Melanoma, Pre-Menstrual Rashes, Dermatomyositis and more

[music] Welcome to Derms on Drugs. A video podcast brought to you by Scholars in Medicine, the best educational platform in dermatology, and Scholars in Medicine happens to be a no-cost offering for health care providers. All you need is an NPI number and you are able to access the hundreds of hours of educational content that is coming from the best lectures in the world. Derms on Drugs is where cutting edge derm meets hitter miscomedy. I'm Mad Zyres and each week I'm joined by my residency buddies, Dr. Laura Ferris and Dr. Tim Patton, to use our 60 years of combined 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 it'll be the most fun you've ever had while learning something useful. New episodes drop every Friday on Scholars in Medicine, Apple Podcasts, Spotify, and wherever else you might get your podcast content. So this week we've got one of our patented six packs, where we are going to discuss the six topics or articles that we've found most interesting in the last couple of weeks. In the same way we'd sit on the back porch and discuss them over a six pack. So we are going to get started off right away with Dr. Ferris. Dr. Ferris, what do you got? Thanks, Cyrus. So my first paper is from Annals of Oncology Grover at all. And this is efficacy of adjuvant therapy and patients with Stage 3, a cutaneous melanoma. So this was a multi-center retrospective study. Okay, for patients with Stage 3, a melanoma that's using AJC-C8 staging, who received either adjuvant PD1 inhibitor, so Pembralysumab or Nevolumab, or the B-Raff Mech targeted therapy to Braffinib, Tremetinib, or did not receive any adjuvant therapy and were just treated. And so what they look at, Cyrus, remind me -- I'm sorry, we're just observed. Yes, remind me. There's Neo-Agevent adjuvant and then rescue. So there is -- yes, so there is Neo-Agevent therapy is -- I give you your chemo or immunotherapy, then I do your definitive treatment, which is surgery. And then adjuvant is I do your -- I remove all of the tumor surgically, and then I give you the treatment to try to prevent recurrence. And then there's also, you know, primary treatment of, like, metastatic disease or unrestectable disease, but we're not talking about that. So we're talking about Stage 3, a patient's -- So as you've been specifically means, you think all the cancer that you are aware of in their body is gone, and you're giving them chemo because you're probably -- there's a good chance there's some in there that you just can't see. There's some chance. So basically, what I'm trying to do is prevent you from having a recurrence of your disease or from having your disease metastasize. And ultimately, preventing you -- my goal is to prevent you from dying of melanoma because it returned or metastasized. And I know we're talking about 3A lesions here, so these would be people who don't have a lymph node, but let's say -- They do. They do. So just a quick review, who's stage -- so what -- who is this patient? You biopsy their tumor, they had, let's say, a T2A melanoma. They had a sentinel lymph -- a sentinel lymph node biopsy, and it was positive. Okay, but it is a small, you know, microscopic -- or, you know, microscopic disease. And it is one node, and it is -- you know, it's sort of the earliest lymph node involvement that you can have. So it's detected just through sentinel node biopsy. You had your sentinel node, you had your resection of your primary tumor. Now what do you do? You can get a treatment, or you can just go undergo observation. Okay, have they had -- have they had that lymph node basin cleared out? So in some cases, because this is resect -- because this is retrospective study. And some patients they did have a therapeutic lymph node dissection. That is not standard of care now. If you have a positive node, you do not get a -- you know, you do not get a resection of the lymph node basin based on, you know, data from MSLT2. Okay. So it's not -- Okay. Okay, there we go. Oncology 101. Reviewed. All right. So -- so we know -- so what is the prognosis for patients with stage 3a melanoma? If you look at their, you know, 10-year melanoma specific survival, it's 88 percent -- 5-year melanoma specific survival, it's 93 percent. So most patients are not going to die of melanoma. Now by contrast, if you look at a patient who has, let's say, stage 3C disease, they are 10-year melanoma specific survival, 60 percent. So big difference, right? What's 3C mean? 3B. So let's say 3B. It's 77 percent. What do you mean? What do you mean? So those are patients who basically have either, like, thicker ulcerated primaries and/or multiple nodes or more -- they have -- you basically sort of a bigger burden of lymph node disease. Okay. All right. So we don't -- so we don't really know a lot about stage 3a patients. Why? They were limited in the prospect of clinical trials that were done looking at adjuvant therapy because they are lower risk, right, if the risk of recurrence is low. So they limited the number of patients to -- so they're kind of underrepresented. So we don't have a lot of data on them too. If you look at some of the earlier staging, it was done under AJCC7. And so the patients, you know, staging changed a little bit with AJCC8. So this -- the thought was here. Let's try to get some more data by sort of aggregating, doing retrospective studies of patients treated, not in the -- not in a clinical trial setting. And so they have 628 patients all who have stage 3a disease, 34 centers across the US, Europe, and Australia. And so there were -- of those 628 -- 256 had PD1, Iage of in therapy, 80 had targeted therapy, so BRAF, Mac, and Abyssin, and 292 were observed. So I like that they're sort of that control group of the group that got nothing. Medium follow 2.6 years, median duration of treatment, about 10.2 months in both groups. Okay, end points were recurrence-free survival, distant metastasis-free survival, and toxicities. So what were -- what were these tumors? Medium tumor thickness was 1.3 millimeters. Okay, so sort of an intermediate thickness group. If you look at the melanoma, you know, nodal deposits. So in about 60% of patients, it was less than a millimeter. And in about 40%, it was greater than a millimeter. So just to give you an idea, of course the only group that would be eligible for targeted therapy are those who have BRAF, B600 mutations, and that was 40% of the population. And then the most common -- and then they looked at, you know, what were the most common reasons for discontinuation? It was toxicity a little bit higher in the targeted therapy group, 21% in that group, versus 13% in the PD1 group. Now, this is a retrospective study. So what you didn't do is randomize them. So there's going to be likely some differences between the groups. So, you know, one of them was age. You know, if we look at patients who had observation were older than those who had PD1 treatment, who were older than those who got targeted therapy. Alceration, lymph node met, greater than a millimeter, and median node diameter being larger. So all higher risk features were seen more commonly in the PD1 group than in the targeted therapy group, than in the observation group. So kind of the patients with the worst disease got -- were tended to be put on PD1 therapy. And then to your -- you know, question mad about completion lymph node dissection, because some of these were done prior to MSLT2 data, there are patients who had that. That was more common among the PD1 group. And then -- which was more common than the observation group, which was more common than the targeted therapy group. Okay. So little differences here. Okay. Were they able to control for all of -- is that stuff you can control for and do statistical mumbo jumbo, which we don't quite trust, but it's better than nothing, or it's just like, okay, they're different. We got to keep that in mind. You can, and they did -- they looked at that a little bit, but mostly they really just kind of reported out the two-year recurrence. Okay. Okay. So if you look at local regional or distant recurrences, it was 23% of the patients in the PD1 group, 1.2% in the targeted therapy group, and 18.5% in the observation group. So actually a pretty significant difference between the targeted therapy versus observation. But remember, the higher risk people were the ones who got PD1. I'm sorry. Higher -- so more recurrence in the PD1 versus the targeted therapy, but the more severe patients got the PD1. Two-year recurrence-free survival was -- so 79% for the PD1, 98% in the targeted therapy in 84 in the observed group. to your distant metastasis free survival. 88% in the PD-1, 100% in the targeted therapy, and 91% in the observation. Okay. So the PD-1s look even, almost look worse than observation, but they were not the same people who got observed versus who got PD-1. Right. Yeah. So the PD-1 people had a much higher baseline risk, so we don't know for sure like. Yeah, we have to remember that, that they're not equivalent groups. So where was this sort of different statistically significant recurrence-free survival and distant metastasis-free survival between targeted therapy and observation and targeted therapy and PD-1? So targeted therapy looked better than both observation and PD-1. So if you've got a graph mutation, do they do them together ever where you get the. They do that not in the edge. I mean, there are trials looking at that, but not in the adjuvant setting. Okay. So not in these patients who don't have any known disease. So if you just took it, so remember only the B-Raff mutation patients are eligible for targeted therapy. Right. So if you just took that group, they did have a statistically significant improvement in recurrence-free survival and distant metastasis-free survival relative to. with targeted therapy relative to anti-PD-1 or observation. So even just that subgroup that could have had any of the treatments, they still did better on targeted therapy. So there. If you took the group that did not have B-Raff mutations, there was no difference in RFS and DMFS when you compared PD-1 and observation. So there really wasn't like a lot of great evidence for the value of PD-1 therapy. So treatment-related adverse events. More common in the targeted therapy group, like 77% of them versus 53% in the PD-1. But if you look at the kind of adverse events that lasted for greater than 12 weeks, that was more common in the group that got immunotherapy. And we know that that is tends to be the case. For all groups, most common toxicity was cutaneous. So rashes, most common grade three or higher, like the bad toxicities in the PD-1 group was colitis and then the targeted therapy group was fever. All right, Ferris. You, Dr. Laura Ferris, had wake up tomorrow and have a three-aid melanoma. Yeah, I've got it and it's B-Raff mutated. It's B-Raff mutated. No B-Raff is B-Raff. You're obviously going to take the target. If it's not B-Raffed and your choices or observation versus immunotherapy, what are you going to do? To be honest with the three-aid, I'm probably going to do observation because one, the bad thing is. I would get castle testing. If it was bad, I would get the PD-1 and if it was class 1A, I would do observation. I was mean to castle and one of our more recent episodes. Theoretically, this could be one of these areas where yes, this could help us. Okay. There you go. Okay. So maybe there is. Now, I think you want a little data to support that. But yes, so I thought that this was interesting. I think that there probably is some bias into who got PD-1. So there is a very important therapeutic study for patients in like, unresectable stage three or stage four disease, where it called dream seek, where they were randomized to either get immunotherapy and then when they and then when they progressed, then they went on to target therapy or they got targeted therapy first and then they switched over to immunotherapy if they progressed on that. So it's like, should you start with one over the other? And the group that got immunotherapy up front did way better than the group who started with targeted therapy. So this was I think like a lot of people would would have thought like, oh my gosh, you should always, if you got a choice, you go with immunotherapy. But this is kind of interesting because it shows that there was that the group seems to do a little bit better. But the author said, well, the date while the data show targeted therapy on its fund face value looks to be better that we should caution recommending one over the other given the relatively no low number of patients in the target therapy group 80 versus 195 in the, you know, in between the other two treatments. And then modest median follow up and only one recurrence was seen in the target therapy group. So, you know, I think this is really interesting, but I think, you know, to Dr. Patton's point, like you got to think about, you know, to me, this was like, gosh, what do you do with the three A patients? And, you know, maybe this is a place where GEP could be helpful. Like, you know, there's some people who are going to recur most or not. And so, to think about giving these, you know, expensive and therapies with a lot of toxicity, if we really could pick out those few that might benefit from it, you know, that would probably be really helpful. So, I thought this was really interesting. Okay. It's totally interesting, right? I mean, it's like, what do you do? I don't know how these oncologists decide. I, I, that'd be a tough visit. So, I were dermatologists. Yep. All right, Pat, Pat, do I not pop this pimple? Do I observe it? I don't know. I just give targeted therapy to it. We're going to target it. We pop that pimple, not the other one. We're not going to target the other one. All right, Pat, what do you got? All right, my first six pack was published online February 2025. It's from Jamma Dermin. It's titled Patterns and Clinical Implications of Nistygnosis and Dermatomyocytus by BOW@OW. This was a single center retrospective cohort study conducted at the Johns Hopkins University. Quick plug, Ferris and I were smart enough to attend Hopkins for our undergraduate training and Zyrus was not. Well, I was there for graduate school. I was not smart enough to go as an undergrad. I was the only one smart enough to go. It was probably murder. Well, I'm pretty much, but so that that Johns Hopkins led to a prestigious DO education. She's. Oh, that's good. I'm clear at that out. The authors, the authors wanted to focus on the fact that DM is often misdiagnosed. So that they wanted to ask what is often misdiagnosed at us and they wanted to compare DM versus clinically myopathic. That's what CADM stands for. Clinically, a myopathic, Dermatomyocytus. Yeah, I swear every time I see it, I want to say cutaneous, only Dermatomyocytus. I can't get away from that. Clinically, a myopathic, Dermatomyocytus in terms of misdiagnosis, they wanted to see what the clinical implications of misdiagnosis were. So they looked at cases of DM diagnosed from 2005, 2003. They had 260 patients, 260 DM patients, 36 patients were misdiagnosed. There was a way that they came up with that. I didn't want to get into that. Just could go straight to the numbers. I mean, we could talk about that if you want, but a higher percentage of clinically a myopathic, cutaneous, andly, Dermatomyocytus patients were misdiagnosed compared to DM patients. So again, just higher percentage of clinically a myopathic DM patients misdiagnosed compared to DM. And it took longer for the CADM patients to be diagnosed compared to DM patients. So it was all at the bottom of the table. One short paragraph that was kind of confusing. So the most frequent inflammatory skin disease diagnosis in the Dermatomyce cohort were Derm, NOS, and Eczema. That's too not too surprising. Overall, cutaneous lupus must not have been as frequent and inflammatory skin disease, but CLE represented the highest rate of misdiagnosis. So my guess there were only like three patients in the cohort who were diagnosed with CLE and two of the three patients had their diagnosis changed to the DM. So it was like 67% of patients who had that diagnosis of CLE eventually want to be diagnosed with DM, even though it was a smaller overall amount. That was kind of the way I teased that out. They didn't like have a table specifically those numbers. So that's a table two compares misdiagnosed patients with diagnosed and the differences that reached statistical significance were overall hospitalization rates within one year of Dermatodagnosis, onset of interstitial lung disease within one year diagnosis, and lower diffusion capacities at the time of ILD diagnosis. There wasn't a significant difference in any of the cancer numbers like at what stage of the misdiagnosed versus diagnosed, those numbers were about the same. So the lung disease is probably what seems to be the most important clinical aspect of what goes wrong when you misdiagnose these patients. They seem to have worse lung disease when that's finally diagnosed. So maybe earlier diagnosis, institute, earlier treatment that actually maybe prevents the lung disease from developing. I don't know. So clinically amyopathic patients are at higher risk of worse interstitial our high risk of it. interstitial lung disease, then my, clinically myopathic, right? - That's what I always learned. The overall rates of interstitial lung disease between clinically, amiopathic versus dramatic were about the same. That was in table one, they kind of broke that down. Yeah, so I was surprised at that. I think way back when we were residents and we talked about malignancy risk, don't you remember at first, like if it was clinically amiopathic, you didn't have to worry about malignancy as much, or am I misremembering that? - I think you're misremembering that. - Okay, 'cause those were about the same too. So I was surprised, like rates of interstitial lung disease actually comfortable between the two groups, rates of malignancy comfortable between the two groups. It was really this with the misdiagnosed patients, that's where you saw the issues with the lung disease. That was worse in those patients when I was diagnosed. - Well, so it's an interesting thing to me because this is one of the more frequent diagnoses that would end up getting referred for patch testing. So I got pretty good at diagnosing what I would call skin only dermatomyositis. So I guess the patent, the patent, right tiny person. - Keep tiny person. - Because the people that I've seen, that I see with Dermato and I probably would get two a year, two or three a year. So probably 20 or 30 of them. None of them ever had any lung disease, none of them ever had anything. It was just, but it was very obvious sort of, you know, they would have gotions, papules and they would have the streaking over the tendons in the upper back and the scalp and all that stuff. And I put a month's of microphenylate or some method of trexate and it would work great. And I was just so bad for them because they would go three years of, you know, people suspecting stuff, the biopsy would not show anything, people'd order labs and A&As and it wouldn't show anything. And so there was never like a diagnostic test. And I also wonder like, hell, maybe I was wrong when I said they had Dermato and my a cytos. And it really was just, you know, brash. But it's just, it's such an interesting disease because there are so many patients who just have no anything other than a rash and itching and no labs, no biopsies, the diagnoses have to make the call on your own. Those people are interesting to me. - Yeah, it's a bad, it's a really uncomfortable disease. I feel bad for them. It's like a, it's not like a, it's like a very, you know, uncomfortable itchy crash, yeah. - Yeah, the last, the last patient I saw with this paper reminding me of, it was just like within the last couple of months. And right, she had interface dermatitis and I just wasn't quite sure. She had horrible lung disease. - Huh. - Yeah. - So the point of this paper was basically that the longer they go misdiagnosed, the more sort of progression there can be of the non-skin disease aspects of it. It wasn't a whole lot about how do you avoid misdiagnosing them? - No, right. They didn't really get much into how, yeah. How do we avoid this? I, yeah. - Yeah. - Yeah. - That's a, do better. - It's always gonna be in the different. I mean, that's what I think about DM is, I probably am not as good as I should be as putting that in my Derm NOS, or what could this possibly be? I certainly missed it with that woman. Fortunately, like she had one day of misdiagnosis by me 'cause she saw rheumatologists and very, very, very, very, very, very, very, very, and he emailed me and he's like, I'm pretty sure this is the, and I'm like, oh gosh, yeah. And she did have like one of the myocytus markers, one of the Oklahoma panel myocytus markers that was elevated and she had bad interstitial lung disease. - Okay. - And I fortunately, I think one of the most jodahopkins now. (laughing) - I graduated with honors, maybe. I graduated, let's just say I graduated. - Wait, they have a satellite campus? - The Erie, Johns Hopkins Erie. - We done. - We done. - Okay. All right, we're jumping over to my first paper, which this one to me is a huge game changer. So basically the title here, effectiveness, tolerability and safety of topical climat is all with oral hydroxychloroquine versus topical climat is all with Naraband UVB in unstable Vitaligo, investigator blinded randomised control trial. So small numbers, the groups were not well randomized, meaning there were significant baseline differences. The people who got hydroxychloroquine did not have as severe disease. The disease was, so meaning they had less Vitaligo and they had had it for less time. That was just the way randomisation sometimes plays out with small numbers. There were 35 people in the Naraband Climators All Group, 39 people in the hydroxychloroquine Climators All Group. Relatively short study, six months. But the main takeaway was that hydroxychloroquine, even at a low dose, really made a difference. So the hydroxychloroquine group, whenever they tried to control for baseline severity, did substantially better. So the hydroxychloroquine group improved close to 50% whenever they adjusted everything, the Naraband UVB group proved more like 15 to 20% now they weren't doing great Naraband UVB. It was only twice a week for six months. And so you know, I usually think of Naraband as working a good bit better if you can get in there three times a week at least. So they said that their results with Naraband weren't as good as other studies because of the lower frequency. But it made takeaways and never freaking occurred to me that hydroxychloroquine might help with Vitaligo. There's not anything else in the literature suggesting this. They went through some mechanistic things where there is some molecular data in cell culture of why this should work. But it really, you know, until we get Jack inhibitors approved for generalized Vitaligo, this to me is now the first reasonable oral treatment we've got. And low dose hydroxychloroquine incredibly safe, right? So your risk of retinotoxicity at 200 milligrams once a day is pretty minimal. Becomes something now where in the past, when I would have said to a patient with widespread Vitaligo, like, here's some obsular for your face for the rest of your body, sorry. Now I'm going to be, here's some obsular for your face, some clubatus on for the rest of your body. And I'm going to put you on hydroxychloroquine 200 milligrams once a day. Really is going to kind of change the way that I approach sort of widespread-ish Vitaligo. So thoughts from you guys. - Curious if it works without the narrow band. - No, no, so they did it without, so it was either hydroxychloroquine and clubatusol versus narrow band and clubatusol. - Oh, sorry, I missed that. I thought that narrow band and it was the other. - Nope, so they got either narrow band or hydroxychloroquine and the hydroxychloroquine people did a little bit better, but they were very unmatched to baseline. - Gotcha, okay. - Pat, any thoughts? - No, I mean, right, that's an easy treatment. I'm doing it my next Vitaligo patient. - Right, it's dirt cheap. - I'm admitting to it. - Dirt cheap, very safe. And I'm interested in what you guys do whenever you start hydroxychloroquine. So I typically, as long as they've seen an eye doctor in the last few years, I usually don't get a baseline up though. I put them on the hydroxychloroquine, give them like three months. And then if it seems like it's working, I'll send them to Optho, 'cause I'm like, "Uh, until I see if it's doing anything, why bother?" 'Cause it's, I can't think of any reason why you need a baseline baseline. There's no acute ocular toxicity with it. And it's not gonna do any, you know, you're not gonna have any issues in the first three months. But standard of care is to get one of baseline before you start the hydroxychloroquine. What do you guys do? - This is a full standard of care to get it before you start. I thought it was something like in the first six months, sir. I, there was, like, those guidelines had changed. I thought, I do not do it when I, before I start, I start and I agree. Yeah. - I am the same way. I don't get a baseline. I tell them to get it within the first three months. - Damn it, I thought I was being edgy. - Yeah, not. - You are, edgy, man. Don't add a little bit. - I'm sorry, so. - All right, let's go to our next article here, Dr. - Okay, Matt, I picked this one because I was like, you're gonna love this so much because you could tie it back in some way or form to do pick sense. So, there you go. - You're going. - In a good way, yes. Skin damage signals, mediate allergic sensitization to spatially unlinked antigen, which would seem like what is that? So this is ways, men, at all, in science, immunology. So this was, They used a mouse model basically to show that if you have injured skin, that you will have an allergic reaction to something that you get exposed to in the gut. What they did was they said, "Oh, we know there's the skin gut connection, food allergy and DNAD and IBD and you're going to have PG or psoriasis and arthritis." All skin disease is systemic. They have this hypothesis that basically having damaged skin could have this adjuvant effect and sort of skew the immune response to something you get exposed to in the gut. And the non-inflamed gut. So what to test this, what they did was they said, "All right, we're going to just tape strip the skin of mice and then we're going to do oral gaubage, like basically where you force feed them, ovalbumen." They said that is sufficient to get allergy associated anti-ovalbumen antibodies, IgG-1 and IgE, but not those that are associated with protective immunity, like IgM, IgG2B. They also got this anaphylactic response. So apparently mouse anaphylaxis is like, "You eat something and your temperature drops, so you can actually measure it." So they actually couldn't introduce that. That was kind of cool, but you're like, "All right, tape stripping. What other forms of skin injury?" They did a punch biopsy to injure the skin, same thing. Chemical ulceration by intradermal acetone injection, same thing. Hydose UV radiation, same thing. All right, well maybe it's like ovalbumen, right? I mean, who's eating ovalbumen? So they did peanut allergens, same thing. Maybe it's the microbiome, maybe it messed up the gut. They did it in specific pathogen-free, germ-free, mouse colonies who don't have a microbiome, same thing. Then they depleted secondary lymphoid organs, basically like things like consul and lymph nodes. That, those mice did not get it. So what they said, and there's a ton of science that I am not going to go into because it's complicated. And it's been a long time since I was at the Johns Hopkins University immunology. So I feel like- I went there too. I heard that. I heard they didn't let you stay long. But it was- So it's key cytokines, IL-33, T-S-L-P, IL-1 beta, and IL-18. But there was also roles for IL-4 and IL-13 for skewing, IgE production. If you basically- If you got the exposed to allergen, IL-4 and IL-13 were key in skewing that to being like an IgE response, which would be associated with the food allergy, anaphylaxis response. So they said IL-33 and T-S-L-P, they're alarmons, which are like things that tell your immune system, like, whoa, be worried. There's something bad going on. Think about like responding to this. And it's definitely complicated. But I thought that that was fascinating. IL-33, you know, cytokine, I think about a lot. But it can prime tissue environments to cause accumulation of intestinal mast cells, ESENophils, innate lymphoid cells type 2. So it's sort of like this type 2 immunity story. And that was like enough to have the, like, sort of enable the threshold where you would actually get anaphylaxis. So the other thing that was interesting is you had to be getting like the allergen for the first time. So if the mouse had ovalbium into eat when it was like fine and the skin was fine, and then he went back and taped stripped or whatever acetone ulcerated them and then gave them ovalbium and again, they're fine. So it's like there's this, this like unique window. So, you know, what do I think, I mean, I thought this was super interesting. I like like the skin gut connection thing, which I sometimes think is BS when patients talk about it. But now I'm like, maybe there is something. But, you know, what about this like linked to food allergies and patients with AD and this like atopic March idea, right? So. Yeah. And we don't tell people like, if you're going to give your, you know, expose your kids early to peanut butter to peanuts or, you know, maybe we should think in kids who have atopic dermatitis, think about those super and now this is all hypothesis. There's nothing in there. But like think about those allergenic foods like, you know, peanuts, think about egg, think about, I don't know, like seafood and maybe say if you've got a kid who's got AD, like don't, if you're going to try to do this oral tolerance, re-expose them early, like avoid those things when they're in the middle of a bad AD flare. Like maybe the time to expose is not when you've got bad, you know, skin disease or maybe like, I don't know if you're kid, like at a horrible sunburn. Don't give them their peanut for the first time. So this is really, I may, I may be admitting I'm wrong about something or at least I have to think about it differently now. I'll do it, man. So we've known for a long time that where you get introduced to an antigen is very important. So if you get transmucosal exposure initially, you become anurgic so actively desensitized. And if you get transcutaneous exposure of antigens, you get sensitized. So you develop IGE and sensitization. So the belief has been that the reason that kids with AD get food allergy is because they've got impaired skin barrier and their smear and food on their skin before they became desensitized. And then whenever they hit five, the reason why food allergy goes away is because they're no longer getting food on their skin. They're only getting it in their gut. But then that kind of beg the question, well why doesn't it go away in all of them and why doesn't it go away completely and why doesn't it, whatever. And this may be the other part of that answer that the systemic, this is again just fascinating because I always think about with nickel allergy, if you ingest enough nickel, we can measure that you get IL-5 and IL-10 release from your intestinal lymphoid tissue and that can drive a rash. Now it had never, I never really bought or thought about that a rash driving intestinal immune changes. That is interesting. That is really interesting. I'm not sure what to do about it yet or what it changes because it gets back to, because what I was initially thinking was like the mice, like you're forcing it down their throat with the gavage and then they're puking it back up and like rolling around in it. Maybe that's interesting. They did, so there's a lot of controlled things within this paper. So they did say if you get foot pad injection, you can and do sit. They also did this in ways where they would just give it in the stomach and they made sure that they didn't ever put them. You could have a mouse who was in a cage. Mouse A got the Oval Buman exposure and mouse B did not. Probably the one who got the oral exposure actually had the reaction because they were like, well, what if it's like in their mouth droppings or their throat? Yeah, yeah, yeah. Then it should be that the mouse who was in the cage but didn't get it orally should also be getting as per Dr. Kaplan. They all needed cones of shame. Exactly. Yeah. I mean, I thought this was, I mean, it was like an elegantly done study. Look it up. If you are interested in this kind of stuff, you know, they do Mac out mice of this and inhibiting that and like, you know, there's a lot more to this than my very simplistic, you know, six pack review, but super interesting stuff. Okay. Patten, you got anything else you ready to move on to your next article? Yeah, I know. I don't understand anything. Well, anything she just said. John Hopkins, you understood that. My second six pack to Jamadurm published online April 2025 titled Epitope Spell. It's spreading in a mutant checkpoint inhibitor associated bullies, Pempagloid by Koga at all. I like the title. It turned out to be a case report. It's kind of lame for me to do a case report, but it's getting late in our six pack. I'm already five beers and this was a case report that described an 80 something year old patient. They actually had that in the in the article 80 something like really. We could use like nine to decade a patient. So it just described an 80 something year old patient with lung on no carcinoma that developed bull after 10 months of nevotherapy diagnosed with BP eventually died of her lung cancer, but the authors had her sera banked. And so they looked at her sera at the time of immune checkpoint inhibitor initiation. So prior to ICI therapy, the patient had antibodies to the C terminus portion of the BP antibody, right? We think of NC 16 A as being the pathogenic target for antibodies. This was at the other end of the BP 180 molecule. So that's where she started. And then when she developed BP, of course, she had a pretty high titer of the NC 16A antibodies to the NC 16A portion. She had antibodies to the BP 230 antigen. And yes, she had some other epitopes on the BP 180 molecule. So it was just kind of a new thing of, you know, they brought up the idea. Maybe we do screen these NIVO, these ICI patients. Now, granted, doing an assay where you can detect antibodies to the C terminus that is not like widely commercially available. But basically this neat article, and she had seven years of pruritis before she got. So they kind of, you know, theory and waving the antibodies to the C terminus. That's what caused the pruritis when she got the NIVO epitope spreading. She developed antibodies against the other antigens and then developed clinical BP. That's it. I mean, I thought it was kind of cool. What do you guys think? It is fascinating to me these, you know, the checkpoint inhibitors. I feel like we're learning a lot more about sort of immune stuff in general. But it's like a natural experiment of seeing what the hell happens whenever you just make people's immune systems go nuts. Like it's an intern and this kind of falls into that category for me. Yeah. I think it's interesting. I mean, you know, that you have a little preexisting autoimmunity, but we can control it. And then you take the brakes off. And it's like, oh, now it goes crazy. Yeah. We did this with one patient. One of the oncologists said, hey, I have this bench serum. It was a patient developed BP after a mean checkpoint inhibitor pm. We actually did the BP 180 Eliza, which most of the commercial tests are specifically to that NC 16 A portion. Her titers were positive at the initiation. She did not have clinical disease. And right, I mean, you think about this. That's an easy screening test to do, right? BP Eliza's at baseline of therapy. Now, I mean, what would you do? Watch them more closely. I mean, I don't know if there's any practical-- and any practical treatment we could do. Put them on doxy. Some print treated with clobate is all like for the other ones that we talked about the-- Put them all on nicotinamide. There we go. Yeah, the vetotin, something something. The anor-- yeah. And fortemant of dentotin. There we go. It's just like the pre-clobatus all helps, right? Yeah. All right, we're moving on to our last six-pack article. And this is a trio, which is designed to make a point. And so the article-- You just get out of ten-- what? So yes, you're true. I made it a nine-pack. So the article that got me started with this-- the impact of the menstrual cycle on exacerbations of atopic dermatitis, the systematic review. So basically, they did a big literature search. And the summary is that about half-- somewhere between a third and a half of women with atopic dermatitis will reasonably consistently experience a pre-mensural flare. So typically starting about seven to 10 days before menstruation's going to start, they will experience a flare of their atopic dermatitis. And there's a lot of theories about why. So estrogen and progesterone are hormones that have immunologic effects. They also, especially progesterone, has some effects on skin barrier permeability. So the mechanisms of this are not terribly well worked out. But it is pretty well established at this point that pre-mensural flares are not rare in atopic dermatitis. And they also looked at psoriasis as kind of a comparator and said, now there's no real pre-mensural changing of psoriasis. But that reminded me of an article from 20 years ago. When was this? Yeah, 20 years ago, 2005. So this was back whenever I was just getting into patch testing a contact dermatitis. And it turns out that at least for nickel, when you patch test somebody at what point in their menstrual cycle makes a huge difference. So I don't want to say a huge difference. But if you-- they way that they did this study, this was nickel contact allergy in the menstrual cycle. They got 30 women who were allergic to nickel. They repeated patch testing. So normally your patch testing to 5% nickel, they did instead these dilution series where they did progressively lower concentrations of nickel. And then you can patch test people to it and see what's the lowest concentration they react to. And the idea is the lower the concentration they react to the more sensitive they are. And what they found whenever they did this was that-- so they half of the women they tested first at mid-cycle and then second pre-mensually. And then the other group they tested first pre-mensually then second at mid-cycle. And basically, they showed that you are much more sensitive to nickel whenever you are pre-mensural. But then the-- so now we know that both allergic contact dermatitis and a topic dermatitis-- and whether that applies to all allergens or it's just nickel, we don't know for sure. Nobody's ever done that study. I actually recommended to the North American Contact Dermatitis group at one point that we start asking all of our female patients at what point in their menstrual cycle are they while we were patch testing them. And the basic response was, we don't want to ask. We never added it. So we don't know if this applies to any other contact allergens. But the big takeaway is I would get so many referrals over the years, kind of like for debatomyocytus for autoimmune progesterone dermatitis. And the main thing that I would say to all of our listeners, you are never going to see a case of autoimmune progesterone dermatitis. So if it crosses your mind, you should be like, OK, this is either a topic dermatitis or allergic contact dermatitis. Because autoimmune progesterone dermatitis in the most recent, like big review I was able to find, there were a total of 89 patients reported in the history of the world who had confirmed autoimmune progesterone dermatitis. And a substantial number of them, I actually think it was probably just a topic dermatitis that was flaring pre-mensually. Because people like to do this-- people would send to me to do intradermal progesterone tests. And the problem with the intradermal progesterone test, there's no instances of like, hey, let's just do this to 1,000 people and see, does it trigger a lot of-- does it trigger just 10% of people who have a positive-- we have no negative control for autoimmune progesterone dermatitis. Do not send them to your local patch tester. Talk if you really, really think you've got it. So meaning either they have a non-spungiotic path. So if it's interface or it's a caria different, that is more because this orthodomium progesterone dermatitis. If you're reasonably convinced, get in touch with the OBGYN, the real way to diagnose it. Like what's used to diagnosing it if you don't have a therapy in mind? The real way to diagnose it is get somebody on one of the GNRH, the gonadotropin releasing hormone, agonist, warant agonist. They both completely get rid of progesterone and estrogen for six months. And if their rash completely goes away, then oh my god, it is autoimmune progesterone dermatitis. And then the question is, do you want to get your ovaries taken out to get rid of it? Or you could also stay on the GNRH forever, but there are a lot of potential side effects with that. If it doesn't go away completely, then it's not autoimmune progesterone dermatitis. But when you see pre-menstrual flaring of a dermatologic disease, your first slot should not be APD. Aramune progesterone dermatitis. It should be atopic dermatitis and contact dermatitis. We know that both of those diseases flare pre-menstrually, but people love to just immediately, when a woman comes in and says, oh, it seems like it always flared right before I have my period. Oh my god, you might have autoimmune progesterone dermatitis in the blood. They don't have autoimmune progesterone dermatitis. Incredibly unlikely, much more likely, it's just AD or contact germ that is flaring due to the hormonal fluctuation. What was the nickel study? I mean, would they not react with at all at certain points in the menstrual cycle? Yeah, so that was just that. That's the interesting. And I don't know that they, so like what they did in all of this was showed the minimal illiciting concentration. And they basically showed that it went up or down usually by one or two things. But there were a few people who like the, so usually the 5% is such a high concentration that like regardless of where you are in your cycle, you're going to respond anyways. But there were a few people who did not respond in their ovulatory phase kind of mid cycle, but did respond to the 5% in their progestinic phase. And so it, It is theoretically possible that you could miss contact or depending on when and somebody's menstrual cycle you patch tested them. Like it's that probably does happen, but how frequently it had like this, 'cause patch testing is, again, it's notoriously non-reproducible for one-plus reactions. You probably have a 50 to 70% reproducibility, which is terrible. Part of that reproducibility might be related to things like menstrual cycle, how much stress somebody's been under blah, blah, blah. But we don't really know. Like it remains a bit of a black box, but the big takeaway was, you're never going to see a case of autoimmune progesterone dermatitis that is extremely unlikely. And now I know that next episode, you're both gonna come back and be like, "Well, last week I saw somebody without autoimmune progesterone." Goddamn it. - I'm gonna have a case series of 13 women. They're gonna be on the show with me. (laughing) - I'm gonna go sit up there and you're a little low ceiling room, we'll see. - Yeah, come up to my ad. God, no, Ricky. (laughing) - There'll be a podcast of two. - Well, we could maybe smuggle something into Pat in prison. - Right. - It was good. - All right, well, I'm not one, that's why we don't give you nine beers. (laughing) - I'll be off its list. - Cut it off. - Cut it off. Well, I wanna thank everybody for joining us today. I hope that you found some of these articles useful. I hope you laughed once or twice. I hope you learned a thing or two, but mostly I hope you're gonna join us again next week. And until then, I'm Matt Cyrus. - I'm Tim Patton. - And I'm Laura Ferris, and we are Derms on drugs. (upbeat music) (upbeat music)