← Derms on Drugs
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- [00:16]
A
Hi, and welcome to Derms on Drugs, a new video podcast brought to you by Scholars in Medicine. Derms on Drugs is where cutting edge dermatology meets mediocre comedy.
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Matt.
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I'm Matt Sires, and each week I'm joined by my residency buddies, Dr. Laura Faris and Dr. Tim Patton. 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'll be the most fun you've ever had while actually learning something useful. So tune in every Friday for the latest scoop only@scholarsinmedicine.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 as 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. It's really fascinating. Really just a great meeting overall. But let's go ahead and get into this week's episode. We're gonna start off with Dr. Farris talking to us about a really interesting topic in melanoma. So, Dr. Farris, why don't you go ahead and take us? Take it from there.
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C
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 cutaneous malignant melanoma proportional meta analysis and regression. So that already tells you it's a little statistically dense, but I'm going to kind of 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, the, you know, targeted treatments like braf, you know, MEK inhibitors. So, you know, 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, you know, stage four disease. Their Prognosis is terrible. They're going to be the most depressed, the most anxious. But that really wasn't the case. So, you know, 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, you know, get screened very frequently, oftentimes more frequently than we recommend. And so, you know, we got to think about how we approach this. And particularly for lower risk patients, we got to be better at kind of communicating, you know, the true risk of recurrence for patients who truly have, you know, thin melanomas, and particularly melanomas in situ. Maybe we think about the words that we use to describe melanoma in situ, things like that. So that was what I thought about this. I think it'd be interesting to look at it in a US population. What did you all think?
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A
So first, my big two thoughts. First, a 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 petering off over time. Did they look at that aspect?
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C
It was more anxious. The patients had greater anxiety at the beginning, but there was still persistent anxiety and depression over time too. Yes, it was greater early.
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A
So in Europe, and I'm 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 one disease, you're like. And if you've got stage four disease, you're like, oh my God, I'm gonna die. And it like. So they're either telling somebody too much risk or somebody else too little risk.
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C
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 of that. Everybody knows people who have had skin cancer, so it feels like it's all over the place. We don't have, you know, obviously the risk of mel, 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.
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A
Oh, we're definitely better at everything. Patton, what do you, let's say you've got somebody who's got a 1.3 millimeter melanoma. You know, you haven't, they haven't had a node or their staging or anything else yet. When you talk to them, what do you, what's your spiel? What do you tell them?
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D
There's this like survival calculator that you can do where you can input everything. The depth where you found a male, female. Breslow thickness, which is the same thing as depth. So that's redundant and it'll like pop up a number. Like it pops up a graph. Survival graph. Melanoma specific survival. Overall survival. Survival. So I kind of do that. But I mean, I, I, if I had a one point something millimeter melanoma and my node was negative, I, 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, I, I don't know. I mean, I, like, I don't know those percentages, are they out of whack for any other cancer? I, I don't know. I, I didn't think it was that. I was looking at it from the other side and like, I didn't think it was that crazy because melanoma is scary and, and even if it's a low percentage, you could be in that percentage.
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A
Okay, all right, well let's, let's move on to our second article from Dr. Patton here. Go ahead, Tim.
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D
Yeah, so my big three was fan et al. And it was a November issue British Journal of Dermatology, Drug survival and safety of biosimilars compared with originator adalimumab for psoriasis. A multinational cohort study. So this, they, these authors looked at three big databases in the uk, Spain and France and know what they kind of wanted to do was let's look at biosimilars and Humira. If you're, if you're naive to both, let's look at those patients and compare overall, like all cause discontinuation versus serious adverse events. And then they also wanted to look at switchers. So these are patients who were on Humira 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 Humira, why'd you switch them?
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Well, I assume that it's because in the, in with all the socialized medicine places that they just say, okay, we're not paying for it anymore.
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D
So in the, in the discussion they say, you know, look, there was a study done in Denmark, but Denmark's totally different because it's mandatory. Like, 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, yeah, why the hell would you know? They didn't really explain it, or they explained it really well and I just missed it. So anyways, when you look at the naive, it was over 7,000 new Humira, 7,000 new biosimilars. No difference in all cause discontinuation, all cause serious adverse events. But with the switchers, there was a difference in all cause discontinuation. They did it more frequently in the biosimilar arm compared to the Humira arm. So the question is why? I mean, the primary findings were presented in two forest plots. Figure 2 just basically showed serious adverse events. That's the same whether they're new, whether they're switchers. Everything's the same. Figure 1 showed the two forest plots of all cause discontinuation between the two groups. No difference in the naive patients. So new Humira, 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, higher rates of higher. I'm butchering these. Heromoz, Emraldi and Amjavita.
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Julio.
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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, or is it a nocebo effect effect where the patients perceive they're on a worse drug, even if in reality there isn't a difference. There was a supplement, figure 5, 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 Amjevita and Emeraldi, 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.
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Okay. I thought the big thing was that my favorite thing was passy at discontinuation.
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D
Yeah.
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So people who are on Humira, they would talk. They tolerated a passy of almost 12 before they quit Humira. People who switched onto a biosimilar quit the biosimilar at a passy of eight. So they were, the ones who were on a biosimilar were like, oh, this drug sucks, it's cheap. They put me on a generic, baloney. I went off of it. I want something else. I mean, that it seems obvious. Like it looked obvious to me. And I jumped to conclusions. But I jumped easily to that conclusion that it was just.
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C
Patients do have this sense that, you know, they don't like being switched and they do think that, you know, the generic is not as good. But I will say, when you look at the head to head studies that were done for biosimilars of 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, that curves, they just overlap. It does look like they really work 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, you know, 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 that they would have seen that in the study design. Maybe I missed that.
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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 gotta be here more.
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I don't have anybody on Huira. I haven't put anybody on humira in like 15 years.
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All right, well, I mean, I'm getting, I'm getting it with HS patients now. Right. Because even though, you know, they did the studies in psoriasis, that was one of the points that the paper brought up is it's, you know, once the class gets that medication, it's for all indications. So you don't need to do a study with HS 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 HS with biologics.
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Every HS patient I have goes into a trial because the Jak inhibitors for HS have been miraculous. Like, it's unbelievable. Every single person I have on a jack in a trial is doing really well.
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Okay.
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Yeah.
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All right, let's move on, I guess, really quick. Has anyone said, like, written to the insurance company and say brand necessary? It's got to be Humira.
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I have not.
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D
Okay.
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I've had one person on Remicade off label for necrobiosis lipoidica. She clearly did worse on biosimilar infliximab. And I did switch her back, but.
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D
I've done it for rituximab, too. I just.
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C
You've added for rituximab, too?
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D
I've done that. And insurances have no problem with it. They're like, okay, fine, we'll go back to the brand.
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Right?
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Okay.
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A
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 atopic 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 atopic dermatitis started getting more common in the 1970s, and it's why atopic dermatitis is more common in cities compared to 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 toluene disocyanate. 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 toluene disocyanate. The other place where toluene disocyanate is is in nylon and polyester. And nylon and polyester. 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 atopic 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 atopic dermatitis if you live close to the interstate. So Ian has figured out, like, why, why it all happened. And that is one of the most, like, crazy, like, we got our answer, right? We were wondering this since we were residents. We got our answer. Now, clinically, is it that useful? Right? And there's one thing that, to me, makes it really useful. Because now, because what do patients with atopic 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. I didn't change anything. Why did I get this? And we didn't used to have an answer. It used to be, basically, man, 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 enclosed, the crap in our diet, has been slowly damaging your skin and creating these gaps. And it wasn't that the gaps got like, suddenly your skin got damaged. It's actually that when your skin got damaged slowly, it finally got damaged enough that now stuff can get in and cause inflammatory reaction. Is really clinically where I have found this useful? Because now when I explained it to patients that way, they get it. Like, they like the idea that chemicals are causing, you know, damaging their skin and causing their problem. And then it makes it easier to go on with the visit because it's just like, you know, sun damage. When somebody says, why get this basal cell? I use sunscreen. I didn't go out in the sun, I stayed shade. Oh, it's the sun you got 30 years ago. It's nothing you did last year. Well, now it's the same thing with atopic derm. It's not the. It's not something that you did this year. It's the chemicals your skin have been exposed to over 30 years of time is the basic idea There. So that, that's. And I really want to direct people to this, to this paper 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 in Practice. Great overview article. And I'm kind of going to stop right there. I know. Patton Ferris, I didn't let you kind of 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. 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. So 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 isocyanates article. And the science in that article is dense, like too 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 ena topic dermot. And so then I started to believe, but I still can't understand the isocyanates paper. So kind of take us through where you got the idea to start with and how you guys proved it in that paper.
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B
Yeah, well thanks for having me. But the. I hadn't heard of isocyanates either until we started fishing for chemical associations. So I had the idea that, as you know, you've discussed that the rates of atopic derm are increasing at a rate that cannot possibly be explained by 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 a pet 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, you know, 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. What are the overlaps of the chemicals that are showing up in places with the most atopic derm and 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 he runs his analysis, and diisocyanate jumps out, and it was in the same boat. Never heard it, 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. Well, that's concern. That's weird. Let's start looking around.
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A
Famous science words. Yeah, that's weird.
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B
That's weird.
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A
That's weird.
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B
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? And it's always industrial lifestyle living near highways. 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, diocesan.
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E
8 in, you know, new furniture. It's like, well, yep, that's what memory foam is made out of. And then it's like, oh, is it in wallpaper glue?
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B
And it's like, yep. And is it in, you know, new hardwood floors? Yeah, that's what polyurethane is made out of. It comes out of automobile exhaust. The explosion of eczema really starts around 1970, as we know. And prior to 1970, no cars produced diisocyanate. And then after 1975, it was mandatory that every new car produced diazocyanate as a unintended consequence of the catalytic converter, which obviously cleaned out a lot of other nasty chemicals from the gasoline, but produced diocyanate 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 diazocyanate was a established mouse model of atopic derm. And I mean established as in the fda. So you could expose a mouse to diasocyanates, give it your topical steroid or JAK inhibitor 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.
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E
Right.
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B
So that, that's not great, that you're just doing some random math associations. And a drug, a chemical that is established to cause eczema in mammals is doing it in humans. 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. 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 mouse model, cell culture model, ceramide 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 atopic dermot.
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A
All right, so Ian, I'm going to interrupt you there because the Patton came across one of the. I'm sure you're aware of it. There's an article out there where they tried using the Roseomonas bacteria as an intervention for atopic derm and it didn't work. So, Pat, why don't you go ahead and kind of take us from there?
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D
Yeah, I guess what I mean, this sounds mean. If the isocyanates are in the environment and they're affecting the bacteria, whatever it's called. Sorry, what is it?
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B
Roseomonas.
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D
Roseomonas. How would you expect a topical cream with Roseomonas to work if they're still being exposed to the isocyanates? What was the thinking there?
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B
We think raw numbers, that if you have enough bacteria and you're using it. Yeah, I do believe that it will have a shelf life, so to speak, on the body. So in our clinical trial.
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A
We.
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B
Gave people roseomonas 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.
- [25:42]
A
Well, that makes it a much better drug. You can't, you can't make a drug that people can use and be cured. Then the pharmaceutical companies won't make any money. They need to be able to keep, people need to be able to keep using the stuff.
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B
Well, it's a probiotic now, and so NIH licensed it out to a private company who sells it over the counter. So some of your patients may already be using it as we speak, as a topical. As a topical, Yeah. I mean, you know, they don't get to, as one as it is with every probiotic. Right. They don't get to say, oh, this is for eczema and all of that. It just doesn't have those, you know, they have those restrictions in terms of, I mean, because 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.
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A
Okay.
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B
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 as what one would anticipate of a placebo response. But the treatment group, it 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, you know, practice parameters or to make some declarative statements. Which is why we're doing an additional trial now where we have a, a prospective, a priori set to say like, all right, we're going. We intend to only look long after we've discontinued the medicine.
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C
Ferris, this is really fascinating. I have a question. What do you tell patients kind of from a practical viewpoint of, you know, what can you do short of moving away from highways? And I saw you had some good, you know, information in your paper. Is there sort of like a concise guideline that you give patients, all right, moisturize, but don't use this. And you know, do you recommend sort of using the Roseomonas? You probably can't really recommend using that. But what do you tell people?
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A
Live like they're Amish.
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B
Yeah, we're slowly going to prove that indigenous populations had it right all the time, I guess. But the, you know, the. We had a review article from JAD International that you're going to test my memory of our mnemonic. But it's 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. Emollients, laundering practices to say which laundry detergent, specific probiotics. You're right. I mean, you can make recommendations and 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, you know, soaking and bathing, which everybody knows. Social support, air quality. And this is where it gets a little more difficult because, you know, intuitively. And it's to finish this D is for diet, which is obviously there's a lot of mystery there still too. And air quality, it's counterintuitive because you would think if there's pollution outdoors, we'll just close all my windows, close all my doors and I'll be protected. And what actually happens is that's great for pollens and really large soot molecules. It's terrible for gases. And so what will happen is the gas will get into the house and.
- [29:16]
E
It'Ll get trapped and it can actually make it worse. So indoor air quality, outside of major disasters, like I'm sure the LA fires and so forth, outside of major disasters, indoor air quality is always worse than outdoor air quality. This outdoor has more room to go and wind and everything, so you need ventilation. And so what you would want to do is set up, you know, just like a box fan. Like you actually see it back there, like one that you would have from college where you'd put in the window and you 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 pollen and stuff.
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A
What kind of a filter, like is a activated charcoal going to be? Is an activated charcoal filter going to pull the VOCs and isocyanates out? Because I assume like a HEPA filter wouldn't do it.
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B
Yeah, the HEPA filter.
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A
Activated charcoal.
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B
No, that. 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 want to 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, you know, filtering as much as you can on the way in.
- [30:52]
A
Okay, Ian, 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 toluene disocyanate and xylene versus stuff you haven't figured out yet, what would like is. Are TDI and Xylene 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?
- [31:24]
B
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 antimicrobials in our diet. But, yeah, if. I think if you could wave a magic wand and take all isocyanates and xylene out of rotation, I mean, I want to say 75, 80%, something like that, you're never going to get. There's always going to have 5% of people floating around who are going to have the kind of monogenic exematous disorders, 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, 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, you know, it's always going to 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.
- [32:37]
D
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 place 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 eczema anymore.
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B
I mean, yeah, rural parts of Africa. I suppose there are other things that go along with that decision, I guess.
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A
Yeah.
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D
Probably not the most practical advice.
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B
I was just curious. Uganda has rates at rates in like the fraction of a percentage.
- [33:09]
A
Let me tell you how I answer that question because I do get patients who ask me that and I want to 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 wind, the prevailing winds are coming off of the ocean. So you're going to get less chemicals in the air.
- [33:35]
B
I gotta say, Los Angeles is like XMA central. You've got boats, you've got highways, you've got wildfires, you've got factories. Like when we got that little map of eczema, 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, you know, testament to public transit, I suppose. But not per capita. Right? Lots of patients with eczema, but not per capita. One last thought.
- [34:09]
C
This is a derm 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 got to be an environmental component. And you may not as an allergist ever see this, but frontal fibrosing alopecia, like, you know, this sort of like 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.
- [34:54]
B
Yeah, we could check. We have a new, our 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, 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.
- [35:23]
A
So, Ian, it's. First, I do want to tell you we did your topical steroid withdrawal paper last week, and that was, again, really cool work. So it sounds like you kind of 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.
- [35:47]
B
I think I need the government lawyer here with me to answer that question. If the argument.
- [35:54]
C
Yeah, we don't have a full time job on the podcast for you, so.
- [35:57]
B
Yeah.
- [35:57]
C
Watch what you say.
- [35:58]
B
No, 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.
- [36:29]
A
Yeah. All right, Ian, I want to thank you for coming on today, and this has been just a fascinating discussion, and I really want to thank you for what you've done for patients and for the. The specialties of dermatology and allergy. It's really making a difference out there. And, guys, we are going to kind of wrap up our deep dive session and move on to part number three of the show where Patton is going to hit us with some trivia. And the usual format here is it's. I think of myself as smarter than everyone else in the world. So it's our guest, Dr. Miles and Dr. Faris, kind of against me. Ian, the rules are it's just like as soon as you think you know an answer, although you got to guess.
- [37:13]
D
I think we changed the rule. Let's. Let me finish the question. Let's set the rules.
- [37:16]
A
Okay.
- [37:17]
D
You jump in her, because I think it's. It's, you know, connections and things like that. I finished the question. Everyone answers ready?
- [37:24]
E
Okay.
- [37:24]
A
All right.
- [37:25]
D
And these are derm heavy, so I apologize. I didn't know you were an allergist.
- [37:29]
B
Yeah, I didn't even know the last disease she was talking about, so I might not do too well.
- [37:34]
D
All right, Very good. All right, so which eponym is the only one used in Hannifin and Rachka's 1980 list of major and minor criteria for diagnosing atopic dermatitis?
- [37:46]
A
Morgan. Denny.
- [37:47]
C
Denny. Denny Morgan.
- [37:49]
D
I think it's Denny Morgan. I don't know if I can give you that.
- [37:52]
A
Damn it.
- [37:52]
C
I got it. Denny Morgan.
- [37:55]
D
All right. The historian Suetonius Described clinical findings consistent with atopic dermatitis and maybe even asthma in this Roman emperor.
- [38:06]
B
Augustus.
- [38:07]
D
Yes. Who was Augustus? Nice. I think that's really unfair to our guests, so I apologize. Of the non topical steroids FDA approved to treat atopic dermatitis, which one was approved in 2016?
- [38:28]
C
The non topical steroids.
- [38:31]
D
Non. 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? It was Ucrissa.
- [38:45]
A
You Chrisa, I forget that that's a drug because it sucks. It doesn't work. I always says it doesn't even count. It's expensive moisturizer that burns.
- [38:56]
D
Hey, it was approved in 2000. The FDA is never wrong, so I.
- [39:00]
A
Don'T know what you're talking about, so. Damn it, I was over. So. Ferris 2, Ferris 1, miles 0.
- [39:06]
D
Cyrus, my Paul, I screwed up that last one. I need a proofreader. I thought I ran these through AI. All right, all right, Ian, thanks so much. Really interesting stuff. It's great.
- [39:20]
C
It elevated the IQ of this podcast significantly.
- [39:23]
D
Thanks for joining us.
- [39:24]
C
It's good.
- [39:26]
E
Thank you, guys. Sorry for being late.
- [39:28]
A
All right, so that was a fantastic deep dive. And again, I just can't emphasize 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 Patton Ferris and I thought were interesting and useful this week. And I believe Dr. Farris, you are leading us off.
- [39:54]
C
Yes, I'm going to talk about a paper in JAMA Dermatology, Jenny Lai and John Barbieri, Acne relapse and isotretinoin retrial in patients with acne. 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 had to have a second course of isotretinoin or had to have treatment with an oral acne therapy. And then they looked at the, you know, the predictors of that. And so, you know, 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 reached a high cumulative dose, which was 220 milligrams per kilogram. 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, you know, one, it's using claims data. So realize you don't. You can't go in the chart and look stuff up. So, you know, one, how did, how do you get somebody's weight from claims data? Well, what you do is you basically, you know, take a standardized age and you know, sex standardized number and you assume everybody's the same weight, which we know isn't really true. So, and you know, so that's one problem. The other thing is that how do you decide when somebody has the come off therapy, relapsed and gone on to another therapy and you know, if they just had a month off of therapy and then went back on, that was considered relapse and restarting. And you know, I think that's just kind of real life. So that was what I thought was, you know, interesting. You know, nice to have big numbers, but you lose something when you just use claims data. So, you know, I thought I'd see what you guys thought about this paper.
- [42:08]
A
So, you know, 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 baloney. But it's even with that, it still showed a relationship between cumulative dose. So it does tell us cumulative dose really is a big deal. But the other thing that was interesting was that women were much more likely. And that probably goes back to the hormonal acne aspect. Patton, anything that jumped. Anything that jumped out to you about this?
- [42:41]
D
No, I buy the cumulative. Cumulative dose. Do you guys use cumulative dose?
- [42:47]
A
Yes.
- [42:49]
C
I have been lazy about it. Now that I'm at unc, this is the high dose accutane 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 isotretinoin for a, you know, female who's 130 pounds, no problem.
- [43:14]
A
You guys get to that kind of a. Are you talking cumulative dose or.
- [43:18]
C
No? I'm talking about daily dose.
- [43:20]
D
They just want to get there quicker.
- [43:22]
C
They get there quicker. But they also are believers in getting to that, you know, to that higher dose and that you really don't. It's still tolerated. You may have a little bit more cheilitis, but, you know, at some point, if we want to do a deep dive on Accutane. We should. We'll bring Dean Morrell on, who kind of started this first paper on looking at, you know, 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 and we don't have a lot of side effects. I'm floored.
- [43:54]
A
Quick, Pearl, in case you didn't haven't seen this, if you guys aren't already doing it. High Omega 3 fish oil has a couple of trials showing it really helps with the cheilitis and the nosebleeds for Accutane patients. So I put everybody on high omega 3 fish oil when I started on Accutane. Now. All right, let's. Let's move on to our next one. Patton, what do you. What do you got?
- [44:17]
D
Risk of malignancy and depilumab use. I don't think I'm overstating things by saying that dupilumab probably cures cancer. The papers from the November says a.
- [44:29]
A
Guy who desperately wants to make a lot of money from going dupilumab speeches. But.
- [44:33]
D
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 in Practice. It was titled the risk of malignancy associated with the use of dupilumab versus other treatments in atopic dermatitis patients. A national database analysis was by Garate or Garage et al. I apologize if I mispronounce. So they used trinetics and they collected data on atopic dermatitis patients over a period of 20 years. 2003, 2023. And then they used propensity score matching to match patients based on demographic characteristics and comorbidities. And then they had kind of three different sets of comparison that are in Table 2. So I made graphs from the tables and if there's discrepancies in the numbers, that's my fault. So starting with figure 3, so non dupy systemic treatments. Azathioprine, cyclosporine, methotrexate, myco, 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 dupy patients to patients with systemic therapies. Difference in SEC bcc, that didn't reach statistical significance, But a statistically significant difference in malignancies, hematologic malignancies, that wasn't surprising because DUPY is not immunosuppressive and these other ones were. What really surprised me was the figure one. So compared to mild atopic dermatitis, DUPY patients had statistically lower risks of SCC and BCC and internal malignancies. And these weren't like slight risks. The risk ratio of 0.35 for BCC SCCs and 0.47 for internal malignancies. There was no different in HE malignancies. But that number surprised me. I don't know if that's real. What do you think?
- [46:41]
A
I mean, it's a big database and they are numbers that, I mean, makes right. We know DUPY shifts your immune system to TH1 and TH17. That's why you get arthralgias and why you get new onset psoriasis. It never occurred to me that there might be a benefit. And we know cancer immunoseurveillance is Th1 and Th17, so it mechanistically makes sense.
- [47:07]
D
What do you think, Ferris? Does DUPY cure cancer?
- [47:10]
C
Thing is, we just did a paper looking at calcipetriene and and 5 fu compounded and found that actually th two responses were seemed like protective from actinic keratosis, squamous cell carcinomas. So this would sort of refute that.
- [47:27]
D
Yeah, counter that.
- [47:28]
C
Yeah, counter that.
- [47:29]
D
Did you buy it? Does dupilumab save us from cancer cures?
- [47:33]
C
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 in 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 coptd. COPD data. That's a high risk for lung cancer patient population. What happens there? Do we see differences in lung cancer incidence for patients who are on DUPI for copd?
- [48:07]
A
I mean, man, think about it. Now, you take one, one shot of Zepp bound every week, one shot of doopie every two weeks and you'll be skinny and cancer free forever. It's fantastic.
- [48:18]
C
Longevity.
- [48:20]
A
Let's move on to our next article. This one was mine and this was looking as it was trilokinumab treatment in adult atopic dermatitis patients. 28 week evaluation of clinical effectiveness Safety, serum proteins and total IGE levels. And the crucial thing here was that they looked at people who switched from DUPY to Trelo and that, you know, we talked last week about an article looking at switching from one aisle 23 inhibitor to 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 doopie or had an adverse event generally did well on Tre low. It was interesting. The people who switched from doopie onto Trelo early on did better than the people who were on nothing and just started Tre low. But then over time, the people who run nothing and started tre low did better than the people who were on dupy first suggests that there was kind of a residual effect from the doopie. And really the thing that that makes me think is that if you want to do a switching trial where you switch from one therapy to another, especially from doopie 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 dupie, only 10 had eye disorders on Trelo. So if you get dupy induced conjunctivitis, 1 in 3 chance that you would get Trollo induced conjunctivitis. But if you did not get Dupie induced conjunctivitis, not a single person who was on dupie without conjunctivitis, not a single one got conjunctivitis on Trelo. 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, want to add to it.
- [50:14]
C
IGE levels, tell us about total IGE levels. Does it matter?
- [50:19]
A
I don't think so. I don't believe that it matters. It's, 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 th2 deviated. Dupy is maybe going to help, is going to do more to unth 2 deviate it than others. But I'm not a believer. I don't check IGE levels. It never even occurs to me clinically.
- [50:46]
D
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 no, this might, this might make a difference.
- [50:57]
A
So this might work. Still good.
- [50:58]
D
Always. Nice guy. Yeah.
- [51:00]
A
All right, let's go into our, let's go on to our next one. So Dr. Fares, I think this is yours.
- [51:04]
C
Yeah, this is Journal of Cosmetic Dermatology. Ferulic acid in the treatment of papula pustular rosacea. Randomized controlled study. 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, you know, what they 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.01 IgA? What, you know, what was the, you know, reduction in lesion endpoints. But you know, there was some, some sign. I don't know. I thought interestingly, more patients on saline complained of feeling that feeling like their skin was greasy. There was less trans epidermal water loss in the group who was on ferulic acid. But you know, also there's a different. I don't know, Matt, I was going to ask you what does, what's saline? What's going to sailing on your face twice a day going to do your transepidermal water loss is this, it's not truly vehicle controlled.
- [52:25]
A
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 want 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, you know, have rosacea and want to know what anti aging thing can they use ferulic acid. To me, this show does something, something you know.
- [53:01]
C
Yeah, something I don't know versus you know, more tried and true proven topical medications. But it's at least something non medical people.
- [53:09]
D
I'm basically yeah or yeah, rosacea is impossible to treat. 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 to now. It's always nice to have more. More things in the armamentarium.
- [53:25]
A
I will say that's definitely my go to for rosacea topically. Now, are those triple creams that you get from the compounding pharmacy with Ivermectin, metronidazone, azelaic acid?
- [53:33]
D
Yep.
- [53:34]
A
I've ever seen for rosacea.
- [53:35]
C
Yeah, I agree.
- [53:37]
A
Yep. All right, let's go on to our next one. Patton, I believe this one was yours.
- [53:41]
D
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 manager. Melasma Systematic review and meta analysis of randomized controlled trials by MAU et al. I apologize if I'm butchering these names. It was a review of seven randomized controlled trials of histamine in the treatment of melasma. Some studies against placebo, some against hydroquinone. Results in Figure 2. Forest plot system is better than placebo and equal to hydroquinone in efficacy when using both the Mazi and Melasqual scoring systems. Side effects of erythema, 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.
- [54:41]
A
Oh. So. Yeah, okay. Because when I looked at the number, I must have looked at it confusedly because I looked at it.
- [54:46]
D
Yeah, by your comment. No, the itching, all that was against hydroquinone. The huge differences were in the trials where it was versus a placebo cream. Not.
- [54:56]
A
Okay, so it was much worse than placebo, but not. But it. Basically equal to hydroquinone. Okay. All right.
- [55:03]
C
Do you.
- [55:03]
A
Do you use this? And I've never, never recommended it or written it for anybody.
- [55:07]
D
I want to get a skin lightening person on. Because you look at our topicals, like tyrosinase inhibitors. It's hydroquinone, it's thiamidol, that new one in the.
- [55:16]
A
In the.
- [55:17]
D
In some of the eucerin moisturizers.
- [55:20]
A
Yeah.
- [55:20]
D
There's arbutin, there's glycerinic acid, whatever that licorice thing is. There's systemine, there's azelaic acid, there's tretinoin. Like, at what point does this. Like, if you give three. Can you lighten the skin anymore? Where. Yeah, I don't. I don't know. Like, what do you guys use to. I know. Matt, you said you use oral. I haven't make that. Taken that step. Oral tranexamic acid.
- [55:47]
C
Yeah, me neither.
- [55:48]
D
I haven't done that.
- [55:49]
C
I. I do like a. I'll. I'll look at whoever compounding pharmacy. I'm like, what's the best, baddest looking combination you got? That's what I do.
- [55:59]
D
So right now, right, I have a tranexemic niacinamic acid, Kojic acid or niacinamide, Kojic acid, tretinoin. And then I tell them this like spot treat with hydroquinone and you know, take breaks on and off from that. I don't think it may be that topical tranexamic acid doesn't work at all.
- [56:18]
A
But I tell you, the oral tranexamic 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.
- [56:35]
D
I. There's a. I know of a physician who makes the patients sign a consent form before they get. Do you do that?
- [56:42]
A
No, I document in the chart that I told them it was off label and at least theoretically possible and create. It causes a blood clot risk. But I don't think it does. Yeah. All right, let's go to our last one. This was mine. This was effectiveness of surgical versus non surgical interventions in the treatment of Digital mucous cysts. This was by Shay et al in the archives of dermatological research. And first thing about this that was interesting was drainage plus intralesional 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 kenalog into the cavity where it was. Then you wrap it up. They compared that to surgical resounding to a hand surgeon. The surgical certainly works better, but there were some meaningful number of people. So 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 surge center for a hand surgeon was not benign. But a big part of this, this was not a well written paper in 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. That was a dumb way to get the numbers. And so then we came up with a different. We asked AI, well, what if you did it this way? And AI gave us a great answer. So the, the, the approach of saying that we came up with really showed us that surgical treatment, this treatment success rate was about 86%. Intralesional kenalog only was about 31%. Drainage only was about 31%. And interlesional catalog plus drainage had a success rate of about 44%. So basically, interlesional kenalog combined with drainage worked about half as well as surgery without any of the risk was the takeaway. So something easy you can do in clinic and, you know, maybe do that two or three times. And then if it doesn't work, go on to surgery or, you know, ask them if they want to get sent to surgery. You guys do anything else for. I actually haven't done an interlegional catalog. I've only drained them. Do you guys do any of this stuff?
- [59:25]
C
I do nothing. I send them out. But I saw this. I thought, I mean, I could drain and ilk it and if it works a third of the time, fine. And maybe they need a new hand surgeon. That was my other thought.
- [59:38]
D
So I had a patient where I. 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 mucosys, 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. 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, I drain them. I don't know. I always sent these people to hand because I'm like, if I drain it, it's going to come back.
- [60:20]
A
Yeah. And that. I didn't realize that. Yeah. Maybe it is just a. It was a single institution thing, so maybe it was just a bad hand surgeon, but the, the rates were significant. So I want to thank everybody for joining us this week. If you got questions, comments or ideas for topics we should cover on the show, shoot us an email@questionsurmsondrugs.com Again, that's questionsurmsondrugs.com and I hope you learned a few things. I've laughed once or twice, and mostly, I hope you're planning on joining us next week. Till then, I'm Matt Zyrus.
- [60:50]
D
I'm Tim Patton.
- [60:52]
C
And I'm Laura Farris. And we're Derms on Drugs.