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Frontline Forum Part 2: A Discussion of the Pathophysiology of Acne and Available Treatment Strategies

Dermatology TimesDermatology Times, Acne Supplement, March 2023 (Vol. 44, Supp. 01)
Volume 44
Issue 03

In part 2 of this Frontline Forum series, Joshua Zeichner, MD, FAAD; Hilary Baldwin, MD; Zoe Diana Draelos, MD; Aaron S. Farberg, MD, FAAD; and Leon H. Kircik, MD, discuss the main pillars of acne and topical treatments available for patients with acne.

Continued from part 1

Zeichner: Dr Draelos and Dr Baldwin, could you comment on skincare briefly, on what types of cleansers, moisturizers, and other skincare products we recommend to our acne prone patients?

Baldwin: No acne visit is complete until we have discussed skin care, including cleansers and moisturizers and sunscreen, making specific recommendations. You can’t just say on your way out the door, “Oh, by the way, make sure you moisturize.” Specific recommendations are necessary.

Draelos: Well, I think the key for skin care is it should complement the regimen that you’ve prescribed in such a way that it minimizes side effects. So, for example, retinoids can be irritating. Many of the newer retinoids are in optimized vehicles, which has substantially reduced the irritation. Nevertheless, if you’re prescribing a high-powered retinoid and the patient has dry skin, you’ve got to compensate for the side effects with what you prescribe. So I think it’s really critical to look at what you’re prescribing, the skin characteristics of the patient, and then come up with your skin care. So for cleansers, even though cleansers are short-contact, they do have a profound effect on the face. You remove excess sebum, so you need something that cleanses well. And then you can incorporate benzoyl peroxide, short-contact benzoyl peroxide into your cleansing regimen. And actually, since benzoyl peroxide is a particulate, it can actually deposit in the osteo, the pore, and you can get prolonged bacterial killing that way. So if it’s possible, I would prescribe a benzoyl peroxide–containing cleanser, and many of those are available over the counter and are quite effective. However, benzoyl peroxide is also drying to the face, so now you have to counteract that. So you want to use a non-comedogenic moisturizer, and the basis for all non-comedogenic moisturizers is dimethicone, your silicone derivatives, because silicone derivatives—even though it’s an oil, it’s not an oil that bacteria or organisms can digest. So you don’t get breakdown products. A dimethicone moisturizer, a benzoyl peroxide cleanser, and then you want to pick a good sunscreen for them as well. And I would recommend the mineral sunscreens, the zinc oxide and titanium dioxide, because they actually absorb oil. And once the particulars, the zinc oxide and titanium oxide absorb oil, they don’t release it again. So that’s a way that you can get oil control as well as photo protection. Those are the basic 3 pillars that I would approach in terms of acne skincare recommendations for the average patient. Now, if you’ve got hormonal acne or if you’ve got people that are very young just entering their acne-prone years, there would be different methodologies.

Kircik: How about this application of the moisturizer and the overall order for application? Unfortunately, we tell patients always use your medication and then apply your moisturizer so that you’re applying your medication and you keep it in there. However, for those who cannot tolerate their retinoids, do we have another way? How about if you apply the moisturizer first and then apply the retinoids?

Draelos: That certainly can be done, especially if people are having trouble. But usually as the face gets retinized over the next 4 to 8 weeks, they can start out moisturizer first and then retinoid, but eventually they should be able to switch so that you get the retinoid on first and the moisturizer on second. So what you might want to do is have them use the moisturizer first with the retinoid on top for the first 4 to 8 weeks of treatment, and then possibly you can reverse it. There are some studies from Emil Tanghetti that demonstrated that it doesn’t matter. But if you look at it from an analysis where you do tape strips from the skin surface and you look to see how much of the retinoid actually got in the skin with liquid chromatography mass spectrometry (LCMS), it actually gets better. But here’s the question: does that little bit matter in the length of time that the study was done? We have an analytical lab in-house, where we have high-pressure liquid chromatography equipment and mass spectrometry, so we can look at the penetration of actives. And so what’sreally interesting is [that] it may not matter in the period of time over which you followed the patients in the study, but in terms of actual nuts and bolts delivery, it does. So one of the things that we really haven’t done in dermatology is a lot of penetration studies to see exactly how deep into the skin these products go. And with tape stripping and 20 tape strips, you can actually get down to punctate bleeding at the base of the dermis. And that’s how those studies are done.

Baldwin: I’ve always wondered about that moisturizer first concept. And as you mentioned, Tanghetti just looked at 1 moisturizer and 1 retinoid, and we’ve never had another study that looked at that combination again, which I find hard to believe. I can’t believe we’ve never done it again. But I recommend it a lot, and I can’t say that I’ve ever seen it reduce…efficacy. However, of course, if you put the moisturizer on first, then the patient’s able to use the medication more frequently. So perhaps the fact that they got better has to do with their compliance. And that the little bit of decrease in the penetration is replaced by more frequent use of the medication. I also wonder if the speed of penetration is useful because, after all, that’s why we used microencapsulation. That’s why we used microsphere formulations to slow everything the heck down.

Draelos: I was just going to say that not all moisturizers are the same. Some are film-forming, and they actually have a methacrylate polymer in them. So if that’s the case, then that is not a good moisturizer to use first. There are some moisturizers that are not film-forming and don’t have a residue or polymeric emulsion that’s laid down on the skin surface. Those, which are your older-fashioned moisturizers, may allow penetration right through the product. So selecting the moisturizer appropriately—if you’re going to do moisturizer first, then retinoid—is important.

Farberg: Although I think there may be an ideal order of operations when applying your topical medications, at the end of the day each patient has to apply them in a way that works best for them. They may prefer the cosmetic elegance of their sunscreen first, or perhaps their moisturizer, and it really comes down to what’s working best for the patient. The reason that skin care is so important is for the same reason that utilizing branded medications is also important. Recognizing that generics are not the same…[as the] branded medications…we can choose from, and the vehicles are completely different. These are all important factors…to consider when…taking into account …complete management for these acne patients.

Baldwin: I sometimes use the more moisturizing medication first if I’m going to coapply.

Farberg: Or if it’s wintertime, I’m using thicker PM creams, such as clascoterone cream 1%.

Kircik: Topical retinoids and topical benzoyl peroxide, I think, are the mainstream treatment for acne, both for initiation phase as well as…maintenance phase.

Baldwin: Many studies show us that the best way to treat acne is with combination therapy. That your average successfully treated acne patient is on multiple different acne medications, and you get more value if you think back to your pillars of pathogenesis and pick things from different pillars to treat your patient at the same time.

Kircik: To be devil’s advocate, what if, Dr Baldwin, I have 1 product that addresses the 4 pillars?

Baldwin: Then you’ve topically completed your tetrad. As we all know, the only drug that does that…as a standalone, as a monotherapy, is isotretinoin. I’m not suggesting that the combination of 2 topicals is better than isotretinoin, but at least we’re hitting all 4
pathogenic factors.

Farberg: So if you were going to consider 1 treatment though, recognizing that patients won’t always be compliant with combination therapy, recognizing that we’ve already mentioned no sebum, no acne...

Farberg: If we have…buy-in from the patient that this will, in the long-term, be the treatment…you can maintain for many years to come, then I would consider it first line.

Draelos: They may not see improvement for months after initiating therapy.

Baldwin: I agree. Because the big leap in efficacy in the clinical trials was between 8 and 12 weeks. So no one is going to apply a medication bid for 8 weeks and see absolutely nothing. The corollary, of course, is at least during that 8 weeks, they’re not going to be experiencing irritation. There was somebody who said this one time, and I just want to share it because I wish I could remember who uttered these words, because I loved them. He talked about that 2 weeks into initiation of therapy with a topical retinoid, he called that moment in 2 weeks a “crisis of confidence” because the acne hasn’t gotten better yet. They still have the same number of pimples that they started with. Now, in addition, they’re red and dry and irritated. “Thank you very much, doctor, for helping me out so much,” right? That 2-week mark is crucial for retinoids, but with Winlevi, there is no crucial 2-week mark because, although it takes a long time to work, at least they’re not irritated during that time. As we mentioned before, it also has a nice moisturizing base.

Draelos: When the patient comes in, you have to administer acute care. They want immediate improvement. Then there’s the investment in the long-term, maintenance care, and in order to get the acne immediately under control and to prevent more from occurring, you do have to have that long-term arm. As the patient gets better, you can withdraw them, leaving them on Winlevi because we get back to no sebum, no acne. I see Winlevi being an important investment at the time of first visit for long-term control.

Zeichner: For which patients? All patients? Being that sebum is the driving factor for acne, would we consider clascoterone cream to be a foundational treatment for all acne patients? Or would this be a medication for selected individuals?

Kircik: What we are missing for clascoterone…

Zeichner: So the only data that we have is the published data from the studies and the promotional information from the companies, which discusses only on-label use of twice-daily monotherapy. In the real world, we are, as Dr Baldwin said, combining actives that address multiple pillars.

Baldwin: Right.

Kircik: Are you using Winlevi twice a day?

Baldwin: Yes, always. Without the twice-a-day, you might not get the effect.

Draelos: That’s one thing we don’t know. We don’t know how long it takes for sebum reduction to occur.

Baldwin: That’s why it takes so long to work, right? Because you’ve got a sebaceous gland full of sebum, which is already premade, and that’s going to have to go away and not be replaced, is my lay explanation for that.

Draelos: You’re shutting down the sebaceous gland. Yeah, you’re not killing it. You’re not delivering a toxic dose of vitamin A, for example, but it would be very important to know when that kicks in because that would give me an idea of when to make an assessment, as the treating dermatologist, about whether Winlevi is providing the results you desire.

Farberg: In summary, I think we’re all hopeful for a better understanding, or better scientific understanding, of the role of clascoterone and its impact on the oil glands.

Baldwin: In the phase 2b study of the safety and efficacy of clascoterone cream [Efficacy and Safety of Topical Clascoterone Cream, 1%, for Treatment in Patients With Facial Acne: Two Phase 3 Randomized Clinical Trials]1, they looked at qd vs bid, and there was an enormous difference between qd and bid, almost 50% in terms of reduction of inflammatory lesions. So I think it’s very important while we’re learning about this drug and…about how it works and how long it takes to work, that we do the bid the way it was intended and cut back later.

Farberg: Do we know why it takes so long?

Draelos: It takes too long because you’re shutting down the sebaceous machinery. As Dr Baldwin mentioned, you already have a reservoir within the gland itself.

Farberg: That reservoir is 2, 3 months’ worth?

Draelos: We don’t know.

Baldwin: How long would it take, do you think, for a sebaceous gland reservoir to empty?

Draelos: Well, it may not be…just the reservoir, but the sebaceous gland. You’ve got to get the Winlevi down to the glandular level and then you have to inhibit each of the acini of the gland. That takes time.

Baldwin: Mechanistically, it makes sense to me that bid would be necessary because we know it’s metabolized very rapidly in the epidermis. As I understand, it takes 5 to 6 hours for it to be completely converted into cortexolone, which means the entire rest of the day, the sebaceous gland is free to chug out as much sebum as it wishes. Mechanistically, I understand why it might need to be bid.

Draelos: The metabolites are just as important as the active drug. I think we need to have a better understanding of how the metabolism progresses in the sebaceous gland—probably some histology studies doing biopsies 1 month, 2 months, 4 months—and look to see, does the sebaceous gland atrophy, how quickly, and to what degree?

Zeichner: It’s a very exciting time for acne treatment specialists to have a new topical medication that addresses oil production, which up until this point has not been addressed…[by] any of our topical therapies for acne patients.

Kircik: So, this is 1 drug that addresses the root of the problem.

Baldwin: We don’t know if clascoterone cream reduces oil production. We think it does, but we don’t know for sure.

Zeichner: There’s in vitro data showing that there’s decreased sebum production and decreased proinflammatory cytokine.

Draelos: I think there’s some key studies post-approval that need to be done. You need to look at the sebaceous gland histology, you need to look at the constituents of the sebum, and you need to look at the sebum output.

Zeichner: What’s really interesting about the drug is it specifically has mechanism of action in the prescribing information, which is pretty unique…[for] a drug in dermatology.

Farberg: We have a drug that topically addresses sebum production, and there’s in vitro data showing that clascoterone does inhibit production of sebum as well as proinflammatory cytokines.


1. Hebert A, Thiboutot D, Gold LS, et al. Efficacy and safety of topical clascoterone cream, 1% for treatment in patients with facial acne: two phase 3 randomized clinical trials. JAMA Dermatol. 2020;156(6):621-630. doi:10.1001/jamadermatol.2020.0465


This Frontline Forum is supported by Sun Pharmaceutical Industries Ltd.

Continued in part 3

[Edited for space and clarity].

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