The treatment of acne involves difficult choices. Should you prescribe oral antibiotics, knowing use of the drugs for acne plays a large role in driving up rates of antibiotic resistance? Are you willing to wade through the complex federal laws regulating isotretinoin before prescribing it to people who can become pregnant? And why do so many patients complain topical retinoids make them feel like their face is peeling off?
But perhaps the biggest challenge in treating acne is lack of compliance: One study found half of patients prescribed a topical therapy had given up on the regimen within 3 months, either because they felt it wasn't working or they could not tolerate the side effects.
Things have changed.
The US Food and Drug Administration has approved several new medications in the last 6 years that address these shortcomings and require only one dose per day, potentially enhancing patient compliance and, as a result, improving outcomes.
Overview of New Medications
Here is the basic approach to acne care, as outlined in 2016 guidelines from the American Academy of Dermatology (AAD):
- Topical treatment (eg, benzoyl peroxide [BPO], antibiotics, and retinoids) is generally used as first-line treatment in cases of mild-to-moderate acne with comedonal and inflammatory lesions.
- Systemic treatment (eg, oral antibiotics and hormonal therapy) can be used as first-line treatment in cases of moderate to severe acne, in combination with a topical agent.
Dermatologists today rarely use oral clindamycin and erythromycin for acne since antibiotic resistance has severely limited the effectiveness of these drugs. That leaves the tetracycline class as the antibiotic of choice, since it also has a strong anti-inflammatory effect. But tetracyclines can disrupt the gut microbiome, and minocycline in particular may cause rare but serious complications like irreversible hyperpigmentation and hypersensitivity reactions.
That's why Hilary Baldwin, MD, a dermatologist and director of the Acne Treatment & Research Center in Brooklyn, New York, welcomed the FDA approval in 2019 of topical minocycline. Far less of the topical formulation is absorbed by the body compared to a 3-week course of oral medication, Baldwin said.
"The concentration in the skin is extraordinarily high, while the concentration in the body is extraordinarily low, which is just the kind of combination we want," she said. And the drug is effective for inflammatory lesions that previously would have required oral treatment with antibiotics or hormonal therapy.
Baldwin also frequently prescribes sarecycline, a narrow-spectrum tetracycline that has been available since 2018.
"It has all of the nice qualities of tetracycline in terms of its efficacy in treating acne, but it is probably less likely to do damage in the gut and hit off-target organisms," she said. Another benefit is once-a-day dosing. Although sarecycline hasn't undergone head-to-head trials with other tetracyclines, Baldwin said she has seen fewer side effects from the drug in her patients.
Although much of the drive to reformulate older topical medications is to allow manufacturers to maintain their patents on the products, research into ways to make a cream or lotion easier on the skin is another important avenue of research. "The vehicles do really matter," said Arash Mostaghimi, MD, MPH, an associate professor of dermatology at Harvard Medical School in Boston. "A lot of the innovation in this space is actually in the delivery."
The payoffs from this line of research include two new versions of older topical agents, tretinoin and tazarotene, which the FDA approved in 2018 and 2019, respectively. The novel technology for these two agents, as Baldwin explained, allows the active ingredient to deposit on the skin in a honeycomb-like mesh that also contains a protective moisturizer. "It has taken a virtually intolerable drug like tazarotene and made it into one of the mildest formulations of topical retinoids that we have," Baldwin said.
The next trick is to use these technologies to create combination products. Although often prescribed together, topical retinoids and BPO creams cannot be applied at the same time because BPO oxidizes the retinoid, reducing its activity. Both drugs also cause significant skin irritation.
A technology called microencapsulation gets around these obstacles. A silica shell traps the active ingredients, which prevents them from interacting with each other while allowing their slow release. Microencapsulated drugs can be packaged in the same bottle and used at the same time, so that patients do not need to apply one medication in the morning and the other at night.
Trifarotene, initially developed for psoriasis, is another topical retinoid worthy of mention. Retinoids are vitamin A derivatives that bind different retinoic acid receptors (RARs); trifarotene is known as a next generation retinoid, because it is the first to selectively bind to RAR-gamma, the most common RAR in the skin. This affinity allows the drug to be effective at low concentrations, reducing systemic absorption and side effects. Studies have shown trifarotene is safe to use over large areas of the skin, so many dermatologists recommend it for people with acne extending to the shoulders and back.
The newest combination drug on the market, approved in October, is the first fixed-dose triple-combination topical treatment for acne. Containing clindamycin, BPO, and adapalene, a retinoid, the product should be available to consumers in 2024. "The amazing thing about the data is that it really looks as though the combination of all three have a synergistic effect. It is not just better — it's dramatically better," Baldwin said.
Mostaghimi said he also has been impressed with the data, and predicted providing triple treatment in a non-irritating fashion once daily would dramatically increase adherence.
Topical clascoterone, approved in the United States in 2020, is the first acne drug with a novel mechanism of action to reach the market in 40 years. Clascoterone addresses hormonal acne, which is related to elevated androgen levels. The condition is most common in adult women, particularly during menses, but also affects men.
Androgens bind androgen receptors present in the skin and stimulate the production of sebum. Although its precise mechanism of action is not well understood, clascoterone inhibits binding to androgen receptors, and may work by disrupting sebum production. The drug also inhibits pro-inflammatory cytokines and inflammatory follicular activity.
Leslie Baumann, MD, founder of the Baumann Cosmetic & Research Institute in Miami, said she considers clascoterone a significant improvement over spironolactone, which often is used to manage hormonal acne in women. "In the past, people took spironolactone pills, which would block testosterone in their whole body," Baumann, a cosmetic dermatologist, said. "Now we can just do it in their skin, which is a lot safer."
A study published earlier this year in JAMA Dermatology found prescriptions for spironolactone for women with acne rose nearly fourfold between 2017 and 2020, nearly matching orders for oral antibiotics by the end of that period.
However, spironolactone cannot be safely used in men, nor in women who are pregnant or breastfeeding. Clascoterone provides a safe and effective topical option for men and women and works for both comedonal lesions and inflammatory acne.
Acne in the Primary Care Setting
Almost everyone suffers from acne at some point in their lives. The AAD estimates that acne affects 85% of people between the ages of 12-24. Although pimples might be considered a rite of passage for teens or dismissed as a cosmetic problem, acne is associated with significant anxiety and depression, and a study published this month found that individuals with acne face stigma affecting their personal and work lives.
So why don't more people get treated successfully, and why do so many people drop out of treatment?
"Let's think about who uses these medicines," Mostaghimi said. "They're kids, right? That may be the first medication they ever take." Many adolescents have trouble using the drugs consistently, put on the wrong amounts, or are unable to stick to regimens involving multiple medications that must be applied at different times of the day. He advised that the best regimens are "anything that is easier to use — and a combined product is better."
Another reason that people don't seek medical help for acne: "There are a lot of people who feel like they're very actively doing something about their skin," Mostaghimi said. "But they're not doing it based on physician expertise. They're doing it based on things that they see online."
As for compliance, Baumann likened the behavior of acne patients to people joining a gym after New Year's. "I notice that 3 weeks is the drop off rate," she said. "It's human nature to want to see results right away, and acne takes at least 8 weeks to see a difference."
And getting in to see a healthcare provider can be a barrier, especially for teens. " Their parents don't think it's important or cannot afford the visit," Baumann said. "Or they [the teen] don't drive, and [the] parents are at work."
Baumann said she has also seen young women with hormonal acne respond well to oral contraceptives, but their parents may have issues with their teenage daughter taking birth control pills.
This list of reasons implies that most patients need more education about what to expect from acne treatment and the medications they are taking: how long they need to be taken before symptoms improve, how to apply them properly, why they might need to use more than one medication, and what side effects to expect.
Many patients experiencing irritation from topical retinoids can manage the condition with moisturizers and milder cleansers. Or they could be switched to a newer topical retinoid in a vehicle that will be better tolerated.
Baldwin generally does her own patient education, but she understands that busy primary care clinicians who must also address patients' other health problems might not have that luxury. Her advice is to train staff on the basics of acne care and use patient cheat sheets with medication instructions and side effects. If patients aren't improving on follow-up visits, the key is to find out how well they have been sticking to the recommended regimen — or not. To get the full story from teenage patients, she added, "You really want to question compliance with the mom not in the room."
As for deciding when patients can be treated in primary care settings and when to refer to dermatology, Mostaghimi said primary care clinicians should feel comfortable treating comedonal acne using topical agents, which should work for a majority of patients. And all three dermatologists felt patients with more severe acne — those that may require oral isotretinoin or oral antibiotics — should be managed by dermatologists.
The availability of newer better-tolerated retinoid formulations, along with combination drugs that improve compliance, should make management in primary care settings more feasible.
But given the effectiveness of oral isotretinoin, why aren't more adolescent boys with severe acne taking the drug, since they wouldn't be affected by pregnancy restrictions? "Denial is the number one reason, but also lack of insurance," Baldwin said. The costs of drugs, multiple visits, and lab tests can add up.
Baldwin said acne is more culturally acceptable for men than women, who care more about a clear complexion because they feel they are being judged on their appearance. "It's Mars/Venus stuff," she said. " Sometimes I see a male patient with really bad acne who has come in for treatment of a wart on his hand and is uninterested in acne treatment."
In Baumann's experience, concerns about side effects associated with oral isotretinoin, such as bone aches and risk for injury to the joints or tendons, may be a bigger deterrent for male athletes engaging in contact sports. And for any athlete who participates in outdoor sports, photosensitivity can be a problem.
"If you're dealing with someone who has primarily comedonal acne, the newer tretinoin lotion, the newer tazarotene lotion, and the new trifarotene cream are your best bets," Baldwin said. She added that the average successfully treated acne patient requires two to three medications, making the fixed combination medications a logical next step. "I think that [triple therapy] will make a huge difference," she said.
Lastly, clascoterone offers a good alternative to oral isotretinoin for treatment of hormonal acne. According to Baumann, "If you have a cystic acne person, it's hard to get that under control with just topicals." But for patients with hormonal acne, she recommended a trial of topical clascoterone first, with oral contraceptives as another option for women.
And Mostaghimi's parting advice to primary care clinicians? "We can do a lot of good for patients with pretty simple and accessible drugs. Don't be afraid."
Baldwin serves on the speaker's bureau, consults for, or attends medical advisory boards for Almirall, Bausch Health, Galderma, and Sun Pharma.
Mostaghimi has received royalty payments from Pfizer for licensing of the ALTO tool; has participated in clinical trials related to alopecia by Incyte, Lilly, Concert, and Aclaris; and has received consulting fees from Pfizer. He reports no acne-related conflicts of interest.
Baumann currently receives research grant funding and consulting fees from AbbVie, and research grants from Arcutis Biotherapeutics; Eirion Therapeutics; Eli Lilly and Company; Pfizer; Q-Med AB, part of the Galderma Group; Regeneron Pharmaceuticals, Inc.; Symatese, and TEOXANE SA.
Ann Thomas is a pediatrician and epidemiologist living in Portland, Oregon.
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