Drugs, Drugs and More Drugs

Welcome to season two of Derms on drugs, a video podcast brought to you by Scholars and Medicine, the best educational platform in dermatology, which was just recently revamped to make it even more user friendly and helpful. And it's provided no cost to medical providers. Derms on drugs is we're cutting edge dera me Tener mis comedy. I'm Matt Cyrus from Doc's dermatology in each week. I'm joined by my residency buddies Dr. Laura Ferris from the University of North Carolina and Dr. Tim Patton from the University of Pittsburgh. And we use our 60 years of combined Derm experience to discuss debate and dissect the hottest topics in dermatology. Does everything you need to know to be on a cutting edge dera me? You probably have some fun listening. New episodes drop every Friday on Scholars and Medicine, Apple Podcasts, Spotify, and anywhere else you might get your podcasts. And a reminder that this is a video, a video podcast. And we do have some of the key figures and tables from the articles we talk about on the video component. This week we've got one of our patents and six packs where we are going to talk about the coolest new stuff we've seen in the literature recently. Let's get started. Dr. Ferris, what do you got? All right. So I have a paper that is hot off the pre-release press from JAD. Efficacy and safety of duroxylitinib and oral selective Janice Kainase 1, 2 inhibitor and adults with alopecia ariata results from the thrive a a 2 face 3 randomized double blind control trial. Some Greek siakus, something at all. Okay. So what is this? This is a phase 3 RCT comparing placebo to two different doses of duroxylitinib. So just a reminder, what does duroxylitinib do? It's an oral selective Jack 1, 2 inhibitor. It's claimed to differentiation. It has a four hour half life. I don't know if that really matters. And it interrupts interferon gammas signaling. And so mechanistically, what is this most similar to baracitinib? Baracitinib, another Jack 1, 2 inhibitor. And then the other one that we have is ritlycitinib, which is on the market. And that's a Jack 3 tech kinase family. So they would argue it's a little more lymphocyte focus. Okay. As somebody who did these trials, it's an interesting thing. I don't know if they talk about this, the article probably not. Do you know what the difference is between it and Ruxylitinib? Jack 1 and something deuteration. That's exactly it. So they basically replaced one of the hydrogens on it with a deuterium. And in theory, that changes the pharmacokinetics. And in theory, well, not in theory and practice now because it is on the market, most importantly, it makes it so that it's not covered under Ruxylitinib's patent. It's that's probably the biggest difference between this and Ruxylitinib is just that it got past the patent attorneys. But that's the deuterium in theory makes the half-life different. Is there a difference? Okay. Does it also give it more Jack 1 selectivity? Did they tell you that? I don't. It's anytime you start to ask the farmer people about Jack's selectivity, they get very, you know, we don't know because apparently differences if you do a self-free assay versus if you do a cellular assay. And it depends on how you do the assay. But nobody will give you a straight answer on Jack's selectivity from farmer. Okay. All right. That's kind of been my experience, too. Okay. So back to our clinical trial, you know, typical adults 18, 65, salt greater than or equal to 50, meaning 50% or more of their hair is gone due to AA. And, you know, six months to 10 years of duration. So I think a lot of these trials have learned to exclude the people who've had, you know, alopecia universalist or totalist for 20 years. So these guys were pretty severe, mean salt around 88. And 60% of the group had, you know, they divided them into the group that was like salt 95 or greater. So 60% of the group fell into that, like pretty severe hair loss. Mostly females, mostly white. Eye rates of eyebrow, eyelash and nail and even nasal hair involvement. Okay. Phase three study over 500 patients randomized one to two to one to do rocks 12 milligrams B.I.D. or eight milligrams B.I.D. or placebo 24 weeks. And they were stratified. Yeah. Just before I forget, did they talk in this article about why it only came out at eight milligrams? I think it was based on the efficacy, but you tell me Matt, because I'm assuming you got some insider information. Yes. Well, as in the trials, they were doing eight and 12. Right. And there were a few DVTs or PEs in the 12 milligram group. So they. In the long term extension. Yes. So they stopped that study and only went forward with the eight milligram from that point forward. Okay. There we go. All right. Primary endpoint salt. They do mention that. Sorry. Yeah. That was, but those were all in the long term extension. Open learn. Yeah. Yeah. They were part of the. Yeah. Right. They did not say that's why we nixed the 12, but they did mention that that happened. Okay. Okay. Primary outcome. Primary endpoint salt 20 or less at week 24. And that's kind of typical to what we see across these trials key secondary endpoint salt 20 at earlier time points and then salt less than 10. So you get 90, you have 90% of the normal amount of hair. And then they have this very, you know, elegant, patient reported outcome, which was how satisfied are you with your hair today? And if you were satisfied or very satisfied, then that was a responder. Okay. So let's talk about. The other results would be if you asked 50 rate random people on the street that how satisfied are you hair with your hair today? I know. I'm like not quite satisfied with mine today, but it is nothing to do with alopecia area. Right. Yeah. Exactly. I know. Okay. Well, it's the fact that it keeps getting grayer, but that I digress. All right. I still are. At week 24. Salt 20 was achieved by 30, about a third, 33% of patients on the 8 BID 38.3 on the 12 and 0.8 on the placebo. Now if you look at just those people who have the salt score of 95% or 95 or greater. So they've lost 95% or more at baseline. So their response, their salt 20 was 20.926% and 0% in the 812 placebo. Group. So not quite as good of a, you know, making it to a salt 20, but still, you know, statistically significant. Salt 10. So 90% of your hair comes back by like 25 and 26.7 in the 8 and 12 versus none in the placebo. So you know, if you take that, you know, super meaningful endpoint, like, you know, you've got 90% of your hair back. There really wasn't a significant difference between 8 and 12. Okay. So I thought that was interesting. And then that satisfied or very satisfied was basically like half of each group versus 1.7 in the placebo. And they did see responses as early as week 12 and they saw that they kept going up at week 24 and we've had lots of discussions on this podcast about Jack inhibitors. When do you give up? And I think we've all agreed that like six months is not your maximum response. If you're getting growth at six months, we know you're going to. Most people will continue to get it. We even talked about that sometimes, you know, patients will have hair regrowth at six months and then are will not have it at six months, but they really do start to get it. That's six to 12 month range. So six months is an early endpoint and they were probably going, you know, to get better. Okay. Our favorite Jack topic safety over that 20. Yep. That I was laughing about that being our favorite Jack topic. Well, okay. Maybe it's not our favorite. I think our favorite one is do you switch Jack's the one you give up on them? So our second favorite. Yes, that's that's better. Our second favorite topic. So treatment, emergent adverse events, 81% on the durox group, 70% and the placebo. Most of them were mild and moderate. It was like COVID, nasophair and gyitis, headache. There was acne, CPL, elevations. There were, you know, one to two percent on active drug had serious AEs, none on the placebo. And those were like influenza pneumonia, no mace events or thromboembolic in that 24 week, you know, period, labs, increased platelets, amylase, cholesterol, decreasing the globe and alkyphos, some neutropenia and anemia. You know, the, and then the, the five potential drug related thromboembolic events, mostly in the 12 milligram BID dose were in that longer open label extension. They do qualify that with they were all in patients who had other, you know, presphosing risk factors. Okay. So, you know, this was, I thought, a pretty standard, pretty good, you know, clinical trial, the early efficacy, you know, they did see some early efficacy at week 12. So, you know, what are the, the faults? I mean, like we talked about, you need some more long, you know, ongoing. going, like we need more long-term data on all of these, both in terms of how much hair to you really regrow, how long do you keep it, et cetera, et cetera. This was also, they did have pretty good hair regrowth, like eyebrow eyelash regrowth as well too. So it's another tool in the toolbox now. I will say, and I'm not gonna go over the whole, I'm not gonna go over the whole paper, but there was a, we do love a good meta analysis here on, on, on, on, on, on, on drugs. And so there was a meta analysis published in the JDD Babble at all, and they did an NMA, and they compared the three approved jacks at their labeled dose. So Berry 2 and 4 once a day, Ritless at nub 50 milligrams once a day, and Duroxel at nub 8 milligrams twice a day. And so they pulled data from all of the clinical trials, and they did say on this NMA that all three drugs were superior to placebo, but that Durox 8BID consistently ranks highest for both salt 20 and salt 10 at 24 weeks. So I'll throw that out there. - So it, you know, one of the things that's fascinating to me is they got more different results between their two trials than you normally see. So meaning, I went back and looked at Thrive AA1, and in that one, the difference between the 8 and 12 was bigger. So it was like 41.5% versus 29.6%. So like-- - It's all 20s. - 12 point difference. Resonance when there was only five point difference between the two. So just that was interesting. It's like that. - Yeah, and I think the inclusion criteria, I mean, those were two like parallel studies. So the inclusion criteria were similar. You know, all it takes is a couple people who grow or don't regrow hair. I mean, you know, it's not a huge difference, but yeah. - Yes. - So do you-- - You know, more later. - Obviously none of us have enough clinical experience to be able to be like, oh yeah, I think this one is better than the blah, blah, blah. The other thing that is interesting about it is I believe in their approval before you can prescribe this, you have to check people's site of Chrome P450 like 2C9 activity or something. So it is a little like, is the thiaprin, where you gotta check a thiapurian methyl transferase. And I don't think they were expecting that during the trials because there was like a protocol amendment near the end of the trial where that's when we suddenly had to test everybody and genotype them for their site of Chrome P450 status. But I think that is in the label now. - It is and people have complained about that that you have to order that, right? So like-- - Yeah. - I think that's probably a little bit of a barrier. So it's almost like, and you know, we all have the experience of you decide you're gonna prescribe drug A for this condition and then the insurance is like, nope, you gotta do this other one. And you know, so it's almost like you have to prospectively think about it and now test everybody with AA because what if you're like, I'll just do bear sittin' it. Well, they may come back and be like, no, you gotta start with, you know, durocks. - So. - Yep. Is that, do you think that is because the higher dose had like three pulmonary embolisms? And so if you're not metabolizing it and you build up, like that's a real risk. I think the PE stuff, that's a little bit scary. I mean, I don't remember that in the news. Like they halted the trial and they're like, we gotta look at this and I know, and yeah, I mean, I don't know, I think that's gonna be a huge knock on the drug. - Yeah. - But they were mostly in that higher dose and it's not gonna, you know, it's not gonna be approved, it's not approved at the higher dose. So. - But has anyone said that, 'cause that's why we have to check that because that's our concern. - I have not seen the reasoning why. No, Matt, you were in the trial, so you would have gotten the protocol amendment. You don't know. - I do not remember seeing what the reasoning was other than I assumed that it was yes, that, that they, that the 12 milligram in theory having a higher risk that they were more concerned about drug levels than they are with other, you know, jacks, that's the only thing I could think of, but I don't know for sure. - Yeah, or was it like this cytophenia, right? Like was it the other side? I don't know. - Yeah, it'll be interesting if they're smart, they will cut that data to see, 'cause it's a low frequency. So in Caucasians, it's like 3% of people are something. It's a small frequency of how many people have that genotype, but if they get enough people in the study who had it, it would be interesting to see if it affects efficacy as well, right? Like it works better, but you're more likely to get a blood clot in your lungs, right? - Right. - But there is some new data out about the relative thrombogenic propensity of different jacks, which I will be covering later in the episode. - Okay, yeah, so it is CYP2C9, and they are actually, I was just looking this up, and I think they actually did say that they were at higher risk of the thrombomolic events. So there you go. So test CYP2C9. - Okay. All right, let's move along, Pat, and what do you got? - All right, first is six pack paper, October 2025, edition of Journal of Clinical Practice and Research, titled Subclinical Spondalo, Our Thritis Features in Patients with Hydride 90 Subvertiva, a real world cross-sectional analysis by Bakede and Bakede. So in 2022, JADP publish screening recommendations in HS patients, and if I read it, I can't say it stuck with me. And I think the reason why is because the authors recommend that we screen for, are you ready to write this all down, acne, dissecting cellulitis to the scalp, pylon, idol disease, powder, magangranosum, depression, generally, anxiety, disorder, suicide smoking, substance use disorder, PCOS obesity, dyslipidemia, diabetes, metabolic syndrome, hypertension, cardiovascular disease, inflammatory disease, spondaloarthritis, and sexual dysfunction. And I think I looked at all that and said, well, I'm not doing that. They also recommend that all patients with Down syndrome be screen-fraged, and I think it'd be funny if you read that wrong and tested all your HS patients for Downs. (laughing) We're gonna do some blood tests, including one, to make sure you don't have Downs syndrome. (laughing) But I don't do all that screening. I have a skincare routine to go over. I don't have time for all that nonsense. Anyhow, this article focused on one of those co-immorbidities spondaloarthropathy. They took 120 patients, systematically valued them for spondaloarthropathy. Is they consisted of some different scoring system, a sacroiliac MRI. That was only in some patients that wasn't in everybody. Some blood work ESRC, RP, and HLA B27. What did they find? Table two list percentages of different diagnoses in these HS patients. 13% of patients had MRI detected sacrilyitis, 12.5 where HLA B27 positive, 10% were diagnosed with peripheral spondaloarthropathy. 12.5% met the New York criteria for ankle osin spondylitis, and 18.3% were diagnosed with endocytosis. So almost 20%, that's kinda high. There was not a strong correlation between HS severity and any of the rheumatology diagnoses. So you could have very, very mild HS and still have one of these rheumatologic diagnoses. So my takeaways that I will try and be better at screening my HS patients for SPA, and maybe start referring more of my patients to room. But the other takeaway is that, you know, with the diagnosis of SPA in our HS patients, you could use on label SPA meds like UPA and TOFA and exocysymab, which could help treat the HS as well. So maybe we start raising the possibility of our HS patients having to get those meds covered, like back when we diagnosed everybody with psoriatic arthritis, because Embrose approved for that, but not for psoriasis. So just, that's all, something that I thought about. I mean, when I have really, really bad HS patients, I know kind of I think, okay, well, maybe this is SAFO or PASHA, and so you start asking about joint pains and things like that. But I can't say that it's on my radar the way that it is in psoriasis with psoriatic arthritis. So when you say, you're gonna start screaming, like are you basically just gonna start asking people about do you have any back pain, do you have any joints that hurt, and then if they say yes, you're gonna send them to room. - I don't know. What I'm gonna say is if they have any of those symptoms and you kind of think, like, okay, well, this doesn't sound like it's anything bad, probably not. I'm probably not gonna send them to room. - Unless you want to, unless you want to try and get them on a drug. - Yeah, but in that case, or just say, like, you know what, you could have spawned, like, are the insurance company gonna be say, like, well, was that rheumatology diagnosed? Actually, these days they probably will. - Yeah, yeah, that's what he would say to me. You're not gonna be able to put them on a jack for spawn a lower, thropathy. That's part of the, a lot of the prioroth criteria nowadays, like only germs can prescribe, germs and allergists, or the only ones that can prescribe dupe. - Yeah, then I would, especially if I run into trouble with getting those meds, like if my HS treatments don't work, I'll be like. You know what, here's a way that we could possibly go about getting that. You know, I thought about that actually because there was this diagnosis of metastatic Crohn's disease. You know, there was a jammed derm paper published early this year. It was like a delphi panel on diagnosing metastatic Crohn's three major criteria, five minor. And because the diagnosis of IBD or like a skin biopsy were in the minor, that's actually don't need either one of those things to make the diagnosis. I had a guy with just really bad groin HS and massive lymphedema of like the genital, like the scrottle skin. And it kind of made me, and he said he had a family history of Crohn's because I told him if he, I asked him if he had any GI stuff, because right, we were running into issues with kind of running out of options and like you could give that patient a patissette and it 45 milligrams a day to treat metastatic Crohn's. It was kind of a strategy of maybe getting some other drugs to your HS patients. That's two things to think of. Spondylorethropathy and metastatic Crohn's. Okay. You would think, I mean, you know, you would also consider like starting with the TNF inhibitor for those patients first. Yeah. In fact, you know, with this guy, we went back to influximab. And that was kind of another interesting thing because he had not tried bimmy and he wanted to do influximab. I don't know why, but he was just like focused on that. And he'd been on it and insurance company insurance company denied the the influximab saying it's not FDA approved. And when I called them up and said Bimmy, Bimmy, Kizimab is FDA approved. They're like, you know what, we'll pay for the influximab. Yeah. Thank you. And if like tophacinib goes generic, you know, it be there may be that there's maybe a way to get them on these other medications. Just what I thought about it. Would he have you guys, is that on your radar with your HS patients, fundal or ortho? No. Yeah. I mean, yeah. I feel like these people are like chronically inflamed. They are miserable. They've got pain everywhere. It's not shocking. Yeah. When you look at their labs, like doing trials, like their CRPs are off the charts. Like, I feel like these people are like, you know, I feel like sometimes we're like, oh, it's inflammation. But now I'm beginning to like believe that. Like they have horrible systemic inflammation. Yeah. Damn it. So whatever I'm like, no, you're like, yeah, actually, I feel like we're like playing good doctor, bad doctor. No, I know. Obviously. I'm glad I today, I'll be playing the role of good doctor. I think that's always your role. That is. I try. Yeah. Mine is generally bad doctor. Let's say bad doctor, better doctor. That doctor not as bad doctor. Yeah. Exactly. Let's move on to my two here. So first there was a article, we talked about it a couple of months ago about the mechanism through which Jack's might increase thrombosis risk. Basically, the idea is in diseases that have too much IL-17A and TNF, those two molecules increase thrombosis risk in diseases like psoriasis, HS, rheumatoid arthritis. And Jack inhibitors don't reverse that. So it's essentially that other drugs, IL-17s, TNFs, reverse it. Jack inhibitors can get the inflammation better, but they don't reverse that specific effect. So it's not so much that they raise the risk as that they don't reduce it like other drugs should. But the next question becomes, okay, if there is this effect, which Jack inhibitors are better or worse? And so these, the same group that came up, I think, that came up with that original one, published this article, Understanding cardiovascular events with Jack inhibitors, similarities and differences between the vascular effects, between different Jack inhibitors on the endothelial cells, exposed inflammatory cytokines. So basically, they took endothelial cells, put them in with inflammatory cytokines and saw what happened to them. And then, you know, they gave them similar micro-molar concentrations. They tested each of the drugs at one micro-molar and ten micro-molars. They did TOFA, so right, so TOFA, IEZL, Jans, Berry, IE, Allumiant, UPA, IE, RINVOC, two cancer drugs, there are cancer drugs and an inflammation one that I've never heard of, per facidinib and fendra, fadratinib, and then they did Ruxilininib, which is jackify. So basically, the takeaway was, Berry showed the least risk, the least affected endothelial cells that would like potentially make it least likely to cause thrombosis, or to be associated with it. RINVOC was second best, Rux was in the middle, and then TOFA, IEZL, Jans was the worst out of the drugs that we've got. And then the two that I'd never heard of, per facidinib and fadratinib were worse than all the other ones. So at this point, I'm comfortable saying AD and alopecia areata since they are diseases that don't have over expression of TNF and or IL-17A, there shouldn't be any risk of thrombosis from jack inhibitors in those diseases. Mechanistically, and then the data, that's what the data has all shown as well. However, when jacks come out for HS, it absolutely is possible to me that cardiovascular risk improvement with TNF or IL-17s could be a real reason to use them instead of jack inhibitors in HS, and that this data might become very relevant. But that's, we'll see if and when they get improved for HS. And basically, I'll take you way, way back to 15 minutes ago when we just discussed the five thrombotic events with duroxilit. And alopecia areata. And alopecia areata. No risk, no risk. Okay. You should call them and see if these assays are easy to do, which they sounded really, really easy to me. Like I could do this in my kitchen. If they could do this with duroxilitinib. Like what does that do to the end of the alice? Is it the worst? Yeah, that's good because it could be different from the rucksilitib. It'd be an interesting thing mechanistically, does it make it different than the rucks? Yeah. There you go. I will email the authors and ask them. It's, I email authors pretty regularly and most of the time they respond because they're like holy shit, somebody read my paper. Yeah. All right. Anyway, I've got it. I've got it. It's kind of a trivia question. That's the other drug that we use in dermatology that is, has the hallmark of deuteration. I have no idea. Do you test or I'd? Nope. I didn't really think that was the answer. Do you have a sittinib? Oh, the new Kravissittinib. It's got the P-E-U. All right. I've seen that lecture. So is there just Kravissittinib? Is that a thing? No. You're a Kravissittinib sometimes, but yeah. That is. All right. The other one that I did was an HS1. It's just an example of the journals are terrible. This was from a jammed dermatology. It couldn't believe that they let this get published. It was ridiculous. Hydrodynamic is separative remission and progression in a community setting and they take away here. So they basically, it was from Denmark. They looked at like a hundred and some, a hundred and seven HS patients followed them for like 10 years and we're just see how many go into full remission. And their takeaway was two thirds of HS patients will go into full remission and only one out of six will have their disease progress. And even if you have severe HS, there's a 50% chance you'll go into full remission. Ridiculous. Like dumb. Right? Dumb. That's the most ridiculous thing I've ever heard. Is it really half of your HS patients who have severe disease will go to full remission? No. So this was done in Denmark. So completely racially homogenous group. Number two, these were skinny people. So their BMI's, all of the groups, the mean was below 30. They were very wealthy comparatively. They actually showed their income bands and they all have universal healthcare. So and all of that is okay. That like, okay, this patient population is totally irrelevant to everyone in the entire rest of the world. Except they never mentioned it. They attribute the difference to, well, this is community based compared to most are hospital based. So it's that, you know, those those hospital based studies are overestimating the severity. It's good. No, it has nothing to do with community based. It had to do with race and socioeconomic stuff. And it drives me nuts because these journals like Hammer Hammer Hammer on, you know, socioeconomic, it's kind of color and you got to include that and you got in the one study where it like is a huge factor. They didn't mention it. Like journals are just put like even the good journal suck nowadays. Like it's just, it's crazy what they will let through and I'm now never going to get another article approved anywhere that I ever submit one. I love jamma dermatology. I'm listening next time I submit something. Wow, it's like, yeah, that like Denmark is the is the antithesis of North Carolina because nobody gets better here. Nobody needs any of the criteria that he's spoke of either, but yes. Right. And it's like, insurance companies Sunday I could say, well, Dr. Ferris, all of the patients you've had with HS for 10 years, two thirds of them should be in remission and they're not. You're a bad doctor. Like, that's why they shouldn't, like, uh, drives me nuts. Okay, that's it. That was a little bit of a soapboxy one. Sorry. Let's, let's, let's move on to our next. Dr. Ferris, what's your next article? Well, I have efficacy and safety of sequential treatment with cryotherapy, followed by 1% topical turbanibulin for actinic carotoses and organ transplant recipients, a randomized clinical trial. Okay, so this it was, I mean, it was like not a big study, but it was sort of interesting. So, um, you know, so couple interesting things out of the intro that I guess are important, but I hadn't really thought about. They said in solid organ transplant recipients, the spontaneous regression rate for, um, of a specific actinic carotosis has been reported to be 0% versus in the immunocompetent general population. It's 28%. And transplant recipients, their AKs are 32 times more likely to develop into SCCs. So kind of interesting. So why this is sort of the why treat, like, why do we worry about AKs? Sometimes you're like, ah, do we need to worry about AKs? Probably the answer is yes in trans solid organ transplant patients. So 40 transplant patients 37 completed the study. They were who you would think they are who get AKs. They are older Caucasian men mostly mean age 71. Um, and they were heavily pre-treated. So they'd had PDT, five FU and Miquamad, Diclofenac, lots of cryo. They had to be at least one year post trans plant and they had to four to eight AKs on a 25 square centimeter area. Um, two of them on their face are scalp like one on each side, like left cheek, right cheek, left scalp, right scalp. So this was a split field design. Um, they could not be on like nicotinamide oral retinoids blah blah blah. Um, so most of these patients were fits to and three, they were all Caucasian. They were mostly kidney transplants. Second biggest group was liver transplants. Um, so okay, so what they did was basically like everybody got cryotherapy and then one half of the face got terminus and then the other half of the face didn't. So what is I got I got to ask you something. Are I have never know I pronounce it terbanabulin or is is the way you were like are you pronouncing it the way the drug company pronounces it or you may I made I made up how I pronounce it. I don't know if I know. No, I think I have. I have been on an advisory board with them. Okay, so so I have been saying not because I'm a huge prescriber, but I think because they needed another female on their advisory board. That was saying it was roughly and I was so much fun to hang out with it is not because you're a woman. It's because you're brilliant. Now how do you say it again? Turbanibulin. Turbanibulin. Okay, turbanibulin. Yes, glycery is the drug because we're allowed to say that. Yeah. Okay, so it is not so this is an anti-prol it's a microtubule disruptor, right? So it's not like inducing an immune response. It inhibits tubulin polymerization. It disrupts our kinase activity and rapidly dividing cells. So it is, you know, basically causes apoptosis. I'm sure you say that apoptosis or something like that, but I say apoptosis, cell cycle arrest, blah, blah, blah. I don't think you're supposed to pronounce the second P because it's a combination of apo and then tosis. Okay, apopt I know, but I know. I say apoptosis. I say apoptosis. It's so wrong. It hurts my ears to hear people say that. From the guy who for years called a pure rightist. Right. Right, it's ironic. Okay, so everyone's they everyone got the double free star five to 10 second and then and then after 30 days, then one side got the glycery. We'll just call it to stop the discussion. Once daily for five consecutive days and the other one didn't get vehicle, they got no additional treatment. The first application was supervised in clinic, but then the rest the other four days they were done at home and then blinded dermatologist did the efficacy and they did all that I've done like one AK study. It's kind of painful like you got to take these transparencies, you map them, you know, blah, blah, blah. And then they looked at and there's this Olsen scale, which is like the Pazie of AKs to classify them. They did it at day 30 and then again at four months. So basically three months after starting the turbine, Ibulin or glycery. And then primary endpoint, percent change in AK count from baseline to month four in each area. Okay. And then secondary endpoints were like a hundred percent clearance. And partial and then partial response was 75 to but less than a hundred percent clearance. Okay, so what happened in four months, both sides got better, but the sequential side did better. So the mean reduction in AKs was 81% on the cryo glycery side versus 53% and the cryo alone. And that was statistically significant. The total lesion count across all the patients went from 197 down to 38 in the sequential therapy group and 195 down to 91 in the cryo alone. And so then if you're like what percent of patients had no visible a total clearance 51% in the sequential 10% in the cryo only that partial response of that 75 to less than a hundred was like two thirds of now hang on what was it? Oh, about a quarter of the patients. I may have that number wrong, forget that. Just go with the full one. Okay, so they basically they're saying like oh, then they also looked at like who got more AKs. So like so they actually did see a rise in the total AK count in the cryo therapy only group about a 34% rise. Whereas in the sequential side, they saw a 36.7% decrease. And this is in new AKs because you're marking and counting every single one. So there you go. He does the like I won't do any more vitiligo trials because they make you like count all the spots of vitiligo and it's a no that's worse than AKs could have got to do the whole body. But it's terrible. So yeah, so and then like you know, all the safety stuff was fine. It was like what you would expect with any sort of topical AK thing, paint, you know, pain scores were low. There was two one SC. So there were two SCs that arose in treatment sites one SCC and site two in the terminal inside one invasive SCC on the cryo side. And the AK quality of life was was low at baseline and remain low. Let's see. I mean, what are we looking at? My quality of life you mean the AKs were not affecting their quality of life much? It was yes. So yes, relatively small. Yes, it was a small impact on quality of life. So, so yeah, I mean, so I like the split face because at transplant patients are so vastly different that I don't think you can take like 40 of them and say 20 and 20 and think that you're going to get something. Now I assume that they did stuff like flipped out like it wasn't always the left was the the glycery, the right was the you know, cryo alone. I you know, they did like seem to do some pretty good, you know, counting and everything. It's small. You know, I I thought this was interesting. I mean, this was actually like it's very few people study that the transplant patient population. They did the study in the way that we're going to actually use drugs like this, which is we're going to freeze a bunch of stuff and then we're going to put on a topical. They had the patients do it home. You know, I I have used glycery in patients who are like, I hated 5FU. I never want to do that again. And so I'm like, all right, well, will you try something else? And so it's sort of like, it's a something else for them to try. So if we take insurance coverage out of it and we're just talking efficacy and tolerability like what's your go to if you if it wasn't about current, if you didn't care about cost, what do you what do you what do you do in a transplant patient? 5FU calcipatrine. Okay. compounded. That is my go to and the reason is we've got good data that prevents future SCCs. I don't have that data for anything else. There's like, you know, that is my go to, but there are patients who they do it and then they refuse to ever do it again. So I liked have another option. Indeed. That is also the NCC and guidelines. Yeah, I'll pay for your guidelines. Okay, Mr. Good, Dr. It helps. But it helps to know what the guidelines are. Yeah. I thought it was interesting that they specifically said 5FU and they actually mentioned if you can get the calc up a train in there because I thought that was relatively new data, but it's already made its way to the NCCN guidelines are updated like twice a year was getting. I feel I don't know. Yeah. Yeah. I didn't know there was that much overwhelming data where they're like, oh my gosh, we got to make that part of the guidelines. Yeah. It is super cool that they've actually shown that it decreases the risk of squames because that's always been my thing of like without data that something decreases the risk of squames, treating a case is basically cosmetic because it's totally plausible that like the 5FU only gets rid of the ones that weren't going to turn into cancer anyways, right? So it it like just because something gets rid of a case doesn't mean it's going to reduce the risk of squames. So the fact that 5FU and calc up trying has data that it does that because other things don't. So that's that's a big deal. Yeah. So I like the fact that they did this study. I thought it was interesting. It is a tough patient population to do it and so good. And the fact that it prevented new ones was kind of interesting to me, not just that it like decree it it improve clearance. So it made me have feel warmer and fuzzier about clasery and transplant patients. All right. Pat, what do you got? What's your next one? All right. Second six pack from December 2025 edition of Anals of Dermatology. Impact of hydrochloroethyazide on non-neilinoma skin cancer, a distributed network analysis of 100 of 11 real world databases. Lead our author was park and 2020 FDA approved a label change to hydrochloroethyazide to include skin cancer risk. And I have to admit I'm not great about canceling my non-neilinoma skin cancer patients about stopping hydrochloroethyazide if they happen to be taking it. I think if you ask most germs does hydrochloroethyazide HCTZ, I'm not going to keep saying that. HCTZ increases skin cancer risk they would say that it does. But to be honest, the data is not like slam dunk. There are some studies that show increased risk, some studies that don't. Some studies say there's an increase in SEC's but not BCC's. And there's studies showing the opposite. And at least I thought that maybe that's why I'm not terribly diligent. It just seems like the data is not dispositive. There's your word of the day. Anyway, I think I'm going to go with the bad doctor on that one. Yeah. Hold on, hold on. So anyway, this study looked at data from 11 health care organizations in Korea. I think that population being Korean is important. Something like 14 million records overall. They fed the records into this OMOP CDM thingy. It seemed like something similar to trinetics. An epidemiologist could explain this better. I mean, anyone could be explaining this better right now. But the authors compared patients with hypertension prescribed HCTZ to patients with hypertension who were prescribed something else for their hypertension. And after propensity score matching, a little over 8800 patients in each cohort. Big takeaway. There was not an increase risk of non-millanoma skin cancer and patients taking hydrochlorothyzyde compared to patients not taking that. Subgroup analysis of patients taking HCTZ for less than one year versus more than one year. Subgroup analysis based on age, subgroup analysis based on sex. All analyses did not show an increase risk. Are we over counseling patients? Or did I just cherry pick a study that justifies with some people may say is my negligent patient care? What do you guys think? The biggest thing about that paper, they're all Korean. It's a totally different group. But it doesn't matter because there's a European study that went back. They did not show an increased risk with hydrochlorothyzyde. There was a transplant patient population. They're like, yes, it does for BCCs, but not SCCs. For having data that this study showed this, this study showed this. And then FDA changed the label. I totally believe the hydrochlorothyzyde thing. I believe it. I feel like I see it all the time. I don't know. I mean, but Koreans are A, different Fitzpatrick skin type. B, totally different sun behavior. If hydrochlorothyzyde increases your risk for skin cancer and you have a population of patients, no matter what their skin type and pup, you're going to see more SCCs in that patient, theoretically. That's what the study should show. If hydrochlorothyzyde increases skin cancer risk. I'm going to say it's among people who are irresponsibly ridiculously out in the sun. That's who I see. It's like those people who are showing like, it's not going to help you if you like, yeah, I got some sun exposure, but I'm not crazy about it versus like a farmer. There's like a threshold where hydrochlorothyzyde is going to push you over the edge. I believe that is the case. I guess I'm trying to find a way of like, why am I not great about this? And I guess the answer comes down to me just being dumb. Who knows? Just lazy. Do we basically agree that the mechanism is photosensitivity, that it makes you more basically magnifies the effect of sun. Yeah, right? That's what's the theory behind it. Yeah. So I don't even tell people, don't use, I specifically don't do not use sunscreen unless you're going to get a sunburn. And you guys have heard me talk about this ad nauseam. There's good data that the more sun, you get the less like the order to die from a heart attack or stroke or get out of immune disease or whatever. So maybe the reason we don't see it in all populations is because sun isn't that big of a deal. No, but sun is a big deal for some patients. I mean, I look at like, you know, the older, fair, you know, Irish skin type guys who spent all this time outside, either bath the shore or working outside. And they are like covered in a case. It does make a difference for those people. I agree. And maybe like in a culture where you don't sit outside in the sun all day, it probably doesn't matter. And you're of a different skin type. I still think it matters. There is, there is a European study like I think it was Danish. No, the Danish study showed the increased risk. But there was another European study that didn't show the risk. I guess you should see it every time if it's like a definite risk. And even the FDA warning to the label, it's pretty wentby. They're like, it may increase it a little bit. And I think they actually give this number of like you will stop one skin cancer in 16,000 patients. Like that's what the FDA, that was like the page. So do they actually have the in there? Yeah, they do. Maybe we could pull that label and put it as a link like for the show of like what the FDA label actually says. And see, just look at affairs being a chair and assigning work. That's not going to be my job. Zyres, that's going to be your job. Please do. I brought it up. I'll do it. Okay. Thank you. Maybe I'll make you a better dermatologist. All right. Let's jump to my last two. So the first one was combination of hormone, oxydyl and baracitinib, frailopeia, rheata, retrospective study of 77 patients. I did this one because the results kind of shocked me. So I've I have been in the camp of like, that Brett King guy, he doesn't know much about alopecia, aryata, and he keep talking about this manoxidil. I thought I thought he was smart. And turns out the manoxidil looks like it actually does do something. So this, this was not a prospective study. This was a retrospective of 77 patients. But here was the big takeaway that with combination starting baracitinib, four milligrams plus manoxidil with a median dose of two milligrams, 50% of alopecia totalis patients, alopecia, universales got to salt 20. And in the, the, you know, the original studies, only 20% of those people got to salt 20. Now they did go longer here. This was a 12 month study as opposed to the 24 weeks and whatever. But it did actually, I'm probably going to start recommending to people that, okay, if we're going to put you on the Jack inhibitor, we're going to also start you on manoxidil 2.5 milligrams. I'm now like, this has been the best data I've seen to support that. There's more where I would put it. You know, it's interesting. There were a couple of other things recently about manoxidil, just that we're also kind of interesting that basically 100% of men who go on manoxidil will get forearm hypertracosis. But they don't care. That was, that was kind of an interesting takeaway. There was another one just out that you, they monitored labs and blood pressure and all that prospectively and a whole bunch of people in the takeaway was it's now in the literature. Literally says there was no need to monitor routinely monitor blood pressure, pulse labs, anything in lotus or manoxidil. But so this convinced me somewhat that it's worthwhile and I'll be sharing it because it's so safe and so cheap. And the other thing, well, first before I go to my other one, any comments, do you guys do this already? Do you think you'll start doing it? I do. I do it. Okay. Pat, I don't know if I do. I use monoxidil and so many other hair loss things. I would be surprised if I haven't also recommended it to. It just seems like it grows hair. Like, how's it going to ever hurt anything? Okay. All right. This is my other one. Kind of some some big-ish new data. So this is from Roca Tinlemab, the Ox 40 receptor blocker. So this is efficacy and safety of Roca Tinlemab for the treatment of Moderna, severe diabetes, dermatitis in rocket, ignite and rocket horizon. Two global double blind, placebo control, randomized phase three trials. Main takeaway for me here. So efficacy. So the you know the when I say what do I mean? So if we look at everybody who got the drug, whether they got rescued or not, and so rescued was just means if they use topical steroids and use it if somebody uses topical steroids, you call them a failure. They reported the data both calling them failures and leaving them in. If you leave them in. So best case scenario of the data. About 50% of people get to easy 75 and about 25% of people get to IGA zero or one. And those just aren't very good numbers. Right. So for the drugs that were used to, it's about two thirds to 70% of people get to set easy 75 and about 40% of people get to IGA zero or one. So the numbers weren't great. The other things that are just interesting about the drug. Small number of people will get fever's and fevers and chills whenever they take their first dose. Don't know if that is indicative of efficacy. Small number of people will also get oral ulcers. So regular apthosis, I've seen that in some of the patients we've had in the trials. Again, unknown if that's correlated with efficacy or not. But so that's going to be the ox 40 drugs are going to be interesting. Totally different mechanism of action could be very broadly usable. Just going to be interesting to see we don't have enough data to really know anything yet. But it was interesting that this data just came out. So yeah. And I think the idea with the Oxford, the Oxford Eli Gampath way is that it increases, decreases the activated T-affecter cells like it rebalances T-affecter T regulatory. So it's like you get more T-regulatory cells and fewer T-affecter cells. Yes. And so there's a hope that it basically retrain your immune system gets rid of the effector memory T cells or they, you know, they just go away over time. And so people might be able to go on these drugs and get better and then go off them and have it be very long term durable improvement in their disease state. That's kind of the holy grail of what that data is still a ways out. Because right, we've got to do the withdrawal and then give it a year before they can even start to look at that data. All right. Well, I want to thank everybody for joining us today. I hope you laughed a few times. I hope you learned a thing or two. But mostly hoping that your plan is to join us next week. And until then, I'm Matt Zyrus. I'm Tim Patton. And I'm Laura Ferris and we are Derms on Drugs.