Frontline Forum Part 1: A Discussion of the Pathophysiology of Acne and Available Treatment Strategies

Joshua Zeichner, MD, FAAD: What is the pathophysiology of acne?

Hilary Baldwin, MD: The pathophysiology of acne has 4 separate pillars, the first being an increase in sebum production, the second…increased colonization of the follicle by Cutibacterium acnes follicular hyperkeratinization, and…the inflammatory process in general. It’s not…a linear relationship or that one necessarily leads to the other. I like to say it’s a very incestuous relationship between the four different factors, each one of them feeding into the other.

Zeichner: Recently, we’ve had a greater understanding of the function of the sebaceous gland as much more than just an oil factory.

Baldwin: We’ve spoken a lot over the years about C. acnes, and I think we understand to some extent…the role that it plays in the pathophysiology of acne. But it’s only been in the last 10 years or so that we switched our mindset from this being more of an infectious process by the C. acnes organism to recognizing C. acnes’ role in the pathophysiology of acne as…the production of inflammation from inflammatory cytokines. And yes, we’re trying to reduce the population of C. acnes, but it’s not possible to kill it, it’s not possible to eradicate it, and perhaps we ought to be focusing more on other aspects of the pathophysiology rather than trying to kill C. acnes, which is ultimately futile.

We have talked a lot about follicular hyperkeratinization. In the recent past, we’ve had many new topical retinoids that act on that pillar of the pathophysiology. We’ve talked a lot about the inflammatory process in the last 10 years as we recognized that acne is basically a chronic inflammatory condition. But we didn’t talk much about increased sebum production, and I think that’s because it’s a given. It’s what happens when you get older, and it’s not something that can necessarily be altered nor should it necessarily be altered in somebody who doesn’t have acne, so it’s an entirely different pillar to think about.… We also didn’t because the drugs that we had to take care of that pillar were all oral. They all had considerable adverse effects, and only one was appropriate for use in men, namely isotretinoin, which of course, is not appropriate in all patients. So…one of the reasons why we didn’t talk about it is because we had nothing…to say, and I think we know the least about the sebaceous gland and…about sebum production and what it does compared to the other 3 pillars. One of the things we don’t know, for example, is…[whether] there [is] an increase in sebum as well as a change in the type of sebum and might the type of sebum and the constituents of sebum in…acne…be part of the pathophysiology of acne, and especially in terms of follicular hyperkeratinization. We have some data that suggest that that’s the case, but it has actually never
been proven.

Zeichner: We know that acne patients not only make more sebum, but the quality of that sebum is different from [that of] non-acne patients, if someone would like to discuss that.

Leon H. Kircik, MD: Regarding the inflammatory state, now we know that there’s something called subclinical inflammation in acne patients, even when there are no apparent skin lesions that are inflammatory, even what we call non-inflammatory lesions are actually…inflammatory [in nature]. If you do a biopsy on regular-looking skin of an acne patient perifolliculary, you’ll see inflammation and inflammatory TA cells, so that…tells us that it’s a primary inflammatory disease rather than a secondary inflammatory disease. Moreover, when it comes to the sebum, I don’t think we should look at sebum just as causing hyperkeratinization, but also it has an inflammatory effect, and we know that the androgen stimulation of the sebaceous gland also releases inflammatory cytokine, such as IL-1β, IL-6, and IL-8, so that also causes further inflammation to the existing inflammatory nature of the skin and hands, creating…the
perfect storm.

Zoe Diana Draelos, MD: The breakdown products, the free fatty acids, it’s interesting that that free fatty acid constituents…[are] found in multiple dermatologic diseases…[as if] free fatty acids are the inciting factor for inflammation in seborrheic dermatitis. Free fatty acids are the initiating inflammatory factor active in acne. And so it’s interesting that we now not only need to focus on the amount of sebum and perhaps its constituents, which we don’t have well laid out as…we mentioned, but also the breakdown products. And so the final common pathway is if you don’t make the sebum, you don’t get the breakdown products, which are proinflammatory, which is kind of a new mechanism that we’ve not really talked about in the pathophysiology of acne, but we can now, because we have an opportunity to modulate sebum production.

Draelos: As sebum oxidizes, that creates another full set of chemicals.… We don’t really understand terribly well…how they interact in dermatology. But the ability to stop sebum at the heart of what it’s produced eliminates all these cascades of very interesting breakdown of products and substances, including oxidization, lipid peroxidation…, etc, that we really don’t understand because we couldn’t modulate. We didn’t have a target, so we don’t have a knowledge base there. But I think the fact that now clascoterone (Winlevi; Sun Dermatology) can modulate these gives us the opportunity to examine this other…aspect of acne related to the breakdown of sebum and the oxidation of sebum and its byproducts.

Baldwin: Do you think it’s a fair statement that in general, no sebum equals no acne? If you wanted to boil it down to something, isn’t that the statement that we’re really making?

Draelos: I agree, Hillary. No sebum, no acne. I also think, though, that the sebum constituents change as you get older, and while I don’t have any proof to back this up, I’ve often wondered as people mature and leave adolescence and don’t have the testosterone, the estrogen drive, or puberty hormonal drive to acne. I wonder if that isn’t one of the reasons why acne gets better as you get older, in addition to the fact that the sebaceous gland hormonal drive is gone and the sebum production decreases. But I think this ability to modulate sebum production topically opens a whole new area of research for a better understanding of what really is happening in acne.

Baldwin: I love that concept in what happens with aging. Why do people get better? And one of the things I came across not too long ago was the concept…[that] bacteriophages in the follicle are good things in terms of acne. The people who don’t have acne have a higher density of C. acnes bacteriophages, and as we age, our C. acnes bacteriophages increase in number and…perhaps we’re doing a better job at killing off the pathogenic forms of C. acnes, leaving behind what we now consider to be the healthy subtypes.

Zeichner: Dr Farberg, would you like to comment on these 4 main pillars of acne and any other factors that we know to be associated with the
worsening of acne?

Aaron S. Farberg, MD, FAAD: I would say we also have to consider the complex interplay between our patients and the environment and recognize that diet and stress also play a part, or a very significant part. I would add that it is a very complex interplay between a variety of different factors, but it all falls back to this old adage of “no sebum, then no acne.” So that’s a critical aspect or a critical point to the pathogenesis of acne. Is it the single most important one? I think it is one that is important because we can actually modulate it at this point.

Baldwin: The bottom line is we have no idea if diet has anything to do with acne, and we pretend we do and we talk to our patients, but we really don’t know. The low glycemic index diet, so don’t consume in abundance, low fat or nonfat dairy products and to not eat whey protein. And those are the only things that we might know.

Kircik: The whey protein is the only one that I think we know could have an impact in this. The bottom line is when it comes to diet, we don’t have really good, randomized, double-blinded clinical studies.

Farberg: But I think it’s important not to forget our own clinical experience. How many times have you had a patient come in and say that I have more significant acne during stress, or I’ve noticed a change with my diet. Perhaps we don’t have a double-blinded trial for that, but we also don’t have a double-blinded trial that parachutes work, but we know that they do.

Baldwin: That’s very true.

Zeichner: How do you stratify the severity of acne? Is it based on lesion morphology? Is it based on body surface area, psychosocial impact, all of the above?

Farberg: I stratify the severity of acne based primarily on the psychological manifestations. I’ll have patients that I might perhaps consider mild acne, but it’s having a significant impact on their life, and therefore, it’s quite severe.

Zeichner: I think we have both objective and subjective measures
of severity.

Kircik: From a clinical study perspective and a research perspective, we know that the severity of acne is measured on either Investigator Global Assessment or Physician Global Assessment, IGA or PGA, or what I call the eyeballing of the patient, and it has to be done without counting the lesions since you might have somebody that has 10 nodules vs somebody with 30 closed comedones or open comedones. Which one’s going to look worse when you look at them? Certainly the first one, not the second one who’s got less lesions but more nodular acne. So, the bottom line is…looking at the patient and classifying them as mild, moderate, or severe.

Zeichner: As you approach a treatment algorithm or a treatment recommendation, how do you select topical vs oral, combination vs monotherapy?

Baldwin: I personally measure acne severity a little bit differently [than Leon]. I don’t use Global Assessment.… I take a look at what kind of lesions the patients have: comedonal, inflammatory, or combination. And within that realm, is it severe? The hardest patient to treat in the entire world is [the one with] severe comedonal acne. So you can’t forget that someone with absolutely no inflammatory lesions can still be severe. Then my next question is, is the trunk involved as well? And then my next question is, is there scarring, and my last question is, is there psychological impairment? And that’s how I start my process, so I’m going to pick drugs that are attacking the particular thing I saw. So clearly, if I saw comedonal lesions, I’ve got a retinoid on board, but actually I like it in all sorts [of acne,] but I’m not necessarily going for a topical antibiotic when I see a bunch of comedones. So that helps me to decide which way I’m going to go. If the trunk is involved, I’m more likely to whip out an oral to treat larger areas at the same time. And then combination therapy for me is in every patient except for the mildest comedonal kid at 11 years old when I generally use a retinoid alone, but everybody else gets combination therapy. I’m a full believer in retinoids for everybody from birth to death, and then adding the other medications
as necessary.

Kircik: To add to that, we should not be forgetting what I call the physical modalities that we used to hear…[about] in the old days, but now because of lack of reimbursement, we sort of stopped or forgot. But still what I call the acne surgery, which is really not surgery but removing the comedones…[is] very, very useful and helpful to a patient. I still do cryotherapy and also intralesional injections. So all the physical modalities that we used to do, I think we should not forget. And then in addition to the old modalities, now we have lasers, we have light devices that are also very helpful for
acne treatment.

Farberg: Perhaps one of the most important aspects to the treatment and management of patients with acne is ensuring that there is a good relationship between the patient and…dermatologist or recognizing that there are, as mentioned by my colleagues, a variety of…treatments. Finding the correct…personalized treatment for each patient is very important. That communication is critical to selecting and…maintaining the right treatment pathway for each patient.

Kircik: I think that’s really important. Whenever I see a new acne patient, I always tell them, you and I, we’re going to become good friends, with the sense that this a chronic disease. This is not a one-time visit. It does require a lot of follow-up. And as we take the disease under control, the follow-ups will be less and less frequent. But in the beginning, I think the follow-up is very important, and there is no magic bullet that’s going to make it go away in one visit.

Draelos: One of the biggest challenges in acne treatment is… compliance. And therefore, I think it’s really important that you pick a medication that suits the person’s personality and their lifestyle and they’re inclined to use it. And then I think you need to also recommend skin care products. So I think the treatment of acne isn’t just focusing on the inflammatory pathways and pustules, but looking at the lifestyle, the individual, looking at how they buy into the treatment and what they’re likely to use. And then looking at total skin care, and that would include cleansers, moisturizers, etc.

Kircik: So again, to Dr. Draelos’ point. A general treatment is very important and keeping in mind that the pH of the skin plays a very important role, not only in the inflammation, but also with their barrier function as well as the microbiome.

Draelos: And then if you recommend total skin care when the disease improves, and you could start withdrawing some of the prescription medications, they then have a good treatment, skin care routine in place that they can continue on when you transition from the treatment phase into the maintenance phase of
the disease.

Baldwin: Something that we all say to our patients is, “This is not a sprint, it’s a marathon.” That’s a nice little statement that I think works very well with the patients.… I tend not to tell patients about how long this is going to last until after the first visit or 2, so that we’ve gotten them under control. Now they have hope, and then I drop the bombshell: “By the way, you’re going to have to do this for 4 years.” Because I think if you tell them that in the beginning, you lose some people who thought that this was going to be like the pneumonia they had last year, where they took antibiotics for 7 days, got better, and never saw it again.

Kircik: Many say, “Hey Doc, give 1 pill a day, and let’s be done with it.” Well, we know that that’s not going to cut it.

Baldwin: Well, education is key and the trick, of course, is figuring out how to educate your patients rapidly so that you can do a good job yet have the turnover that’s necessary in today’s practice of medicine. In previous discussions, we’ve talked about how the education and the training of derm residents is extraordinarily different in the treatment of acne, and I’m sure it is in other diseases as well. I just know acne well from department to department. And your knowledge of acne is the knowledge that …your mentors have. And in some institutions, there’s nobody who knows acne. There are institutions that believe exclusively in using generic medications and don’t even educate the residents on the newer medications or the branded medications. So part of the problem here is that you don’t know the education level of the doctor in question. And with clascoterone cream, since it’s not in the guidelines yet, because the guidelines were written in 2016, payers are reluctant to allow us to reimburse it. And doctors are less likely to prescribe it. I remember one time…I went to a program and I thought I was leaping into what was already well known about acne surgery. And I said, “It’s very important to extract comedones to make the patient look better initially, make them feel better about themselves, more likely to use their medications.” A third-year resident asked me how you take out comedones. I said with a comedone extractor. And she said, “What’s that?” They also didn’t know what I meant when I said intralesional steroids. They had never heard of it, and they were third-year residents. So never underestimate how much people don’t know about acne.

Draelos: We’re familiar with it, but we trained in a different generation.

Baldwin: I fear that acne gets lost.

Draelos: We were trained in a generation when it was reimbursed. Now, it’s not reimbursed, and so that’s really changed…how you treat acne.

Farberg: Are you currently utilizing those treatments with your patients?

Draelos: Oh, yes.

Farberg: I’m just curious, how does that get reimbursed?

Draelos: It doesn’t get reimbursed.

Baldwin: It’s the right thing to do.

Kircik: Some still do, but it’s a fight. In the old days, I used to do cryotherapy, intralesional injections, and acne surgery at the same time, and there were no questions asked. God forbid now if you do more than one…[on] the same day. Forget it. You have to fight for it, even for one.

Disclosure

This Frontline Forum is supported by Sun Pharmaceutical Industries Ltd.

Continued in part 2

[Edited for space and clarity].