuss, debate and dissect the hottest topics in Dermatology. It's everything you need to know to be on the cutting edge of Derm and there'll be the most fun you've ever had while actually learning something useful. New episodes drop every Friday so make sure you stick your calendar and boy do we have some cool stuff this week so over the last for those of you who are not like itch you know live and die love the itch research world. We've had some of the most fundamental questions in the history of Dermatology answered in the last couple of months here and I am so excited to have Dan Kaplan from University of Pittsburgh on to talk about his article on scratching and itching which was published in Science. Science for God's sake. That's like as real as a journal gets I personally am convinced that it is the first time that an article about scratching has ever been in science but I didn't look that up to confirm it but so let's just go ahead and jump right into it and I'm gonna start just with an article that I think is is fun and it's been around for a long time so this was a study out of roughly 10 years ago done by Gilias of Povitch the the Godfather of itch and what so it's brain-reward circuits mediated it's really for functional MRI study of active scratching and basically here's what guilt it he put people in an MRI machine and then induced so first just scratched like an area on their forearm and then induced itching using cowhage which is itch powder and then either an investigator scratched it or the person scratched it and so the investigator scratching his passive scratching the person scratching it is active scratching and he looked at what parts of your brain lit up and the main takeaway from this was that itch relief active scratching and itch activates the same parts of your brain as having sex gambling using drugs all these addictive behaviors and so there is a strong he what he proved was that there's a strong pleasure ability aspect to itching and that has always fascinated me because of the idea that like why did evolution make why was it so valuable that evolution put it on the same level as getting sugary foods fatty foods you know whatever and we really have a good answer to that and I think the papers were going to talk about today's start to give us some of that answer so when it was only if you did the scratching and you were actually itchy so it's not the scratching it's the quelling the itch that is what creates that pleasure circuit is that right yes so it was that's exactly right and interestingly because it is an interesting question of what feels better you know you scratching an itch your own itch or somebody scratching it for you then this really looked like it was somebody scratching it for you because that's an interesting question if you think about like an itchy spot on your back like how good it feels whenever somebody hits the right spot but they never did exactly right and that was actually part of this article because part of me wondered is it did the other people scratching it feel better just because they got it just because not feel as good because they just didn't quite get it right they weren't in the right spot the right you know strength and it turned out that whatever you scratch your own itch it actually it activates different parts of your brain than if somebody else scratches your itch so there is a fundamental difference just you know it fascinating I never knew what to make of it but it was just fascinating patent you got anything you want to say about this one no I think we talked about this like I think that you know you you we scratched to get shipped off our skin that was going to be bad for us and I know you talk about mosquito bites and that doesn't happen until later and how ticks don't itch but if you think about a flee infestation or louse or mites or lice you got to get that shit off you or it's going to probably give you some bad disease so that always I was happy with that explanation I'm not saying that these other explanations are wrong I was good with that one okay I still say man that by the time it's itchy the bug is gone from the spot that was not what if you think about fleas in general though right you're you're we're prehistoric little mammals we're covered in fleas and like you they start biting you and you start to get itchy but they're still on you and so you just got to scratch them off but they're not in the spot that's itchy if I hear it it doesn't it doesn't just leave it here yesterday right because it takes a month to get the adaptive response right to to fleas and like scabies takes about a month right before you start to get itchy you think about people who can't scratch like in a nursing home or something they get Norwegian scabies right so the scratch really does have have a benefit to removing my scabies but it's probably the same for body dice damn it yeah it's hard for me yeah no more smart people on our we don't have an extra damn yeah you have a partner trying to convince me for a week and I'm like no no no you got me with right there no reaching scabies and they're in nursing home all right but in the case of like ticks from mosquitoes you'd argue that well they have evolved to actually avoid the immediate I was gonna say the same thing otherwise they get the other way they'll be taken out right I think maybe that's why ticks evolved to like there were probably ticks that did induce that it's right away but you start scratching them off and you know maybe it got rid of it all right let's move on to our next article here so uh Dr. Patton what do you got why did this one from January 2025 J.I.D. entitled epidermal mechanical scratching induced ROS so reactive oxygen species exacerbates the itch scratch cycle via TRP a1 activation on mass cells in atopic dermatitis by you at hour who at hour along title but that's really the takeaway you scratch keratinocytes make reactive oxygen species ROS activate mass cells via TRP a1 mass cells release all their things and you get more itchy and so they did it with a bunch of experiments I don't you know the first experiment they stretched these these keratinocytes cell lines and that made keratinocytes release reactive oxygen species that was suppressed by anacetyl cysteine second experiment they irritated mousekin with a chemical and tape stripping and they show that you have increased mass cells and triptase and the dermis tape stripping which did you know higher levels of both they took this mass cell line they showed if you stretch the keratinocytes you take the supernatant you add it to a matrix thingy that they made with the LAD2 cells which are this mass cell line it makes these mass cells release triptase similar to if you just posed LAD2 cells to H202 they did gene regulations 945 genes up regulated 654 genes down regulated I think we should go through each one of these for completeness sake no they did cluster analysis on those genes and the summary from the gene studies was operation seen in genes involved in mass cell activation type 2 inflammation redox processes eye and channels I don't you know there were four other experiments I don't really feel like going all through the whole things this is all zyruses fault he was like hey you should do this paper and I was like yeah and then I went to print it out and it was like 47 pages of stuff it was really hard you needed a PhD to fully understand everything but the take away yeah the take away was right stretched hack out supernatant appeared TRP a one expression on mass cells that led to the release of trip taste and and you know so that's why we itch it and also had these other pro inflammatory cytokines I you know I'm guessing Dan you understood this paper way better than I did what were your paper I thought it was a really interesting paper I guess it's not out yet so I'm glad you sent it to me I like reading papers in the the J.I.D. cutting edge always and so what it does is it adds to the list of things that caroteno sites get that release things that caroteno sites can release that are itchy right so when you scratch the skin you release one side of kind called TSLP it's very well characterized and it's very you know it can activate mass cells and other cells as well right and can be important in triggering itch and IL-33 is another example of things that can be released so it's a really nice paper to just add to the list of the complex stuff. I'll use the word stuff that is released by carotensites that can have biological effects on mass cells and on many other cells in the skin as well. So I thought it was really really really interesting for that reason. What you might might take away from it was that they made this gel and put carotensites in it and then they went basically and showed that moving the carotensites like deforming them just a little bit. Generated these reactive oxygen species that then activated the mass cells and the whole thing because I've always had a big problem with the it scratch cycle. Like people like to talk about the it scratch cycle and this finally made me buy into it. And the reason I never really bought into it was that if it was just that the scratching is mechanically damaging the skin surface, then in all of our topic patients that ought to be that we can see manifestations of scratching everywhere that they've got a rash and you can't the majority of places where they've got a rash. There's no evidence of scratching. So I've always been like, that's below me, but this is some of the first stuff in day of the day as well that really says to me scratching itself might have a way that it's generating inflammation. Yeah, a good example is is people who are dramatic graphic right that that's a perfect example of it where now you've got mass cells that are not fully activated, but they sort of have this heightened reactivity. And now if you scratch the skin, the stimuli from scratching is sufficient to push those mass cells over the edge, degranulate and you'll get you know you get or to carry a wherever the scratching has occurred. That's interesting. So yeah, so it's really and it's not like you're scratching and excoriating your it's really just the pressure of the scratching. Yeah, so I like the idea of from this paper that it's like the mechanical stretching of the carotene site that's the signal. The other thing I thought was interesting is that NSSETL system inhibited this and we know that there's some data that NSSETL system can also be helpful in like skin picking disorders, right. So maybe it sort of squelches the reactive oxygen species and the you know downstream effects. I don't know. I mean, I always kind of wondered why does NSSETL system work. Do you think it fits into this mechanism or do you think it not really. That was the last experiments they did were yeah, let's let's welch or whatever, gather up these reactive oxygen species within a seat of cysteine. They also had a medication that blocked that TRPA1. I think it's like a channel on the mass cells. And so we're both of the you know in doing them combined was better than each one on its own. And so, you know, potential therapeutic for itchy stuff is the TRPA1 blocker along with something that sort of clenches the reactive oxygen species. I'm going to put in a quick plug for the tamah here because the tamah to pin her off actually has data that it is a direct that the molecule itself is a strong antioxidant in addition to up regulating endogenous antioxidant pathways. And every time they brought that up, I've been like you guys are out of your mind. ROSs have nothing to do with a topic dermatitis. This is below me. Don't even talk about it blah blah blah. And some of a bitch it turns out I was well they pay you for which is they pay you for this. Yeah, yeah, we don't have disclosures on drugs on dermatology, but yes, germs on drugs. I mean, worth worth every penny. Anyway, I got one thing I got to ask what you guys think about this. So the other thing that the stretching made me think about this. And Ferris, I don't know if you remember this was a discussion we had in residency. It's always fascinated me that psoriasis in a topic dermatitis happen in areas that have the most skin stretching right the places where your skin is most actively deformed at right. And then there's some sort of your elbows, backs of your knees, you know, extensors of those areas. And I, and I, we had a conversation where I was like do you think it could be like the mechanical stretching of your skin that is doing this and your answer was basically, I don't know. Like I don't know how to bring. But maybe this is what is in residency. But yeah. I think that there's probably like why is one extensors surfaces. I think that there's probably something to like trauma right tell those the knees that's different than maybe the stretching. But yeah, maybe we'll maybe we'll figure this out today. I always thought that it was the what the hell do you call it the sweating in your in your flexures, but maybe it's both the sweating in this. So let's go ahead and move on here. Dan, why don't you. So I'm a basic science idiot. I have no idea what happened patterns less of an idiot about basic science than I am. Ferris is actually smart. So can you explain your your article in in a way that I would understand. I think you undersell yourself, but I will try. So the lab for a long time has been interested in how neurons in the skin are able to control or affect inflammation in the skin. And so we've been focusing on these sensory neurons in the skin because of course there's all different types of neurons. Right. And so some of the neurons consenst like painful stimuli and this would be like heat and they express a receptor that's called TRP V1, trip V1. And that's actually the receptor for capsaicin in chili peppers. Right. And so these are neurons that are activated by you know by trauma heat things like that. And you know we and others have found that these neurons are really required to trigger all kinds of inflammatory pathways in the skin, whether it's like a psoriasis type or a dermatitis type or just just about anything in the skin requires those neurons. And Dan, the latest stuff has been that immune cells kind of cluster at the tips of the sensory neurons. Am I. Yeah. So the neurons into the sensory neurons in the skin run along the neurovascular bundles and you can see that lots of cells are hanging out right next to them. Dendritic cells are there and a particular interest is the mass cell. Right. And they're just hanging out right along those neurons. Obviously they're you know they're talking to to one another. Now Dan, I'm going to say right now when I think mass cell, I think histamine and that's it. Right. The mass cell releases histamine. That's it. I'm. I know obviously at this point I've learned better than I'm wrong about that. But I think a lot of a lot of people still think mass cell you think histamine. That's it. Well, mass cells released a lot of release a lot of histamine. But you know if you look what's inside the granules, there's like a you know a witch's brew of different proteases and inflammatory means. And they also make cytokines and chemokines and you know all kinds of things. It's this incredibly complex mixture. Histamine is part of it. And you know if you also think this is apropos what we're going to talk about if you also think about how mass cells are activated. Right. Everyone is going to think about. IGE you know that's made by B cell and it's pre bound to the you know the antibody the IGE receptor on the surface of mass cells and it just hangs out in that state. Until an allergen comes cross links the IGE and then you get mass cells to granulated right. That's the classic way of activating math activating a mass cell. It turns out there are many many many ways to activate a mass cell. And I think one of the most exciting ones is through this new type of receptor. It's called MRGPR X2 and might have one called MRGPR B2. And so this is a receptor for many many types of ligands like for instance some products of the microbiome on the skin can activate it. The catalyst side which is made in rosacea by carotenocytes can activate it. But most importantly for this discussion is that there's this neuro peptide released by the neurons that sense pain called substance P. And substance P is a ligand for this receptor on mass cells and causes the mass cells to be activated. So the neurons like these pain sensing neurons when they get activated they release substance P. And one of the things they do is they cause mass cells to get activated. Then is MGPR X2 or if I don't even if I got that right is it specific to mass cells because like in mice in mice it is specific to mass cells in human. It seems like it's specific to mass cells but I will defer there are a lot of people working on MRGPR X2 as a therapy for both erdicaria and atopic dermatitis and it's unclear if it's maybe also expressed on some types of neurons. But certainly mass cells and it seems within the immune system and within the skin it's pretty much on mass cells and maybe neurons and certain contexts. So that'll be interesting because there is I'm doing a clinical trial right now with a drug that targets sea kit. And that is not specific for mass cells it also is on melanocytes right so you get hair whitening whenever you attack sea kit. - Thanks so much. the MGPRX2 is going to be an interesting other target. Yeah, so that is under development anyhow. So that's a little bit of background. So we had been working on these pain sensing neurons and we started to think like, well, what about itch? You know, there are other neurons that are responsible for itch. And so we got another mouse strain from, you know, Zhang Dong, who's at Hopkins, who's really one of the leaders in this field. And that allowed us to delete one subset of neurons that was responsible for itch. And I had this idea that, you know, since the pain sensing neurons were required for a type 17 response, that I thought maybe the itch neurons that would be required for a type two response. So we kind of round up that and that, unfortunately, like so many of my great ideas turned out not to be true. But what we did find is that if we were doing models of allergic contact dermatitis where you put small molecules, you know, you make the mice allergic to the molecule, and you challenge them a little bit later, that the mice that didn't have this itch sensing neuron, they wouldn't get inflammation, right, in this allergic contact dermatitis model. And what was interesting, and this was the weird part, this is what got us started, is if you did happen that we knew required i.g. in mass cells, you needed the itch neurons. But if you did a happen that didn't seem to require i.g. it was fine, the mice were fine. And so we scratched our heads for a little while thinking like, well, what are the neurons releasing? And then we just did this super simple experiment where we did the dermatitis model, but we put the mice in Elizabethan colors. Imagine a very small cone of shame, you know, that you have for your dog or cat, they make them from mice, and you just put the mice in this cone of shame, so they can eat the drink, they're fine, they just can't scratch their ears. And it turns out that you didn't need the neurons per se, you needed the scratching. So you needed the neurons to trigger the itch sensation, resulting in the scratch. And that's what you needed for the inflammation. That's one of one of our sayings here on Derms on Drugs, is that one of the most important phrases in all of science is, that's weird. And when you got away from the itch, you get rid of the itch neurons and the inflammation didn't happen, and you said that's weird. Then you did, you expand, oh my god, so the itch neuron, it's the scratching, but it's the tracking down the weird stuff that you don't expect, that leads to breakthroughs. So the hard part was to figure out why is scratching required for inflammation? So we talked earlier about all the things that scratching can release in the skin, right? I mentioned TSLP, you know, we talked about IL-33, and so we went down this list. And it's like, yeah, scratching does trigger them. Oh, sorry, that when you do the dermatitis, it does trigger them, but plus or minus the Elizabethan collars, there was no difference. So that didn't seem to be at least in this model triggered by scratching. So it turns out that what's happening is, you need the scratching to activate the pain sensing neurons. These pain sensing neurons release the substance P, remember, and that binds to the MRGPR X2 on the mass cells. And that activates them, but that's not enough, right? What really needs to happen is, if you activate a mass cell using this classic IgE pathway, like a regular allergen will do, you get like level one of mass cell activation. If you activate just with the MRGPR X2, you also get level one of activation. But if you activate both pathways at the same time, you get this big synergistic response, and that's what's required for the inflammation. And so that's why scratching was important. And so the idea then is that, you know, so scratching is actually making the mass cells more likely to degranulate. And a way to think of this is that if you have an allergen that's maybe sort of subclinical, like it's not quite enough to trigger the mass cells, if you now start scratching the area, now it'll degranulate and you can get the inflammation going or the protection against the helmet, or the protection against whatever it is. Right? So it's like, it's lowering the threshold or increasing the efficiency of mass cell activation. So it's mass cell activation through IgE versus through MGRX, whatever. Is it the same kind of activation? It doesn't like, does it cause different substances to be released if you trigger through one or the other? Super cool question. So we've known about this for a while. In fact, Brian Kim has a very nice paper on this, a number of years ago, and others as well before him have found that if you activate a mass cell through IgE or through this MGRX2, different sized granules are released. Right? So that was known. And it was known that like the cytokine TNF, which is very important for inflammation, if you activate through the FC epsilon through IgE, you'll get TNF, but MGRGPRB2, you don't get a lot of TNF. Right? And so, you know, we did this and we found that TNF was one of the main things that was different, but we have not looked properly. I'm sure if anyone like systematically really looks at it in detail, there'll be a lot of changes. And up until now, it was kind of unclear why mass cells should be releasing different stuff than what it all means. So, Dan Kim and I have been direct pattenics, excuse me, even the by the way, if anybody is watching and thinking, why is patent just not look as good as this? His computer, in addition to using an Android phone, which is just unbelievable. He also, his computer is apparently from 1987 and it crashed. I have an Android sponsorship, so I don't know. So we have been talking about if mass cells are actually involved in a topic dermatitis, and my answer and his answer up till now has been no. Like, man, why do you say that? Because mass cell therapies. I always thought it because mass cell therapies didn't work, right? That's what we're talking about. Right. What mass cell therapy? Anti-histamines. Yeah, well, anti-histamines is blocking like one of like 500-- I know, really. We're dumb. And I say homolysmab doesn't work either, but homolysmab is IgE-specific. So you're, is your argument that there are mass cell pathways that we will discover that are going to completely change our treatment of atopic term? I'm saying I don't know, but I do know that there's quite a bit of pharma interest in blocking the MRGPR-X2 pathway, a number of companies, some of which have been acquired by bigger companies, there are a number of clinical trials going on. And I'm not privy to them, so I don't know if they're working. I would think it'd probably be very effective in urticaria, right? In urticaria-related disorders. And whether it also works for atopic dermatitis, I think it probably should. But I don't know the answer to that, but I bet we're going to find out pretty soon. So Dan, if I can, let me see if I can summarize how I think about this now and see, tell me how wrong I-- I'm sure I'm wrong, but the question is how wrong? So because I'm always thinking from an evolutionary perspective, why would have gone this way? And so I now think of it as being the scratching activates an immune response that is not just removing stuff from your skin, but is also, let's say that the bug that bits you put a little bacteria in there too, and you start scratching it before it turns into an infection, you're like priming your anti-infection response. Is that-- I think that's 100% right. So we've focused up till now talking about how scratching makes more inflammation, which I think the upshot from this first part I've talked about is that scratching makes your rash worse, makes the inflammation worse. And I think this tracks very well with everyone's experience, right? If you have eczema, you scratch it. It feels awesome, but you're going to pay for it, your rash is worse. If you have a mosquito bite and you ignore it, it usually goes away pretty quickly. But if you scratch it, you'll get a persistent urinary carol pathule that can last for a week or so. So the question we asked at this, this is the second half of the paper, is, you get more inflammation from scratching, is there a benefit from it? And what we found is that if you look at the microbiome of the skin of these mice, when the mice scratch, their microbiome is less diverse. Some of the bacteria are no longer present. And if you do a model, a staff-orius model, this is just a really a super-- an epidermal staff, like an epitagol model, basically, that the scratching reduces the amount of staff on the skin by a fair bit. And if you either have mice where they don't sense the itch or you get rid of the itch sensing neuron, or if you put those cones of shame on them so they itch, but they can't scratch. Now, they have a normal level. They have a high level of staff. So the idea then is that scratching, while being detrimental, if you have an allergic situation, like Eczema, is actually beneficial, at least in the short term, because it helps reduce the amount of staff orius on our skin. And I think that's one of the reasons why scratching may have evolved, may have persisted. And I think it's also one of the reasons why it feels so good to scratch. action. because it's actually a reinforced behavior, right? It's a good thing. - Fascinating. So do you think, does those are role in like fullest pimpagoid, like thinking about things that really itch? And like, do you think that the itchingness of fullest pimpagoid causes sort of out of control inflammation and older people? And that's why we get recruitment of eosinophils and blistering or I don't know, maybe it doesn't. - It's a super interesting question. I don't know. Do you, I don't know. So if you, but now we think of these medications that let's get rid of itching. It's like what gets rid of itching the quickest? Is itching purely evolutionary? Do you think we still derive a benefit? Or do you think there's any sort of potential harm of, you know, if you could completely knock out itching? Do you think that would hurt us? - Only if you had scabies. - Okay. - Right? - No itching, itching. Okay, itching is like a useful behavior, right? A useful sensation leading to a often useful behavior, right? So what's the point of pain, right? Pain is to let you know that, A, you've got some trauma or something going on, you should attend to this problem, fix it. But also you should remember, it lays down memories that whatever you just did that caused that pain, don't be an idiot and don't do it again, right? But scratching is very different. It's reinforced, right? So you want to do it more and more and more. So I think they're fundamentally different. - Interesting. - It's the carrot. - All right, we're good. - Itching. - Dan, this has been a fascinating discussion that has been a ton of fun. And we're now going to move on to what it turns out as everyone's favorite portion of the show, where Dr. Patton is going to pull out his trivia machine, which is really just himself. - It's not a knock, that would be trouble. - It's not a what? - It's not on your lap, talk to it. - I printed it out. I have a backup plan. - Wow, you use paper, impressive. - Paper and printer. - All right. So Dan, we reviewed before we started, Dr. Patton, let's go. - Yeah, by the way, as I was reading your paper, I kept thinking you really need to make like, if you give a mouse a cookie, but with your research. Like if you give a mouse dip theory a toxin, you'll knock out MRG-PRA two neurons. If you knock MRG-P with like little cartoon drawings and like I would have understood this much, much better. - There is, did you get to supplemental figure 48? 'Cause there is no there. - No, no, that's the thing that kills me. There's, you had, you know, however many experiments and these six separate experiments. And then you're reading along and it's like, oh, check supplemental, and like, no, no, I don't understand these six experiments. - Well, yeah, yeah, it's just a necessary evil. - No, it's not. - It's just, it's smarter than, way smarter than I am. So it frustrates me. - All right. - And it should differently smart than you. - Differently sancted. - My therapist, Matt. All right, so these are questions about trivia, about pureitis, which that's how I say it. - Where are you? - Don't stop me. All right. - Here we go. What cartoon duo known for their over the top violent antics often entertains Bart and Lisa on the Simpsons? - It's just crappy. - That's Kaplan. Buy a hair, buy a hair. - Huh. (laughs) - What, 1955 film? - This is what I want, Kaplan beat me by a hair. It's all I'm gonna say, go ahead. - Oh, not, that's not nice. What 1955 film features Marilyn Monroe and her famous white dress scene, standing over a subway grate with her skirt billowing upward? - Seven year- - Seven year-age. - Kaplan again. He's just, what was it? It's seven year-age, but Kaplan's in earlier from where I am. Just, he's-- - He's put her on the bus. - He's put her on the bus. - I have an orth Carolina. It's like why they put the traders in New York. - Well, you could be a dictator. - Electronics delay. All right. - Third and final question, what bacterial disease caused by Barton Ella Henselay shares its name with a Ted Nugens song? - Cat scratch fever. - Cat fever. - Yep. - Once, Zyres, oh, four, three, man. - It's fair, fairs beat me to that. - I did. - You may be on a delay. Your little choppy today. - Okay, that's it. - That's it. - That's it. - That's your video. - All right, let's-- - Well, damn. - So again, I remain on the losing streak for the entire season. So we'll stick with that. - Can I ask a man? - Since I had two out of three, can I get your voice on my voicemail? Like a prize? - What do I get to do with that? - Wait, wait, don't tell me, type thing, yeah. - Do you know what my voicemail actually says? - Don't leave me a message. That's it. It's the voicemail. All right, well, damn, thank you for joining us. This was such a fun discussion. And I want to thank all of our listeners for joining us as well. If you got questions, comments, ideas for topics we should cover on the show, shoot us an email and questions on DermsOnDrucks.com. Again, that's questions at DermsOnDrucks.com. And I hope you learned a few things. I hope you'd laughed once or twice. Mostly I hope you're planning to join us next week. So until then, I'm Matt Zyrish. - I'm Tim Patton. - And I'm Laura Ferris and we are DermsOnDrucks. (upbeat music)