The Causes of Chronic Spontaneous Urticaria

[music] Welcome to season 2 at Derms on Drugs, a video podcast brought to you by scholars and medicine the best educational platform in dermatology and provided to no cost to medical providers. Derms on Drugs is we're cutting its Derm meets hitter miscomedy. I'm Matt Zires and each week I'm joined by my residency butters, Dr. Laura Ferris and Dr. Tim Patton to 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 you'll actually have fun listening. New episodes drop every Friday on scholars and medicine, Apple podcasts, Spotify and other major platforms. And the video component does have some of the key figures and tables from the articles we're going to talk about. Now this week we are super excited to have Dr. Mark Sarota from Colorado joining us. Dr. Sarota for those of you who do not know him is a triple-borted in pediatrics, dermatology and allergy. And this week we're going to be talking some about chronic spontaneous erudicaria and we're bringing some new cool interesting stuff this week. So let's go ahead and get into Dr. Sarota. You want to say hello to everybody. Everybody happy to be here. Thanks for having me. You got it. So we're going to start with an article from the annals of allergy asthma immunology called endotypes phenotypes and biomarkers and chronic spontaneous erudicaria. And basically really what I want to talk about here is we now think of CSU as having three different mechanisms. Number one and you think of this as type one CSU is you're actually allergic to yourself. So you have IGE against something like double-stranded DNA or some other endogenous antigen. And so you're literally you're allergic to yourself. It is technically not an autoimmune disease. It is literally auto allergy. And that behaves a little differently, responds a little differently to therapy than the other types. So then the other types that you've got you've got IGE that is autoimmune either directed against IGE or directed against the IGE receptor. And that IGE when it binds either the IGE or the IGE receptor in the right way, activate your mast cell the same as if you got exposed to something you were allergic to. And then there is a third group. So that's type 2B, right? The second group that I just talk about and they behave differently than type 1. And I forget about the 2B I just call it type in my mind I think of type 1 and type 2. And then type 3 is not running through the IGE receptor. So the type 1 and type 2 are both running in some way they're activating the mast cell through the IGE receptor. Type 3 is sort of anybody who's not running through the IGE receptor. And there are different ways. That one is kind of nebulous where nobody's really sure exactly what you know it could be complement mediated. It could be coming through the MRGRPRX something receptor. It could be coming through other stuff. So first I'm going to stop there before we talk about kind of the differences between the three types. Dr. Sarota, any problems with my description of this? Is there anything you would describe differently than kind of how I laid that out? No, I think that was a good summary. I think probably the take on point is that this is not a homogeneous disease. This is a heterogeneous disease from a phenotype and from a genotype perspective. But mainly from a genotype perspective. So for example, asthma is not all one thing. Some is neutrophilic, some is eosinophilic, etc. And you have to target your treatment sometimes to the genotype that you're treating and not necessarily the phenotype. So asthmatic phenotypes could look very similar. But if your treatment is not being effective, you don't necessarily have to think that you're in the wrong diagnosis immediately. You could just think that maybe I'm targeting the wrong genotype. And that's a little bit of an unfamiliar concept in maybe the dermatology world. So I would think to myself, first, does that look like highs and doesn't meet the criteria for chronic redicaria? If yes, and I target the allergic cell pathways and I'm not getting a response, either I have the diagnosis wrong or I need to broaden my therapies to account for other genotypes of that pathway that are not being accounted for as part of blocking the allergic cell receptor pathway essentially. So, and I think if it's not perfectly clear, the way doctors are as described is because the basic science is not clear yet. So we're still evaluating what all these cell types mean and what all the subtypes of CSU means. I think for the practicing dermatology practitioner listening to this, it's more important that you understand that it is a mix of potential sources for why they're getting chronic eyes and you just have to know that fact so you can adjust your treatments if things aren't working. All right. So, we're going to have like, concomonant autoimmune disease, like, you know, they've got maybe positive A and A, so they've got some joint pain with it. Are those more the type 2s? Yes. Okay. So is that a little bit of a clue like, is that more going on or? Let's move on. So there's a really nice diagram in this article where it kind of breaks it into type 1, type 2, and then the non-type 1, type 2. And so type 1 tends to be younger age of onset, other atopic diseases. So as my atopic dermatitis, allergic rhinitis, high IGE levels, so normal or high IGE. And those people tend to respond very well, very quickly to Omalizamab. And they also respond well and quickly to DuPillamab, right? So to Zolaire or to Dupy, we don't really have data on that yet of if there are differential responses with Dupy or Remi. But the type 1 CSU people, they're the ones who are, you think of them as allergic to themselves. And they are likely to have other allergies pre-existing. And those people like really rapid good responses to Zolaire. Then you get the type 2, or the type 2B. Those people tend to be concomitant autoimmune disease and lower IGE levels. So the lower the IGE kind of the more likely they are to have this type. And if you do kind of the funky testing, the autologous serum skin test or some of these urinary indices or whatever they're there, they're people more likely to be positive. If they respond to Zolaire, it tends to be slower. And those are the people that I'm thinking will be the people that I would be probably most likely to use Remi Brutonib in immediately first line whenever they came in. So the allergic people are more thinking Zolaire or Dupy, the people who don't have a significant history of allergy, I am more thinking will be using Remi first line. And then the type 3 is sort of clinically a little like the type 2, but probably has the poorest response to therapy, but also probably has the least severe disease. So the way that I'll be thinking about this in clinic is going to be when I see somebody with CSU. Okay, do you have allergies? Do you have asthma? If I maybe I'll order an IGE, maybe I won't. But if you've got allergies or asthma, then Zolaire or Dupy, if you don't have allergies or asthma, then Remi. And if whatever we try first, if it doesn't work, I'll probably switch. Because it's not like the allergic people, they'll probably respond great to Remi 2. And the people who are more of the autoimmune, there's a good chance they're going to respond to Zolaire or Dupy. But it's just if we're trying to think about tailoring our therapies, we can think about it that way. And that's sort of my, you know, the pearl that I took from all of this was, was I'm going to use that to sort of define which drug I'm likely to use first. No data to back that up just makes sense to me though. Dr. Shrota, what are your thoughts? Yeah, I agree. And I mean, if you look at the Dupixen studies, the second trial they did was for Zolaire failures. And what they found was they weren't meeting their efficacy endpoints, which could mean that because this is a diagnosis of exclusion, perhaps some of the people being enrolled just weren't actually CSU patients. But if we assume the primary investigators were pretty good at the criteria for diagnosing CSU, then the other option is if people failed Zolaire, they may not have been in that category of people that were going to respond to the allergic cell pathway. And if you put them on a BTK inhibitor, then you're now targeting the intracellular protein, so it kind of doesn't matter if they were in the allergic cell pathway to begin with or not. So I think we have some pretty good data that lends itself to that sort of logic. Okay. So Dr. Serold, we had Dr. Hawks on earlier. We talked about CSU and one of the things we talked about was testing. And do you do any of this testing to the histamine release assay from the Bayes of Fills? Do you order IgG? Do you order IgG, I'm sorry, IgG, do you order IgG TPO antibodies? And our takeaway then was not really because it's stepping up on the four times the recommended dose of the non-sedating antihistamines and then moving to Omalizmab because that's what was FDA approved. In allergy world is that, is that different? Do you do that work up and then do you see that guiding therapy from the get go or do you still think because of the algorithms that have been established by these consensus panels? It's still going to be four times anti histamine and then on to Omalizmab. So I'm in the second camp, which is I order lab testing if it's going to either change my management or if it's going to give some sort of diagnostic or prognostic information. So if you already know that you've diagnosed CSU, then any testing you do is not going to change your management. It's going to rule out mimics and bolster your diagnosis. So I don't routinely order lab testing for CSU patients. Like any CSU patient that comes in, I'm not just ordering lab testing. And there was a Cleveland Clinic study that looked at like 10,000 labs and essentially found that it didn't make any difference. There was one patient where they were hypothyroid, they knew they're hypothyroid and that, you know, they did something about it. But other than that, essentially lab testing is very unhelpful. So what I recommend doing is follow the treatment algorithm and then you order lab testing if people aren't behaving like they're supposed to behave. So if your treatment's not being successful or if you're worried about a mimic, certainly, then you can order some lab testing. I definitely advocate it. I don't order. What lab? So, right. So if it doesn't, you know, Zola, or Dunwerk, or the Dupy Dunwerk, or the Remi Dunwerk, then what do you order then? Right, Bates? You do like it's, it's more to rule out, it's more to rule out mimics. And the reason I do that is because this is a diagnosis of exclusion. So until you've excluded other diseases, you can't say that this person does or doesn't have CSU, they can meet the criteria, but part of the criteria is that they don't have any other reason to have hives. So what, for example, yeah, what mimics, for example, if mimics we rule it out. So, so my allergy fellowship, I was kind of, I was, I notoriously missed a patient that was diagnosed as just a high patient and turned out they actually had a chronic parasitic infection and they had chronic GI symptoms, for example. So you're going to get hives if you actually do have a GI parasite for example, where you would do stool oven parasite to diagnose that. Or if a patient looks like they have hives, but they actually have urticarial vasculitis or urticarial phase bulls-penforgoid and those things, there's lab tests and you can do to look for that. The other test you mentioned that I do think is of utility. And if you're going to order labs to look for other potential comorbid conditions or other reasons someone has hives, I highly advocate for the chronic urticaria index. So what they do is they take the patient's serum, they take donor serum and they expose them both to donor basophils and they look to see how much histamine is released. And if you're releasing three times as much histamine as the donor controlled serum, that shows that you have antibodies that are circulating, that are capable of stimulating much more histamine released from basophils than the normal healthy person. Now that is not diagnostic of CSU. However, it is suggestive and it is prognostic, meaning now you can put a name to the actual face of their disease and say this, I mean that literally the lab test has the name chronic urticaria in the title. So I see most practitioners if they do order the screening lab test, you know, and they just shotgun, you know, CMP, CBC, TSA, Chaturna, ESR, CIR, let's just, anything we can think of that could be possible, they don't order a chronic urticaria index, which actually you can tell the patient this is suggestive and you're most likely going to have this for two to five years or longer. This is not something that's going to, you know, distill out relatively quickly. So we need to put you on some some chronic treatment. And then lastly, I advocate for skin biopsy, again, if you're not confident that you're actually dealing with Hives. So what if you have a positive CU index, what, like how does that drive your, it's great. I think it is really helpful to be able to tell patients this is long term because they do like to know that does it drive you toward one therapy or kind of, you know, a multiple combination therapy or how does that drive you? It wouldn't make me more likely to recommend any of the FDA approved therapies. I think you would still follow the treatment algorithm. So I think it's more prognostic and at least bolstering your diagnosis, because you have to remember, I think at least in my experience for dermatologists, you walk in the room and the person has, person has psoriasis plaques, you can diagnose psoriasis or, or eczema. But when you walk in the room and the person has Hives, that's simply a exam finding. And I do want to say that Dr. Shorota did not mean that you walk in the room and the person has psoriasis and you can, you can, you can diagnose psoriasis or eczema. No, if you walk in and have psoriasis, you can diagnose psoriasis. He meant if you, they walk in the room and they have eczema, you can diagnose eczema. However, I would say that that is a very poor choice of diseases because if you walk in the room, you can say they have spungiotic dermatitis, but you cannot say they have a topic dermatitis or allergic contact dermatitis, I'm giving Dr. Shoroto a hard time on purpose here, Mark, just so that you know we. the the the the the the the stick of our podcast is that we give each other a hard time. That's that's fair now. Yeah. So I mean, but the physical exam finding for most diseases in dermatology, you're at least very confident in your diagnosis. Whereas the physical exam finding for Urdicaria is unique in that it's just simply a physical exam finding. It doesn't tell you anything yet about what diagnosis you're going to attach to that physical exam finding. So I think that's why it's a little bit difficult and because it's all diagnostic criteria based. You have to meet this diagnostic criteria, comma and rule out other potential causes for high. So you could meet every diet definition of CSU. But if you have a GI parasite, you don't have CSU. Right? So I think that's sometimes trips people up and why I think having the chronic Urdicaria index just gives you that extra little data point to say, okay, we do have evidence here that they have antibodies that are overstimulating their bees. It fills which can push you over the edge to say, okay, maybe I don't need to, you know, look, look so much further at every other possibility of highs. I'm probably on the right track. Yes. Do they have snitchlers syndrome or muckwell syndrome or one of the auto inflammatory syndromes or all of that stuff that if it crosses my mind, I'm sending them to an allergist right away. Yeah, the, well, let's let's jump on to Dr. Patton's article. Dr. Patton, why don't you take us through this. All right. Yeah. So it was called comparative efficacy and safety, biologics and systemic and immunomodulatory treatments for chronic Urdicaria systematic review and network meta analysis, another network meta analysis is brutal. Two at all available online July 2025 journal of allergy and clinical immunology. So patients don't, we see us you don't respond to four times the recommended anti histamine dose. I don't know if this matters or if it makes a huge difference. I actually start with fix a fennedine 180. Do you guys have a favorite non sedating in a histamine you like to start with. If they have trouble with pills, lyratidine because lyratidine pills are by far the are more smaller than fixed fennedine 180s. So fixed fennedine 180 and four top four of those right. So four 180s to give you 720 or four lyratidine to give you 40 milligrams of lyratidine. I often add 20 milligrams tears in at night. Just because the tears in at higher doses does often make people a little sleepy. Dr. Shorota thoughts. Yes, the state is in if you just think about sedation levels to tears in probably a little more sedating fix a fennedine a little less sedating and then leave us to tears in which is eyes all is the least a dating. So that's five milligrams instead of the state is in 10 milligram. So I tend to use to tears in because it's easy for the patient to dose because it's 10 milligrams. So you can just take say take one to two versus effects of fennedine where it's 180 milligrams. It's a little more complicated people look at those numbers and you know necessarily figure out what dose they're taking. But one of those two is fine. But if you're getting any degree of sedation, you might want to consider leave us to tears in and then I don't know how others feel, but I don't personally recommend the sedating and I his to means even at night. Because number one, it complicates the regiment number two, they're going to they're going to mess it up and take take it in the morning and then they're going to go drive a fork lift or something. And number three, there's much better there's much better options to treat people sleep. So if you want to treat someone to help them sleep. So dating and a histamine is not the one. So for that reason, I just stick to one pill, take a bi big bottle, this one pill and take one to two in the morning, one to two at night. I tend to use a little more satirisine, but I wouldn't fault you for using any of those three. I will say allergies do not like loradidine, like just they think that's weeks. sauce, you know, so interesting. It's the Irish. He's calling you weak. It's not unreasonable. Right. I do the lyridine just because they're small pills. I've never seen any day. The data have always, oh, you're using lyridine. Oh, okay. I do use lyridine. I take it myself actually from my cat allergy because I have cats. Yes. There's another solution to that. But yeah. All right. Well, yeah. I don't know that the only FDA proof therapy was on malisma, which a personally a good result with first three doses in the office. And that's, you know, can be a little bit tricky. FDA proved to treat CSU way back in 2014 where like past 10 years and had nothing else. But now Dupy was approved in April this year. Remi, Bruteon Tyronees Tyrosine, Chinese inhibitor. Pretty good data that was published in New England Journal. Probably going to be FDA proved. Hills of Bruteinib and other BTK inhibitor had some data published in JAMA Derms. So it looks like we're going to have a lot of options for our patients. And so what works best? How do we choose? So this paper, it had like 100 authors. It was like 33, but that was a lot of people. Performed a network met analysis for systemic treatments. Once again, whole lot of description. I did want to pull out one sentence like this is why NMAs are just, they're baffling to mean always will be. This is an actual sentence from the method section. It's a quote, "Gelman Rubin statistics of less than 1.01 after a burn in of 10,000 sampling of 50,000 in thinning of 10 confirmed convergence in all cases for four chains." Does that mean anything to anyone in the marks nodding like yet sounds right? All right. So the authors looked at 83 randomized control trials. There are also 10 non randomized trials that looked specifically at mycophinally and self-asalzing. Over 11,000 patients. Figure two is a network plot of the studies analyzed and these plots remind me of that video game from the 80s called Tempest. So they should call these Tempest plots. We're going to make it happen. Let's start it going. Like it. Yeah. What's the big takeaway? Figure three is a table. Lays things out pretty nicely. The dark green boxes were the drugs with high or moderate certainty. And the greatest mean decreases in UAS 7 were in order. Standard dose on was a map. Remi Brutonib, barzo volumab. That's an antibody against sea kit. Legolas a map and doopy. Paper goes through a bunch of other measurements, but it's a lot of different stuff. Cycle sporn, which is part of the CSU algorithm, had a lower certainty rating, but got a quote maybe among the most effective. It was also the only drug listed in the table is getting a quote maybe among the most harmful. I've talked about how I personally would use micaphenylate instead of cyclesporn. I see us at UX experts can go to hell. I'm using micaphenylate first. Micaphenylate actually had the best UAS 7 number, but those studies just were not good. I mean, they vary. Let me give you a dose. You use a micaphenylate. What's that? Don't you use thousand twice a day? Yeah. Okay. The only reason I think about that is because I had two patients on OMA and cyclo and they still have bad disease. The allergist sent him over to me. He's like, I don't know what else to do. I said, I use cyclesporn a lot. I don't think allergists do. It worked for both patients. I stopped the cyclesporn because I didn't want to do both. I put them on cell sept. It was two patients relatively close to each other. I'm like, if this worked in cyclesporn didn't, why not start off with cell sept. I'm way more comfortable with that drug than I am with cyclesporn. That's an end of two. I mean, smarter people got together and said no cyclesporn. But personally, is cyclesp—I'm sorry, is micaphenylate crazy to go to as the next line with OMA failures? No. Is micaphenylate—how quickly did you see a work in those people? Oh, I don't know. Within the month. Okay. Yeah, they were miserable. The horrible CSU patients. It's kind of quick follow-ups, right? If something's not working, you want to move on to something else kind of quickly. But I don't know. Mark, what do you think about micaphenylate? I haven't used a lot of it, but I like this idea of bridge therapy, honestly. I think the wrong thing to do is to bridge people with steroids for CSU because then you're going to get rebound. But I think we don't talk enough about bridge versus maintenance. You can bridge someone with something like cyclesporn. And let's say you put them on OMA and they're not better. And then you put them on cyclesporn, for example. They get better. You don't have to be that afraid of that because you can just withdraw their cyclesporn. Now you've made their disease quite excellent. Now you're just trying to maintain that as opposed to this is going to be my long-term treatment. So if you say, "What's going to be my long-term treatment?" I would much rather do cell sept. But if you say, "I need to make someone better and then maintain them on something that has a really good safety profile," then I think that's where acute cyclesporn, like followed with, you know, OMA is a maverick to Pyliumab maintenance makes a lot of sense. But if you needed to target something more broadly because they're not responding to your targeted therapy, I think cell sept is a great choice for the side effect profile. And I think cyclesporn, at least in my experience, is probably a bit more effective more broadly. Reasonable. Reasonable. Very patent. So what else you got from this article for us? That was it. That chart pretty lays it all out. You have your most effective medications, biggest drops in the UAS7. None of these, I think, were head-to-head. It was mostly the drugs against placebo. So yeah, I mean, you know, I'm sorry, OMA is a maverick and Pyliumab, the only FDA approved options that we have at this point, but I think the BTK inhibitors. And I thought that the barzole, barzole volumab looks interesting too, but I don't know where that kind of stands in the pipeline against, or, you know, when we expect approvals there. I know their phase three is still going on and it's going to be an interesting kind of, yeah, I guess before we talk about barzo, in terms of remy. So Mark, how fast does remy start to work? I mean, that's it's big. You know, the way that I describe it looks like it doesn't work in any more people than does Zolaire or Dupy, but it works heck of a lot faster than either of those two drugs. How fast do you kind of expect to see it working once it's out there? Yeah, and there's no head-to-head right now, although they are doing those trials. So we will see head-to-heads with remy, which is kind of impressive that they're willing to do that. The efficacy numbers look pretty similar in the long run, meaning you're a UAS7 and other metrics at something like week 16 or week 24, it's tend to look pretty similar, although I'm not making head-to-head comparisons. But in terms of how rapid-to-head comparisons are. You are allowed to make head-to-head comparisons. Oh, I can do whatever I want here. This is not TME. I can do it every week. I can use brand, whatever I want. You have brand name, you can share anything you want. Oh, awesome. So what I would say, where it really shines, like a lot of the small molecules, just like your Jack inhibitors, because they're small molecule intracellular targets, they work really quickly. So, I mean, I've even had people ask me like in a topic term, like, do you just do an oral Jack as, you know, bursts a couple times a year for people's flares or replace pretenism with it? And the same for Remy here, where it's going to be maintenance, because you can't do that, but you're going to get people better significantly faster, you know, probably within the first two to four weeks, you're going to see, like, if they're getting a response, you're probably going to see it within the first few weeks, as opposed to biologics where you're waiting several months. I mean, the baggage with Remy, it's a new mechanism of action, so people aren't familiar with Brutans tires and kinase. And if you Google it, you'll get a little scared, because if you have mutations in that protein in babies, you're going to get a significant immune deficiency syndrome. But the trick to this drug is it binds the inactive confirmation of BTK. So, it's not when it's trying to work, it's when it's being quiescent. So, because of that, you're not effectively affecting their ability to fight infections or develop immunoglobulins. In fact, they looked at immunoglobulin production in these studies, and they found that essentially they were the same as healthy, as a healthy control ability, where in the normal range. No, I had also understood, I often understand things incorrectly, or at least partially, partially incorrectly, that another reason Remy was safer than older BTKs was that it's also more selective, that like BTKs, there are tons of BTKs and that Remy is more selective, more targeted, and that's another reason why it's not immunosuppressive and has the hematologic side effects that some of the others have. That's right, it's much more selective for the BTKs associated with this receptor pathway, and because it binds the inactive confirmation, that being said, they did see, quote unquote, bleeding events in some patients in the trials, I think it was like 9%, but bleeding events included PtK or Purpera, which was the vast majority of them. I don't think anybody actually discontinued drug because of it, and there was no like sequelae from those quote unquote events, so it's something to be be aware of, but they don't even recommend that you, and the label isn't out yet, but I don't think there's going to be a recommendation to even do any kind of screening lab testing or anything like that. It's going to be essentially significant liver disease, or if you're actually taking anticoagulants or have some other predisposition to bleeding, but I wouldn't think of this as highly anticoagulating or anything like that. I think it's just, that's the side effects you should be aware of that's a little bit unique. Yeah, the POTEKIAI. That's because yeah, that was my, that my understanding was that nobody actually bled. There were things that were called like, you know, bleeding events or POTEKIAI or whatever, but nobody actually bled. It just does not make you susceptible to that is what all of the data is showing us so far. Now, Barzo, which I have no idea, Barzo Lava Mab, or how to actually say it, that's going to be a super interesting drug because it, it is the one that really is mechanistically very different. It's just getting rid of your mast cells. It's an interesting thing that there are some people who go on Barzo and still there are to carry, doesn't go away. And that really suggests that Bayes of Fills might be playing a bigger role than we think in some people with CSU because if the Barzo got rid of you, like it seems like Barzo should be like 100% effective if it's getting rid of your mast cells. But it's, it's not 100% effective, it's just highly, highly effective. I'll just say it's an interesting one. It's a monoclonal antibody, so it's, it's a biologic, it's going to be injected. It targets C-Kit, which is a mast cell protein. The other place you see C-Kit that we're familiar with in dermatology is melanocytes. So there's targets for that for melanoma. So the side effect that we have to see how much of a big deal it is or not is it can cause hypopigmentation of the skin and hair. So I think that's one, again, a unique mechanism of action. You could understand scientifically why you would target that, but then you have to look at the side effect profile. And I would need to see more data on the hypopigmentation issue because I don't think your patients would necessarily be happy with you if that was a significant problem. So I'll have to see how that plays out. Yeah. How far down the pipeline is that like do we have phase two trials or where? I'm a site for their phase threes. So the phase threes are ongoing. I have patients who've been on it for like close to a year now. So I imagine it's not real far out another year or two would be my guess. But you know depends on how long. You'll have lightning, skin or hair. I don't want to talk about that. If there's like a confidential anything about being in my patients, but I will say I want to become a platinum blonde. I can come see you if you've got hives. And I say it's it has been stunningly effective for people who were highly therapy resistant. I will say that. And that's in line with kind of the known data that is out there for it. But it's yeah, it's going to be an interesting that risk of hypopigmentation is yeah, will that make it like a last line therapy where for sure for some patients will care a lot of other people with if it's more effective than the other drugs. I think some people won't care at all. Some people will be like, well, you know, if that's what is most likely to get me to stop itching quickly, I want to do that. Right, that that wouldn't surprise me. I think it also lends itself to the idea there's other receptors on mass cells that can cause his immune release. So when we talk about looking at other causes and mimics, there's two that I always highlight. The first is the opioid receptor. So your patients are not going to tell you that they're taking oxycontin or oxycodone or percusets and stuff like that. But if someone's having chronic or de-carrier, if you think about your patients who are like taking narcotics or you think about like the heroin addict, they're like picking at their skin all day. And it's because they're actually itchy because their mass cells are releasing lots of histamine. In fact, in the allergy world, before we had histamine as a positive control for skin testing, allergies would prick to coding because you would reliably get a hive from pricking someone's skin and coding. So I always ask about opioids. And the other one that's kind of interesting is the number one cause of people getting hives is infections, up arrest for infections. Right. So there's receptors on your mass cells for C3A and C5A, which are the complement breakdown products. They're called anaphylaxo toxins. So if you have an infection and you're elaborating lots of complement, you're breaking down lots of C3A and C5A, you're going to release histamine. So when you're evaluating a high-the-patient, you want to ask them if they've had an infection recently, and you want to ask them if they're taking opioid pain medications because that's going to form you on other causes for their itching and hives that are not necessarily CSU. So yes, you have the C-Kit receptor. Yes, you have the IgE receptors, but you also have these other receptors that are not related to these pathways. So why doesn't everybody on an opioid get hives? Well it's somewhat of a dose dependent response. Because you know opioids are notorious for developing tacky phylaxis. You actually get more tacky phylaxis to the pain effects than you get to like constipation or hives. So it's kind of if you're a drug addict, you got to take more and more medicine to get the same high, or the same pain effect, but you'll get increasing and increasing constipation and itching. So somewhat of a dose dependent response, but everyone's going to behave a little bit differently. But in general, if you're taking lower doses or if your body's gotten used to it, you might have burned out all your muscles where they're just, they don't have granules that are constantly ready to go. So it's going to be a little bit of a variable, but you definitely want to ask that question. Now I do want to go back to one of the TSHs because I do, you know, if I got hives, CSU next week, and then six weeks later I'm still having the hives, I would want a TSH checked. Just not because it's going to change management of my hives because I know I'm at increased risk. And if I do have the hypothyroidism, then I'm going to feel a lot better if I get some TSH. Or not if I get some TSH, if I get some leave-o-thyroxene. So it does always strike me as one lab that I think is worth checking even once a year in CSU patients because even if they don't have it now, they're at risk for getting it eventually. Patent is a bit of a nihilist or nealist. I don't even know how to say it for order stuff. One of those words mean. Are you a TSH orderer? Me? Yeah. No, I am anti-lab for CSU. Okay. Very fair. I think it is. I mean, hypothyroidism you can find, you don't need a baseline to know if you're hypothyroid. Like we have pretty good lab values for TSH. And I'm not saying you ignore that. I do ask patients, you get into a little bit of trouble because you're like, well, are you hot all the time? They're like, yes. And then you're like, oh, geez, okay, fine. But I think it's good to be aware of. But like, you know, be a good doctor. Take a history, ask for symptoms and do your workups based on that. Otherwise, you chase stuff, right? Well, you know that. Yeah, fair. All right. So let's, let's, I'll say if someone's hypothyroid and they have CSU and you replace their thyroid, I don't have a scientific mechanism to explain this, but people tend to get better. Like your thyroid is such a regulator of your overall metabolism in your body that I just think if you find it and autoimmunity kind of begets autoimmunity, I think it is, if you're going to order labs and I don't, I don't routinely do screening labs just for that. But if you find it and you treat it, you will find it. The subset of patients, their highs will get better. And I don't have big data sets to support that. Just clinical experience that I do think there's something to be said for. If you find it and you treat it, their highs may improve. If you build it, will they come? The other thing I thought was interesting looking at the tempest plot, I'm still sticking with that. Just a lot of the, the drugs that have been like tried and failed. And just some of the other things that stood out. So an omelisma biosimilar was one of the drugs. And that's already approved in Canada and Europe. I don't know how commercially available it is. It's probably going to be FDA approved next year. That'll be another interesting twist and sort of what insurances are going to guide us to. I mean, if that's a lot cheaper, we may be looking at that. There was a Jack inhibitor, TLL018. So I don't think it was an established Jack inhibitor. I think they called it like a Jack one slash tick two inhibitor that was studied and that data was pretty decent, smaller study. So I don't even know that it made it into that final table. And then you only other thing I thought was interesting because if you look at bars, Zol volumat, I mean, sea kit, that's on mass cells. That makes a lot of sense. But there was this other drug. It was an anti-siglic eight protein. And it didn't mean it's primary. I mean, that seems so mass cell specific. Is there any idea about why something that is that mass cell specific? number one, number two, that MIG-PUR, MIRG-PUR-X, whatever. As far as I could tell, that wasn't part of that whole tempest plot. Is there drugs inhibiting that protein that are being looked at? - Yes, they're being developed, but I don't know how far along they are. - Okay. - I will say that in there has been, I just, I think in the last week, saw a case report, about Jack and Hibber, about I think it was you had a CIDA nib for CSU. So I do, and Jack inhibitors, we think of as working for essentially everything, but I did see it, I'm looking it up right now to see if I'm right about that. Pacia, somebody who had urinary refractory CSU and rheumatoid arthritis and their urinary carrier went away completely, whatever they put him on your patisserie nib. That was just this week that I saw that. All right, well, I think we've scratched or urinary raw at this point. And so Dr. Seroda, I don't think I warned you that we do have a trivia portion of the show. So Dr. Patton will have three trivia questions for us. And basically the rule is, you have to let him finish reading the question and then you just can shout out an answer. Patton, go ahead. - Urticary relative. (laughing) - Get the way till I finish. The first non-sedating antihistamine to come to market in the US was Turfinidine brand name Selding, which was removed from the market in 1997 because of what side effects? - Qt per elongation, Tursaid to point. - Wow, yeah. He was ready. - Oh, you have to just shout out. - Yeah, yeah, yeah. - Got it out. - Oh, Seroda's like, oh, I knew that. I just didn't know I was supposed to shout out. - Well, she knows. - Yeah. - Zyrus has been practicing medicines a little longer than me. And he knows like all the different humors in the body and stuff. I wasn't old enough for Selding. - He still has leech therapy on his armamentarium. - Yeah. - True. - All right, number two. - By the way, I gotta say, screw worms are terrifying. Have you guys followed the drug? - On screw worms at all? - No. - Not up to speed with that. - There are these flesh-eating maggots. So like the female lays 200 things on you. Normally maggots will only eat like rotting meat. These things literally eat animals alive. And they can eat people alive as well. It is just, they were eliminated like back in the 50s or something from the US, but they're slowly maybe making a comeback. - I did see, 'cause there was a report in the US. - Yeah. - Yeah. - It's their woo. - Woo. - Yeah. - I didn't delve into it the way you did, but I saw that headline. I'm like, that sounds bad. - Yeah. - All right. - All right, thanks. - Number two. - Right now. - What a ponomous name is associated with the triple response. - The triple response. - So that's your red line. And then the flare and then the wheel. - Oh, Darry Aeson? - No. - No, that's scratching a mess as they don't know. - Yeah. This one was kind of obscure, but I, like when I was reading through it seemed vaguely familiar, but who knows? It's the triple response of Lewis. Is that Ring of Bell at all? - Not bad. - Not bad. - Not bad. And that's a weak trivia question. That's terrible. - That's a bad, we're gonna scratch that one out. Let's move on. Name anyone of the four foods that have the highest likelihood of triggering the symptoms of latex fruit syndrome. - Mango. - Avocado. - Avocado. Mango is considered like moderate. It's like, I think I can do all four. I think I can do all four. Okay, go ahead. - Okay, go ahead. - You're going to be a points if you get them all. - Yeah, you'll win it. You'll come away with a win. - I knew Avocado banana. Okay, now I never-- - I know, I know, I know, I know. - Are you not going to win it? - Okay, go ahead. - Kiwi. - Yeah. - Kiwi. - And something that starts with the sea. - Yes. - It's a fruit, I think, that starts with the sea. It's not cherries. - Not fruit. - Because the mnemonic for it is black. - Would you say, Mark? - Is it like a nut? Is it a nut? - Chestnut. Chestnut. Chestnut. - Chestnut. - You want to get black? - You guys worked together to got that, everybody wins. - Yes, but-- - Definitely. - Banana latex avocado chestnut and kiwi. - Yeah, that's it. - All right. - Well, Dr. Shorota, IE Mark, I want to thank you for joining us today. It was a pleasure having you on the show in this exciting time for CSU. I want to thank all of our listeners for joining us. We hope you learned a few things. We hope to laugh once or twice. Mostly, we're hoping you're planning to join us next week. Until then, I'm Matt Zyris. I'm Tim Patton. - And I'm Laura Thyris, and we are Germs on drugs. 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