A (2:32)

Yeah, I couldn't figure it. I, I, I couldn't figure it out.

B (2:35)

Couldn't yeah.

A (2:36)

Okay. All right.

C (2:37)

Okay.

A (2:38)

Okay.

B (2:39)

So this is the DECIDE study, Sentinel Lymph Node Biopsy. The test is Decision DX Melanoma. The 31 GEP test from Castle Biosciences. Okay, so this is a prospective study. 912 patients, stage one and two melanoma, 30 US centers. And it's basically sort of trying to be prospective and sort of trying to be real world. And so who got enrolled in this? People who had cutaneous melanoma who were being considered for a sentinel node biopsy and who happened to have had the 331 GEP test ordered. And then they were. They were then, you know, offered to be in this study. So it's a prospective study, but these are patients for which the test was already ordered. So unlike other studies where you say, we're going to randomize you or we're going to enroll you, then, you know, order a test and blind you and compare the outcomes, it's like you've got the test, you're being sent to somebody for a. To be evaluated for sentinel node biopsy. Okay, so what they did was they wanted to use the outcome. So the GEP test gives this i31, which is basically, how likely is it that if you got a sentinel node biopsy, it would be positive? Is it less than 5%, 5 to 10%? Greater than 10%. Kind of in the NCCN framework of when we recommend, discuss and consider, or don't recommend. Okay, so who are these people? They mostly had thin melanomas, medium breslow thickness of 0.8 millimeters. About a third of them actually had T1A lesions. About a third of them had T1B lesions. 18% of them were T2A. There is a smattering of thicker lesions. So, you know, T1A lesions. We would normally say those aren't people for whom we would consider sentinel node, but they will say, well, they were high risk, meaning maybe they were transected at the base, maybe they were less than 42 years old, high mitotic rate, et cetera. About half of the. So the way that this study worked was you had your result, your G P result, and then you met with the surgeon and you said, well, here's your, you know, percent likelihood. And then together you made a decision based on, you know, did you want to do a sentinel node, yes or no. They, if you did, they followed what was the result. And in everybody, they looked at like, recurrence free survival, three year recurrence free survival. So about half of the patients in the study ended up getting a sentinel node. And in this study, of those people who got it, 89.8% of those had a negative sentinel node. So you would say as a group, they sort of fell in that, like, 10% positivity rate. Okay, 4, 474, which is roughly half of those patients were predicted to have a less than 5% probability of a positive node. And of those, 114 still decided to get the sentinel lymph node biopsy. Okay, so this is so again, they did not all get sentinel nodes. So if you just looked at those group who did get sentinel node, remember, they're not randomized. So we. We don't know if we can say, you know, they are. You know, the unique thing is just that they got the node, maybe for some reason they were higher risk. But if you look at it, among the 430 patients who actually underwent sentinel node, those the test pegged at a less than 5% rate had a 2.6% positivity. So they looked at actually T1 to T4 lesions across the the entire study. So 2.6% of those had a positive sentinel node, and 1.8% of those, if you just limited it to T1 to T2A, had a positive node. Okay, so that's in the group who we called low risk. So the risk was predicted to be less than 5%. And we saw that it was 1.8 or 2.6% in the group where they were predicted of greater than 10%. So the high risk group positivity was 21.4 overall, or if you broke it down, 16.7% positive rate in the T1 to T2A. And so if you look at, like, how did that differ? So having a high risk test made you eight to nine times more likely to have a positive sentinel node biopsy. If we look and then, you know, trying to, like, do some backwards math, because what they did not do here was like, break everything down by T stage. Here's the percent that were considered to be low risk, medium risk, high risk. Here's the number who got sentinel node. Here's their rate. But if we look at the numbers, you know, you could say that in the. That in that group that composed the entire T1 to T4 group, there basically were three patients who had T2B or thicker tumors who actually were predicted to have a less than 5% risk of a positive node. So most of those T2B and thicker patients, their risk was greater than 5%. And so, but of those Those ones who did have a less than 5% risk and then had a. And then had a sentinel node done, one out of the three was positive. So really, although it's not like a statistically high powered thing, you could say a third of those patients still did. Of those predictive less than 5%, 33% had a positive node. Does that make sense?

A (8:13)

I think so.

B (8:14)

Okay.

A (8:15)

If you do have a thicker melanoma and you have a low probability on Castle, you are kind of taking your. The small number. We have said it's not very predictive.

B (8:29)

Yeah. So, yeah. So tumor thickness, I guess like my take home message on that is tumor thickness does still matter. And I would not have the comfort level to say, you know, hey, no worries. You know, you. It says less than 5% even though you got a T4 melanoma, you're good. Right. So that group, a third of them still had a positive sentinel node. Again, it was only out of three people. And then if you took that, that thicker group, T2B to T4, with the, with the. Who had a greater than 10% risk, 27% of them had a positive node. So really kind of the same number. Right. So again, to break that down, your T2B to T4 group, in the less than 5% group who got sentinel nodes, 33% of those were positive. In the greater than 10% risk group who got sentinel nodes, 27% of those were positive. I would argue those are two very similar numbers. So back of the envelope math. But it didn't seem like this did a good job of stratifying for those thicker tumors. I'd love to get all the data, data and numbers and look at it.

A (9:36)

As you can guess, back of the envelope math is really the only kind that I do.

B (9:40)

Yes, I know you're a big fan of this.

A (9:44)

Yes.

B (9:46)

So, so basically, if you. Again, a little more back of the envelope or not even this is. This is in the paper map. So the set. The i31 test identified 65.1% of patients with T1 tumors as having a less than 5% predicted risk and about 4.7 of patients with T1 tumors as Having a greater a 10% or greater risk. So, you know, most patients are going to fall in that lower number. Among Those patients with T2 tumors, 21.5% had. Were predicted to be low risk. So, you know, what, what do we do with all of this? It's good because it's a bigger. It is like prospectively followed patients. It is a bigger subset of patients but, you know, they are still primarily patients who have thin melanoma. So they did also have this table where they compared, you know, their accuracy to cpgp, but it's kind of apples and oranges. They're two different study designs. And Overall, Merlin, the Merlin 001 study, which is the other test, they had 1761 tumors. Their sentinel node positivity rate was 17.6% versus like, around 10ish in the casel study. So that's sort of a higher risk group. Only 1.5% of patients in the MERLIN study had T1A tumors, and 27.3% had T1BS, versus like a third and a third. And about half of those. Half of the patients in the Merlin study had T2 tumors. So, you know, strength is size. You know, size matters. Size. Size matters.

A (11:34)

Size matters.

B (11:35)

I set you up for that one.

A (11:36)

I've already staked out my territory that I no longer can under. Can figure out how I think Castle should be used. And I'm relying on the two of you. Does this change anything? For, like, okay, if it's one where you're really not sure, okay. It's reasonable to order. And Pat, I know for you it's the. We should never order it. The oncologist can order it if they want it.

C (12:02)

Right. I'm, you know, if you have a T1A, that's high risk. If A, you have a T1B or you have a T2A, and obviously above, those patients should have a discussion with a surgical and medical oncologist about whether or not they want to do the sentinel node. If they're hemming and hawing and they're like, is there anything else I can do? Like, that would help me. I think Castle's not unreasonable. Right. If you have a low Castle. But I think that's a tricky situation to put those physicians in because that's outside of guidelines. Now you can do stuff outside of guidelines. It's not like you're going to be arrested or hauled away by ICE and deported. I mean, maybe I. Who knows?

A (12:45)

Just don't go to the airport, just. Right.

C (12:50)

It's not an unreasonable discussion. What? What? Yeah, so that's fine. But I think when you. My experience has been when sentinel node is in play, patients just really like that idea of, yes, let's do that test. We can see if my cancer spread. And if I'm going to die for melanoma. It's. It's a misconception that they have, but they often will go for the node and at that point, what. There's no point in doing the Castle test. So, you know, I think Castle is way, way over ordered. I think something like this is kind of encouraging. Like, yeah, there's a specific scenario where it would be kind of helpful. But is anyone going to do that? I, I just don't know that they're going to go outside of NCCN guidelines, which is offer them this node. And I, like, I think I had one patient who didn't even want to talk to the oncologist. It was a 0.9 millimeter melanoma. She was like, I'm not doing that sentinel node thing. Like, I understand it. I don't really like if this is going to metastasize. I'm going to learn about it one way or another. I wouldn't accept the chemotherapy if they offered it to me, but that was like n of 1. Every other patient that's a candidate for sentinel node wants to know.

B (14:01)

All right, let me, let me explain the recurrence resurvival better because I did not do a very good job of it. So I pulled up the figure in front of me. So what they say is that the patients who have a low risk, a low risk, the less than 5% group versus the greater than 5% group, they looked at recurrence free survival, and it was 97.8% in the less than 5% group. And it was 91.1% in the greater than 5% risk group. Okay, so those are different numbers. The group is the, the greater than 5% group does have a higher risk of recurrence. However, what I, you know, what I was trying to say, and I didn't say it very clearly, was that there are far more T1 tumors in the less than 5% group than there are in the greater than 5% group. So you would expect that there'd be a difference, that you would have a higher recurrence rate in a group that has like 91% T1s versus or 50% T1s versus a group that has 91% T1s. Does that make more sense?

A (15:18)

I think so.

B (15:19)

Okay, so basically what you need to do is use it and stratify it by T stage and look at the data that way, I think, to decide where you're going to. Where you're going to use this test.

A (15:34)

So which, what's your. Boil it down into one sentence for me, Ferris. This. Did this, did this study change anything for you?

B (15:45)

No, not yet. Because I don't. I want to see it by what I really, really want to see is the data for the group who I think the hardest decision is for sending making a decision about sentinel node biopsy, which is T1B melanomas. So what I want to know is, can I take just T1Bs because I really don't want to do this with T1As. Can I take T1Bs and can you tell me just among T1Bs with a less than 5% risk, am I truly less than 5%? And can I safely not send those patients for sentinel node biopsy? But unfortunately, we keep getting them all lumped in, and that's what's making it hard for me to know how to use this.

A (16:29)

You know what that's like? It's like the. The research. Did you know what research there is about how bad screen time is for people and it makes you dumb and the brain rot and all that kind of stuff. You know, in all of that research, they never separate out, like, sub stack or, like, smart people stuff versus, like, cat videos on Tick Tock. All. They just. They lump it all together. I'm not. I. I don't know if I agree anymore. All right, It's. That's just. Casel's just doing the same thing.

B (16:59)

No, I just think, like I would say, if you look at the Merlin paper, they actually just break it down by every T stage, show you the numbers, and then you can think about it. Now, their study was a somewhat negative study, meaning that they did not. Their low risk group had a 7.1% positive sentinel node, which makes it hard to say how you would use it. And their T1B group, their low risk was 5.2% were positive. So that again, I would. I want to see them beat. I want to see Castle compared it for T1Bs compared to Merlin, and that would be, to me, really helpful. These are the most challenging times when I'm like, do we really want to be doing a sentinel node? That's where I stand.

A (17:43)

Okay. All right, Patton, what do you got?

C (17:47)

My first six pack is a JAD pre proof article from March 2026 titled US expert opinions on the treatment of Bullis pemphigoid based on guidelines from the European Academy of Dermatology and Venerealogy by Michael Kasperkowitz et al. I'm probably pronouncing that wrong. Donna Colton was a senior author. Ferris, you give your faculty, like, a $10,000 bonus when they get published.

B (18:11)

25,000. Yeah. Yeah.

C (18:15)

Don is buying drinks at the Word.

A (18:18)

We're not cutting that Out Ferris, cut it out. We're not cutting that out.

C (18:22)

I think that's. Yeah, that's a standard anyway, so. So European published guidelines of ANGBP in the Journal of the EADV in 2022. It's a good paper, it's very thorough, goes through how to diagnose and what to look for. There is a table that goes over management recommendations for different levels of disease, like if you have mild to moderate or if you have severe, if you have questions. Cortis, corticosteroid dependent. I don't really agree with the recommendations but they're all like smart European dermatologists. So I, I wouldn't tell anyone that I disagree with them. The. So I was interested to see like how do other dermatologists practice when what they thought about the European guidelines. So surveys were sent out to 75 derms that specialize in immunobullous disease. 46 responded. So for mild to moderate disease, 70% of u. S. Immunobulla specialists would use systemic corticosteroids over topical. I mean that should be 100, but whatever. I mean nobody should be using topical steroids to treat like widespread bp. That European study New England journal of medicine article was like those patients got hospitalized, they had nurses come in and apply clad is all over the body. Like that just cannot be done realistically for in an outpatient sort of setting. I mean they couldn't even pick up the, the amount of clobatazole that they would need. Right. The pharmacy and the insurance would be like, you're not getting like 1,000 grams of clobatazole for the month. So get. Don't nobody use topical corticosteroids. That's a European thing. We're Americans are smarter. We don't do that.

A (19:57)

That's right.

C (19:58)

90% would use doxy over dapsone as a second line treatment. So that's fine. I mean I see this was disagreements like just put everyone on doxy. It's cheap and it might work. And it does work in a patient here and there. And then like why not consider dupy early on? I don't think dupy works really, really great for severe disease or what I would say is severe disease. Like that should be a candidate where you would give rituximab. And when you have rituximab, you know, are you really gonna go with doopie on board? I think that'd be really, really hard to get. Insurances I don't think would cover that. So all sorts of like in Full disclosure, Regeneron pays me. They give me money for stuff. So I could be just totally biased there for sure. Severe BP. 83% of American dermatologists preferred systemic corticosteroids. If you're treating severe BP with topical corticosteroids, don't be treating severe BP. Refer those patients. If severe BP doesn't respond to systemics. 91% of respondents would increase the dose of steroids versus adding topical steroids. So two people actually said, well, okay, if they're on steroids and it gets worse, I would just add topicals. Donna should kick them out of that group. I'm gonna, I'm gonna run that by her. So, yeah, and this is where I disagree. So European guidelines, when they say severe bp, they're like, okay, use a higher dose of corticosteroids and if they don't respond, bump up the dose. There's no mention of rituximab. Like, that's where you introduce rituximab for those patients. Like, you have them on a pretty good dose of corticosteroids and they're not responding. So I don't know, maybe it's harder to get rituximab in Europe than it is in the US So whatever. Steroid but dependent patients. Mycophenolate, Mofatil is the preferred steroids bearing agent over methotrexate and isothioprine. I think that's probably true. I mean, that's consensus of talking with immunobilous people. Again, I would use rituximab. I wouldn't go to mycophenolate, azathioprine or methotrexate. If rituximab is an option. I mean, again, this is steroid dependent patients. You can't get them off a reasonable dose of steroids. Use a drug that's going to let you get them off that medication, the corticosteroids. Rituximab does it better than anything. Recalcitrant BP. Mycophenolate still preferred recalcitrant BP in the US 60% of dermatologists preferred DUPY and 17 said use rituximab. Like, I just totally disagree with that. I think rituximabs has a longer track record. I think it's a more effective steroid sparing medication. So I don't. I would be in that 17 saying rituximab is probably the preferred agent over dupy.

B (22:51)

Do you think you'd be hanging out with the topical steroid people in your 17 or yeah, maybe, I don't know, you guys could all go get a drink together at aed.

C (23:02)

Omalizumab, ivig, amino absorption. That got no votes in the treatment of a calcitrant disease. I do agree with that. I don't think those are very useful medications. Moving on to DUPY specifically, more than half of respondents said they would initiate the Pilumab for all degrees of BP patients, first line for mild disease treatment, refractory patients, et cetera. So when looking at the European guidelines, more US Practitioners found the European guidelines to be applicable versus inapplicable. So it was like not applicable at all, Moderately applicable, mildly, and then the other way with inapplicable. So 67% applicable. They said these guidelines are applicable to how I practice. And 33% said inapplicable. And I'm pretty sure I was in the inapplicable group. I just have a lot of disagreements with what the Europeans recommend. Topical steroids are pointless, right? I mean, don't even have them in the treatment algorithm. Rituximab should be considered way earlier, right? I mean, they have rituximab way down at the bottom, like corticosteroid refract. How do they classify it? They say treatment recalcitrant, BP resistant to 0.75. That's where you start to consider rituximab. Completely disagree. You have severe disease that, you know, so severe bp, that's like the second line. That's where you start bringing rituximab into the discussion. What else? Yeah, there's other tables, bar graphs, summarizing responses. And the only number I want to call out, that was one of the respondents said that they see 120 BP patients a month. Like, no, you do not. Get out of here with that. That was the only thing I wanted to bring up about the, you know, the bit, the characteristics of the people answering the survey. But yeah, I don't know. I mean, do you guys treat BP?

B (25:00)

I only treat like 119amonth, so I don't know that I could be helpful.

C (25:06)

That was you?

A (25:07)

Oh, I have, I have one that I'm treating right now. One there. And we're being very careful to, to taper the prednisone slowly, the same way that it got tapered in the dupilumab trials. Because I think that's the biggest mistake that people make is they're like, okay, I got him on doopie. I can taper them in three weeks. No, you can't. You gotta. No, he can't do it slow.

B (25:30)

Yeah, Yeah. I don't treat that many. Mostly like somebody else is out of town and somebody needs to get in. They're like, we can put you in with this person. I think that's my niche and treating immunobolus disease. But yeah, I, I think like the thing I've learned most from Tim over the years is like, it has to be the slowest prednisone taper ever and that, that's the way to get people better. And I feel like I saw maybe more of these people earlier in my career when we didn't have dupy and we didn't really have like rituximab. And that was the, like, the take home lesson is use some doxy, but like taper them really slowly. Like 5 milligrams a week. I don't know. Is that 5 milligrams every two weeks? What would you define really slowly? Patton?

C (26:19)

I would put them on like max of 60. A lot of these patients are elderly, so sometimes the max is 40 and it, that shuts down the disease and it's too weak. Minimum. I mean, for like, Matt, you bring up a good point. Like regeneron, that, that, that protocol of how to taper corticosteroids. I mean, just really, really good. Right. I mean it's like a 16 week, you know, six weeks. They had them on the high dose. I mean that's actually way higher than what I usually do. 60 or 40 milligrams. And then every two weeks you kind of reassess. I'll usually go down 10 milligrams every two weeks. Maybe 20 milligrams. It like completely melts away in that first two weeks. But. Right. It's two weeks. And that's when you decide, okay, am I going to taper or not?

A (27:10)

So just be based on my no experience in doing this. I go from 60, I go by 20, from 60 to 40 and then from 40 to 20 and then once it gets to 20, I go to 10. So go 20 to 10 and then I go 10 to 5 and then 5 to 0. Now I have no idea if that's.

C (27:31)

But that's, that, that's, that's beautiful. I mean, trust me, it's, it's 100 times better than 60, 40, 20, 10, five days of each.

A (27:40)

Yeah.

C (27:41)

Which is done all the time.

A (27:43)

Okay. All right. All right, moving on to, to my two. So we've got, we've had a lot of serious stuff so far. So first I'm going to throw something out there that is primarily for our listeners who have their own children and are struggling with diaper rash, because that comes up all the time on the board certified dermatology group. Like, I'm a dermatologist. If I can't have diaper rash and I can't get them better. Something came out that was pretty interesting. Green beans. So this was a study out of a medical center where they were having a lot of problems with the diaper rash in their little kit in the neonates. So they figured this out. This is some University of Minnesota. So you put some pureed green beans into the formula. So you start with 30 mls of green bean into 8 ounces of formula, and then you slowly ramp up how much green bean you're putting in the formula. And that there's some fiber, and so it makes their poop a little bit less runny, and it probably slightly acidifies their poop because whenever you metabolize the fiber, it makes some short chain fatty acids. And when the poop's a little more acidic, it reduces the activity of the proteases in the poop. And they've been doing this for 12 years at this institution. They think it really works. Just never heard of such a thing. So that one. That was a nice, easy one to put out there. I might. Neither of my kids ever had any diaper rash. You guys ever have any diaper rash problems with your. With your kids? Do you remember back that part?

B (29:19)

I remember, definitely. And no. Did you, Patton?

C (29:23)

Yeah, yeah, my kid had sensitive butts.

B (29:26)

Okay, here's my theory is that I like.

C (29:29)

I like any paper where Matt can say the word poop, like, seven to 10 times. That really brings the discourse to a level that I think people expect from this podcast. So. Bravo. Bravo, Matt.

A (29:44)

Thanks, man. Thanks.

B (29:45)

Okay, my theory is that having a working mom is associated with lower rates of diaper rash because we send our kids to daycare, and my kids at daycare, like, there was like a chart, and they got a diaper change every two hours whether they needed it or not. And I would have never done that at home.

A (30:07)

At home, they get them once every eight hours whether they needed it or not. It's a totally different type of whether they need it or not.

B (30:16)

Yeah, yeah. There's just competing priorities. If you're at home at, you know, a daycare, they're just. They're doing it.

A (30:23)

I like that. All right, my second one. This one is more of a mechanistic interest. So now that everybody's gotten, you know, approvals for chronic urticaria now people are going after inducible urticaria, Sindhu term we use chronic cind, inducible urticaria, Sindhu. And so dupilumab released their results and it does not work at all. Literally nothing. So 82 people randomized exactly the same response rate than the people who got the DUPY versus duplicate people who got the placebo. On the other hand, remibrootinib and barzilivumab or barzo something both seem to work very, very well for sindu. Specifically, in this study, they did cold induced urticaria, but that's usually the marker for sindu. And it, it mechanistically makes sense because, you know, we think DUPY is somehow working through reducing Th2 activity. So the mast cells have the, the IL4 receptor on them. So DUPY binds directly to that and dupy reduces the IgE level. And in this study, it did reduce the IgE levels, but it had no impact on the Sindhu. And that, that makes sense because we think that, you know, the way that I think about all of the, the physical urticarias is not that you're. It's not autoimmune or allergic. It is literally your mast cells being too sensitive. So that like if in demographism it's the scratching causes them to pop and it's cold makes it whatever. So it just made sense that DUPY doesn't work for Sindhu, and it does not. And it. That does make me wonder, and there's no data on this, if a reasonable way to try and predict who's going to do well on doopie versus who's not would be like, do they have any physical urticaria type stuff? Like, do they have CSU plus dermographism? Do they have CSU plus some cold urticaria? And if they do, maybe that makes it less likely that dupy's gonna work. That's. That was the, the takeaway, but just interesting, that's all.

C (32:38)

Yes. And just for the listeners, it's Barzol volumab. I don't know what you, what you called it. I don't think it was that.

B (32:48)

What's the mechanism?

A (32:49)

Oh, okay. Yeah. So barzo, really cool drug. So it binds to the C kit receptor on your. So it just literally kills all your mast cells. But. And it's phenomenally effective for urticaria. The thing that's fascinating about it though, is it makes your hair turn white and it makes some people get spots on their skin. So these, they're not fully depigmented but they are very noticeably hypopigmented. Then when you drug their melanocytes come back. What I've always wondered is why don't we see people getting meningeal signs? Because we always learn about you've got those meningeal melanocytes or retinal stuff like why are people going blind if it's getting all your other melanocytes?

B (33:36)

I'm going with it has to. It doesn't penetrate the blood brain barrier because it's an antibody.

A (33:43)

Fair. That seems. And I guess the eye, the retina is also immune immunop privilege site. Okay, so there we go.

B (33:52)

What was I going to ask? I had a really great question to ask you. Oh, why don't we use it for mastocytosis?

A (33:58)

I bet we will. But they, they'd be out of their mind to go after mastocytosis as their first indication. I think, I think it will work great for mastocytosis. I think it's going to work great for a lot of stuff. I think we're going to, I think we're going to find out that mast cells are involved in a lot more than we realized. That's, that's my guess.

B (34:17)

All right.

C (34:18)

I want to say like the abstracts I read when they're looking at Sindhu with Barzil volumab like colder to carrier. It worked. Okay. It worked. It worked.

A (34:30)

Yes.

C (34:30)

But they, they had a comment of it was also studied in dermatographia and I don't it from the way they phrase like this little abstract report it almost looked like maybe it only worked for cold urticaria and not dermatographism. I could be totally wrong. Whereas Remy, they specifically I think said cold dermatographic and cholinergic and, and Remy showed benefits in awe.

A (34:59)

Interesting.

C (35:00)

Don't know the, the AAAAAAAI just had their meeting and so there's a lot of abstracts like coming out of that meeting about the CSU stuff. It's very, very exciting.

A (35:16)

It's. I will say dermagraphism is hard to study. So we did a dermagraphism study and you get this little dermagraphometer that is like a little looks like a credit card that has different length little pegs sticking down. So then you run that across their skin and you see which like how long do the pegs have to be for it to matter? Yes. All right, let's move on. Ferris, what do you got?

B (35:41)

All right, I'm continuing on the urticaria train. So my next paper was recently published online in JAMA Dermatology in February of 2026. Dupilumab in patients with CSU Phase 3 Liberty CSU CupID randomized clinical trials, Casal et al. Okay, so they say, interestingly in the intro that even with up to fourfold second generation antihistamines, about half of patients are still, you know, symptomatic. Miserable omalizumab gets about 6, 70 to 75% of those H1 refractory patients to complete control. But there's still this unmet need. So that's why dupilumab. And so this is basically like a replication of the Liberty CSU Cupid. A study which I know you all remember because we covered it in the, in the, in the past. So this is a phase 3 omalizumab, naive H1 antihistamine refractory patients. And so, so Cupid C was basically designed to be similar. So 24 week multicenter randomized, double blind placebo controlled phase 3. In patients who had never had an IG Anti IGE and who were still symptomatic on fourfold H1 antihistamines, these patients could be down. They looked as low as 6 years old, 6 to 80 years of age. They had to have a UAS 7 of 16 or higher and a itch severity score 7 of 8 or higher. So that's like the standard stuff that they're itchy and they do have active hives and they basically background H1 Anahistamine could be continued. They were randomized to DUPY or placebo for 20 weeks. It was that, you know, the weight based regimen we know, which when I heard Matt give a talk, he's just like, just look it up. So look it up. I also have to look it up by age and et cetera. Thank God. I mostly treat adults, so it's not that hard. Primary endpoint ISS7 or UAS7 depending on the regulatory region. And they were looking at change in baseline. And then they also looked at some things like, you know, were you a good responder? Which meant a UAS less than 7 or a ISS reduction of 5 or more. So 151 patients randomized, 60% of them had a UAS 7A greater than 28. So that's like considered severe disease. And they were at 24 weeks. The placebo DUPY beat placebo for itch and urticaria. So the ISS 7 least, you know, the change was basically 9 minus 8.6 in the DUPY group, minus 6.1 in the placebo group. So not this huge spread, but they were different. UAS7 went down by 15.9 in the DUPY group, 11.2 in the placebo group. So then the other thing that they did was then they also like did a combined analysis where they included the cupid A and the cupid C. See, so what did they see? Similar things, basically that there was a Greater reduction in UAS7 and ISS7 in the DUPY group versus the placebo group. And if they looked at the percentage of patients who got to well controlled, it is roughly like 43% of patients on Dupy versus about 23% of patients on placebo. So that's a UAS 7 less than 6. Complete control, which is basically no hives, was about 30% of patients on Dupy and about 15% of patients on placebo. Another interesting thing that was in here was that they looked at IgE, Total Serum IgE, and they found that it dropped by about 50% in the DUPY group. While what really didn't drop in the placebo group. But they also said, you know, the clinical benefit was seen, like it didn't matter. Your IGE threshold, baseline target or baseline IGE didn't really matter. Whereas with omalizumab, it really works better in patients who have a higher ige. So I thought that that was interesting. So that's kind of all that I had. It was sort of, you know, continuing getting more data. It wasn't anything that was super new, but, you know, sort of doubled the numbers that were out there. Again, a reminder, if you look back at the other study where they looked at, if they look where they looked at omalizumab failures, dupy did not meet its endpoint. So, you know, I don't think this is a good place to go for patients who are omalizumab failures. But it does seem to be, you know, an option for patients, you know, maybe as a more first line, something that's easier to give and more familiar to us as dermatologists.

A (40:55)

Agree. I think I still, I think at this point it's hard for me to, to rationalize not using Rhapsody as our first line in the world, in the world of dermatology, it's just such a safe, easy drug and it's so much faster. You know, you give it two weeks and if they're not better, then okay, that's not the drug for you. We'll move you over to doopie. Whereas if you put them on dupy, you got to give it probably three months. Before you were going to say didn't work like that. The rapidity ofo makes it an easy. An easy catch for me. All right, Patton, what do you got?

C (41:32)

I al. I think Barzo actually did okay in dramatographism too. I want to take that back. I don't want Barzo reps harassing me. I just. I. I don't need.

B (41:41)

You're gonna start getting Barzo hate mail.

C (41:44)

Yeah, yeah, just add it to the pile. All right. My second six pack. A brief report from. From December 2025. Jad, you guys are going to kill me for this paper because it's so dumb. I went back a few months for this one because I think it's an interesting side effect that maybe will shine some light on Hydra pathophysiology. Are you guys intrigued with that little lead in intrigued? All right. The title of the report is Dermatologic adverse events associated with Gamma secretase inhibitor Neurogest. Probably not pronounced right. A retrospective multi center cohort study by Rue et al. Nirago Sestat, brand name Oxivio is FDA approved for the treatment of progressing desmoid tumors. We've all had them. This study evaluated 28 patients at mass Gen and Dana Farber that were treated with that medication. Most common dermatologic adverse event, morbiliform drug. No surprise there. But the second most common adverse event was follicular based adverse events including things like HS, inflamed EIC's KP. So I remember, I thought this was interesting because there was a report about genetic defects and gamma secretase complex genes being affected in familial cases of hs. And so I thought hs, what is gamma?

A (43:03)

What is? What is. Are you going to tell us what gamma secretase is?

C (43:07)

I am going to try.

A (43:10)

All right.

C (43:10)

Based on my 5 minute review of what the hell's a gamma secretase inhibitor. So from what I could tell.

A (43:17)

All right, good. Okay.

C (43:18)

I. Gamma secretase is like by Notch protein, right? So the Notch protein is involved in keratinization, follicular type things, maybe some immune things. And for Notch to work, something binds to it and then the gamma secretase comes by and like clips a internal portion of Notch, therefore activating it and letting it do what Notch does. And so when you block that, Notch can't do what it does, including things like follicular and differentiation keratinization. So the fact that you have this drug that blocks that and HS is a side effect. It's not a lot of patients. But like that's a weird Side effect. Right. And then there's also this familiar form of HS wherein the patients have a defect in the gamma secretase gene. I thought maybe a drug that could stimulate. That would be a good target. But then I like read some more about gamma secretase back being actually elevated in some HS lesions. And I don't know. I thought it was worth mentioning. I thought it was an interesting thing. And it kind of put the gamma secret test. Like maybe something with notch is the root cause of hs. And maybe someday that'll be. And people will be like, I remember the derms on drugs. People talking about that. They're visionaries.

A (44:46)

Is it not? Somehow I want to. When you say knots. I always want to put wint w n T together with it. Was that. I thought.

C (44:55)

You see. Yeah. I have no idea.

A (44:58)

For.

C (44:59)

I was getting confused with Notch and patch. Like patch. I'm like, notch. Isn't that the Basil cell in the evis? But no, that's patch. So is. Is wi with patch?

B (45:08)

Maybe don't learn your basic science from here. Dermatology residents. So is. Is it a. Is it a. Like a protease? Basically,

C (45:21)

it's a secretase. It's right in the name.

B (45:24)

Okay. Okay.

C (45:28)

It seems like it cleaves things. Isn't that what proteases.

B (45:32)

Yeah, it's a cleaver.

C (45:34)

Yeah, it's a cleaver.

A (45:36)

Okay. That's the official dermatolog term for proteases from now on.

C (45:40)

Got it.

A (45:41)

Cleavers.

C (45:42)

All right. That was my paper.

B (45:43)

Move along. Okay.

A (45:45)

We don't have to discuss this anymore.

B (45:46)

I pulled up with Dr. Sayad on also another great UNC physician in department of Dermatology who did identify loci associated with HS susceptibility. One of them is SOX9. SOX9 triggers the activation of matrix metallopretinase 1 and 2. Which is what made me think. Is that like. Is it. Does it all sort of fit together in that pathway? So.

C (46:11)

Yeah. And it's. So the.

A (46:12)

The.

C (46:13)

The gamma secretase. It does. It was like an Asian study. And I think Dr. Syed did his. On like Chapel Hill people. He. He probably expanded it to samples outside of that. But he had two totally different genes. Like the. The gamma secretase didn't even come up in the study that he did. There was one on chromosome 13 and one on 17, I think in Dr. Syed study. And I think that gamma secretase is on chromosome one.

B (46:42)

It is. Okay.

C (46:43)

Kind of different. That's why, like, I was all excited. And as I was reading more and more about this but at that point, I couldn't change my paper. I don't, I don't do that. Once I start working on something, I'm committed.

B (46:53)

You're committed to it.

C (46:55)

Okay, I should be committed.

A (46:56)

I mean, you have been married forever. See, that's a good. Like, I'm like, ah, forget that paper. I moved to this paper. I'll be. That's some divorce. Twice. It just plays it all.

B (47:07)

It all comes full circle.

C (47:09)

Yeah, there's a.

A (47:10)

This is full.

C (47:11)

Makes a lot of sense. All right, Matt, what are your last.

A (47:13)

All right, my last two. First one, just a nice study. That's a follow up from something that came out a few years ago. This was melatonin supplementation in adult patients with atopic dermatitis. A randomized clinical trial. This was in the Journal of Pineal Research. And most importantly, it came out of Iran, my favorite country for come out of. So this is a randomized double blood venture, controlled trial with 80 patients, melatonin versus no melatonin in people who are otherwise getting standard of care. So very applicable to real world. Like they were giving them whatever, you know, topical steroids, whatever they want to give them. And it was actually pretty darn good. So score ad dropped from 31 to 11 in the melatonin group and it dropped from 31 to 22 in the placebo group. So it, it was like substantially. There was like a 60 some percent reduction versus a 30 some percent reduction. BSA went from 6% to 1 1/2% in the melatonin group. It went from 6 1/2% to almost 4% in the placebo group. Pruritus scores same. Like everything that they looked at. The melatonin made a big difference. This now makes three randomized double blind placebo controlled trials that we have that are showing that melatonin makes a difference in atopic dermatitis beyond just that. They're sleeping better. The other thing that I dove into a little bit for this is people will often ask me, oh, but I'm worried about taking melatonin. Is it going to suppress my endogenous melatonin production? And no, it does not. So your endogenous melatonin production is not on a feedback loop. So it, it is purely driven by light, dark. So light, dark cycles are what drives melatonin expression. The one thing that they can't rule out, though, is when you're taking supra physiologic doses, which they did 10 milligrams in this QHS, it might downregulate Your receptors. So even though you're still making enough melatonin, you may not be as responsive to it. So you might get hooked on the melatonin, but that they were like. When I looked this up, my main takeaway was, no, that doesn't happen. It was like, we can't. Like, we don't have absolute proof that it doesn't happen, but people have looked and it doesn't seem to happen. So that was number one. Melatonin seems to work well as we

B (49:44)

know, like the market, like what the mechanism. So I know we don't know a mechanism, but I know in your mind have a mechanism, and I'd like to hear what it is.

A (49:55)

So there was a study earlier this year that showed that taking melatonin affected your intestinal microbiome in a way that increased propionic acid and that somehow improved your cutaneous microbiome. Let's. It's a stretch, but there was. That study came out this year because I had been like, why was melatonin work in those two pediatric studies? There is apparently melatonin receptor is in your skin, so it could be a direct skin effect as well.

B (50:32)

Why don't we just give people propionic acid?

A (50:37)

That's a good.

B (50:37)

I don't know, maybe we need to do that trial.

A (50:40)

That's. We'll see if we can get my. See if I can get my hands on some propionic acid.

B (50:44)

Okay.

A (50:45)

I know how it affects my poop.

C (50:48)

There you go.

A (50:51)

I have my last one. Just this.

C (50:53)

Wait, wait. Real, real quick with the melatonin, I mean, isn't it just related to sleep? And maybe you said this and I, I.

A (50:59)

It could be. It is theoretically possible that it's just that, oh, they're sleeping better. But that's hard. That's hard for me to believe that, like. Okay, it's like, it could be, though. It could be because it's.

B (51:10)

Randomize them to melatonin versus Ambien. Ambien will make you sleep better. Yeah, that's the trial.

A (51:18)

There we go.

C (51:19)

Get addicted, but no problem.

A (51:21)

Yeah, fine. All right. By my last one, this is just kind of a warning one for dermatologists. There's some data that Taiwan the association between gabapentin or pregabalin use and the risk of dementia. Analysis in the National Health Insurance Research database In Taiwan, basically 34,000 ish users matched 1 to 5 to 172,000 non users kind of, you know, propensity score matching whatever hazard ratio overall was about 1.5. If you were on a gabapentinoid. So you were 50% more likely to be diagnosed with dementia. And there was a very clear dose response that the more gabapentin you got, the more likely you were to have to get dementia. And younger patients were the main people at significantly increased risk. So if you were under 50, your hazard ratio was 3.16. If you were over 50, your hazard ratio was 1.3. Big problem with this study, it didn't control for other drugs. So, like, if you're on gabapentin because you have pain, you might also be on an opioid, or you might also be on, you know, other stuff that also affects cognitive function. But it's at least for all the times patients are like, oh, gab, it made me feel like a zombie. Like, we have this sense in derm that gabapentin is a safe drug. It is not a safe drug.

B (52:45)

Couple things. Relative risk versus absolute risk. The absolute risk of dementia in somebody under 50 is very low. So even if you triple it, who cares?

A (52:54)

Damn it. Fares. Stop being the smart one.

B (52:57)

Well, all right, I'm sorry, if you're

C (52:59)

going to keep saying the word story,

B (53:01)

I'm going to have to. Somebody's gonna class this up a bit.

A (53:07)

So judge rules on class. Anybody who says they're classy that abs immediately means you're not classy.

B (53:14)

Okay, well, there you go. Okay, so that's the one thing. So the other interesting thing is, did you all see the study that Shingric's vaccine was associated with lower risk of dementia? So I wonder if pop part of that is that when older people get shingles, what do we do? We throw them on some gabapentin.

C (53:35)

It's a. It's a didn't have problem. Not a gabapentin problem.

A (53:41)

Yeah, yeah. So for anybody out there, Shingrix reduces your risk of dementia by like, 30%. The other thing that's been shown to significantly reduce the risk of dementia being on tadal on as a daily dose.

B (54:01)

Which is Cialis, right?

A (54:03)

That's Calis. Yes.

B (54:05)

All right. I knew you were seeming so bright. Now I wonder why. Wonder why you've been doing the research.

C (54:12)

Perky, as we said. Keep that camera pointed up.

B (54:22)

On that note, I might make you edit that out. We'll see. We'll see. You said it, not me. You can keep it.

A (54:30)

Thanks for joining us this week. We hope you learned a few things. We hope you last once or twice. And mostly we're hoping you're planning to join us next week. Until then. I'm Matt Zyrus.

C (54:42)

I'm Tim Patton.

B (54:43)

And I'm Laura Faris. And we are derms on drug.