Thank you very much for letting me talk with you guys again about acne and rosacea, except this time we're going to do it backwards. We're going to talk about rosacea and acne. And I can tell you in the dermatology world, that's really backwards because when we talk about these two things, they're frequently together, even though they're very distinct conditions. And for some reason, acne always goes first, but not today. We're going to talk about rosacea first today. This is my conflict of interest statement. So let's jump in with rosacea. So first of all, what is rosacea? Well, rosacea is complex. I think that's the take home here. In the past, we have tried to subtype rosacea. We've wanted to say that one person has papulopustular rosacea while somebody else has erythematotelangictatic rosacea or ETR. But you can take one look at these images and recognize that the very same people who have papules and pustules also often have background redness. They may also have FIMO, which is that thickening like rhinophyma that we see there of the nose. And that's a pretty mild case. They can have ocular disease as well. So I think one take home when you have a person in front of you with rosacea is to really realize that it's multifaceted. We can't make rosacea all one thing. And because of that, we're almost always going to be using combinations of treatment to make rosacea better. And I always use this analogy. I don't want to talk down to you. I can tell you that I always use this with dermatologists too, just to get us to realize what we're talking about. So it's very analogous to going out to have a nice dinner. And I've said this before, I think, because I use this all the time, but you go out for a nice dinner and you're having steak and potatoes. I don't know what this picture is. It looks kind of disgusting. But maybe you're having soup. Maybe you're having dessert. Would your waiter or waitress ever come up to you and say, okay, please pick one utensil. That wouldn't work very well. You know, you might pick the fork, but then you go to eat your soup and it doesn't work very well. You have different utensils. You need at least most of them in order to get the job done here. And the very same thing is true with rosacea. If you look at a person with rosacea and they have redness and that requires one set of treatments, they have bumps that requires another set. They have telangiectasia or FIMA, and that requires yet another set. And so just a simple way to keep this separate in our mind is to think of our treatments as forks, spoons, and knives. So the forks are those treatments that are FDA approved for the bumps or the papules and the pustules. And that's not to say that they won't help some with redness in the background. They might, but that's not how they're studied. That's not how their FDA indicated. And this is your list. We'll look at it a little bit more on, on one of the next slides. We also have spoons though, and those are the products that are FDA approved to treat the background erythema. And so you can get rid of bumps all day long, but still have background erythema. And then you need to use a different tool. And then we have knives and the knives can be used for telangiectasia. They can be used for background redness as well. That would be like a pulse dye laser or KTP, or maybe even IPL. And then sometimes we need our knives for electrosurgery or even laser that we could use for FIMA. So once that big bulbous nose has developed, is there anything we can do to get rid of it? And the answer is yes, but it's probably not going to be in the form of a pill or a topical. So let's start by talking about some of our forks. And so this is the list, and I think it's good to know this whole list. So this is for bumps, papules, pustules, whatever you want to call this. You could do topical ivermectin. It's a very effective drug. People do well with that. It's well tolerated. Metronidazole has been around for a long time. People do pretty well with it too. It's a little older school, but you can certainly still use that. And it comes as lotions and creams and gels. You can use azelaic acid that comes as a gel. It also comes as a foam or a mousse. Sodium sulfacetamide and sulfur, kind of old, but still works for some people. But I'm going to focus today on these last three. So we're going to talk about modified release doxy because it is the only oral medication that we have FDA approved for rosacea. I'm going to talk about minocycline foam because it's kind of new. And then the real new kid on the block is encapsulated benzyl peroxide, and we'll talk about that as well. So let's start with modified release doxycycline. So this is modified release, 40 milligrams. It is the only oral tetracycline FDA approved to treat rosacea. In fact, it's the only oral FDA approved to treat rosacea. There are no others at this point. It's not new. This was FDA approved in 2006. I will tell you this does come available also as a generic. And the point of this drug, it's a fork. It reduces inflammatory lesions of rosacea. It is not specifically indicated for background erythema, but why we like it so much is that it doesn't act like an antibiotic. And you want to pause here for a minute and think about what the pathogenesis is of rosacea. And in the pathogenesis of rosacea, we don't have a bacteria listed. So we think people with rosacea just have super sensitive skin. So, you know, heat or spicy food or stress or whatever it is, turns on a much bigger response in a person with rosacea than in a person who doesn't have rosacea. But it's not caused by a bacteria. So why would we need to use full doses of an antibiotic if we can isolate? The reason we're using these, which is we think this is an anti-inflammatory property of this drug. We can isolate the low dose and still get the anti-inflammatory benefit without exposing our patients and their GI tract and their entire bodies to a full dose of an antibiotic. So this is called modified release because it's not just 40 milligrams. So you can't try to just keep cutting your dose down and get to the same place, at least not most of the time. This is 30 milligrams of immediate release doxycycline that's going to release in the stomach and then 10 milligrams that's going to release later in the small intestine. And so it keeps this low even dose over a 24 hour period, never allowing the concentration of the drug in the blood to become high enough that it's actually acting like an antibiotic. So this maintains what we call a sub antimicrobial dose. And when you're doing that, you're not then killing the bacteria that are sensitive to you. And when you do that, you naturally select for the resistant organisms. That's not happening. We're not putting that type of selection pressure on the system. But do remember that using sub antimicrobial dose is not just the same thing as using low dose. Okay. And this is, I think, the perfect diagram or chart to drive that home. So when you look at this, the orange here is the doxycycline modified release. That's the orange. And you can see, now the timeline across the bottom is not, you can see that it does release mostly in the first six hours, but it stays below that horizontal hashed line that's acting, that is kind of a average antimicrobial threshold. So for bacteria that would be sensitive to doxy, once you pass that concentration on the y-axis, now you're acting like an antibiotic. So you don't want to come up over that horizontal threat, kind of hashed line there. But what the comparator is, there is not doxycycline 200 milligrams a day. It's not even 100 milligrams a day. It's doxycycline 50 milligrams a day, five zero. And so again, I think most of us would be like, oh, that low dose, I would feel pretty good about using a low dose like that. Well, again, low dose is not the same thing as this modified release. And so that's kind of the main message with using that dose in rosacea. Now I think that doctors and prescribers for the most part are good souls. Like we want to do what's best for our patients. We want to do what's best for everybody else's patients. And so we see that and we're like, yeah, I'm on board with this. But some pushback that I'll hear every now and then is, well, you know, what if I just start with a high dose and get in and get the work done? And then maybe then I'll end up on this modified release dose. Well, you can't really outrun resistance. This was an interesting little study that was done. It looked at just, I think it was 29 people who were treated, 29 were treated with doxycycline 100 milligrams a day, 29 were treated with placebo. And they were, the ones with doxy were treated once a day for 14 days. And what they looked at, if you look at the Y axis, they're looking at the percentage of doxycycline resistant isolates. So these very nice volunteers were having their nose and their throats swabbed. And the percentage of doxycycline resistant isolates was being measured. And what you'll see is that it doesn't take long. In fact, at day seven, it might've happened sooner than that, but at day seven was the second time that these people were being swabbed. And you can see as early as day seven, that we have an increase in doxycycline resistance strains. And at day 14, it's even higher. You stop doxycycline at day 14. And guess what? The resistance does not just fall back down to zero. And so I think just the take home here is you can't outrun resistance. It happens quickly. And this, by the way, is not anything evil. We have to do this when we need to use full doses of antibiotics for an infection. But we don't have to do this when we're treating a condition that is not an infection and doesn't really have a bacterial pathogen. And we also wouldn't use this, by the way, if it wasn't as good as doxycycline 100 milligrams a day. And we do have a study, the author of that, the investigator was Jim Del Rosso. And he compared 100 milligrams a day to modified release 40 milligrams and found that they worked equally. And even one was not faster than the other. So there's not really a reason even to think that the higher dose is necessarily going to work better in rosacea because we would have a study that says otherwise. Okay, so let's move on to minocyclin foam. So this one and the next one are new players. And so you're going to see the designs of the study. They're very similar. These are two 12-week, usually in acne and rosacea, they're 12-week studies. We wish they were longer, but they're not. They're 12 weeks. They're phase three. Of course, everything you would expect, randomized, multicenter, double blind, vehicle controlled. This one has over 1500 people. To be in the study, you had to have moderate to severe rosacea. So you had to have an IGA, that's an investigator's global assessment score of three or four. And the baseline lesion count was about 30. And in these studies, what we're looking at, now this is a fork again, okay, so we're not in there measuring redness with this, we are measuring bumps. And so the two endpoints are, what is the reduction in inflammatory lesions? If you start with 30, how much do we go down over time? And then we're also looking at the IGA treatment success. And so how many people who start out as threes or fours end up as zeros or ones, clear or almost clear. And sometimes the IGA score in rosacea, in fact, I think every other time, except this one, the IGA does talk about having a few bumps, but it always talks about redness too. And for this particular study, they pulled the discussion of redness even out of the IGA. And so this is very much a fork. And you see it here. So we see this person at baseline, that's pretty significant rosacea. And then we see her at week 12, and she is a ton better. In fact, she is a treatment success, she's almost clear. But I've been having fun on the dermatology circuit with my dermatologist flipping these pictures. So I'll show them the after picture first. And then I'll build the slide and bring in the before picture, because the point is, this drives on that point of combination therapy. If you looked only at her week 12 picture, and you didn't see the baseline, I think we would all still think she had rosacea, maybe not real bumpy rosacea, but she's still pink and red. And I bet you she still knows that. And I bet that still bothers her. So even though we see how beautifully this fork has done, getting rid of the bumps, we have still got some redness there. So this is that combination that we need. So some unique things about minocycline foam is that it's yellow. The minocycline itself is yellow, and it can stain fabrics. It also is a little bit oily, which most of my patients love. It feels good, it contains coconut oil, soybean oil, and light mineral oil. But for both of those reasons, this is a product I like at bedtime. You certainly don't have to do that, but it is once a day, you don't have to use it twice a day. Okay, the other new player in rosacea, this is the newest, is benzoyl peroxide. And it's a little bit interesting in the dermatology world because benzoyl peroxide as a molecule, as an agent that we use, for example, in acne, is certainly not new. It's been around for a long time, but I can tell you that we would really almost never use benzoyl peroxide in rosacea because we would be concerned about irritation. It can be kind of drying and a little bit irritating, particularly when you put it on that rosacea skin. And again, one of my favorite analogies for rosacea is to think of a person who doesn't have rosacea, their skin is going to respond to things in the environment or things that they eat with a very measured response. So it would be like a house that has an alarm system with one alarm on the front door and maybe one on the back and maybe a motion detector. And so if somebody invades through that front door and they're not supposed to, you're going to get a measured response and the right response to that. But a person with rosacea skin is like Ocean's Eleven. They have 20 alarms on the front door and the back. They have motion detectors and heat sensors and laser beams and whatever else you can have. And now a feather drops and they get this huge response. And so benzoyl peroxide on people who don't have rosacea is no big deal, but benzoyl peroxide in the past in people who have rosacea could really cause a big response. And so we've hesitated to use it. And so the one we're going to talk about today is not just benzoyl peroxide. And it's hugely important that you understand that so that you don't go reach for now just any old benzoyl peroxide and try to use it in rosacea. This one is micro encapsulated. I've been calling it the gift wrapped benzoyl peroxide and we'll talk a little bit more about that. But we even, I have to say, why does this even work in rosacea? When we think about benzoyl peroxide in acne, we think of it being an antimicrobial. And we just said, again, we don't really think there's a pathogen, a bacterial pathogen in rosacea. Well, maybe we're wrong because this data looks so good. If that's the chief way that this drug works, maybe we're wrong. So we'll wait and see. But I think it's more likely that benzoyl peroxide is having an impact on Demodex, which is a skin mite that is on all of us. And in people with rosacea, its presence acts as a trigger on that easily triggered skin and it turns on more of an immune response than it should. And so if benzoyl peroxide kills Demodex, which is triggering a pathway of inflammation, that may be one way that benzoyl peroxide can be anti-inflammatory then in rosacea. So this is the clinical trials with this drug. Also again, new. So two phase three double blind studies. These are once a day dosing, 12 weeks, smaller than the last study, 733 people. This was randomized two to one. Again, everybody had to have moderate to severe disease, but twice as many people were going to be exposed to drug as they were to vehicle. And you can see here, it's not just BPO, benzoyl peroxide, it's EBPO. That's encapsulated benzoyl peroxide, 5% cream once a day versus vehicle cream once a day. And this is still not published in any of our major journals yet. It has been in many posters. So this is just a clip that I took from one of the posters from just last year. When you look at the treatment success rate, the IGA success rate, we're at about 50%, at least in study two. So we're going from three to four, moderate to severe to clear or almost clear in 12 weeks in about half of the patients. We're reducing those lesions. And again, we start out around 30, we're reducing them down by about 70% at week 12. But I think what's most important, look at this, it's the two studies side by side. You can see the endpoint, which is week 12. And again, I added the percentages there, close to 70% at week 12. But clearly, I want you to see week two. And so by week two, we have already reduced those lesions by over 40%. And I would bet that there is something, maybe everything in your field that's like dermatology. And that is we have people who want things to work overnight. And that's just not very realistic. But this works fast. And the faster it works, the more buy in I think we get from our patients. And I actually tell my patients this number, like with this drug in clinical trials, people got more than 40% improvement in bumps in two weeks, in two weeks. So just hold on tight, get going, let's do it. Now to get your full effect, it's going to take 12 weeks or longer. But when you can reduce more than 40% at week two, I think our patients are very encouraged. And this is this is a nice example. Here's somebody at baseline. And that is a tremendous improvement by week two. Also, by the way, this is a fork, she's still a little bit pink, but boy, the bumps are like nearly gone. And at week 12, she's even better. And I do think her redness looks better. But we'll talk about this in a minute, you have to be a little careful, because the bumps are inflammatory bumps, and they have their own perilesional erythema. And so as you get rid of red bumps, you are going to get rid of some redness, too. And you got to be able to separate the background redness from the perilesional redness. Another example here, she doesn't get better quite as fast, although look at the difference between baseline and week two, I bet she can see that difference for sure, even though she's gone from a moderate to a mild. And then at week four, she's almost clear. At week eight, she is clear. And at week 12, she's clear. So lots of improvement there. And so this is what I'm talking about when I say it's gift wrapped, this is 5% micro encapsulated benzyl peroxide, not just something you can go get over the counter. This is a benzyl peroxide that is wrapped up in a multi layered silica shell. And that silica shell is there to help control the release of the drug. I think it acts a little bit like a speed bump. And so instead of getting all the dumping out on the skin of this benzyl peroxide, it's coming out of this shell slowly. And that helps to maintain the way that the product works, but it minimizes potential irritation in our patients with rosacea. And this was interesting from the tolerability in phase three studies. So it's one thing to work, but your patients have to be able to tolerate it. And here, this is a little bit different. We have study one on the top and study two on the bottom. We have itching on the left and burning and stinging on the right. Maybe a little hard for you to see some of the white print there. Sorry about that. But at baseline, people with rosacea, many of them have itching and burning and stinging. But what's important is as you put this product on their skin, the itching, burning and stinging doesn't go up. And I can tell you, even though week two is not on here, it didn't go up at week two. It went down at week two, and it definitely went down at week 12, signaling to us that this is a product that's very well tolerated, even in this Oceans 11 type of skin. And then this is the adverse events. We're really looking at the bottom half here. And that's because that's what we're now talking about related AEs. So those adverse events that would be related to the study drug, that would be things like application site pain, erythema, pruritus, edema. And what you see is the numbers are very low, 2%, 2%, 1%. And remember to look at percentages here, because if you go back and look at the top, remember this was two to one. So the actual number of people on encapsulated benzoyl peroxide is twice as many as we see on the vehicle. Okay. Let's talk a little bit about some spoons. So when we're looking at our spoons here, we're looking at two. We have oxymetazoline and bromonidine. Bromonidine was the first one to come to market. It's an alpha-2 adrenergic receptor agonist. The other one is an alpha-1A. So their receptor selectivity is a little bit different, and it may mean that they respond a little bit differently in our patients, and I think that is true. This one, excellent product, might be associated with a little more of what we call rebound, where the redness as the product wears off, or sometimes even in the middle of the day, this one, the redness will come back worse than when you started. Now we think that happens in 15% of people or less, but it is something to be aware of with this drug in particular. With FDA approved in 2014, this is not going to do anything for telangiectasia. They are sitting there almost like a scar. They're going to take a laser. This is not going to do anything to them because they don't have smooth muscle that can contract anymore. Also, not specifically studied, tested for flushing. Probably helps flushing, but that's not what it was FDA approved or studied for. In the pivotal trials here, you could only have two bumps. This is what I mean about you've got to be careful separating perilesional redness from background redness. In a study where we are now looking at a spoon, we are really going after PFE, persistent facial erythema. Now we want to not look at bumps. We want to just isolate the redness. This was a hard end point too, because both the investigator and the subject got to rate the facial erythema. Neither of them got to look at a picture of baseline, so they were just doing these static assessments at different time points. By the way, most of the time points were on day one. They would do it again on day 29, but in those other studies, they were 12 weeks and we saw continued improvement over time. This is a vasoconstrictor. It's going to work on day one. It's going to work in 30 minutes, and that's what we'll see here. I'll just have you take a quick look. We see this person before treatment on day one, and then we look at this person across even at 30 minutes, improved, and we see continued improvement through 12 hours. I think all of those pictures look better than her baseline picture. This is oxymetazolin. This is also a spoon. This is the alpha 1A. Probably definitely less of that rebound, although we don't have a head-to-head study. This was the second one to come to market. This was 2017. Study design, very similar. And now we see her before the dose. And then we see her on day one. And then at the bottom is day 29. And all of those pictures, they're all 10 of them, look better than her baseline pre-dose. And so these products don't just work through 12 hours. They seem to work through 12 hours. But one thing we learned when this came out is people, they like to be able to use thing at bedtime. One of my own employees was using this at bedtime for a while and I'm like, wait, no, you're sleeping through the best part of this. So these are products that should be used in the daytime, unless you're working the night shift and you'd want to not have facial redness overnight. This was a little bit of a game changer for us too. This was now the 52-week safety study with that second one with the oxymetazoline. And so now, when you do the 52-week long-term study, it's all about safety. There's not a comparator arm. You're trying to get everybody exposed to the drug because you're really looking for any safety signals or adverse events that might pop up more after continued use. But we were kind of surprised with this because we learned something else. So take a minute to look at this. The blue is going to be pre-dose. The orange is at hour three, and the gray is hour six. Across the bottom of this, we're looking at day one, then week four, week 26, week 52. The y-axis is patients achieving CEA, which is clinician's erythema assessment, and SSA, subject self-assessment, composite success. So they had to agree without talking to each other on a two-grade improvement of redness reduction from baseline. So day one, not bad. You know, we got almost 20% of people having that success at hour six. But then we had started learning this has an additive effect. At week four, more people are doing better. And at week 26, a lot more people are doing better. And what's really interesting is at week 26 and at week 52, we've got people meeting the endpoint before they apply the drug. And so is something happening here? Are we improving vascular tone over time by having people use this? We used to say, just use it on the days you don't want to be red. And then we saw this and we're like, no, use it every day, because it might be really changing the course of the disease. And I have a friend who's a dermatologist who says it's kind of like when somebody comes in with bad stasis dermatitis of their lower legs, we would never say, you know, just use your compression stockings on the day you don't want to be puffy. And on the other days, just be puffy and expect that that's going to help. You've got to do that compression all the time in order to really get the change. So it's not a perfect analogy, but not bad. These are pictures. Look at this guy pre-dose on day one and look at him pre-dose on week 52. I'll help you there. I mean, they're at the bottom. He hasn't even applied it yet. And this looks very, very different than before he started this 52-week study. Okay, flushing. We have nothing specifically FDA approved for flushing. So we're talking about off-label here. But what we use is beta blockers. I use Carvedilol the most. You could use Natalol or Propanolol. None of these though, again, are FDA approved specifically for this. They do have adverse events, including they can decrease heart rate, lower blood pressure. They could cause you to feel dizzy, vertigo symptoms, or feel weak. We don't have any big studies with this. We have little case series. This was one with Carvedilol, looking at five patients who had severe frequent flushing episodes and or persistent erythema. And they've been treated pretty good with lots of our other tools. So in Europe, this was out of Europe, they use more antihistamines there than we do with Rosacea. But also on doxycycline, on isotretinoin, which is Accutane, combined with topical application of metronidazole gel, ivermectin, and just not getting enough improvement in the background erythema. So Carvedilol was added, started at 6.25 milligrams twice a day up to 12 and a half milligrams twice a day and continued for at least six months. And you can see reductions here in erythema. And again, both, if you like more objective data, the CEA is Clinician's Erythema Assessment. The PSA here is Patient Self-Assessment. Before therapy, not so good. During therapy, reduced on both of these. So in a nutshell for Rosacea, remember it's probably gonna take more than one tool because Rosacea is complex. And so take a minute to look at the patient in front of you and really see what features they have, what bothers them, and then pull out more than one tool. Okay, let's talk about acne for the rest of the time. Last time I felt like I short-changed Rosacea. Today I'm probably gonna short-change acne a little bit. Acne comes in lots of varieties as well. That one on the bottom, we just really hate to see that. We know that's gonna leave some really tough scarring. That is probably an example of acne fulminant. That is not my patient. Acne fulminant is what we see oftentimes. It can be just, it can happen idiopathically, but oftentimes it's after somebody started on too high a dose of Accutane and it makes their acne just explode and worsen. And so if you've got somebody who's got bad acne and you're gonna use a product like Isotretinoin, and I will call it Accutane some even though that's, there are other brands and other generics of it out there. I want you to know what I'm talking about. If you see somebody with bad acne, particularly a young male, which may not be any of you guys, and they have severe acne, you gotta start low and go slow with that drug. Okay, so in Rosacea, we're looking at all these features and we're trying to match up our treatments to the features. In acne, we're really thinking about the underlying pathogenesis. So we're always targeting our treatments to these four things, follicular plugging and hyperkeratinization in the pore, in the follicle, inflammation, cutobacterium acnes, or C. acnes, and sebum. So here we do have a bacterial pathogen. And I have put this together. I showed this last time to you too. I think it's worth looking at every time. I hope maybe this is something that you even take a picture of or print off, whatever you wanna do, I don't mind. Because you're trying to hit as many of these four things across the top as you can. Retinoids are the best thing we have for follicular plugging. We have lots of things that do inflammation. C. acnes is pretty much benzoyl peroxide in our antibiotics, whether topical or oral. Sebum is hard. That one we're using either isotretinoin. In our female patients, we can use spironolactone or oral contraceptives. And we do have a new topical, Clascoderone, that we've had now for, I guess, a couple of years, that is a topical androgen receptor inhibitor that we can use in men and women. The lesions of acne are comedones. That's the blackheads and whiteheads. They are inflammatory, by the way. They just clinically don't look it. Clinically, the inflamed lesions are the papules and pustules. Nodules are just awful. We'll look at a picture of that. And then you've got the sequelae, which is the hyperpigmentation. People hate that too. Even the leftovers, erythema, and then scarring. So these are examples of comedones. Man, if I saw this, we'd be putting a retinoid all over that. This is retinoid territory. And our retinoids are adapalene. One of those is even over the counter. The 0.1 is. The rest are gonna be prescription. We have tretinoin. We have triferatine. And we have tazeratine. So adapalene, tretinoin, triferatine, and tazeratine. Those are your options here. And when you see comedones, that's really what you're gonna be going after. This is a mixed bag of comedonal and inflammatory acne. And you can see on the picture on the left, a little more comedonal, but certainly some inflammatory lesions in there as well. And the picture on the right, a little more inflammatory. But it's usually gonna be a mix, especially in adolescence. I keep jumping over myself here. And then this is the horrible nodules. And some people will call these nodulocystic lesions. I guess we use the word cystic sometimes because they feel kind of fluctuant. But they're not cysts. Cyst has a true lining. These are nodules of inflammation. And they're usually five millimeters. Sometimes people will use the cutoff of one centimeter in diameter. These are the undergrounders. These are knots under the skin. They're painful and they certainly can scar. Granted, all of this type of acne can scar, all of it. And then the truncal acne is very important. And this is that phenotype. When we see this on the lower face and neck and jawline, sometimes we, I think, wrongly call this hormonal acne. And I say wrongly because all acne is hormonal. There's a reason that we get acne in adolescence. There's a reason even that sometimes babies have acne. And it's because of this underlying hormonal influence. And so I think we have to be a little careful calling things hormonal acne. I would just call this adult female acne because we don't see this presentation very often in men. This does seem to be something that we see mostly in women. All right, so what are we gonna do for acne? This is the guidelines from the American Academy of Dermatology. These were published in 2016. They are right now being redone because these have sunset and we certainly have some new products out since these were published, sorry. I think the thing to notice here, though, is across the top, we have mild, moderate, and severe. And down here, we've got a lot of plus signs. Kind of like rosacea, this is combination world. We're gonna be using things in combination. The only time we're not doing that is in the mildest acne, when we can get by with one topical, or in the most severe acne, when we can get by with just oral isotretinoin. But otherwise, for the most part, we're gonna be using things in combination. Our topicals. Topical retinoids, if I could impart one piece of wisdom to you in the acne world, it would be that make sure that like 99% of the people you treat for acne are on a topical retinoid. I still don't let these in people who are pregnant, so I still don't do that. They're probably scientifically, it wouldn't matter, but I still don't. I wish I was with you right now because we could talk about that. But otherwise, use these. They are the cornerstone of treating acne. If you have people who find these drying or irritating, you just use them every other day. You put moisturizer on first and then put the product on top of them. But usually after four weeks, people get used to them. So if you can get people to just stay with it through those first four weeks, they're gonna do pretty good. And these are the cornerstone because they normalize that follicular hyperkeratinization. They get rid of the comedones that are there. They prevent the new ones from coming. And so their first line and their long-term maintenance treatment. So even when somebody is doing great, then these are the ones that you keep on board. Benzoyl peroxide is the runner up. If retinoids are like the main event, these guys are the runner up. Benzoyl peroxide is a safe product. And in acne patients, it's usually pretty well tolerated. We like these because they kill C acnes. They're also anti-inflammatory and they kill C acnes without inducing the development of resistance. I have a friend dermatologist who calls benzoyl peroxide the dirty bomb. And I steal that from Dr. Hilary Baldwin, I think it's just a great representation. The way benzoyl peroxide kills bacteria is it just kind of oxidizes them. It blows them up and there's not a resistance mechanism to that. And so we love benzoyl peroxide, especially if you're using an antibiotic and I would say oral and topical. Topical probably makes more sense, but with both of them, because what happens is again, if you're using the antibiotic, you're selecting for resistant organisms. And so that portion starts to take over. Well, benzoyl peroxide comes in and just evens the playing field because it's going to kill the resistant ones and the sensitive ones. So we really like these. They come as washes and leave-on products. The leave-ons are better. They can bleach fabrics and they do come in fixed-dose combinations where we use them as a fixed-dose with retinoids or a fixed-dose with an antibiotic. So my old analogy on that, that young people don't even know what I'm talking about anymore is it's like aquafresh toothpaste. So these fixed-dose, you have two different products in there, but the patient pumps once and gets both of those active ingredients out at one time. Here's a couple examples. We have a dapoline, both the 0.1 or the 0.3 as a fixed-dose with benzoyl peroxide. We have micro-encapsulated tretinoin with benzoyl peroxide. That is a new one. And you have to have the micro-encapsulation of the tretinoin and separately, the micro-encapsulation of the benzoyl peroxide or the dirty bomb benzoyl peroxide in this case would oxidize the tretinoin and it wouldn't work. You can't use those things together normally, but gift wrapping these two separately allows now these two important players in acne to be used together. And that's kind of new. So if you've been using those as generics on top of each other, that's not gonna work very well because benzoyl peroxide is going to oxidize and inactivate the tretinoin. Topical antibiotics, just don't use them alone. I think probably all specialties kind of talk about other specialties. We are driven a little crazy when primary care writes just clindamycin topically alone or really even minocycline orally alone. Don't do that. Don't do that. With clinda, you're probably getting resistance in the first seven days. It's easy to tolerate. It's inexpensive. It's easy to get, but you're causing resistance and you're not really using the best tool that we have for acne. And I would say always couple with a benzoyl peroxide. As far as oral antibiotics, our guidelines from the AAD say to use them for more moderate to severe acne. That's not because they're the most powerful, it's because they have risk. And so we're gonna wait until we have more risk from acne to bring these in. We are gonna use them if people are not responding to topical treatments by themselves, but we're not gonna replace the topical treatments and only do the oral. We're gonna add it to what we're already doing. We're usually gonna use doxy, minnow, or now saracycline. Saracycline came in after these guidelines were published, so it's not on there, but these aren't monotherapy. We do wanna try to limit to three to four months. Well, sometimes we have to go beyond four months. You know, what do we do then? I would say if you have to use an antibiotic longer than four months, then you might need to use isotretinoin, or you might need to add spironolactone, or a birth control pill, or just switch it up somehow. Really, really, really try to avoid exposing people to long-term antibiotics for acne. We have other treatment options. Okay, let's end with two hormonal treatments. Probably you guys are really familiar with these. Spironolactone is first. So, you know, dosage range is 25 to 200 milligrams. I prefer a max dose of 100 milligrams. I really kinda like 50. I like low doses, and I'll tell you why here in just a second. Usually, these are QD. You can divide the dose. BID, especially if somebody is, feels like they're getting the diuretic effect, or if they're getting lightheaded, you can divide that dose. It's harder, I think, for patients to remember. We're gonna use these in combinations with other medications, because spironolactone is mostly affecting sebum, and so we're gonna use it in combination with other things in particular, topical retinoids, and maybe BPO. We can use it with oral medication. Sometimes we even overlap this with isotretinoin. Frequently, we use this with a birth control pill. And why would we use it with a birth control pill? To lessen both the main side effects, which is menstrual irregularities, but also to prevent pregnancy, because we are, at least in theory, concerned about this risk of feminization of a male fetus. I wish I was with you again right now to talk about that, but I believe that's late in the first trimester. This drug has a very short half-life. It doesn't stay in the body. I think the half-life is maybe like 24 hours. It's short, and so we don't have to stop this drug months in advance of somebody trying to get pregnant. The side effects, though, are things like menstrual irregularities, breast swelling and tenderness, fatigue, headaches, diuresis, orthostatic hypotension. And then the higher you drive the dose, the higher rate of side effects. So that's why I like 50, at least for starters. Many people are gonna do fine on 100. So this was a nice little review pulling different studies together of spironolactone. So on the left, we have two columns of randomized controlled trials. On the right, two columns from case series, but all of this just pulling data together with spironolactone. And I put it in here just to show you that the biggest number on here, as far as side effects go, is menstrual irregularities. And I have a feeling there's a little background noise there, but I do think it's a common side effect. So one little nugget of information is if you've got somebody who's already on a birth control pill, or they have an IUD, or they've had an ablation, or they've had a hysterectomy, if we don't have to worry about their periods, we can feel better driving that dose up or even starting a little bit higher because we're not gonna have to worry about that particular side effect. Some things we've learned over the last couple of years with spironolactone, probably no need to check potassium in healthy women between 18 and 45. That's my first reference at the bottom. You can look that up. No evidence of an increased risk of breast cancer in women with exposure to spironolactone. That's my second two references. So large epidemiologic studies that look at people exposed to spironolactone and then see if they subsequently have a breast cancer and the answer appears to be no. Could take three months to kick in. By the way, in Durham right now, we have an ongoing study that's comparing doxycycline, 100 milligrams a day, to spironolactone, 100 milligrams a day. So in a couple of years, we'll have an answer to which one kicks in faster. Likely long-term treatment. People are gonna be on this not for three to four months, but maybe for three to four years. And again, usually we're gonna be using this in combination with other treatments. This was a recent publication from 2021. It's looking at 403 women treated for acne with spironolactone by one of two dermatologists, I believe at Penn. And it was just that these two Derms used the same way of assessing improvement in their charts. So that's why these two were picked. The most common dose prescribed was 100 milligrams a day. 68% were prescribed to topical retinoids. So yay, I would even want higher. And about 40% were on an oral contraceptive. But look at the very bottom here. What was the mean drug survival? So how long were they on this on average? 470 days. So this is long-term. But what I noticed is that they had a patient in this study who had a personal history of breast cancer. And we've always kind of worried about spironolactone in breast cancer because it's got a black box warning that says it's been shown to be a tumorigen in chronic toxicity studies in rats. Well, of course these rats were given super high doses. This is not what we've seen now in women, but how do we feel about this? And I can tell you, I've seen this come a long way in this discussion. When I first started using this and talking about it, dermatologists would be like, okay, what if somebody has a family history of breast cancer should I not use it at all? And we really didn't know then. And now we feel way better about that. And now we're even talking about, can I use it in somebody who's had breast cancer? So this was another interesting study using a large insurance database. And it looked at women who'd had breast cancer and it was 29,000 of them. And then they looked to see of those 29,000, how many had been prescribed spironolactone after their breast cancer? And it was 746. Now this was not for acne. These people were 70 to 79 years of age. I mean, maybe it was for acne, probably not. But when they looked to see in this two-year window of follow-up, how many of them, was there an increased risk of spironolactone having an increased risk of breast cancer recurrence? The answer was no. And so we had this 29,000 who'd had breast cancer, 700 plus exposed to spironolactone, no increased risk of breast cancer recurrence in the two years of follow-up. Now, the other arrow I put on here is that we had five people who were known to be hypercoagulable. And that's something that catches our attention because we know that oral contraceptives can do that. So do I have to worry about spironolactone? And we know from the hypertension literature that if anything, it seems to be, spironolactone seems to be protective. It seems to kind of correct because in people with hypertension, they have an increased risk of clotting and spironolactone seems to kind of undo that. And so just recently this year, we've had a publication in 2023 that looked at spironolactone and clotting. And so they did a retrospective cohort study to compare the risk of developing a DVT or a pulmonary embolus in people treated for acne with either spironolactone or oral antibiotics. And you can see here, it was big numbers, 33,500 people on each group, spironolactone versus oral antibiotics, had to have at least 60 days of exposure to these two. The cohorts were matched for age and oral contraceptive use. And in the end, there was not a difference. Those on spironolactone were not more likely to develop a DVT or a PE than those treated with a tetracycline antibiotic. Okay, pregnancy and lactation. Again, we're not going to, on purpose, have anybody on this who's pregnant. You can use this in somebody who's nursing, but be careful if you're driving the dose very high, you may diurese them and that would affect milk supply. So again, I say 50 to 100 milligrams, beware of side effects and higher doses does equal higher rates of side effects. Okay, I'm not going to teach you guys anything about oral contraceptives. I have one slide here and I have two, sorry. Which ones work for acne? Well, we know there are four that are FDA approved, but probably all of them work unless they're not a progestin-only pill. The progestin-only pills might actually make acne worse. There is one exception, I guess, with drospironone. But which ones work? Probably all of them do, but they're not fast, okay? This was a meta-analysis that looked at efficacy of oral contraceptives versus oral antibiotics. Now this is just looking at inflammatory lesion counts. Look at the three-month column. Oral antibiotics are outperforming oral contraceptives and placebo. But look at the six-month column. If you wait till six months, the oral antibiotic and the oral contraceptive are now equal. And so we love this because it gives us a chance to write oral contraceptives to get the efficacy. Now we might need to co-prescribe an antibiotic upfront to get people better faster, but we don't have to use the antibiotic long-term. We don't need to be because we have something coming in behind it that can do just as well and is not an antibiotic and then we don't have to worry about resistance. Okay, I'm not gonna teach you anything else about oral contraceptives. I know there were some new things in there. I hope that gives you guys some help as you have some of your patients come in who have rosacea and or acne. Thanks a lot.

rosacea

acne

treatment options

combination therapy

redness

bumps

telangiectasia

topical treatments