Tissue Issues: A Deep Dive into Cutaneous Connective Tissue Disease

Welcome to season two of Terms on Drugs, a video podcast brought to you by Scholars and Medicine, the best educational platform of dermatology and provided in no cost to medical providers. Terms on Drugs is where cutting edge term meets hitter miscomedy. I'm Matt Zyres from Dr. dermatology and each week I'm joined with a residency buddy, Dr. Laura Ferris from the University of North Carolina, Dr. Tim Patton from the University of Pittsburgh. And we use our 60 years of combined term experience to discuss debate and dissect the hottest topics in dermatology. There's everything you need to know to be on the cutting edge of dermatology and you'll hopefully have some fun listening. New episodes drop every Friday on Scholars and Medicine Apple Podcasts, Modifying, other major podcast platforms. And there is a video component that should be available wherever you get your podcasts and it has the key figures and tables from the articles we talk about. So this week we are doing one of our deep dive episodes that I'm so excited about because it is a topic that I do not follow at all so I will be learning lots this week. We're going to be doing a continuous connective tissue disease and we've got Dr. Lauren Graham from the University of Alabama Birmingham. Dr. Graham, great to have you on the show. Hi, thank you for having me. I'm excited to be here. Oh, that's so what is your how did you end up being a connective tissue disease person? Like what was your what was kind of your pathway to where did you do residency and all that how did you pick this all that stuff? It was a long path. So I did the MD PhD program at UAB at University of Alabama at Birmingham had no idea what I wanted to do. Dermatology was not on my radar and ended up doing my PhD work on collagen regulation. And so then I said, oh, what what could be relevant for that and actually anything could right? And then I found a dermatology I tried it. I did a rotation in third year med school and really liked it. And then did a reticent. And then I did a reticent. And I did a reticent. Like one of the world experts for scleroderma guy named Tom Medsker, who I assume he has to be dead by now. We're tired. We're tired. We're tired. So he was there was a, yeah, a looop is person a dramatic person a scleroderma person. Just yeah, really they were great people are is what was her name man Z is she still around? She's a man Z. Does she still have amazing hair? She always had. She does quite very nice. a lot of our. Achan and do I stop talking to her? She's chair of medicine at the competing health with them across the town and fun fact marry to my PhD advisor. Oh wow. And fun fact. I went to the other school across town for undergrad. What what's other school? Oh yeah. I went to do. I have heard of that. Hey, it's a big week for basketball coming up. Go go. It is. It is. I know. Good thing we get to be friends now because I don't know what's going to happen. Come Saturday, Lauren. Well, think. All right. Well, let's let's go ahead and get into it. So Dr. Ferris, what you've got our first paper. What are you talking about? Yeah. So so this paper I picked it's an auto immunity reviews and it is de crap. Sitnib shows superior efficacy and safety and cutaneous lupus erythematosis compared to various biologics and small molecules, a systematic review and meta analysis. So you know, this was kind of interesting because as we all know, de crap is sitting of is not FDA approved to treat cutaneous lupus, but it's a tough it's a tough disease. And so what they did was they looked to see do crap a sitnib, but I had seen some clinical trials, sort of early data showing that it works in cutaneous lupus and maybe it's a little more promising there than it is, you know, so tick two for psoriasis. So you know, so what they did was they compared it up to the other drugs like anaphylomab, litaphylomab, and I hope Dr. Graham's going to fill us in on prononthaliation. I was very used to kinemab et cetera. Do I do it? Okay, good. All right, good. So, okay, so what this paper did was it looked at 53 different studies. Now they weren't all like randomized control trials, 21 of them were some of them were observational series, some of them were even just case reports, when they looked at novel systemic therapies for CLE or SLI with active skin disease, and they really looked at all studies that use the clasis score, and the primary outcome that they looked at was clasy 50, which is at least a 50% improvement in the clasiae. So just to go like the a little quick and dirty about that, the clasiae is the cutaneous lupus area and severity index, and the a is the active part, right? So we all know discoyt lupus, you can get a patient's disease totally quiet, but their skin's not going to necessarily look normal. You're going to have the damage part of it too. So you're really just looking at activity. Okay, so what works sort of the main players that they looked at do Kravisitnib oral selective tick two inhibitor and a pholeumab, and how does that work? It binds to the interferon alpha receptor one and a blocks type one interferon signaling, little philomab, and that is an anti-BDCA2 monoclonal antibody. So what does that do? It binds to plasma cytoid dendritic cells and decreases inner type one interferon activity. Barocetnib, we all know, Jack one, two inhibitor used to kinemab, IL 2312 inhibitor, and then they also looked at some other data on things that were like um um bilimumab, which is a B cell activating factor drug retoxamab. I'm going to be, I'm going to be still activating drug work. Like it seems that you know what the opposite is. So it's itself, I'm sorry, it is an anti-B cell activating amplified bath. So bulimiumab. So it decreases B cell activity. So they looked at some other things like other Jack one inhibitors, but these were sort of the ones that you know that they focused on. Now important to think about. So de-Cravicetnib is like what made the title, right? Like this is look at works, but there was really only one phase two, randomized control trial and patients with SLE with active skin disease, consisting of 91 patients. So I'm sorry 91 patients on 218 patients of whom like 91 were on the high dose, 93 were on, no 91 on low dose, 93 on mid dose, 89 on high dose, and then 45 on placebo. So this is not, it's a big study for lupus 218, but it's not like tons and tons of patients. So just keep in mind only one of the studies actually had de-Cravicetnib. Yeah. Okay, so they used, so they looked, then they looked across you know multiple different studies. So what did they find? So first of all, they looked at like who's more likely to get you to a clasy 50. And so looking at, and they used placebo as their like one for looking at odds ratio. So de-Cravicetnib and an odds ratio of 8.28 versus placebo. Lid of philimab, it was 2.54, an anifroleumab, it was 2.25. So that's how many more times likely that drug was then placebo to get patients to reach a clasy 50. So I often get in trouble when I interrupt Dr. Ferris, but I have a question I have to get into right now because I have no sense of this. So Dr. Graham, clasy 50, like I know very well in my head like okay, this is what easy, easy 75 looks like, this is what easy 90 looks like, this is what passy 90 looks like, like whatever is clasy 50 like, the patient's going to be like, I am a lot better, but I still like, or is clasy 50 like, I'm okay, like what's good at clasy 50? I think that's a good question. And I think it depends on how bad they are to start because it's 50% better. That makes sense. You know, if they're really bad, 50% better is a good decent amount. The standard is that thought that a 50% change is clinically significant. And currently people are working on getting an actual number for the clasy, so that, you know, we can have an absolute number for improvement, which makes a clinical segment. Yeah, but the activity is based on erythema and scale. Okay. So you can have, you can go for from really red and really scaly to less red and less scaly. And you could get to a classic. - Like with so with DLE, it doesn't take scar, obviously it shouldn't take scar in to account 'cause that's what I think is better. - That's the damage part. - Does it take depigmentation into account at all? 'Cause that's-- - Yes, but again, that's on the damage side. - Okay. - The other theme in scale and hypertrophy are on the activity side and then despigmentation, atrophy, those kind of things are on the damage side. - So there's the classy and the clud's cludsy? Like is what's the-- - So there's both part of the class you, so there's classy A, which stands for a classy, A is activity and then there's the D for the damage part. - Okay, all right, all right. - Which part also usually look at the A part, which is the activity. - Okay, so the A is mainly arithema and scaling. Okay, all right, got it. All right, Dr. Ferris, I give you the lesson, you can go on again. - Because-- - Thank you so much. - Because that's what-- - Zero time looking up anything related to lupus. He just brings it up during the-- - My job is to be like our listeners, who like they didn't look anything up ahead of time, so I gotta ask the questions they would ask. Plus, if you've been excused for me to do less work. - Good, that works. - No, I like the idea of like what's a clinically meaningful classy score, so I do a lot of psoriasis. We say like, oh, what percent like treat to target? Like what's a Pazzy, a BSA less than 1% or a Pazzy score less than I think it's like two. So it would be great to have a classy score. If you said if your classy is less than two, that means you really have barely significant disease, whereas 50% of horrible is still kind of bad. - Right, and most of the studies require a classy of at least 10 to even get into trials, but you know, you can have up to 20s and the 30s. You can divide each area of the body into sections and you count those separately. - So since we're gonna keep saying the word classy, I've gotta just put this out there that the best way to know if someone is classy or not is if they describe themselves as classy. The minute you describe yourself as I'm a classy, no, you are not. That is you can't, it's kind of like you can't call yourself humble. You can't call yourself classy. It just, it doesn't work. - It doesn't work. - It doesn't work. - Okay, words to live by. Nothing to do with lupus, but thank you. All right. So the other like little pearls here was they said, well, okay, does do crab is sit, okay, what works better than like used to kidney, Mab? And basically like all, do crab is sit and let a philomeb, and a philomeb, all were significantly better than used to kidney, Mab. And interestingly, bear is sit and nib came out significantly less effective than do crab is sit and nib and let a philomeb. - So we know those things. - Like it's a great joke. We're 0.11 or 0.37. - We know what dose they use because like berries got such a dope like from two milligrams to eight milligrams is like berry seems like it'd be a hard one to meta analysis. Because it depends completely on the dose. - I think when they're doing those odds ratios, like usually those trials have a dose ranging 'cause these are all gonna be like phase two studies. So I don't know that we have that answer, but I'll see if I can. - I think they use two in two grams in four milligrams. - Yeah, so two in four. - Two in four. - That shit doesn't work at all. - Okay. Oh yeah, you're right. There is the little plot. Okay, so yes, that is true. Okay, so then the other thing that they looked at was safety. And basically they didn't really see overall adverse event rate differences and they did not for serious adverse event rates. They really did not see a big difference for like do Kravissitnib or Anna Frolemab or Littofilomeb versus placebo. However, they did show a higher odds ratios of serious adverse events for Barissitnib versus placebo. - Okay. - Ferris, can I ask you another question now? - Knit picking questions. - This one I don't have a thickest two knit picky. Why are you asking? - BMS. - I am asking that. - I'm just following the trial. - Thank you. - Thank you for asking. - So BMS, like is, it seems I don't know the BMS people I haven't worked on with the BMS people. They're the ones who make do Kravissitnib, right? - Why is that taken? - What's wrong with them? They are like, this is a good drug and it has done terribly in psoriasis. It would be a great atopic drug. They never did any studies. It would be like if they had done a lupus study and gotten a lupus approval, like it's like they don't want to make any money. I don't understand. Like have you worked with them at all? Do you know why they are so incompetent? - I have, yeah. So I have not BMS saying you are incompetent. That is my advice, just in case you're listening. No, but so I think it's just a bigger market, right? Like they're not a big skin disease company traditional. If you're like, what are you, that's like, why do you rob banks? That's where the money is. Why do you test your drug and psoriasis? That's where the volume and money is. That is my guess. It is interesting because I actually think this is a better lupus drug than it is a psoriasis drug, right? - It looks like it. - And it's just a more saturated market. So. - Yeah. - Whoever the consultants are that these companies hire, they need to stop hiring them and hire me instead. I would have told you, I would have told you people and they're like, you're out of your minds. Like, yeah, okay, yes, it's a huge market. Oh my God, you could make a trillion dollars. If you can get everybody to give up all the drugs they love already, which. - That are work in our state. - Good luck with that. - Yeah. - I think they are. - I think they are moving to concentrate more in libus. - Okay, good. - Yeah, I've heard that too. And I think that would be great. 'Cause it's also just like an area where we have so much need for something that's easy for us to use and relatively safe. And, you know, so it's obviously not yet approved for SLE or CLE and it's not in the ULAR 2023 guidelines or anything like that. But, you know, I think it's something that is, that looks promising and interestingly, it is, you know, probably looks a little more promising than some of the drugs like anifrololeb, anifrololeumab and litofilomab that we're actually pursuing. - I'm gonna try to say that again. - Yeah, don't try to do that. So, you know, quick like strengths, this is a good meta analysis that included 21 randomized controlled trials and also did try to put in like case reports and case series. You know, downsides, one phase two study that was actually in SLE patients where they had a, a, a clasie as an outcome so they did look at patients who had ketanious disease. There's really not many of these were head to head studies. So, you know, it's better to do it from my limited understanding meta analysis. Better if you've got a bunch of head to head and you know, drug to placebo, you know, comparisons. So, you know, other things that were interesting. So, I did take a quick like literally just five minute review of that 2022 paper that SLE do crabocetinid paper. And so, they did look at the doses of three milligrams, BID, six milligrams BID are 12 milligrams a day. So, keep in mind like those are not, we have one, six milligrams, one a day pill of de crabocetinid. So, we don't really have that dose that they looked at available and they did add it to like standard therapy. And why, like you'd be like, well, so what? Who cares if it's not that dose more is better. What's actually kind of interesting is that when you look at their data, it actually looks like patients did better on that three milligram BID dose. Like the 12 milligram a day dose was actually a little bit worse. So, good news is that six milligrams a day and that's what we have, you know, available to us. The baseline clasy, so in the patients, in that study was around eight. And as Dr. Graham just said, for most dedicated loop of studies, you have to be 10 going in. And then if you look at the clasy 50 response, it was like 70% of patients on the three BID, which was the best responder versus 16.7% on placebo. So that's a pretty big difference. So I thought that that was interesting. And then the other thing, and I'm gonna give Dr. Pat and credit because he has far more time on his hands than I do. He actually went on to it and just for those of you don't know, he doesn't work most Mondays. So, which is, so he was able, he even had a whole day to look at this. - I thought that was just between us, but. - And for those who are not watching that video, he's kind of a, kind of a, kind of a deeter look going on. (laughing) I like that, like that. - I like that. - That's nice. - That's nice. - Black. - Yeah. - That's good. - Yeah. - So, but there was actually data on clinicaltrials.gov for a dedicated, do crabocytinib and cutaneous loopist study. And so thank you as much as I like to make fun of you for actually pulling this out of this unpublished data out. So what they did show was that if they looked at the meme, change in Clasie A in this study. Placibo was about 27% reduction in Clasie A and the two doses of de-cravicetin of 3 milligrams BID and 6 milligrams BID were both pretty similar at about 49% change and the percent of patients reaching Clasie 50, 21% placebo, 60% 3 milligram BID dosing and 54% it's 6 milligrams BID dosing. So there is some data. So I'm kind of excited. I think that this will be a good option for a leopus patient. So Dr. Graham, are you ever using this? Are you using de-cravicetin of bauflapal and your ketenic sleep is- We have done it a couple times. As you mentioned, it's off-label. So we have a hard time getting it approved. But when they've failed everything else, we can get it. Or if you actually you know hydroxychloroquine is a risk factor for psoriasis. So sometimes these patients do have psoriatic dermatitis, that sometimes can be a little easier to get because they really do have some psoriatic areas. So I like it. I've had success with it, but I've had success with the other ones too. I think we're in an exciting time for skin lipists. Still, we still have room to go, but it's better than it was 5, 10 years ago. I remember it's like as a resident, whenever he's to manage like a fair amount of this, I still can remember some of those patients where like pretty much it had like plaquenil chloroquine. I was doing a lot of plaquenil chloroquine plus quinnichrin because it was supposed to be more potent that way and putting it together with methotrexate. Stuff that if I tried to do any of that now, I would be like, oh my god, I'm so terrified of it. I mean, we're still having to do it, unfortunately, but less so, which is nice. Okay. Okay. All right, Pat, what do you, what do you got over there? All right. My deep dive paper was based on the exciting announcement made by the FDA January this year, granting breakthrough therapy designation to Lidofilomab. They're making Lidofilomab great again. That measles. Yeah, the article is titled Lidofilomab efficacy on skin outcomes in cutaneous leopards, the erythematosis in the phase two lilac study by Wuerth and Marola at Al. In the intro, the authors point out medications like hydroxychloroquine, methotrexate corticosteros, mycophine, like quote, fail to provide satisfactory efficacy and have sub-toxicity concerns. Sure. You can see how biogen is downselling all these drugs that we used to treat lupus. Nothing is FDA approved to treat cutaneous lupus as a stand-alone disease and as germs, we see that fairly frequently interferon 1 seems to be playing a significant role in cutaneous lupus, hence the efficacy of anaphylomab and antibody which blocks type 1 interferon receptors. Where does that come from? Plasma siteoid dendritic cells or PDCs as cool immunologists probably say. I would know I'm a cool dermatologist, not an immunologist. Lidofilomab is a humanized monoclonal antibody binds to the BDCA2 protein. That's the blood dendritic cell antigen on plasma siteoid dCs that inhibits them. So back in 2022, New England Journal medicine published results from a phase two trial called lilac. I do you guys remember that? I sure as hell don't. That was like CLE dedicated. Three different lidofilomab. I think we looked at doing that study at pit, which was probably the main reason why I didn't remember when that came out. It seemed like a big deal and I totally off my radar. So the deep dive paper basically goes through that exact trial. They didn't redo any trial. They just went back to that lilac. I think that was the lilac 2 trial. Lilac 1 was on systemic lupus. So lilac 2 trial and they looked at some additional skin specific outcomes. So I mean it was a ton of data. I guess I don't want to go through all of it. So we'll go through the first one. So proportion to patients raising, Clasie 50, Clasie 70 at each time point. And they followed the patients out to week 16. These patients, this is sub Q. They got doses at zero week zero to that was kind of loading dose. And then it was week four week eight week 12. And then they followed the patients out to week 16. So looking at Clasie 50, which is the clinically meaningful. This data was already published, but it was only the highest dose, the 450 milligram dose that reached statistical significance at week 16 at week 12. All three doses reached statistical significance compared to placebo. But for whatever reason, and it was weird, the placebo group got better from week 12 to week 16. And it made the other two doses not statistically significant. Whereas the 450 dose was Clasie 70, which is really, really hard in most studies. I don't think even look at this. The 150 and the 450 milligram dose was statistically significantly superior compared to placebo. Do you have any sense of like how far this drug is from like being on the market? Yeah. So it's in phase three studies right now. And full disclosure, I am a PI. That's one of the we're a site for that study. But yes, I mean, they're moving for they're in the phase three. You know, obviously they're still gathering data. So there's been no data published on the phase three. But I mean, the phase two look good. And one thing I want to point out was the week four that the drug works fast. And they saw a difference at week four, which is exciting. So here was, but this is what I was thinking, looking at the Clasie fit. So figure one B, Clasie 50. And if you look at placebo, like it goes up and up and up and up and up. And as we know, like this is not placebo, these patients are on like maintenance. Do you think like is it entirely possible that patients say that they're on a stable dose of hydroxychloroquine because it had to be stable. It had to be like stable therapy, like a 12 week wash in or something like that. Do you think they enter a trial and they just start being more compliant with her hydroxychloroquine? And that's why you see this nice little rise in the placebo from week two to week 16. How, how much of having the patients take through other medications and maybe being more compliant with those medications, do you think that interferes with maybe some of the data? I think that's a really good point. And that's something that we talk about in the industry, both in for Lupus and Dermatomyitis, is you see a big placebo. And as you correct, it's not really placebo, right? They're on baseline treatments. I think rarely these patients are on nothing else. They're almost always on something. So placebo is probably in not the right word, but let's just use it because that's what it says in the studies. But there's a big placebo effect in these trials. And I think you bring up a good point. A lot of these patients aren't always very compliant. They've been sick for a long time. They get sick of their medicine. So there, I think there is an element of that. I do think there's a little maybe rater element to, you know, it's subjective. You're rating, is that deep red? Is that red? Is that pink? You know, so it's in it's a numeric scale and, you know, skin of colors harder to do than light skin. Also, these diseases have been flow with the season. And, you know, the clinical trials are rolling all year wrong all year long. So you think that would level out. But, you know, there is some availability with ebbing and flowing and autoimmune diseases too. And Dr. Pat on behalf of my good friend, Steve Feldman, I've got to give you a shout out for, for blaming it on changes in adherence, which is exactly Steve. I'm sure, if you're out there listening, Steve, I'm trying to, trying to channel you. He would fully blame this on, on exactly what you described that when people are coming in frequently for visits, because he's shown that repeatedly that when, when people come in for visits, regularly, they are much more compliant with anything. And so he would certainly be 100% on board with that idea that their background therapy, they got more compliant with. Right. Yeah. We were always taught during residency, like hydroxychloroquine is not fast acting, right? Like you tell the patients, you may not see a difference, like you may not start to see a difference until you're at least three months in. So, so I wonder if that played into that week for you don't see much. But, you know, in the placebo, but it does actually get better week 16. But in any of them, figure two shows that a higher proportion of patients receiving, Liddy reached clear or almost clear skin. I don't know if any of those are statistically significant. They don't have any little little asterisks above the little bars. And the paper says, quote, more participants achieved clear or almost clear skin status at week 16 with Lidda philomab, 22, then with placebo three. But like, why percent like that? There were like 94 patients in the Liddy groups and 32 in the placebo. Like, why would you do absolute numbers? That bothered me. All right. Some of the supplemental data percentage is a patient with a seven point or greater decrease in the clasis scores. And like it, you know, statistical significance kind of varied when you got to the very end of week 16. It was only the 450 milligram dose where you had a statistically significantly higher proportion of patients received or that dropped seven points in the clasiae score. So that's another one. Like, if you drop seven points in the clasiae, is that like a big deal, no matter where you start? Like, are you like, oh, that is a noticeable difference? I think so. Yes. I think that is a clinically significant amount. Like I said, they're still doing the studies on the help exact numbers, but just from experience, experience that can make a difference. - They broke down patients. If you had a low classy at baseline, so you had to have at least a classy of eight, but then they broke it up into, well, if you were less than 10 greater than 10, if you had systemic lupus with that, or you didn't, if you had discoid lupus or not lupus, but like the Littofilomeb kind of numerically did better than placebo in all those groups and just varied in statistical significance. I mean, it just didn't seem like, the only one was if you were greater than 10, all of them were statistically significant. Like it seems to work better for worse disease. What's I guess kind of makes sense? But all the other stuff with or without SLE, with or without DLE, nothing really jumped out at me as like, here's where it seems to work better. - I think it was that paper where it seemed like the group that did not have DLE, maybe their skin did better, so it's sort of like the SCLE type patients. Did that, I think those numbers-- - What did you take away from the grouping? I mean, it was small amount of patients, so I think-- - It's a small number. I don't know. Lauren, do you think SCLE is easier to treat than DLE, or is it easier to score? I mean, it's probably easier to score. - It's definitely easier to score 'cause you're just judging the Ayrothema and they don't have as much hyperpigmentation kind of within it to make it harder to see the Ayrothema. So I do think it's easier to score, and then you don't have as much damage afterwards that kind of masks the Ayrothema. - Okay. - Can I almost say that, sorry, that, when your score is lower, it's harder to see a difference. So is it actually better for more severe disease or is just the scoring system better to see a difference with higher numbers? - Is it set up like passy and easy, where it's like zero to 10% of that body area, 10, 11 to 30% is two-point like blah, blah, blah. - No, it's just what the area of the body is, and then what's the most red or most scaly of each of those areas? - Okay, 'cause it gets definitely true that easy gets way less sensitive to change at lower BSA. Like that's one of the, it's like a terrible measure of disease activity. If you're starting with less than 10% BSA, and so, okay, classy is not quite as bad in terms of BSA-ness, but it sounds like it may be in terms of severity of redness and those kinds of things. - So Pat, what's the safety profile of this stuff? So it should be that it causes herpes infections out the wazoo. - You know what, I don't know. Like that was a, I think that's a signal for Anafrolemab. I don't know that there was an adverse event that was like specifically concerning for a little philomab, but there was so much stuff going through this. I don't even know if I like focused on that. I, one of the most interesting tables was in figure four and the supplemental stuff. And it was like the physicians global impression. So this was like, did the patients get much improved, moderately improved, slightly unchanged, slightly worse, which is probably what we do in real life, right? Patients come back and you're like, oh my gosh, you're way better. I think you're a lot better. Look at this before picture or whatever. So it's kind of subjective, but I think that kind of relates to how we practice. So the top two rankings, much improved, moderately improved, all right? So at week 16 for the 50 milligram dose, 41.7, much in moderate improved, for the 150 dose, 60%, for the 450, 46.7, and for placebo, 44%, like it was better than the 50 milligram dose, really close to the 450, the 150 just overall, that they seem to be just a better responders overall in the whole study, but that really jumped out at me. How, like physicians global impression, is that something where you're like, that's the hardest part to interpret from these studies, or do you really feel like that's a useful sort of metric to use? - The first, I'm gonna jump in first, Steve Feldman, who again, one of my favorite guys, has published the three-point dynamic global assessment with the, as an outcome measure that he strongly endorses, which is, are you doing better? Worse, are the same. Those are the three points of the three-point dynamic global assessment. So yes, that is exactly how we practice. Okay, now shut up, I had to put that out there. I think, I, you know, I think the FDA for a while is requiring companies to have an IGA, which in then I think now they're starting to go back to less the IGA is what I've been hearing. I don't wanna speak for the FDA, but because I think sometimes it is hard, unless you're staring at the pictures from last time and staring at the pictures from this time, sometimes it's hard to know if they're better or worse, if it's just an incremental change. - Yep, so Dr. Graham, any side effect issue, so the reason I said they probably should get herpes out the wazoo is that, that is what interferon is highly relevant in all herpes viruses. That actually really interesting side note, they just showed that patients who get exome herpeticum are much more likely to have auto antibodies against interferon. So they're basically neutralizing their own interferon and that puts them at high risk for exome herpeticum. But maybe it comes from something other than blood plasma, cytoid, whatever's. Yeah, so Dr. Graham, any side effect issues that you are aware of with this drug? - There aren't any large side effects that in a phrylamab studies had definitely had herpes signature and they do recommend this officer vaccine before an interferonumab. - Okay, all right, Pat, anything else? - There's a lot of other tables, but I'm willing to call it there. I think little phylamab, like numerically looks like a better drug. I think a larger study, he probably do start to get statistical significance, but man, like it's like the anaphyromab study on systemic lupus. I thought this was the funniest thing. So the first, they had like a lie, no, a tulip, tulip one study for anaphyromab and systemic lupus. The primary endpoint placebo did better. - What? - Yeah, it was like 40% of placebo versus 36 of anaphyromab met the primary end. - For SLE. - SLE. - Yes, for the health. - Yeah. - And you even use for an endpoint in SLE? Is it like, - Well, that's the difference because-- - There's like, lead out. - Yeah, there's a lot of rheumatology, sleigh day or sleigh day and a couple other scoring systems for SLE includes arthritis, serocytus, pleuritis, lupus cerebritis. - There's a lot of stuff in there. - Yeah, they went and did a tulip, two trial and they're like, forget that primary endpoint. Let's do the primary endpoint where the secondary end points in the first trial looked good. And they read the study and that's how they got the approval. That's my understanding of the anaphyromab history. So anything else with all the data in that paper, Dr. Graham, that jumped out at you. - No, I think you did a good job. There's a lot of data in the paper. - Yes, I was like, - I'm fat and fat and-- - I think they're excited about it. Like we've said, there's nothing approved for Coutanus Sleibus. So it's exciting that there's anything that shows that it's helpful. - Yeah, yes. So all right, let's go on. I got two, one, the first thing I want to go over just relatively quickly. So since, I don't know how to say it, an ifrignol note-- - Anaphyromab. - Anaphyromab. - Did they make it in Iran? - That would be Iran, you pull a map. And they did not. - For anybody who's not a long time listed, I frequently get mocked by Pat and Ferris 'cause I can, I don't say it the correct way. Say it the right way. - No, no, no, I would say here. Yeah, no, I would say you say Iran just fine. You pronounce it like an American does and there's nothing wrong with that. We don't call France France. (laughing) - Okay, sorry. - All right, all right, sorry. - So this, this, the, an ifrignol note. So this was one of the studies that looked at a fricutaneous lupus. It was a retrospective study where they were, they looked at a bunch of patients. When I say a bunch, like a fair number, I think they had eight maybe, they got treated with it. And whenever you looked at the classy scores in figure one C, it was like insane. Like this had to be a 80% drop on average. I mean, these people just did incredibly well. And I think I have this job. So I've heard, been sitting in on a few lectures where people have been talking about using this drug in cutaneous lupus patients who have SLE, so you're able to get the drug covered. And they're like, oh my gosh, it is like miraculous. How good this stuff is. So I definitely want to, since it is like an FDA prescribable drug, if somebody's got SLE, I figured it's worth talking about. Certainly I have no experience using it. So like Dr. Graham, what is your take on? 'Cause like it wasn't, this was like a patience of data. It's like, no, sorry. Yeah, there's more patients. They went back and looked at the classy scores of the patients in the SLE trial, and they looked really good. So we've been using it a lot. So a lot of us that are in room during clinics, so I do combine room during clinics so I'm with the rheumatologist a lot. Any patient who has systemic lupus, who's skin is not under control. The first thing we're giving him is anaphyllumab, and it works really well. It works really well. And it works fast. What's his name? Seth Nello, that's easier to say. It's not that much easier to say. What's it like? I'm sure. [LAUGHTER] It's a little easier. But yeah, it looks-- I mean, in real life practice, it looks really good. Patients love it. They don't want to get off of it. There is an infectious signature for sure, and so you do have to be careful of that. But patients are really good. This is going to turn lupus on its head for us, because remember how people would have cutaneous lupus, and we'd be like, you don't have systemic lupus. Like, stop it. Stop worrying. Now we're going to be like, I think you also might have systemic lupus. We can get to that. It's in clinical trials. It's in clinical trials right now for a sub-Q version. Because so this was the systemic lupus was IV, but they're studying it in sub-Q right now for cutaneous lupus. If that's in trial. I actually read over in Europe as of December 2025, they approved the sub-Q dose. And it's 120 milligrams a week, whereas the IV is 300 monthly, is the sub-Q dose different than the IV? Like in terms of efficacy. No, like dosing it. Like you give the IV 300 milligrams once a month, right? Is that the dosing? Yeah. Is the sub-Q trial 120 a week? I do not know offhand. I'd have to look that up. I don't know. So do people get both Herpes and Zoster in it? Because so-- like I'm a believer with Jax. Everybody who has AD and goes on a Jax, I put on Valtrex. Like I don't care if they get Herpes, Shingles vaccine or not, because I'm way more worried about exomeherpeticum than I am about Chingles. And the Shingles vaccine is not going to protect you at all against exomeherpeticum. So I put everybody on Valleysycliv here. Now, I assume that there's not like a lupus herpeticum. So it's not like a disaster if somebody gets a cold sore, the way that it is. It can be an atopic germ. But do people get both more frequent Herpes things? And I guess every-- like do people have to get vaccinated for Zoster before they can be in the trial? The recommendation is to get the Zoster vaccine before you start it. Did they have-- So you start the IV? So in Ford trial-- Since a lot of them are going to be younger than 50, do they have to get-- if they haven't been vaccinated, can they be in the trial? Or do they have to get vaccinated before they can start? That's a good question. I am not a PI on the trial. So I don't-- Yeah, I wouldn't know either. But you-- and it shouldn't be broadly immunosuppressive. So getting vaccinated while you're on it should be completely fine. OK, that's useful. So could you see it as a drug that germs like normal dermatologists could be using someday? Or do you think of it as a drug that's only going to be in academic centers and combined clinics? I would hope, especially if a subcue version is approved, that hopefully dermatologists would be comfortable with it, especially if the safety signature continues to be relatively safe. I think the dermatologist always take a little bit longer to adopt things, although now with all our shots available for psoriasis and atopic dermatitis, I think we're much quicker to adopt than we were maybe 10 years ago. So I hope so. I think to be determined, but I hope so, because at least the IV version looks really good in this skin. So I'm hoping the subcue version looks as good. OK, Pat, and what you made me think about is we need to start working on how to coach our patients to go to the rheumatologist and be like, yeah, I get mouth-- I don't have any today, but I get mouse hoors all the time. And yes, I have my-- oh, my joints, they hurt so much. It's terrible. I can't-- I can't remember what all the criteria are, but we got to work on coaching them up on what to say when they go to the rheumatologist so they can get on the good stuff. Yeah, so Dr. Grant, you may not want to admit to this on air. And you can just plead the fifth if you don't want to say, are you selling these patients on having SLE? More than you think you may have done at the time. I would totally be like, so if you had-- if you tell me you get this, I can put you on this really great drug. And if you tell me you don't, then I can't put you on it. So do you want to tell me you do get it? Like, that's how I would be asking. Yeah, I think everyone's different. You can have a positive A and A. You can have a positive A and A and still have just cutaneous lupus. But that-- When the 40 spec hold it, you've got it. You can have arthritis, joint pain. So I'm not going to speak for other people, but I do think-- You've been thinking-- You carefully go through the criteria. But I will say, I think if anything, this tells us we need to own cutaneous lupus, right? So patients don't have systemic lupus. Again, right now we have nothing FDA-approved. But if we do get things FDA-approved cutaneous lupus, I think the dermatologist really need to be empowered to take care of it. OK. We've talked a lot about therapy for lupus. Anything new in the diagnostic realm. Obviously, there's the clinical aspect of diagnosing at you. You do biopsy. We check double-stranded DNA and A and A and both. Like the stuff I learned in residency 20 years ago. Like, dermatomyositis now. You do all of this testing. And we'll talk about-- we're going to get to dermato after this. But anything that-- like I should know about diagnosing lupus that I don't-- no, is it still your order of the same labs you've always ordered? I don't think there's anything. There's not much new things, unfortunately. I think the biggest thing is just recognizing the difference between lupus and dermatomyositis. Yeah. Because a lot of the dermatopathologists just say interface and people assume it's lupus. So if you do a good clinical exam, make sure it's not dermato. OK. So we're going to jump over just one quick paper on dermato. And then we're going to talk a little more in general about dermato. So it was a paper looking at a premalast and dermato from a long time ago. This was like-- this was published like 10 years ago, I think. Or published in 2022, so about 10 years ago. But the trial was done a pretty long time ago. And obviously, nobody's ever going to use a premalast for a ketanist dermatomyositis, because you're never going to be able to get it covered. But the takeaway is it worked pretty well. And so based on this-- right, so they had a very good reduction in the cadassie, the cutaneous dermatomyositis. Yes. You did. OK, see Dassy. OK, that's better than cadassie. So that had a pretty good reduction in cadassie or seedazie. And then whenever they stopped the drug, it looked like people got worse again. And so based on this article, I've been using oral reflumalast. And so I can't go an episode without talking about oral reflumalast. So that has now become my go-to, because I actually take care of a fair amount of amyopathic dermatomyositis patients because they would get referred for patch test clinic because it was a pretty non-specific rash. The biopsy for cutaneous dermatos, often like, oh, there's a little spongiosis, a little interface. So people would send it for patch testing. And I'd be like, you don't need patch testing. You've got dermatomyositis. And for years, I was always using methotrexate and microphenylate. But I have now moved over to reflumalast as my first line for all of these people. And it seems to work pretty reliably for me. So Dr. Grahamwood-- so generally so first, what are your go-to drugs at the moment in normal cutaneous dermato, not like horrendous-- you've got real dermatomyositis and your week and the blood-- but like the people that we as derm see, how are you approaching cutaneous dermato? So I think it depends on how, like you said, severe they are. Thankfully, we do have one thing that's FDA approved for a dermato, and that's IVIG. So I do use a lot of that, especially if they're bad, or can't get anything else under control. But I do use-- Like how good is IVIG for the skin aspects of it? OK, good question. It is good. It's not perfect. It can definitely get people better. Sometimes they still have some leftover disease, but it gets them to a place where they can almost-- with they can tolerate it. It's not always getting them clear. We still use methotrexate. We still use mycophenylate. There's a new phase three-- there's a phase three trial that had very good data called Repacitinib, which they're hoping to get to the FDA soon. So that hopefully-- What is repacitinib? --it's a tick to Jack one. OK. So that-- Yeah, so that's a novel-- Compos. --law of the wool. And so I'm hoping that's going to be-- You know, 2026 maybe early 2020. 97 is what the company is saying. So that's exciting too. How nervous do you get with IVIG? So my take, because I haven't prescribed IVIG since I was a resident, but my takeaway was that like you, you can get some hyperviscosity. Like if there is some cardiovascular risk with IVIG because when you dump all that protein into their blood, they can get a little thicker or a little, maybe they're like, there's an increased risk of heart attacks and strokes and that kind of stuff. Is that still like people think that or? Yeah, so it's all a label increased risk of VTE, but there's been some studies have been done. Both interest or minimize side us and in patients who are on a jack and dramatic because that's another one that people are starting to use jacks off label. And there was not an increased risk of clots being on IVIG versus something like prednisone, right? Yeah, yeah, yeah, yeah. The cardiovascular events for prednisone and clots on prednisones up there too. So do you see your, so let's assume that 20, 27 at the latest, tofacidinib is going to go generic and we'll be able to start prescribing tofacidinib for these people because right now, trying to get somebody on a jack for anything other than an approved indication is so hard. Do you see yourself using tof, if it's easy to, if it's generic and cheap and easy to get, do you see yourself using tof or, you know, because if any of the jacks have a real risk of Mason VTE, it's, it's tof, like, do you see yourself using it? Yeah, I've used it. So yes, the dose, you know, it's dose dependent. So the lower dose has less risk than the higher dose, the 4mg BID. But I have used it because I've had patients who are so bad, they're developing calcinosis. We can't get them under control. And there have been lots of papers published that tofacidinib can help. It's not, it hasn't worked for all my patients, but I've had success with a lot of them. And so yes, but I'm hoping this new repacidinib will be better than tof with less side-effect risks. And then some people are using a patisidinib to off-label, obviously. This is a matter of getting it covered. We should get some on the bafsi, like, that's exactly right. Overlapped ADDM, right? It's all good. So the, are your dramatic workup at this point? So Dr. Patton has done a few articles over the last year or so about like the scoring systems to determine how likely somebody is to have malignancy. I remain like, well, the first two years after you got your rash, then we're worried about it after that. We don't care. What is your rule of thumb for deciding how much to work somebody up for malignancy and when they've got a cutaneous dramatic? Yeah, so that, you know, the new paper and the guidelines came out for the the International Myasidus. Is that the one that you reviewed? That's where we cover. So intermediate high. Yeah. Yeah. And so, dramatic. Myasidus was under the high category, no matter what. So I do all my I do all my patients. I do all the cancer screening yearly for three years. Three years from onset of rash or three years. So say they've had it for four years. Yeah, onset of rash. Yeah, four years. They're like, man, nobody ever frigid this out. Now they sent me to you and you're like, oh, you got dramatic. Oh, you've had it for four years. Okay, we don't need to worry about like cancer. Is that how you approach? I would still probably do at least one time full screening. It would make me feel better to give in. Like you get a full body CT on these. I do a full body CT, um, mammogram, CA 125 pelvic ultrasound, PSA colonoscopy. Making it a colonoscopy, you just let them poop in a can. I tried to convince them to do a colonoscopy. I believe that people of cold blood is on the I'm fairly certain that's what's on the recommendation. Well, like colaguard is right. So I'm very much avoid I'm over 50 now. So I'm very much avoiding getting cold colonoscopy. So I pooping again every three years and mail it to the people who then, you know, say, well, you're okay. I think that's better than fecal of cold blood, but not as good as colonoscopy. But yeah, do you so for the antibodies, do you pretty much like do you guys have your own lab at UAB? Do you just send them to quest? And because I think they have like that myocytus antibody panel that you can just order so that you don't have to remember like the 19 antibodies or something. Like do you do that in everybody or what do you do in terms of blood work? I think that's a good question because if you read the literature, a lot of the, you know, leading researchers and germanomyocytus, all these new antibodies are coming out and profiling them and I think that's really great. So I do do a myocytus panel, but I don't wait for it to get started on treatment because sometimes these are sendouts that can take three or four weeks. It's also lab dependent. I think you can get a lot of false negatives. I have a lot of patients who are antibody negative, but they still have it, right? And is it just that we don't, they have an antibody we don't know about yet? Yeah. Maybe. So I do do the screening for the myocytus panel. There's different companies and there's different differing opinions on which labs are better than others and which labs pick up the antibodies better than others do. So no, we don't have the myocytus panel. We do that. We do a send-up to Mayo, but then there's a lab in Oklahoma that does a lot of it too. And is it still, again, as a resident, I learned that 50% of dermatopatients are A and A negative. So like literally, you'd like, well, we're checking A and A. We'll check this and there's nothing serological that you can find in them. And is it still a meaningful number? Like is it unlike lupus where you're like, look, your A and A is normal. You don't have lupus or the systemic lupus. Is is Dermato still something we're like, and a lot of people have Dermato and a negative A and A. That's like not a rare thing. Yes. I don't, I'm not for Dermato, my son. It's not used the labs to if it clinically, they look like they have it in the biopsy, you know, I, I diagnosed it. What do you think is the most useful clinic so that the thing that I always find that, obviously you look at the people's that they're cuticles. But then for me, it seems to be the upper back and the outer arms are like, would I see that pattern? And they can have other places too. But for me, upper back kind of outer arms, a little bit vial ACC, like that, like bells are going off, Dermato, myocytis, Dermato, myocytis, no matter what else I see if the other cuticles are fine, they're having it in the, but just that rash is like, my, what do you, what do you're, like clues that you would tell people like, this should make you at least really think about Dermato, myocytis. I always teach my residents recalcitrant scalp, erythema. That's a good one of you to mention it to recalcitrant, I mean, you know, we all see a ton of itch on the scalp for several different reasons. But real, you know, vialacious or pinky plaques with itch that just, you know, won't go away, you know, reconsider it as not subderm or contact germ, which it could be too. So those should be on your difference all, but I think the back rash, the shaw sign. And then if you look at the fingers a lot of times, they do have the gochins, papules on the, you know, PCPs and PIPs, DIPs. Although, you know, the traditional teaching is that lupus is interflangial and dermatoidemysitis is on the knuckles, but, you know, sometimes patients have an all over I need to get to. Right. Heliotrop to me is one of the most over hyped. Like, Heliotrop to me is now something where I'm like, I identify Heliotrop after I know they have dermatoidemysitis, kind of like you identify the burrows and scabies after you know they have scabies is like the, like, but maybe I'm just not good at picking it up. Like, do you think Heliotrop is a common thing at all? I think that Heliotrop can be one of the harder things to diagnose, for sure, especially, you know, I practice in the South. My ladies don't like to not have makeup on. I'll tell you. Anything else to patent affairs that we wanted to get to, Dr. Graham, anything we haven't talked about that you think we should have? I think you guys did a great, I think we did a great job. Okay, that's that's I think that's new. I think you covered every connective tissue disease, that was good. And I still can't pronounce any of the generic names of the drugs. Yeah. So I'm right on par. All right, Patten, let's get to trivia. So, Dr. Graham, we talked about the rules before the show. We got to let Patten finish reading and then it's just the first person to shout out the correct answer. All right, Patten. What's our what's our topic this week? Do you want a guest? Do you want to play your new game? I'm going to go with my guess. I think that it's going to be something related to wolves for going off of this systemic lupus erythematosis. Yeah. Fairies. Yeah, you got I guess I'm going to guess it's related to tissue. It's in some way. Oh, connected tissue disease history. I just read a bunch about the history of connected tissue diseases. It's pretty interesting stuff. I spent way too much time and I don't take these questions out of that grade, but here we go. We'll be there, Doug. In 1953, J.C. She reported the beneficial effects of anti-malarials had in treating SLE and RA and what group of people? People with malaria. People with malaria. I knew you were going to say that. No. Dr. Graham Gesson. Tromb. Parris and I both used to get this. It was a group of people who were at really, really high risk for malaria. So they were treated prophylactically and he was like, my God. People like countries with my risk. African countries? No. Oh, like Peace Corps volunteer. You're getting closer. 1953. Medical missionaries. Korean soldiers. Soldiers going to Korea. US soldiers World War II. It was a lag time after the war. Okay. So yeah, it was crazy. So malaria was horrible. Like there was one area. This is great. It was called Milne Bay. I don't know if I'm saying that right. The incidence of malaria per year was 4,000 per 1,000 soldiers. Every soldier pretty much got malaria for 4,000 years. Wow. And it wasn't fatal, but it wiped them out. And so there was this huge campaign of like wearing, you know, deep and spray and DBT and one of my great uncles died of malaria that he got during World War II. I think he was like, he was all happy because I think he got deployed. I have to say I never knew him. I think he got deployed to like Panama or something. And he got malaria and died. And that was like, he was like the only, they had like six brothers. He was the only one who died. They had something like that. Well, apparently, fair number of soldiers, I guess the criteria wasn't a strict. They had autoimmune conditions. And their autoimmune conditions got better when they were taken. Huh? Do we still do we have any idea yet? How or why they work for containers for autoimmune disease? They inhibit autoimmunity. That's what Dr. Graham, do you know if there's any actual answer to what? I know there is. And I know I should be able to round on all off. But I don't. All right. Number two, cells from a laryngeal epidermoid carcinoma are used in what common assay to test for autoimmune disease. A and a. And it's a anna. Who I was first. Do you know that in the 60s, they actually realized way back then that the hep 2 cell line was actually contaminated by the helix cell line. So it's actually heela cells that Henry had a lack cervical cancer line. That's what those hep. Yeah, that's what that cell line is. Wow. Well, that family, they just got a big settlement where they got. The vortice, I think. From was it no vortice? All right. If they're listeners, the germs on drugs go after the anna people too. Go to question. They owe you. All right. Last question. Heinrich Goatron. We spoke of Goatron papules. We all still use that term. He was a member of the Nazi party. And I know we leave us on a roll note. All right. He became head of the Brez-Low Dermatology Clinic in 1934, forcing out this man whose name is associated with a cosmetic chemical peel. Jessner. Yeah. Is it yes or a job? I'm going to answer yes. No. Well, we that's probably the man from the man from Iran is saying yes. Max Jessner. He was forced out because of his Jewish heritage. And Goatron took over his spot. Hmm. I'm surprised. I feel like we've changed a lot of names of things that were named after Nazis, but we haven't changed that one. Well, apparently, like, you know, even among Nazis, there were worse Nazis than others. So like writer, writer was bad. Like he did typhoid studies on prisoners. And that's why some writers disease that's gone. And Wedners was the other guy. He actually got put up on like wartime charges. Goatron, he's got a good job and he actually wasn't that bad of a dude apparently. I remember. I can't remember if it was an OSU or a pit when Elston came to give a lecture on connective tissue disease. Yeah. And he was proposing that they be renamed dirt bagpapules instead of he was ahead of his time. He was ahead of life. He wasn't caught on. That's here to start. I don't think patients would like the name dirt bag. Yeah. To get an icy. I love Dr. Elston about. I don't think patients would like that. Yeah. Not a good. Not a good. All right. That's all I got. All right. That was pretty good stuff. I mean, the A and A one was a little easy. That was a little low you. But otherwise that was pretty good stuff. I think I really wanted to talk about how it's actually heal. I thought that was interesting. Okay. It's my own little fact. Okay. That's fair. Dr. Graham, thank you for joining us this week. And I want to thank all of our listeners for joining us this week. We hope you learned a few things. We hope you laughed once or twice and mostly we're hoping you're planning to join us next week. And until then, I'm Matt Zyrus. I'm Tim Patton. And I'm Laura Ferris and we are Derms on drugs. [BLANK_AUDIO]