Rewind: Melanoma Meltdowns, Biosimilar Betrayals, and the Eczema Enigma Exposed!

Hey, Derms on Drugs Family. We took a little Memorial Day breather this week, which means no new episode, but we did not want to leave anybody hanging. So we're bringing back one of our favorite episodes from the archive. This is the second episode we ever did, and it is with a genius from the National Institutes of Health, the allergist named Dr. E. Admiall's, who literally figured out what caused the exome epidemic and answered fascinating questions like, why is it mainly in industrialized countries? Why is it more common in the city than it is in the country? Why is it me getting more comments since the 1970s? So trust us, it is worth a second listen. Enjoy. And we are going to use our 60 years of combined experience to discuss, debate, and dissect the hottest topics in dermatology. It is everything you need to know to be on the absolute cutting edge of Derm, and it will be the most fun you've ever had while actually learning something useful. So tune in every Friday for the latest scoop only at scholarsandmedicine.com. So for those of you who are tuning in today, you might notice I'm wearing not my normal scrub top, but my Hawaiian shirt. And that's because I am on the beautiful island of Maui for Maui Dermatology, which I think of is the best meeting of the year. If you've never been here, it is spectacular. Whales jumping in the background on the sunset at the beach at night and incredible content that's really fascinating. Really just a great meeting overall. Let's go ahead and get into this week's episode. We're going to start off with Dr. Ferris talking to us about a really interesting topic in melanoma. So Dr. Ferris, why don't you go ahead and take it from there. Thanks. So I'm going to talk about a paper that was published in the British Journal of Dermatology, Prevalence and Odds of Anxiety and Depression and Coutaneous Malignant Melanoma, a proportional meta-analysis and regression. So that already tells you it's a little statistically dense, but I'm going to cut to the chase. So this was a meta-analysis of several studies. I will say they were all European studies. And they looked at patients with melanoma and they looked at anxiety and depression. And so what they found was that the highest levels of anxiety and depression were in women, patients who were younger, patients who had lower levels of education. And then they also looked at their therapeutic modality and using immune checkpoint inhibitors as sort of the baseline. They found that patients who are in chemo are interferon. Some of these were older studies, had higher anxiety, less with targeted treatments like B-Raff, Mac inhibitors. So I think what was interesting here is if we also look at stage of disease, you would think, oh my gosh, it's the people who have stage 4 disease or prognosis is terrible. They're going to be the most depressed, the most anxious, but that really wasn't the case. So I thought this was interesting. This is definitely something. If somebody sees a lot of melanoma patients, patients with melanoma are incredibly anxious. They want to come in for every single spot. They want to get screened very frequently, oftentimes more frequently than we recommend. And so we got to think about how we approach this. And particularly for lower risk patients, we got to be better at kind of communicating, the true risk of recurrence for patients who truly have thin melanomas and particularly melanomas in site 2. Maybe we think about the words that we use to describe melanoma in site 2, things like that. So that was what I thought about this. I think it would be interesting to look at it in the US population. What did you all think? So, first, my big two thoughts, first question, did they look at all at time after diagnosis? So I think of my melanoma patients as being super anxious for like the first year and then it kind of peering off over time. Did they look at that aspect? It was more anxious at the patients I greater anxiety at the beginning, but there was still persistent anxiety and depression over time too. Yes, it was greater early. So in Europe and remember, remembering these are European dermatologists, not like awesome American dermatologists like us, do you think they are over making people feel too risky who have mild disease, who have low stage disease or you think they're making people feel not at risk enough who have later stage disease? Because it should be that like if you got stage 1 disease, you're like, and if you've got stage 4 disease, you're like, oh my god, I'm going to die. So they're either telling somebody too much risk or somebody else too little risk. I don't know that this is, we could say that this is the physician or the dermatologist. I think this is the patients. I think there's so much out there, patients read a lot. Everybody knows people who have had skin cancer, so it feels like it's all over the place. We don't have, obviously the risk of death from melanoma, it's a small fraction of all cancer deaths. But everybody knows somebody who's had skin cancer. I think patients have a hard time understanding the risk. I don't think we're better at it than in the US than they are in Europe. Oh, we're definitely better at everything. Patent, let's say you've got somebody who's got a 1.3 millimeter melanoma, you know, you're having, they haven't had a node or they're staging or anything else yet. When you talk to them, what do you, what's your spiel? What do you tell them? There's this survival calculator that you can do where you can input everything, the depth where you found a male, female, breastless, which is the same thing as depth, so that's redundant. It'll pop up a number. It pops up a graph, survival graph, melanoma specific survival, overall survival. So I kind of do that. But I mean, if I had a 1.0 millimeter melanoma and my node was negative, I'd freak out, right? I mean, there's a percentage of patients that are going to die from that disease. It's a small percentage, but it's not zero. And so being, you know, if you're pessimistic and it's melanoma, that's a killer. I don't know. I mean, I don't know those percentages, are they out of whack for any other cancer? I don't know. I didn't think it was that, I was looking at it from the other side and I didn't think it was that crazy because melanoma is scary. And even if it's a low percentage, you could be in that percentage. Okay. All right. Well, let's move on to our second article from Dr. Patton here. Go ahead, Tim. Yeah. So my big three was fan at Al and it was a November issue British Journal of Thermatology, drug survival and safety of biosimilars compared with originator at a limo map for psoriasis, a multi-national cohort study. So this, these authors looked at three big databases in the UK, Spain, and France. And you know, what they kind of wanted to do was let's look at biosimilars and humera. If you're naive to both, let's look at those patients and compare overall, like all caused discontinuation versus serious adverse events. And then they also wanted to look at switchers. So these are patients who were on humera and then got switched to a biosimilar, not because of lack of efficacy, not because of any sort of side effect, they were just switched. And that was like, why were they switched? They didn't really say one would assume it's some sort of insurance thing, things like that, but they don't say if somebody's on humera, why do you switch them? Well, I assume that it's because in the, with all the socialized medicine places that they just say, okay, we're not paying for it anymore. So in the discussion, they say, you know, look, there was a study done in Denmark, but Denmark's totally different because it's mandatory. The switches were mandated. And what they said about UK, France, and Spain was that decision to switch depends on, quote, clinician patient consultation. So they didn't really explain it or they explained it really well and I just missed it. So anyways, when you look at, when you look at the naive, it was over 7,000 new humera, 7,000 new biosimilars, no difference in all caused discontinuation, all caused serious adverse events. But with the switchers, there was a difference in all caused discontinuation. They did it more frequently in the biosimilar arm compared to the humera arm. So the question is why? I mean, you know, the primary findings were presented in two forest plots, figure two, just basically so it's serious adverse events. That's the same whether they're new, whether they're switchers, everything's the same. Figure one showed the two forest plots of all caused discontinuation between the two groups. No difference in the naive patients. So new humera, new biosimilar, same. But where you saw the discontinuation, and it was like a 1.35 hazard ratio of discontinuing the medication. And it did differ between biologics. So there were differences between the biosimilars. similar is higher rates of higher, I'm butchering these. Here amaz, M. Raldi and Amjavita, Hulio, there was no different in all cause. So the question is, why are the switchers stopping their biosimilars? Are they less effective? Are there more adverse events? Is it a nocebo effect where the patients perceive they're on a worst drug? Even if in reality there is no difference. There was a supplement figure five and it looks at risk of discontinuation due to ineffectiveness. There was only one database that had this information and it does look like in the case of Amjavita and Amjavita and Amjavita, it was because they were less effective. But then why was that not seen in the new starters? Like what was special about a switching population where those drugs would be less effective compared to starting the new? So I don't know, I guess. Okay, I thought the big thing was that my favorite thing was passie at discontinuation. So people who were on Humira, they tolerated a passie of almost 12 before they quit Humira. People who switched onto a biosimilar quit the biosimilar to passie of 8. So the ones who were on a biosimilar were like, "Oh, this drug sucks, it's cheap." "I put me on a generic, bloating, I want off of it, I want something else." I mean, it seems obvious. It looked obvious to me and I jumped to conclusions. But I jumped easily to that conclusion that it was just. I think the patients do have the sense that they don't like being switched and they do think that the generic is not as good. But I will say, when you look at the head-to-head studies that were done for biosimilars and biologics, where people were switched back and forth and they didn't know when they were switched or what they started on, what they ended up on. Man, that curves, they just overlap. It does look like they really worked the same. Now the one thing I thought is, you know, why do some. Why in some cases does it look like the people who switch don't do as well on a biosimilar? But if it's not randomized switching, if they're switching for a reason, did somebody say, "Gosh, you're not doing that great on Humira?" Let's try one of these biosimilars and see how you do versus if people were doing fine. Maybe they continued. I don't know if that's. Maybe they would have seen that in the study design. Maybe I missed that. My question is, have any of you seen this personally? You know, we're kind of getting into that era where the insurance companies are like, "Nope, no more Humira. It's got to be here or more." Hi. I don't have anybody on Humira. I can't even put out all these things. And I haven't put anybody on Humira in like 15 years. All right. Well, I mean, I'm getting it with H.S. patients now, right? Because even though they did the studies in psoriasis, that was one of the points that the paper brought up is, once the class gets that medication, it's for all indications. So you don't need to do a study with H.S. to show that the biosimilars. I don't know if they have. I think the randomized control trials were only in psoriasis. I could be wrong about that. But so, no, I mean, you don't treat H.S. with biologics? Every H.S. patient I have goes into a trial because the jack inhibitors for H.S. have been miraculous, like it's unbelievable. Every single person I have on a jack in a trial is going really well. Okay. All right. Let's. I guess really quick, has anyone said, like written to the insurance company and say, "Brand Necessary? It's got to be Humira?" I have not. Okay. I've had one person on Remicate off-label for Necrobiosis LaPoidica. She clearly did worse on biosimilar inflixamab and I did switch her back. I'm going to for Rituxamab too. You've had it for Rituxamab too. I've done that. And it's. Inchurances have no problem with it. They're like, "Okay, fine. We'll go back to the brand." Right. Okay. All right. Let's go on to our final article here. This was one. that actually was a review article and it's because this is just such a fascinating topic and I want people to. we'll put the link to this. So it is talking about the link that we now are aware of between a topic dermatitis and environmental conditions in particular air pollution. And whenever we talk about air pollution, we're not just talking about outdoor air pollution and we're not talking about air pollution in the sense that we generally think of it. So first, this has all been figured out by a guy named Ian Miles at the NIH who really. this is our answer. This is why a topic dermatitis started getting more common in the 1970s and it's why a topic dermatitis is more common in cities compared to the rural areas. And really, there are two primary chemicals that we know for sure and we know mechanistically what they're doing. The big one is called Talluein Dysosyanate. And this is a chemical that is created in car exhaust when there's a catalytic converter. So a catalytic converter takes things like sulfur dioxide, which causes acid rain and turns it into less toxic stuff for the environment. But it creates this Talluein Dysosyanate. The other place where Talluein Dysosyanate is is Ian Nylon and Polyester. And Nylon and Polyester, right, when you think about fashion from the 70s, what do you think about Nylon and Polyester? And so catalytic converters getting implemented in the 70s and Nylon and Polyester in the 70s turns out are what has driven the topic epidemic and what has caused the urban rural gradient because cars are way more dense in urban areas. And then also we know that even if you live in the country, you are more likely to have a topic dermatitis if you live close to the interstate. So Ian has figured out why it all happened. And that is one of the most like we got our answer. We wonder in the sense we have residents, we got our answer. Now clinically is it that useful, right? And there's one thing to me makes it really useful because now, because what a patience with a topic dermatitis always ask you, why did I get this? Why did I get this? I didn't change anything. I didn't change my products. I didn't move. I didn't change my job. I didn't change my diet. Why did I get this? And we didn't use that answer. It used to be basically, "No, your skin got old. "Shit doesn't work when it's old. So now your skin doesn't work and you got eczema." The correct answer is when you were born, your skin looked like this. Now if you're a kid who has genetic barrier deficiency, when you were born, maybe your skin looked like that. But so when you were born, your skin looked like this. The chemicals you've been exposed to your whole life. Air pollution, the chemicals in clothes, the crappin' our diet has been slowly damaging your skin and creating these gaps. And it wasn't that the gaps got suddenly, your skin got damaged. It's actually that when your skin got damaged, it finally got damaged enough that now stuff can get in and cause inflammatory reaction. It is really clinically where I have found this useful because now when I explain it to patients that way, they get it. They like the idea that chemicals are damaging their skin and causing their problem. And then it makes it easier to go on with the visit because it's just like sun damage. When somebody says, "Why get this basil cell? I use sunscreen. I didn't go out in the sun. I stayed in the shade." "Oh, it's the sun you got 30 years ago. It's nothing you did last year." When I was the same thing with a topic derp. It's not something that you did this year. It's the chemicals your skin have been exposed to over 30 years of time. It is the basic idea there. So that's, and I really want to direct people to this paper. It really goes over mechanistically what these chemicals are doing, where they're coming from. And it's in the journal of allergy and clinical immunology and practice. Great overview article. And I'm going to stop right there. I know Pat and Ferris, I didn't let you comment on this. But fortunately for us, we've got the author on for our deep dive. And so I really want to introduce everybody to Dr. Ian Miles. So Ian, I believe Ian is an allergist. I've actually never looked if he's an allergist or dermatologist, but since he's doing real research, I actually assume he's an allergist at the NIH who really did all of this work. And so Dr. Miles, I could not be more excited to have you here. I've been a fanboy for the last couple of years. Really interested in your work because you've answered questions that nobody else has been able to answer in 30 years. But really, I want to kind of stop there and have you kind of walk us through because your first article that really caught my attention that I saw first was the I so cyanase article. And the science in that article is dense, like two dense for me. I couldn't figure it out, tried really hard. So I didn't believe it. I was like, ah, this is, if I can't understand that it's baloney, then more and more stuff came out about air pollution, having a bigger role than genetics, and then I started to believe that I still can't understand the Isocianase paper. So kind of take us through where you got the idea to start with and how you guys proved it in that paper. Yeah, well, thanks for having me. But the, I had nerd advice of cyanates, either, until we started fishing for chemical associations. So I had the idea that, you know, you've discussed that the rates of atopic derm are increasing at a rate that cannot possibly be explained by just. genetics, there's a huge signal for immigration. So something in the environment had to be there. And we had the idea of taking clinical databases. So every time I pay you bill for a patient visit that gets anonymized and sent to, you know, sold from one group to another to another. And this is pharmaceutical companies use that to micro target medications to providers. And so there's a record of where people with atopic derm are being seen. And so then we could access now the EPA databases that have a record of what chemicals are in each zip code. And doing various geospatial analyses, which is a level of math that I don't fully grasp either, but thankfully Jordan Zeldin in the lab did. We were able to ask that question. You know, what are the overlaps of the chemicals that are showing up in places with the most atopic derm in the chemicals that are absent in the places where atopic derm rates are lower than you would anticipate for access to care and age and so forth. And you know, he runs his analysis and diasoscienate jumps out and it was in the same boat. Never heard it. I wasn't sure I was pronouncing it correctly type thing. And that was one model. So he went back and said, well, just in case the model is quirky, let's pick a different model and, you know, random forest and lasso and ridge and all these different statistical approaches and all of them say the same thing. And so, all right, well, that's, that's weird. Let's start looking around. - Famous science words. - Yeah. - That's weird. - That's weird, right? That's weird, but that's consistent. And so then we start looking for, we'd already seen some of the papers and they're scattered, but you know, what are the things that have been associated with atopic derm in general? You know, and it's always industrial lifestyle, living near highways, you know, patients complain about synthetic fabrics. And then there's a few mostly out of South Korea with mostly survey data, which is like new furniture or wallpaper and all these other things that just seemed weird and disconnected and hard to wrap your head around. So you start searching, you know, the guys diosycionates and, you know, new furniture. It's like, well, yep, that's what memory foam is made out of. And then it's like, oh, it's it in wallpaper glue? It's like, yep, and it's it in, you know, new hardwood floors, it's what's polyurethane is made out of. It comes out of automobile exhaust. The explosion of X-Men really starts around 1970. As we know, and prior to 1970, no cars produced diosycionate. And then after 1975, it was mandatory that every new car produced diosycionate as a unintended consequence of the catalytic converter, which obviously cleaned out a lot of other nasty chemicals from the gasoline, but produced diosycionate as an unfortunate byproduct. And it just kept going on like that. So there's just all these kind of epidemiologic signs. The most concerning one was that diosycionate was a established mouse model of a topic term for, and I mean, established as in the FDA. So you could expose a mouse to diosycionates, give it your topical steroid or jack-in-hybrid or whatever it is that you wanted to use, show that the mouse got better, and use that to justify to the FDA. I want to expose humans to my drug, right? So that, you're like, that's not great that you're just doing some random math associations and a drug, you know, a chemical that is established to cause X-Men in mammals is doing it in humans. So then we took the chemical into the lab under the hypothesis that whatever these chemicals are, they're having effects on the microbiome and the skin. And so we could basically show that you can get healthy skin bacteria to stop doing all of the beneficial factors that it should be doing, all of mouse model, cell culture model, seramide production being one of the bigger ones, it'll just shut off those lipids because the bacteria are trying to survive that chemical exposure. And so they will change their physiology to adapt, but when they do, they give up the beneficial properties that we have. So you can basically make a healthy commensal act like one that came off of somebody from a topic term. All right, so, you know, I'm gonna, I'm gonna interrupt you there because the patent came across one of the, I'm sure you're aware of it, there's an article out there where they tried using the rosyamonis bacteria as an intervention for a topic term and it didn't work. So Pat, let you go ahead and take us from there. - Yeah, I guess what, I mean, this sounds mean. If the isosignates are in the environment and they're affecting the raw bacteria, whatever it's called, sorry, what is it, rosyamonis? - Rosyamonis. How would you expect a topical cream with rosyamonis to work if they're still being exposed to the isosignate? So what was the thinking there? - We think raw numbers that, you know, if you have enough bacteria and you're using it, that yeah, I do believe that it will have a shelf life, so to speak, on the body. So in our clinical trial, we gave people rosyamonis for four months and then they stopped completely. And eight months later, they maintain their benefit, but the PCR, we can show that our specific organisms are now living on the skin. And what that said to us is that maybe that colonization is beneficial. I do believe, I don't have evidence for it yet, but we're now doing a secondary clinical trial to look into that, that the bacteria will be less effective in, or less long lasting in places that have high pollution, because you'll spray it on and then your ambient pollution will rob it of its abilities and then you'd have to spray on fresh bacteria, so to speak, to replace it. - Well, that makes it a much better drug. You can't make a drug that people can use and be cured than the pharmaceutical companies will make any money. They need to be able to keep, people need to be able to keep using the stuff. - Well, it's a probiotic now. And so the NIH licensed it out to a private company who sells it over the counter. So some of your patients may already be using it and we speak. - As a topical? - As a topical, yeah, I mean, they don't get to, as it is with every probiotic, right? They don't get to say, oh, this is four, X, M, and all of that. It just doesn't have those restrictions. In terms of, I mean, 'cause we're co-authors on all the papers, so the one that you said where it didn't work, like I'm a co-author on that one too. So there's a difference. It didn't hit its pharmaceutical development endpoint, which was set for what the FDA wants. - Okay. - What we saw was that as soon as patients, that was the placebo control, as soon as everybody stopped taking their intervention, the placebo started to wear off. Exactly is what one would anticipate of a placebo response. But the treatment group had held tight. And so you had, at the end of the study, you had a significant difference, but the end of active treatment you did not, and typically you file for active treatment with the FDA. That is certainly not sufficient to put it into, practice parameters, or to make some declarative statements, which is why we're doing an additional trial now, where we have a prospective a priori set to say, all right, we intend to only look long after we've discontinued the medicine. - Fairies for you. - This is really fascinating. I have a question. What do you tell patients kind of from a practical viewpoint of what can you do, sort of moving away from highways? And I saw you had some good information in your papers. They're sort of like a concise guideline that you get patients, all right, moisturized, but don't use this and do you recommend, sort of using the rosyomonas, you probably can't really recommend using that. But what do you tell people? - Live like the aromis. - Yeah, we're slowly gonna prove that indigenous populations had it right all the time, I guess, but we had a review article from JAD International that you're gonna test my memory of our pneumonic, but it helps AD with two S's. So it's like home decor, we kind of go through all the different things in your house that you would have to worry about, emolience, laundering practices to say, which laundry detergent, specific probiotics, you're right. I mean, you can make recommendations in general guidelines, like if somebody's using a probiotic, it needs to have a strain identifier on it. You'd like to have some kind of validation that somebody's checked to make sure it has those organisms in there. Soaking and bathing, which everybody knows, social support, air quality, and this is where it gets a little more difficult because intuitively, to finish this DS for diet, which is obviously, there's a lot of mystery there still to. And air quality, it's counterintuitive because you would think if there's pollution outdoors, well, just close on my windows, close on my doors, and I'll be protected. And what actually happens is that's great for pollens and really large molecules, it's terrible for gases. And so what'll happen is the gas will get into the house and it'll get trapped. And it can actually make it worse. So indoor air quality, outside of major disasters, like I'm sure the L.A. fires and so forth, outside of major disasters, indoor air quality is always worse than outdoor air quality. So outdoor has more risk to go and get wind and everything. So you need ventilation. And so, So what you would want to do is set up, just like a box pan, like you'd actually see it's like there, like one that you would have from college, where you'd put in the window and you'd put a filter on it blowing in so that all the air that you're sucking into the house goes through a filter so you don't pull in a bunch of polymers. - What kind of a filter, like is a activated charcoal, gonna be, is an activated charcoal filter gonna pull the VOCs and a cyanates out? 'Cause I assume like a hepa filter wouldn't do it. - Yeah, the hepa filter won't-- - Activated charcoal. - Yeah, so the hepa filters won't pull out, like so in an ideal world, if money was no object, then yeah, you want the most expensive hepa filter or activated charcoal, none of them are actually rated against these specific chemicals yet. So we don't genuinely know what specific ingredients you'd want in an air filter to best remove all of this stuff. For ventilation sometimes though, it doesn't matter, you just wanna flush the air out and just get air moving. And so even just a regular hepa filter will work to just keep the soot and the pollen out. And then having another fan on the other part, another part of your house blowing out so that what you're doing is you're kind of shuffling the air through your residence, but not pulling in filtering as much as you can on the way in. - Okay, so if you had to, and I know this is pure speculation that I'm asking you to do, if you had to take a guess as to how much of the atopic epidemic is explained by Talia Wingdice Assignate and Zylin versus stuff you haven't figured out yet. What would, like, is, are TDI and Zylin like 90% of the answer, or do you think they're like 30% of the answer and there's still a lot more to figure out? What would your guess be? - My, I mean, I'm obviously biased. Of course, but the one wrinkle in there is whether or not we need to have bad diets, you know, all of the different processed ingredients and other things that can cause harm or antibiotics and to microbials in our diet. But yeah, if I think if you could wave a magic wand and take all isoscionates and Zylin out of rotation, I mean, I want to say 75, 80% something like that. You're never gonna get, you're always gonna have 5% of people floating around who are gonna have the kind of monogenic extremitous disorders, - Yes. - Job syndrome and nethertons and so forth. It's hard. So we're starting a few international projects with the goal of looking at places that have high levels of these pollutants, but still eat a fairly what you call traditional diet. So they still eat whole foods that they cook themselves and they have burgeoning rates of atopic derm and asthma, but really no food allergy. And then it's always gonna be difficult to separate the dietary restrictions and the dietary influences because any place that has these chemicals almost certainly has processed foods to go along with it. - If money was no object, like you were saying with the filters and somebody came to you and said, I need to move to a plate, like the best place to live in the world. Do we know that? Like if they said, I can work from home, just send me somewhere where I don't have to deal with my ex-oanning more. - I mean, yeah, rural parts of Africa, I suppose. There are other things to go on with that decision, I guess. - Yeah, probably not the most practical advice. I'm just curious. - Like Uganda has rates in like the fraction of a percent. - Let me tell you how I answer that question 'cause I do get patients who ask me that and I wanna see if my answer theoretically holds any water. I tell people move somewhere that is on the West Coast of somewhere. So West Coast of Florida, California, Portugal, Spain, where the prevailing winds are coming off of the ocean. So you're gonna get less chemicals in the air. - I gotta say Los Angeles is like, ex-muscentral. (laughing) - You can do this like that. - You've got boats, you've got highways, you've got wildfires, you've got factories. Like when we got that little map of ex-mother, there's a few places that just, you're like, "Whoa, what is that?" And it's like Memphis actually, surprisingly. Los Angeles, not Manhattan. Maybe that's testament to public transit, I suppose. But not near per capita, right? Lots of patients with ex-mus but not per capita. - I'm one last thought. And this is a Durham thought that is probably not as relevant. But when I think about like, what do we see now that we never saw before that there's gotta be an environmental component? And you may not as an allergist ever see this but frontal fibrosin alopecia, like this sort of variant of hair loss that we see in like middle-aged women, it's inflammatory. We never used to see it and now we see it all the time. Or at least I think I see it all the time. It's one of these things that has been some speculation that maybe it's oxybenzone, sunscreens that are involved. But I think that the methodology you use would be really interesting to probably look at some of these other emerging inflammatory diseases too. - Yeah, we can check, we have a new project is to take a different database from the federal government that'll let us look at every disease versus every EPA chemical. And so the idea would be, you know, I gotta say, the preliminary data at this point, but a lot of neuroinflammatory behavioral disorders showing up with strong environmental signals asthma as one would have anticipated so we can check our data and look for that one. - So, at first I do wanna tell you, we did your topical steroid withdrawal paper last week and that was, again, really cool work. So it sounds like you kinda think RFK might be barking up at least in some respects, some respects might be barking up kind of the right tree in some of the things that we're talking about. - I think I need the government lawyer here with me to answer that question. (laughing) If the argument-- - Yeah, we don't have a full time job on the podcast for you, so. - Yeah. - That's what you say. - I mean, if the arguments, I don't know all the nuances of every statement ever made, but the arguments of environmental exposures, harming children in ways that are not adequately assessed, I think that's correct. I think concerns about the lack of long-term safety evaluation for pharmaceuticals as a broad category. Yes, specific pharmaceutical interventions are probably safer than others, but yeah. - Yeah. All right, wait, Ian, I wanna thank you for coming on today and has it been just a fascinating discussion and I really wanna thank you for what you've done for patients and for the specialties of dermatology and allergy. It's really making a difference out there. And guys, we are gonna kind of wrap up our deep dive session and move on to part number three of the show where Patton is gonna hit us with some trivia. And the usual format here is, I think of myself as smarter than everyone else in the world. So it's our guest, Dr. Miles and Dr. Ferris, kind of against me, Ian, the rules are, it's just like as soon as you think you know an answer, although you got a guess. - I think we changed the rule. Let me finish the question. Let's set the rules. - Okay. - You jump in her, 'cause I think it's, you know, connections and things like that. - Okay, I think so, no. - I'll finish the question. Everyone answers, ready? - Okay, all right. - And these are Durham Heavy, so I apologize. I didn't know you were an allergist. - Yeah, I didn't even know the last disease she was talking about, so I might not do too well. (laughing) - All right, very good. So which eponym is the only one used in Hanuffin and Racheca's 1980 list of major and minor criteria for diagnosing atopic dermatitis? - Morgan Denny. - Denny, Denny Morgan, I'll say it. - I think it's Denny Morgan. I don't know if I can give you that. - I got it. Denny Morgan. - All right. The historian, Satonius, described clinical findings consistent with atopic dermatitis, and maybe even asthma in this Roman Emperor. - Augustus. - Yes. - Who was it? - Augustus, I'm very glad. - Augustus. - Nice. - All right, this one is the Roman Emperor. - The Roman Emperor. - I'm very unfair to our guests, so I apologize. Of the non-topical steroids, FDA approved to treat atopic dermatitis, which one was approved in 2016. - The non-topical steroids. - Non-steroid, I'm sorry. Did I say, oh, I'm sorry. Non-steroid topicals, FDA approved, non-steroid topicals, which one was approved in 2016? - Not that. - It was Eucrissa. - Eucrissa, I forget that that's a drug because it sucks. It doesn't work. I always, it doesn't even count. It's expensive moisturizer that burns. - It was approved in 2000. The FDA is never wrong, so I don't know what you're talking about. - So, damn it, I was over. So, Ferris, two Ferris, one miles, zerozyris. - My poll, I screwed up that last one. I need to approve for you. I thought I ran these through AI. - All right, all right. Ian, thanks so much. Really interesting stuff. It's great. - You elevated the IQ of this podcast significantly. Thanks for joining us. - Thank you guys. Sorry, Ian late. All right, so that was a fantastic deep dive. And again, I just can't emphasize. I just want to what a big deal it is that we finally got this stuff figured out. Thanks to Dr. Miles. We're now going to move into our final session after after our trivia, our six pack where we go through six more articles that Pat and Ferris and I thought were interesting and useful this week. And I believe Dr. Ferris, you are leading us off. Yes, I'm going to talk about a paper in JAMA dermatology, Jenny Lai and John Barbieri, Acne relapse and isotrentinoin retrial in patients with acne. So this was based on market scan data, so claims based data. And basically what they did was they looked at claims data and looked at how often did patients have to have a second? Did they retrial meaning that they either ended up a second course of isotrentinoin or had to have treatment with an oral acne therapy? And then they looked at the predictors of that. And so what they found was that cumulative dose, which I think we all kind of know, is significantly associated with the decrease rate of acne relapse. So higher cumulative dose, less likely to relapse. They did not find, as long as you reach to high cumulative dose, which was 220 migs per gig, if you went higher than that, they didn't really see that there was some benefit, that there was additional benefit. But if you were in sort of the low to conventional higher doses were associated with lower risks of relapse. Now, what was interesting about this paper, one, it's using claims data, so realize you can't go in the chart and look stuff up. So one, how do you get somebody's weight from claims data? Well, what you do is you basically take a standardized age and sex standardized number and you assume everybody's the same weight, which we know isn't really true. So that's one problem. The other thing is that how do you decide when somebody has come off therapy relapse to gone on to another therapy? And if they just had a month off of therapy and then went back on, that was considered relapse and restarting. And I think that's just kind of real life. So that was what I thought was interesting. Nice to have big numbers, but you lose something when you just use claims data. So I thought I'd see what you guys thought about this paper. So the fact that they basically just said, well, if you're 42 and female, you probably weigh this much, right? The cumulative dose data is basically below me, but even with that, it still shows a relationship between cumulative dose. So it does tell us cumulative dose really is a big deal. So the other thing that was interesting was that women were much more likely, and that probably goes back to the hormonal acne aspect. Pat, anything that jumped out to you about this? No, I buy the cumulative dose. Do you guys use cumulative dose? Yes. I know. I have been lazy about it. I doubt it. I'm at UNC. This is the high dose acutane capital of the world. Okay. And so now I am better about it because the residents make me do it. And man, I mean, 120 milligrams a day. I sat wet knowing for a female who's 130 pounds. No problem. So we do it all. You guys get to that kind of a way. Are you talking cumulative dose or? No, I'm talking about daily dose. They just want to get there quicker. They get there quicker, but they also are believers in getting to that higher dose and that you really don't. It's still tolerated. You may have a little bit more calatist, but at some point, if we want to do a deep dive on acutane, we should will bring Dean Morrellon who kind of started this first paper on looking at high dose reaching that 220 milligram dose. And we can talk about it. But I'm amazed at what they do, but patients do great. We don't have a lot of side effects. I'm, I'm, I'm, Lord. Quick pearl in case you didn't have seen this, if you guys aren't already doing it, high omega three fish oil has a couple of trials showing it really helps with the key lightest in the nose bleeds for acutane patients. So I put everybody on high omega three fish oil when I started my acutane now. All right, let's move on to our next one, patent. What do you got? Risca malignancy into pillium ab use. I don't think I'm overstating things by saying that the pillium ab probably cures cancer. The papers from the November is. It says a guy who desperately wants to make a lot of money from going to pill a map of speeches, but okay, well, I'm just going to add that. That'll be my top line point. My paper, November issue, the journal of allergy and clinical immunology and practice. It was titled the risk of malignancy associated with the use of the pillium ab versus other treatments in atopic dermatitis patients, a national database analysis. It was by Gerate or Gerate at all. I apologize if I mispronounced that. So they use trinetics and they collected data on atopic dermatitis patients over a period of 20 years, 2003, 2023. Then they use propensity score matching to match patients based on demographic characteristics and comorbidities. Then they had three different sets of comparison that are in table two. So I made graphs from the tables. If there's discrepancies in the numbers, that's my fault. So starting with figure three, so non-dupe systemic treatments, azithyprin, cycloscore, and methotrexate, mygo, UV versus mild AD. So only treated with topicals. There's no difference in rates of SEC or internal malignancy. That was a little surprising. You basically have immunosuppressant medications versus just using topical steroids. I'm surprised you didn't see increased rates of either of those. There are increased statistically significant difference in hematologic malignancies. The second analysis was dupe patients to patients with systemic therapies. It's an SEC BCC that didn't reach statistical significance, but a statistically significant difference in malignancies, hematologic malignancies. That wasn't surprising because dupe is not immunosuppressive and these other ones were. What really surprised me was the figure one. So compared to mild atopic dermatitis, dupe patients had statistically lower risks of SEC, a BCC and internal malignancies. And these weren't like slight risks. The risk ratio of 0.35 for BCCSCC and 0.47 for internal malignancies. There was no different in hemalignancies. But that number surprised me. I don't know if that's real. What do you think? I mean, it's a big database and they are numbers that, I mean, it makes, right? We know dupe shifts your immune system to TH1 and TH17. That's why you get arthrauges and why you get nuances psoriasis. It never occurred to me that there might be a benefit. And we know cancer immunosurveillance is TH1 and TH17. So it mechanistically makes sense. What do you think, Ferris? Does dupe care cancer? I think healing is something we just did a paper looking at calcipatrine and 5FU compounded and found that actually TH2 responses were seemed like protective from ectinic care to see squamous cell carcinomas. So this would sort of refute that. Yeah, counter that. Yeah, it's counter that. So you buy it, does dupe doing that save us from cancer? Cures it. I can see, I mean, at the very least, it doesn't increase our risk of cancer. I feel better using it to treat dermatitis and patients on checkpoint inhibitors. But you know, we do think TH1 responses are largely protective against cancer. So I can buy it, but you know, I think it'll be interesting to see when we have the COPD data. That's a high risk for lung cancer patient population. What happens there? Do we see differences in lung cancer incidents for patients who are on dupe for COPD? Yeah, I mean, and tick about it now. You take one shot, a zep bound every week, one shot of dupe every two weeks and you'll be skinny and cancer free forever. It's fantastic. Long-jeivity. Let's move on to our next article. This one was mine and this was looking as it was trial and kinemab treatment in a dodey topic of dermatitis patients, 28-week evaluation of clinical effectiveness, safety, serum proteins, and total IgE levels. And the key, the crucial thing here was that they looked at people who switched from dupe to traloe. And that, you know, we talked last week about dead article looking at switching from 1 to 23 and have her do another and it turns out that failing one doesn't predict failing. The other, say the takeaways from this article were that people who either lost efficacy on dupe or had an adverse event generally did well on traloe. It was interesting. The people who switched from dupe on to traloe early on did better than the people who were on nothing and just started traloe. But then over time, the people who were on nothing and started traloe did better than the people who were on dupe first, suggest that there was kind of a residual effect from the dupe. And really the thing that that makes me think is that if you want to do a switching trial where you switch from 1 therapy to another, especially from dupe to something else, you have to do longer than a 16-week trial. You've got to do a 28-week trial. So most patients who got, who had an eye disorder on Dupy, so 32 patients had an eye disorder on Dupy, only 10 had eye disorders on Trello. So if you get Dupy and Duce conjunctivitis, one in three chance that you would get Trello and Duce conjunctivitis. But if you did not get Dupy and Duce conjunctivitis, not a single person who was on Dupy without conjunctivitis, not a single one got conjunctivitis on Trello. So not getting it on Dupy was highly predictive of not getting it on Trello. That's kind of the takeaways from this study. You know, anything that either you guys want to add to it. IGE levels tell us about total IgE levels. Does it matter? I don't think so. I don't believe that it matters. It's arguable. There's some element of belief that the higher the IgE, maybe the more Dupy is going to benefit you because IgE is kind of a marker that your immune system is TH2DB-A-D Dupy is maybe going to help, is going to do more to untd2DB-A-D than others. But I'm not a believer. I don't check IgE levels. It never even occurs to me clinically. I think it's nice to have the data because when the patients say, well, if it works similar to Dupy, it's really probably not going to work. And now you can actually point to something and say, well, now this might make a difference. So it's my worth. Still good. All right. Let's go into our next one. So Dr. Fares, I think this is yours. Yeah. This is German cosmetic dermatology, ferulic acid in the treatment of popular plusular rosacea randomized controlled studies. So this was a randomized controlled study, 30 patients in each arm, ferulic acid, 3% versus saline. So the ferulic acid was in a polyol base versus saline is obviously just normal saline. Six week study, everybody was also on doxy 100 a day. And so what they've showed was that there was a little improvement if you just looked at IgA scores in the group that got ferulic acid versus the group that got saline. You didn't have traditional endpoints, which is like what percent of patients had a zero one IgA. What was the reduction in lesion endpoints? But there was some sign, I don't know, I thought interestingly more patients on saline complained a feeling that feeling like their skin was greasy. There was less trans epidermal water loss in the group who was on ferulic acid, but also there's a different, I don't know, Matt, I was going to ask you, what's saline? What's going to saline on your face twice a day going to do your trans epidermal water loss? Is this, it's not truly vehicle controlled? I wouldn't expect the saline to do much for trans epidermal water loss, but it did also show that the saline group had a higher skin hydration. So I certainly think that the saline would hydrate your skin by putting water on it. But yeah, I mean, my general takeaway from this was if your patient, because there's a lot of ferulic acid serums out there now over the counter. And so it might be a nice recommendation for some of our patients who have a sensation and want to know what anti-agent thing can they use for a ferulic acid. To me, this show does something, something, you know, something. I don't know versus, you know, more tried and true proven topical medications, but it's at least something non-medical people want to sling non-medical. Yeah, or, yeah, rosacea is impossible to treat. Do they have all these topical agents? And now we're going to have another one when they say, well, I tried all my triple combination cream. We have something else we can point them through now. It's always nice to have more things in the armamentarium. I will say that it's definitely my go-to ferulic acid. Typically, now we have those triple creams that you get from the compound infarmystine with hypermectin metronidazone as late acid. That's a good thing I haven't received ferulic acid. Yeah. I agree. Yep. All right. It's going to our next one, Patton. I believe this one was yours. Yeah, systemine. I'm not sure if I'm saying that right. 5% cream for the management of melasma. December 2024, archives of dermatologic research, efficacy and safety of systemine, 5% cream for the management of melasma. Systematic review and meta-analysis of randomized controlled trials by Maewu at Owls. I apologize if I'm betraying these names. It was a review of seven randomized controlled trials of systemine in the treatment of melasma, some studies against placebo, some against hydroquinone. Medicine figure two, forest plot, systemine is better than placebo and equal to hydroquinone and efficacy when using both the Mazze and Melasqual scoring systems. Side effects of air-thema burning, itching irritation, dryness, systemine is worse than placebo, no big surprise, but comparable to hydroquinone. So it's like rosacea. Now we have one more drug we can throw at somebody to lighten their skin. Oh, so yeah, okay. Because when I looked at the number, I must have looked at it confusedly because I was not in it. Yeah, by your comment, no, the itching ear to all that was against hydroquinone. The huge differences were in the trials where it was versus a placebo cream, not hydroquinone. Okay. So it was much worse than placebo, but not, but basically equal to hydroquinone. Okay. All right. Do you use this and I've never recommended it or written it for anybody? I want to get a skin-lightening person on because you look at our topicals like tyrosin acinhibitors. It's hydroquinone. It's thiamadol, that new one in the in some of the usern moisturizers. There's our butan. There's glycerinic acid, whatever that licorice thing is. There's systemine. There's azaleic acid. There's treteno. Like at what point does this like, if you give three, can you lighten the skin anymore? Yeah. I don't know. I'm like, what do you guys use to? I know Matt. You said you use oral. I haven't made that that taking that step oral tranaccemic acid. Yeah. I haven't done that. I do like a, I'll look at whoever compounding pharmacy. I'm like, what's the best baddest look in combination you got? That's what I do. So right now, right. I have a tranaccemic nice, cinemic acid, Kojik acid or nice, cinamide Kojik acid, treteno and then I tell them this like spot treat with hydroquinone and, you know, take breaks on and off from that. So I don't think it may be that topical tranaccemic acid doesn't work at all. But, okay, the oral tranaccemic acid is actually pretty impressive. You do a half a pill once a day. No evidence that it increases risk of blood clots. Now it still might, but it really, it's a very low dose compared to the normal dose. Do you have, I, there's a, I know of a, a, physician who makes the patients sign a consent for before they can. Do you do that? No. I documented the chart that I told them it was off label and the theoretically possible and create it causes of what clot risk, but I don't think it does. Yeah. All right. It's going to our last one. This was mine. This was effectiveness of surgical versus non-surgical interventions in the treatment of digital mucosis. This was by Shayette Al in the Archives of Dermotological Research. And first, the thing that about this that was interesting was drainage plus interleasional catalog actually worked fairly well, right? So to me, right, that's the, you drink, you poke it with a big needle, you squeeze the jelly stuff out, you show it to the patient because they think it's cool. And then you inject a little bit of catalog into the cavity where it was, then you wrap it up. They compared that to surgical, where you send it to a hand surgeon. The surgical certainly works better, but there were some meaningful number of people as about 10% of people got actually 20, almost 25% of people got a complication, either an infection, pain requiring a prescription pain therapy or limited range of motion that required a subsequent clinical visit. So the surgical surgeon was not benign, but a big part of this is it was not a well written paper and that it was hard, really hard to figure out, like where did they come up with their numbers? And so, you know, when Pat and I were going back and forth about this, we actually fed it into AI and asked AI, like how do you know, these numbers don't make any sense and AI explained how they got the numbers and I was like, that was a dumb way to get the numbers. And so then we came over the different, we asked AI, well, what if you did it this way? And AI gave us a great answer. So the approach of saying, of that we came up with really showed us that surgical treatment, this treatment success rate was about 86%. Intrallegional catalogue only was about 31%, drainage only was about 31%, an interlegeal catalogue plus drainage had a success rate of about 44%. So basically interlegeal catalogue combined with drainage, which is about half as well as surgery without any other risk was to take away. So something easy you can do in clinic and maybe do that two or three times and then if it doesn't work, go on to surgery. You know, ask if they want to get sent to surgery. Do you guys do anything else for, I actually haven't done an interlegeal catalogue, I've only drained them. Do you guys do any of this stuff? I do nothing, I send them out, but I saw this, I thought I could drain and I'll pay it. And if it works a third of the time, fine. And maybe they did. I needed a new hand surgeon, that was my other thought. (laughing) - So I had a patient where I took out a few and I did like an excision. She had these nodules on her knuckles. I didn't know what they were. So I actually did an excision and they're like digital mecha cysts, which just didn't look like that. - Yeah. - They were deeper, you know what I mean? They weren't like the blue thing right by the nail. So I sent her to the hand surgeon. And I mean, like it's, she said, I'm not doing it. Like he said, he's gonna put me in a cast and I'm gonna be like immobile for like four to six weeks. And so she just lives with these things on her knuckles and she says they hurt. I mean, maybe I drain them. I don't know. I always send these people to hand 'cause I'm like, if I drain it, it's gonna come back. - Yeah. And I didn't really like that. Yeah, maybe it is just they, it was a single institution thing. So maybe it was just a bad hand surgeon, but the rates were significant. So I want to thank everybody for joining us this week. If you got questions, comments or ideas for topics which cover on the show, shoot us an email and questions at termsundrucks.com. Again, that's questions at termsundrucks.com. And I hope to learn a few things. I feel afterwards twice and I'm mostly, I hope to blend them on during this next week. Till then, I'm Matt Zyrus. I'm Tim Patton. - And I'm Laura Thyrus and we're Derms on Drugs.